P R IN C IP LE S o f P H A R M A C O LO G Y

T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n
P R IN C IP LE S o f P H A R M A C O LO G Y
T H E P AT H O P H YS I O LO G I C B A S I S O F D R U G T H E R A P Y

Fo u rt h Ed it io n

David E. Go lan, MD, PhD

Editor-in-Chief

Ehrin J. Arm s tro ng , MD, MS c

April W. Arm s tro ng , MD, MPH
Associate Editors
Acquisitions Editor: Matthew Hauber
Product Development Editor: John Larkin
Marketing Manager: Mike McMahon
Production Project Manager: Bridgett Dougherty
Design Coordinator: Holly McLaughlin
Manufacturing Coordinator: Margie Orzech
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Fourth edition

Copyright 2017 Wolters Kluwer.

Copyright 2006, 2011 Wolters Kluwer Health/Lippincott Williams & Wilkins.

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Library of Congress Cataloging-in-Publication Data

Names: Golan, David E., editor. | Armstrong, Ehrin J., editor. | Armstrong,
April W., editor.
Title: Principles o pharmacology : the pathophysiologic basis o drug
therapy / David E. Golan, editor in chie ; Ehrin J. Armstrong, April W.
Armstrong, associate editors.
Other titles: Principles o pharmacology (Golan)
Description: Fourth edition. | Philadelphia : Wolters Kluwer Health, [2017] |
Includes bibliographical re erences and index.
Identif ers: LCCN 2015048962 | ISBN 9781451191004
Subjects: | MESH: Pharmacological Phenomena | Drug Therapy
Classif cation: LCC RM301 | NLM QV 38 | DDC 615/.1dc23 LC record available at http://lccn.loc.gov/2015048962

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To our students and the patients they will serve
 Contents
Preface ........................................................................................... ix S e c t io n IIB
Preface to the First Edition............................................................. xi Principles of Autonomic and Peripheral
Nervous System Pharmacology 126
Acknowledgments........................................................................ xiii
Contributors....................................................................................xv 10 Cholinergic Pharmacology............................................. 127
Alireza Atri, Michael S. Chang, and Gary R. Strichartz
S E C T IO N I 11 Adrenergic Pharmacology ............................................. 150
Fundamental Principles of Pharmacology 1 Nidhi Gera, Ehrin J. Armstrong, and David E. Golan
12 Local Anesthetic Pharmacology ................................... 167
1 DrugReceptor Interactions .............................................. 2 Quentin J. Baca, Joshua M. Schulman, and
Francis J. Alenghat and David E. Golan Gary R. Strichartz
2 Pharmacodynamics ........................................................... 17
Quentin J. Baca and David E. Golan S e c t io n IIC
3 Pharmacokinetics .............................................................. 27 Principles of Central Nervous System Pharmacology 183
Quentin J. Baca and David E. Golan
13 Pharmacology of GABAergic and
4 Drug Metabolism ............................................................... 43 Glutamatergic Neurotransmission................................ 184
F. Peter Guengerich
Stuart A. Forman, Hua-Jun Feng, Janet Chou, Jianren Mao,
5 Drug Transporters .............................................................. 56 and Eng H. Lo
Baran A. Ersoy and Keith A. Ho master
14 Pharmacology of Dopaminergic
6 Drug Toxicity ....................................................................... 70 Neurotransmission .......................................................... 206
Michael W. Conner, Catherine Dorian-Conner, David G. Standaert and Victor W. Sung
Vishal S. Vaidya, Laura C. Green, and David E. Golan
15 Pharmacology of Serotonergic and
7 Pharmacogenomics .......................................................... 87 Central Adrenergic Neurotransmission ....................... 227
Amber Dahlin and Kelan Tantisira Stephen J. Haggarty and Roy H. Perlis
16 Pharmacology of Abnormal Electrical
S E C T IO N II Neurotransmission in the Central Nervous System..... 249
Principles of Neuropharmacology 96 Susannah B. Cornes, Edmund A. Gri f n, Jr., and
Daniel H. Lowenstein
S e c t io n IIA 17 General Anesthetic Pharmacology............................... 265
Fundamental Principles of Neuropharmacology 97 Jacob Wouden and Keith W. Miller
18 Pharmacology of Analgesia ........................................... 288
8 Principles of Cellular Excitability and Robert S. Gri f n and Cli ord J. Wool
Electrochemical Transmission......................................... 98
19 Pharmacology of Drugs of Abuse ................................. 308
Elizabeth Mayne, Lauren K. Buhl, and Gary R. Strichartz
Peter R. Martin and Sachin Patel
9 Principles of Nervous System
Physiology and Pharmacology ...................................... 110 S E C T IO N III
Joshua M. Galanter, Susannah B. Cornes, and
Principles of Cardiovascular Pharmacology 335
Daniel H. Lowenstein
20 Pharmacology of Cholesterol and
Lipoprotein Metabolism.................................................. 336
Tibor I. Krisko, Ehrin J. Armstrong, and David E. Cohen

vii
viii Contents
21 Pharmacology o Volume Regulation ........................... 358
Hakan R. Toka and Seth L. Alper
22 Pharmacology o Vascular Tone ................................... 385
William M. Oldham and Joseph Loscalzo
23 Pharmacology o Hemostasis and Thrombosis .......... 403
Ehrin J. Armstrong and David E. Golan
24 Pharmacology o Cardiac Rhythm ................................ 433
Ehrin J. Armstrong and David E. Clapham
25 Pharmacology o Cardiac Contractility ........................ 454
Ehrin J. Armstrong
26 Integrative Cardiovascular Pharmacology:
Hypertension, Ischemic Heart Disease,
and Heart Failure ............................................................. 469
James M. McCabe and Ehrin J. Armstrong
S E C T IO N IV
Principles o Endocrine Pharmacology
27 Pharmacology o the Hypothalamus
and Pituitary Gland .......................................................... 498
Anand Vaidya and Ursula B. Kaiser
28 Pharmacology o the Thyroid Gland ............................. 514
Anthony Hollenberg and William W. Chin
29 Pharmacology o the Adrenal Cortex ........................... 524
Rajesh Garg and Gail K. Adler
30 Pharmacology o Reproduction..................................... 541
Ehrin J. Armstrong and Robert L. Barbieri
31 Pharmacology o the Endocrine Pancreas
and Glucose Homeostasis .............................................. 561
Giulio R. Romeo and Steven E. Shoelson
32 Pharmacology o Bone Mineral Homeostasis ............ 580
David M. Slovik and Ehrin J. Armstrong
S E C T IO N V
Principles o Chemotherapy
33 Principles o Antimicrobial and
Antineoplastic Pharmacology ....................................... 603
Donald M. Coen, Vidyasagar Koduri, and David E. Golan
34 Pharmacology o Bacterial In ections: DNA
Replication, Transcription, and Translation ................. 622
Alexander J. McAdam and Donald M. Coen
35 Pharmacology o Bacterial and Mycobacterial
In ections: Cell Wall Synthesis ...................................... 641
David W. Kubiak, Ramy A. Arnaout, and Sarah P. Hammond
36 Pharmacology o Fungal In ections .............................. 661
Chelsea Ma and April W. Armstrong
37 Pharmacology o Parasitic In ections .......................... 674
Louise C. Ivers and Edward T. Ryan
38 Pharmacology o Viral In ections .................................. 694
Jonathan Z. Li and Donald M. Coen
39 Pharmacology o Cancer: Genome Synthesis,
Stability, and Maintenance ............................................ 723
David A. Barbie and David A. Frank
40 Pharmacology o Cancer: Signal Transduction .......... 750
David A. Barbie and David A. Frank
41 Principles o Combination Chemotherapy ................... 770
Quentin J. Baca, Donald M. Coen, and David E. Golan
S E C T IO N V I
Principles o Inf ammation and Immune Pharmacology 782
42 Principles o Inf ammation and
the Immune System......................................................... 783
Eryn L. Royer and April W. Armstrong
43 Pharmacology o Eicosanoids ....................................... 794
David M. Dudzinski and Charles N. Serhan
44 Histamine Pharmacology ............................................... 819
Elizabeth A. Brezinski and April W. Armstrong
45 Pharmacology o Hematopoiesis
and Immunomodulation .................................................. 830
497
Andrew J. Wagner, Ramy A. Arnaout, and George D. Demetri
46 Pharmacology o Immunosuppression ........................ 844
Elizabeth A. Brezinski, Lloyd B. Klickstein, and
April W. Armstrong
47 Integrative Inf ammation Pharmacology:
Peptic Ulcer Disease ....................................................... 864
Dalia S. Nagel and Helen M. Shields
48 Integrative Inf ammation Pharmacology: Asthma ...... 877
Joshua M. Galanter and Stephen Lazarus
49 Integrative Inf ammation Pharmacology: Gout ........... 895
Ehrin J. Armstrong and Lloyd B. Klickstein
S E C T IO N V II
Environmental Toxicology 904
50 Environmental Toxicology............................................... 905
Laura C. Green, Sarah R. Armstrong, and
Joshua M. Galanter
602
S E C T IO N V III
Fundamentals o Drug Development and Regulation 918
51 Drug Discovery and Preclinical Development ............ 919
John L. Vahle, David L. Hutto, and Maarten Postema
52 Clinical Drug Evaluation and
Regulatory Approval........................................................ 933
Mark A. Goldberg and Alexander E. Kuta
53 Systematic Detection o Adverse Drug Events ........... 946
Jerry Avorn
S E C T IO N IX
Frontiers in Pharmacology 954
54 Protein Therapeutics ....................................................... 955
Quentin J. Baca, Benjamin Leader, and David E. Golan
55 Drug Delivery Modalities ................................................ 979
Joshua D. Moss and Robert Langer
Credit List .................................................................................... 987
Index............................................................................................ 991

The editors are grate ul or many help ul suggestions rom
readers o the f rst, second, and third editions o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy. The ourth edition eatures many changes to re ect
the rapidly evolving nature o pharmacology and drug de-
velopment. We believe that these updates will continue to
contribute to the learning and teaching o pharmacology both
nationally and internationally:
Comprehensive updates o ull-color f gures throughout
the textbookabout 450 in all. Every f gure has been
updated and colorized, and over 50 f gures are new or
substantially modif ed to highlight advances in our un-
derstanding o physiologic, pathophysiologic, and phar-
macologic mechanisms. As in the f rst three editions, our
collaboration with a single illustrator creates a uni orm
look and eel among the f gures that acilitates under-
standing and helps the reader make connections across
broad areas o pharmacology.
Comprehensive updates and additions in the undamen-
tals o pharmacology. Along with extensive updates in
the chapters on drugreceptor interactions, pharmaco-
dynamics, pharmacokinetics, drug metabolism, drug
toxicity, and pharmacogenomics, a new chapter on drug
transporters has been added. The f rst section o the text-
book now provides a comprehensive ramework or the
undamental principles o pharmacology that serve as the
oundation or material in all subsequent chapters.
Comprehensive updates o all 37 drug summary tables.
These tables, which have been particularly popular with
readers, group drugs and drug classes according to mech-
anism o action and list clinical applications, serious and
common adverse e ects, contraindications, and therapeu-
tic considerations or each drug discussed in the chapter.
Comprehensive updates o all chapters, including new
drugs approved through 20142015. We have ocused
especially on newly discovered and revised mecha-
nisms that sharpen our understanding o the physiology,
Preface
pathophysiology, and pharmacology o the relevant sys-
tem. Sections throughout the book contain substantial
amounts o new and updated material, especially the chap-
ters on drugreceptor interactions; drug toxicity; pharma-
cogenomics; adrenergic pharmacology; local anesthetic
pharmacology; the pharmacology o serotonergic and
central adrenergic neurotransmission; the pharmacology
o analgesia; the pharmacology o cholesterol and lipopro-
tein metabolism; the pharmacology o volume regulation;
the pharmacology o vascular tone; the pharmacology
o hemostasis and thrombosis; the pharmacology o the
thyroid gland; the pharmacology o the endocrine pan-
creas and glucose homeostasis; the pharmacology o bone
mineral homeostasis; the pharmacology o bacterial DNA
replication, transcription, and translation; the pharmacol-
ogy o bacterial and mycobacterial cell wall synthesis;
the pharmacology o viral in ections; the pharmacology
o cancer; the pharmacology o eicosanoids; the pharma-
cology o immunosuppression; the undamentals o drug
development and regulation; and protein therapeutics.
As with the third edition, we have recruited a panel o
new, expert chapter authors who have added tremendous
strength and depth to the existing panel o authors, and the
editorial team has reviewed each chapter in detail to achieve
uni ormity o style, presentation, and currency across the
entire text.
Finally, we would like to acknowledge the immeasur-
able contributions o the late Armen H. Tashjian, Jr., MD,
to the conception, design, and implementation o this text.
Armen was our riend, mentor, and close colleague, and his
indomitable spirit lives on in this ourth edition o Principles
o Pharmacology: The Pathophysiologic Basis o Drug
Therapy.
David E. Golan, MD, PhD
Ehrin J . Armstrong, MD, MSc
April W. Armstrong, MD, MPH
ix

This book represents a new approach to the teaching o a
f rst or second year medical school pharmacology course.
The book, titled Principles of Pharmacology: The Patho-
physiologic Basis of Drug Therapy, departs rom standard
pharmacology textbooks in several ways. Principles of
Pharmacology provides an understanding o drug action
in the ramework o human physiology, biochemistry, and
pathophysiology. Each section o the book presents the
pharmacology o a particular physiologic or biochemical
system, such as the cardiovascular system or the in am-
mation cascade. Chapters within each section present the
pharmacology o a particular aspect o that system, such as
vascular tone or eicosanoids. Each chapter presents a clini-
cal vignette, illustrating the relevance o the system under
consideration; then discusses the biochemistry, physiology,
and pathophysiology o the system; and, f nally, presents the
drugs and drug classes that activate or inhibit the system by
interacting with specif c molecular and cellular targets. In
this scheme, the therapeutic and adverse actions o drugs are
understood in the ramework o the drugs mechanism o ac-
tion. The physiology, biochemistry, and pathophysiology are
illustrated using clear and concise f gures, and the pharma-
cology is depicted by displaying the targets in the system
on which various drugs and drug classes act. Material rom
the clinical vignette is re erenced at appropriate points in the
discussion o the system. Contemporary directions in mo-
lecular and human pharmacology are introduced in chapters
on modern methods o drug discovery and drug delivery and
in a chapter on pharmacogenomics.
Preface
t o t h e Firs t Ed it io n
This approach has several advantages. We anticipate that
students will use the text not only to learn pharmacology but
also to review essential aspects o physiology, biochemistry,
and pathophysiology. Students will learn pharmacology in a
conceptual ramework that osters mechanism-based learning
rather than rote memorization, and that allows or ready incor-
poration o new drugs and drug classes into the students und
o knowledge. Finally, students will learn pharmacology in a
ormat that integrates the actions o drugs rom the level o an
individual molecular target to the level o the human patient.
The writing and editing o this textbook have employed a
close collaboration among Harvard Medical School students and
aculty in all aspects o book production, rom student aculty
co-authorship o individual chapters to student aculty editing o
the f nal manuscript. In all, 43 HMS students and 39 HMS ac-
ulty have collaborated on the writing o the books 52 chapters.
This development plan has blended the enthusiasm and per-
spective o student authors with the experience and expertise
o aculty authors to provide a comprehensive and consistent
presentation o modern, mechanism-based pharmacology.
David E. Golan, MD, PhD
Armen H. Tashjian, J r., MD
Ehrin J . Armstrong, MD, MSc
Joshua M. Galanter, MD
April W. Armstrong, MD, MPH
Ramy A. Arnaout, MD, DPhil
Harris S. Rose, MD
FOUNDING EDITORS
xi

The editors are grate ul or the support o students and aculty
rom around the world who have provided encouragement
and help ul suggestions.
Stuart Ferguson continued his exemplary work as an execu-
tive assistant by managing all aspects o project coordination,
including submission o chapter manuscripts, multiple layers
o editorial revisions, coordination o f gure generation and
revision, and delivery o the f nal manuscript. We are extraor-
dinarily grate ul or his unwavering dedication to this project.
Rob Duckwall did a superb job to update the ull-color
f gures. Robs standardization and coloration o the f gures in
this textbook re ect his creativity and expertise as a leading
medical illustrator. His artwork is a major asset and highlight
o this textbook.
Quentin Baca electronically rendered the striking image
on the cover o this textbook. We are most grate ul or his
creativity and expertise.
The editors would like to thank the publication, editorial,
and production sta at Wolters Kluwer or their expert man-
agement and production o this handsome volume.
David Golan would like to thank the many aculty, stu-
dent, and administrative colleagues whose support and un-
derstanding were critical or the success ul completion o
this project. Members o the Golan laboratory and aculty
and sta in the Department o Biological Chemistry and
Acknowledgments
Molecular Pharmacology at Harvard Medical School and in
the Hematology Division at Brigham and Womens Hospital
and the Dana-Farber Cancer Institute were gracious and sup-
portive throughout. Deans Je rey Flier and John Czajkowski
were especially supportive and encouraging. Laura, Liza,
and Sarah provided valuable insights at many critical stages
o this project and were constant sources o support and love.
Ehrin Armstrong would like to thank colleagues at the
University o Colorado and the Denver Veterans Adminis-
tration Medical Center or providing academic support and
guidance. Greg Schwartz and Jim Beck were especially en-
couraging. Ki any, Larry, and Ginger were a constant source
o support and love throughout.
April Armstrong would like to thank Drs. David Golan
and Laura Green or their constant support over the years.
She thanks her dedicated coauthors Eryn Royer, Elizabeth
Brezinski, and Chelsea Ma or their hard work. She also
thanks Drs. David Norris, David West, and Fu-Tong Liu
or ostering her career. She is grate ul or the love o her
amilyAmy, Yanni, and Susan.
Credit lines identi ying the original source o a f gure or
table borrowed or adopted rom copyrighted material, and
acknowledging the use o noncopyrighted material, are gath-
ered together in a list at the end o the book. We thank all o
these sources or permission to use this material.
xiii

Gail K. Adler, MD, PhD
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Division o Endocrinology, Diabetes
and Hypertension
Department o Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Francis J . Alenghat, MD, PhD
Assistant Pro essor
Department o Medicine, Section o
Cardiology
University o Chicago
Chicago, Illinois
Seth L. Alper, MD, PhD
Pro essor o Medicine
Harvard Medical School
Renal Division and Molecular and
Vascular Medicine Division
Department o Medicine
Beth Israel Deaconess Medical Center
Boston, Massachusetts
April W. Armstrong, MD, MPH
Associate Dean or Clinical Research
Director o Clinical Research, Southern
Cali ornia Clinical and Translational
Science Institute (SC CTSI)
Vice Chair, Department o Dermatology
Associate Pro essor o Dermatology
University o Southern Cali ornia
Los Angeles, Cali ornia
Ehrin J . Armstrong, MD, MSc
Associate Pro essor o Medicine
Division o Cardiology
University o Colorado School
o Medicine
Denver, Colorado
Sarah R. Armstrong, MS, DABT
Consultant in Toxicology
Amherst, Massachusetts
Ramy A. Arnaout, MD, DPhil
Assistant Pro essor o Pathology
Harvard Medical School
Associate Director, Clinical
Microbiology
Department o Pathology
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Alireza Atri, MD, PhD
Ray Dolby Endowed Chair in Brain
Health Research
Ray Dolby Brain Health Center
Cali ornia Pacif c Medical Center
San Francisco, Cali ornia
Visiting Scientist in Neurology
Harvard Medical School
Boston, Massachusetts
J erry Avorn, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o
Pharmacoepidemiology
Brigham and Womens Hospital
Boston, Massachusetts
Quentin J . Baca, MD, PhD
Chie Resident in Anesthesia
Department o Anesthesiology,
Perioperative and Pain Medicine
Stan ord University School o
Medicine
Palo Alto, Cali ornia
David A. Barbie, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Contributors
Robert L. Barbieri, MD
Kate Macy Ladd Pro essor o
Obstetrics, Gynecology and
Reproductive Biology
Department o Obstetrics, Gynecology
and Reproductive Biology
Harvard Medical School
Chairman, Department o Obstetrics
and Gynecology
Brigham and Womens Hospital
Boston, Massachusetts
Elizabeth A. Brezinski, MD
Resident in Dermatology
Harvard Combined Dermatology
Residency Training Program
Boston, Massachusetts
Lauren K. Buhl, MD, PhD
Clinical Fellow in Anaesthesia
Harvard Medical School
Resident in Anaesthesia
Beth Israel Deaconess Medical Center
Boston, Massachusetts
Michael S. Chang, MD
Assistant Pro essor o Orthopedic
Surgery
University o Arizona College o
Medicine
Complex Spine Surgeon
Sonoran Spine Center
Phoenix, Arizona
William W. Chin, MD
Bertarelli Pro essor o Translational
Medical Science, Emeritus
Harvard Medical School
Boston, Massachusetts
Chie Medical O f cer and Executive
Vice President
Pharmaceutical Research and
Manu acturers o America
Washington, DC
xv
xvi Contributors
J anet Chou, MD
Instructor, Department of Pediatrics
Harvard Medical School
Assistant in Medicine
Department of Immunology
Childrens Hospital Boston
Boston, Massachusetts
David E. Clapham, MD, PhD
Aldo R. Castaeda Professor of
Cardiovascular Research
Professor of Neurobiology
Harvard Medical School
Chief, Basic Cardiovascular Research
Department of Cardiology
Childrens Hospital Boston
Boston, Massachusetts
Donald M. Coen, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Cohen, MD, PhD
Robert H. Ebert Professor of Medicine
and Health Sciences and
Technology
Director, Harvard-Massachusetts
Institute of Technology Division of
Health Sciences and Technology
Harvard Medical School
Director of Hepatology
Division of Gastroenterology,
Hepatology and Endoscopy
Department of Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Michael W. Conner, DVM
Vice President
Theravance Biopharma, U.S., Inc.
South San Francisco, California
Susannah B. Cornes, MD
Assistant Professor, Department
of Neurology
University of California, San Francisco
Department of Neurology
UCSF Medical Center
San Francisco, California
Amber Dahlin, PhD, MMSc
Instructor in Medicine
Harvard Medical School
Associate Epidemiologist
Channing Division of Network
Medicine, Department of Medicine,
Brigham and Womens Hospital
Boston, Massachusetts
George D. Demetri, MD
Professor of Medicine
Department of Medical Oncology
Co-Director, Ludwig Center
Harvard Medical School
Department of Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Catherine Dorian-Conner, PharmD, PhD
Consultant in Toxicology
Half Moon Bay, California
David M. Dudzinski, MD, J D
Clinical Fellow in Medicine
Harvard Medical School
Fellow, Department of Cardiology
Massachusetts General Hospital
Boston, Massachusetts
Baran A. Ersoy, PhD
Instructor in Medicine
Harvard Medical School
Investigator
Brigham and Womens Hospital
Boston, Massachusetts
Hua-J un Feng, MD, PhD
Instructor in Anaesthesia
Harvard Medical School
Assistant in Pharmacology
Massachusetts General Hospital
Boston, Massachusetts
Stuart A. Forman, MD, PhD
Associate Professor of Anesthesia
Harvard Medical School
Boston, Massachusetts
David A. Frank, MD, PhD
Associate Professor of Medicine
Harvard Medical School
Departments of Medicine and
Medical Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
J oshua M. Galanter, MD
Assistant Professor, Department of
Medicine
University of California, San Francisco
San Francisco, California
Rajesh Garg, MD
Assistant Professor of Medicine
Harvard Medical School
Associate Physician
Division of Endocrinology, Diabetes
and Hypertension
Department of Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Nidhi Gera, PhD
Research Fellow
Department of Biological Chemistry
and Molecular Pharmacology
Harvard Medical School
Boston, Massachusetts
David E. Golan, MD, PhD
Professor of Biological Chemistry and
Molecular Pharmacology
George R. Minot Professor of Medicine
Dean for Basic Science and
Graduate Education
Special Advisor for Global Programs
Harvard Medical School
Senior Physician, Hematology
Division, Brigham and
Womens Hospital and
Dana-Farber Cancer Institute
Department of Biological Chemistry
and Molecular Pharmacology,
Department of Medicine
Harvard Medical School
Boston, Massachusetts
Mark A. Goldberg, MD
Associate Professor of Medicine,
Part-time
Harvard Medical School
Boston, Massachusetts
Advisor
Medical and Regulatory Strategy
Synageva BioPharma Corp.
Lexington, Massachusetts
Laura C. Green, PhD, DABT
President and Senior Toxicologist
Green Toxicology, LLC
Brookline, Massachusetts
Edmund A. Gri f n, J r., MD, PhD
Assistant Professor of Clinical
Psychiatry
Department of Psychiatry
Columbia University
Attending Psychiatrist
New York-Presbyterian Hospital
New York, New York
Robert S. Gri f n, MD, PhD
Clinical Assistant Professor of
Anesthesiology
Weill Cornell Medical College
Assistant Attending Anesthesiologist
Hospital for Special Surgery
New York, New York
F. Peter Guengerich, PhD
Professor, Department of Biochemistry
Vanderbilt University School of
Medicine
Nashville, Tennessee

Stephen J . Haggarty, PhD
Associate Pro essor o Neurology
Harvard Medical School
Director, Chemical Neurobiology
Laboratory
Center or Human Genetic Research
Massachusetts General Hospital
Boston, Massachusetts
Sarah P. Hammond, MD
Assistant Pro essor o Medicine
Harvard Medical School
Associate Physician
Brigham and Womens Hospital
Boston, Massachusetts
Keith A. Hoffmaster, PhD
Director, Global Program
Management
Translational Clinical Oncology
Novartis Institutes or Biomedical
Research
Cambridge, Massachusetts
Anthony Hollenberg, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Metabolism
Beth Israel Deaconess Medical Center
Boston, Massachusetts
David L. Hutto, DVM, PhD, DACVP
Corporate Senior Vice President and
Chie Scientif c O f cerSa ety
Assessment
Charles River Laboratories, Inc.
Wilmington, Massachusetts
Louise C. Ivers, MD, MPH, DTM&H
Associate Pro essor o Medicine
Harvard Medical School
Associate Physician
Department o Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Ursula B. Kaiser, MD
Pro essor o Medicine
Harvard Medical School
Chie , Division o Endocrinology,
Diabetes and Hypertension
Brigham and Womens Hospital
Boston, Massachusetts
Lloyd B. Klickstein, MD, PhD
Head o Translational Medicine
New Indications Discovery Unit
Novartis Institutes or
Biomedical Research
Cambridge, Massachusetts
Vidyasagar Koduri, MD, PhD
Clinical Fellow in Hematology/
Oncology
Dana Farber Cancer Institute/Harvard
Cancer Center
Boston, Massachusetts
Tibor I. Krisko, MD
Instructor
Department o Medicine
Harvard Medical School
Boston, Massachusetts
Sta Gastroenterologist
Department o Gastroenterology/
Medicine
Boston VA Medical Center
Jamaica Plain, Massachusetts
David W. Kubiak, PharmD
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Massachusetts College o Pharmacy
and Health Sciences
Adjunct Assistant Pro essor o
Pharmacology
Massachusetts General Hospital
Institute o Health Pro essions
Adjunct Clinical Assistant Pro essor
o Pharmacy Practice
Northeastern University Bouv
College o Heath Sciences
Co-Director o Antimicrobial
Stewardship and Advanced Practice
In ectious Diseases Pharmacy
Specialist
Brigham and Womens Hospital
Boston, Massachusetts
Alexander E. Kuta, PhD
Vice President and Head o US
Regulatory A airs
EMD Serono, Inc.
Rockland, Massachusetts
Robert Langer, ScD
David H. Koch Institute Pro essor
Departments o Chemical Engineering
and Bioengineering
Massachusetts Institute o Technology
Cambridge, Massachusetts
Senior Lecturer on Surgery
Childrens Hospital Boston
Boston, Massachusetts
Stephen Lazarus, MD
Pro essor o Medicine
Division o Pulmonary and Critical
Care Medicine
Director, Training Program in Pulmonary
and Critical Care Medicine
University o Cali ornia, San Francisco
San Francisco, Cali ornia
xvii Contributors
Benjamin Leader, MD, PhD
Chie Executive O f cer
ReproSource
Woburn, Massachusetts
J onathan Z. Li, MD, MMSc
Assistant Pro essor o Medicine
Harvard Medical School
Brigham and Womens Hospital
Boston, Massachusetts
Eng H. Lo, PhD
Pro essor o Radiology
Harvard Medical School
Director, Neuroprotection
Research Laboratory
Departments o Radiology
and Neurology
Massachusetts General Hospital
Boston, Massachusetts
J oseph Loscalzo, MD, PhD
Hersey Pro essor o the Theory and
Practice o Medicine
Harvard Medical School
Chairman, Department o Medicine
and Physician-in-Chie
Brigham and Womens Hospital
Boston, Massachusetts
Daniel H. Lowenstein, MD
Pro essor, Department o Neurology
University o Cali ornia, San Francisco
Director, UCSF Epilepsy Center
UCSF Medical Center
San Francisco, Cali ornia
Chelsea Ma, MD
Resident Physician
Internal Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts
J ianren Mao, MD, PhD
Richard J. Kitz Pro essor o
Anaesthesia Research
Harvard Medical School
Chie , Division o Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
Peter R. Martin, MD
Pro essor, Departments o Psychiatry
and Pharmacology
Vanderbilt University
Director, Division o Addiction
Psychiatry and Vanderbilt
Addiction Center
Vanderbilt University Medical Center
Nashville, Tennessee
xviii Contributors
Elizabeth Mayne, MD, PhD
Resident in Pediatrics and Child
Neurology
Department of Pediatrics
Stanford University School of
Medicine
Palo Alto, California
Alexander J . McAdam, MD, PhD
Associate Professor of Pathology
Harvard Medical School
Medical Director
Infectious Diseases Diagnostic
Laboratory
Boston Childrens Hospital
Boston, Massachusetts
J ames M. McCabe, MD
Assistant Professor of Medicine
University of Washington
Director, Cardiac Catheterization
Laboratory
University of Washington Medical
Center
Seattle, Washington
Keith W. Miller, MA, DPhil
Edward Mallinckrodt Professor
of Pharmacology
Department of Anaesthesia
Harvard Medical School
Pharmacologist, Department of
Anesthesia, Critical Care and
Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua D. Moss, MD
Assistant Professor of Medicine
Heart Rhythm Center
University of Chicago Medical Center
Chicago, Illinois
Dalia S. Nagel, MD
Clinical Instructor, Department
of Ophthalmology
Mount Sinai School of Medicine
Attending Physician
Department of Ophthalmology
Mount Sinai Hospital
New York, New York
William M. Oldham, MD, PhD
Instructor in Medicine
Harvard Medical School
Associate Physician
Pulmonary and Critical Care Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Sachin Patel, MD, PhD
Assistant Professor, Departments
of Psychiatry and Molecular
Physiology and Biophysics
Vanderbilt University Medical Center
Nashville, Tennessee
Roy H. Perlis, MD, MSc
Director, Center for Experimental
Drugs and Diagnostics
Center for Human Genetic Research
and Department of Psychiatry
Massachusetts General Hospital
Associate Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts
Maarten Postema, PhD
Director of Chemistry
EISAI Inc.
Andover, Massachusetts
Giulio R. Romeo, MD
Instructor in Medicine
Harvard Medical School
Staff Physician, Adult Diabetes
Section
Joslin Diabetes Center
Staff Physician, Division of
Endocrinology BIDMC
Boston, Massachusetts
Eryn L. Royer, BA
Medical Student
University of Colorado School of
Medicine
Aurora, Colorado
Edward T. Ryan, MD
Professor of Medicine
Harvard Medical School
Professor of Immunology and
Infectious Diseases
Harvard T.H. Chan School of
Public Health
Director, Tropical Medicine
Massachusetts General Hospital
Boston, Massachusetts
J oshua M. Schulman, MD
Assistant Professor of Dermatology
University of California, Davis
Director of Dermatopathology
Sacramento VA Medical Center
Sacramento, California
Charles N. Serhan, PhD
Simon Gelman Professor of
Anaesthesia (Biological Chemistry
and Molecular Pharmacology)
Department of Anesthesiology,
Perioperative and Pain Medicine
Harvard Medical School
Director, Center for Experimental
Therapeutics and Reperfusion Injury
Brigham and Womens Hospital
Boston, Massachusetts
Helen M. Shields, MD
Professor of Medicine
Harvard Medical School
Physician, Department of Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Steven E. Shoelson, MD, PhD
Professor of Medicine
Harvard Medical School
Associate Director of Research,
Section Head, Cellular and
Molecular Physiology
Joslin Diabetes Center
Boston, Massachusetts
David M. Slovik, MD
Associate Professor of Medicine
Harvard Medical School
Endocrine Unit
Massachusetts General Hospital
Boston, Massachusetts
Chief, Division of Endocrinology
Newton-Wellesley Hospital
Newton, Massachusetts
David G. Standaert, MD, PhD
John N. Whitaker Professor and Chair,
Department of Neurology
University of Alabama at Birmingham
Director, Division of
Movement Disorders
University Hospital
Birmingham, Alabama
Gary R. Strichartz, PhD
Professor of Anaesthesia
(Pharmacology),
Harvard Medical School
Director, Pain Research Center,
Department of Anesthesiology,
Perioperative and Pain Medicine
Brigham and Womens Hospital
Boston, Massachusetts

Victor W. Sung, MD
Associate Professor, Department of
Neurology, Division of Movement
Disorders
The University of Alabama at
Birmingham
Birmingham, Alabama
Kelan Tantisira, MD, MPH
Associate Professor of Medicine
Harvard Medical School
Associate Physician
Channing Division of Network
Medicine and Division of
Pulmonary and Critical Care
Medicine
Brigham and Womens Hospital
Boston, Massachusetts
Hakan R. Toka, MD, PhD
Assistant Professor of Medicine
Division of Nephrology and
Hypertension
Eastern Virginia Medical School
Norfolk, Virginia
J ohn L. Vahle, DVM, PhD, DACVP
Senior Research Pathologist, Department
of Toxicology and Pathology
Lilly Research Laboratories
Indianapolis, Indiana
Anand Vaidya, MD
Assistant Professor of Medicine
(Endocrinology)
Harvard Medical School
Division of Endocrinology, Diabetes,
and Hypertension
Brigham and Womens Hospital
Boston, Massachusetts
Vishal S. Vaidya, PhD
Associate Professor of Medicine
Head, Systems Toxicology
Program, Laboratory of Systems
Pharmacology
Harvard Medical School
Brigham and Womens Hospital
Associate Professor of Environmental
Health
Harvard T.H. Chan School of
Public Health
Boston, Massachusetts
xix Contributors
Andrew J . Wagner, MD, PhD
Assistant Professor, Department of
Medicine
Harvard Medical School
Medical Director, Ambulatory Oncology
Center for Sarcoma and Bone Oncology
Dana-Farber Cancer Institute
Boston, Massachusetts
Clifford J . Woolf, MB, BCh, PhD
Professor of Neurology
and Neurobiology
Harvard Medical School
Director, F.M. Kirby
Neurobiology Center
Childrens Hospital Boston
Boston, Massachusetts
J acob Wouden, MD
Radiologist, Washington Hospital
Medical Staff
Washington Hospital Healthcare Group
Fremont, California
 I
Fundamental Principles of
Pharmacology
 B C

1
DrugReceptor Interactions
Fra n c is J . Ale n g h a t a n d David E. Go la n


INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
INTR Int GD
G DP
n racee llular Recep
nt e tors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
CONFORMATION AND D CH
CHE EMISTRY Y OF IInt
ntrra ce
cellllular Enzymes and Signal
DRUGS AND D RE
RECE
CEPT
PTOR
ORS S ..................................2 Traa ns
nsduduct
c ion Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
IImp
mpaa ctt of Drug Binding on the Receptor . . . . . . . . . . . . . . . . . . . 5 Transcription Factorss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Membrane Effects on DrugReceptor Inter erac
acti tion
ons . . . . . . . . . . 6 Structural Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
MOLECULAR AND CEL LLU
LULA LAR R DETERMINANTS OF Nucleic Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DR
RUG SEL ELECECTI
TIVITY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Extracellular Targetss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Cell Surface
Surfrfac
acc e Ad
Adhheesion
sion
sion R
Receptors
eceptors . . . . . . . . . . . . . . . . . . . . . . . . 14
MAJ OR TYPES OF DRUG RECEPTORS . . . . . . . . . . . . . . . . . . . . . . . 6
Tra
Trans
nsme
memb mbra
rane
ne Ion Cha hannels . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 PROCESSING OF SIGNALS RESULTING FROM
Transmembrane G Protein-Coupl pled
ed Recepec epto tors . . . . . . . . . . . . . 9 DRUGRECEPTOR INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . 14
Tra
rans
nsme
memb mbra
rane
ne Receptors with Linked Enzymatic Domains . . . 11 CELLULAR REGULATION OF DRUGRECEPTOR
Receptor Tyrosine Kinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Receptor Tyrosine Phosphatases . . . . . . . . . . . . . . . . . . . . . . 12 DRUGS THAT DO NOT FIT THE DRUGRECEPTOR MODEL. . . . . 16
Tyrosine
y Kinase-Associated Receptors p . . . . . . . . . . . . . . . . . 12 CONCLUSION
CONCL
ON CLUSUSIO IONNA AND
ND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 16
Receptor Serine/Threonine Kinasess . . . . . . . . . . . . . . . . . . . 12 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Receptor Guanylyl Cyclasess . . . . . . . . . . . . . . . . . . . . . . . . . . 12

INTRODUCTION Drug receptors are macromolecules that, upon binding to a

Why is it that one drug a ects cardiac unction and another
alters the transport o specif c ions in the kidney? Why do
antibiotics e ectively kill bacteria but rarely harm patients?
These questions can be answered by f rst examining the in-
teraction between a drug and its specif c molecular target and
then considering the role o that action in a broader physi-
ologic context. This chapter ocuses on the molecular details
o drugreceptor interactions, emphasizing the variety o
receptors and their molecular mechanisms. This discussion
provides a conceptual basis or the action o the many drugs
and drug classes discussed in this book. It also serves as a
background or Chapter 2, Pharmacodynamics, which dis-
cusses the quantitative relationships between drugreceptor
interactions and pharmacologic e ect.
Although drugs can theoretically bind to almost any
three-dimensional target, most drugs achieve their desired
(therapeutic ) e ects by interacting selectively with target
molecules that play important physiologic or pathophysi-
ologic roles. In many cases, selectivity o drug binding to
receptors also determines the undesired (adverse ) e ects
o a drug. In general, drugs are molecules that interact with
specif c molecular components o an organism to cause bio-
chemical and physiologic changes within that organism.
drug, mediate those biochemical and physiologic changes.
CONFORMATION AND CHEMISTRY OF
DRUGS AND RECEPTORS
An understanding o why a drug binds to a particular receptor
can be ound in the structure and chemical properties o the
two molecules. This section discusses the basic determinants
o receptor structure and the chemistry o drugreceptor
binding. The discussion here ocuses primarily on the inter-
actions o drugs that are small molecules with target recep-
tors that are mainly macromolecules (especially proteins),
but many o these principles also apply to the interactions
o antibody- or other protein-based therapeutics with their
molecular targets (see Chapter 54, Protein Therapeutics).
Because many human and microbial drug receptors are
proteins, it is use ul to review the our major levels o protein
structure (Fig. 1-1). At the most basic level, proteins consist
o long chains o amino acids, the sequences o which are
determined by the sequences o the DNA that code or the
proteins. A proteins amino acid sequence is re erred to as
its primary structure . Once a long chain o amino acids has
been synthesized on a ribosome, many o the amino acids

2

In te n t o n e n jo yin g h is n e w ly o u n d
re tire m e n t, Mr. B h a s m a d e a p o in t o
p la yin g te n n is a s o te n a s p o s s ib le d u r-
in g th e p a s t ye a r. Fo r th e p a s t 3 m o n th s ,
h o w e ve r, h e h a s n o te d in cre a s in g a -
tig u e . Mo re o ve r, h e is n o w u n a b le to
f n is h a m e a l, d e s p ite h is typ ica lly vo ra cio u s a p -
p e tite . Wo rrie d a n d w o n d e rin g w h a t th e s e s ym p -
to m s m e a n , Mr. B s ch e d u le s a n a p p o in tm e n t w ith
h is d o cto r. On p hys ica l e xa m in a tio n , th e p hys icia n
n o te s th a t Mr. B h a s a n e n la rg e d s p le e n , e xte n d in g
a p p ro xim a te ly 10 cm b e lo w th e le t co s ta l m a rg in ;
th e p hys ica l e xa m is o th e rw is e w ith in n o rm a l lim -
its . Blo o d te s ts s h o w a n in cre a s e d to ta l w h ite b lo o d
ce ll co u n t (70,0 0 0 ce lls /m m 3 ) w ith a n a b s o lu te in -
cre a s e in n e u tro p h ils , b a n d o rm s , m e ta m ye lo cyte s ,
a n d m ye lo cyte s , b u t n o b la s t ce lls (u n d i e re n tia te d
p re cu rs o r ce lls ). Cyto g e n e tic a n a lys is o m e ta p h a s e
ce lls d e m o n s tra te s th a t 90% o Mr. Bs m ye lo id ce lls
p o s s e s s th e Ph ila d e lp h ia ch ro m o s o m e (in d ica tin g a
tra n s lo ca tio n b e tw e e n ch ro m o s o m e s 9 a n d 22), co n -
f rm in g th e d ia g n o s is o ch ro n ic m ye lo id le u ke m ia .
Th e p hys icia n in itia te s th e ra p y w ith imatinib, a h ig h ly
s e le ctive in h ib ito r o th e BCR-Ab l tyro s in e kin a s e
u s io n p ro te in th a t is e n co d e d b y th e Ph ila d e lp h ia
ch ro m o s o m e . Ove r th e n e xt m o n th , th e ce lls
begin to interact with nearby amino acids in the polypeptide
chain. These interactions, which are typically mediated by
hydrogen bonding, give rise to the secondary structure o a
protein by orming well-def ned con ormations such as the
helix, pleated sheet, and barrel. As a result o their
highly organized shape, these structures o ten pack tightly
with one another, urther def ning the overall shape o the
protein. Tertiary structure results rom the interaction o
amino acids more distant rom one another along a single
amino acid chain. These interactions include hydrogen bond
and ionic bond ormation as well as the covalent linkage
o sul ur atoms to orm intramolecular disulf de bridges.
Finally, polypeptides may oligomerize to orm more com-
plex structures. The con ormation that results rom the
interaction o separate polypeptides is re erred to as the qua-
ternary structure .
Di erent portions o a proteins structure generally have
di erent a f nities or water, and this eature has an additional
e ect on the proteins shape. Because both the extracellular
and intracellular environments are composed primarily o
water, hydrophobic protein segments are o ten drawn to the
inside o the protein or shielded rom water by insertion into
lipid bilayer membranes. Conversely, hydrophilic protein
segments are o ten located on a proteins exterior sur ace.
A ter all o this twisting and turning is completed, each pro-
tein has a unique shape that determines its unction, location
in the body, relationship to cellular membranes, and binding
interactions with drugs and other macromolecules.
The site on the receptor at which the drug binds is
called its binding site . Each binding site has unique chemi-
cal characteristics that are determined by the specif c
properties o the amino acids that make up the site. The
C h a p t e r 1 DrugReceptor Interactions 3
co n ta in in g th e Ph ila d e lp h ia ch ro m o s o m e d is a p p e a r
co m p le te ly ro m Mr. Bs b lo o d , a n d h e b e g in s to e e l
w e ll e n o u g h to co m p e te in a s e n io rs te n n is to u rn a -
m e n t. Mr. B co n tin u e s to ta ke im a tin ib e ve ry d a y,
a n d h e h a s a co m p le te ly n o rm a l b lo o d co u n t a n d n o
a tig u e . He is n o t s u re w h a t th e u tu re w ill b rin g , b u t
h e is g la d to h a ve b e e n g ive n th e ch a n ce to e n jo y a
h e a lthy re tire m e n t.
Questions
1 . How does imatinib interrupt the activity o the BCR-Abl
tyrosine kinase usion protein?
2 . Unlike imatinib, most o the older therapies or chronic
myeloid leukemia (such as inter eron- ) had signif cant
u-like adverse e ects. Why did these therapies
cause signif cant adverse e ects in most patients,
whereas (as in this case) imatinib causes adverse
e ects in very ew patients?
3 . Why is imatinib a selective therapy or chronic myeloid
leukemia? Is this selectivity related to the lack o ad-
verse e ects associated with imatinib therapy?
4 . How does the BCR-Abl protein a ect intracellular
signaling pathways?
three-dimensional structure, shape, and reactivity o the
site, and the inherent structure, shape, and reactivity o the
drug, determine the orientation o the drug with respect to
the receptor and govern how tightly these molecules bind to
one another. Drugreceptor binding is the result o multiple
chemical interactions between the two molecules, some
o which are airly weak (such as van der Waals orces)
and some o which are extremely strong (such as covalent
bonding). The sum total o these interactions provides the
specif city o the overall drugreceptor interaction. The a-
vorability o a drugreceptor interaction is re erred to as the
a f nity o the drug or its binding site on the receptor. This
concept is discussed in more detail in Chapter 2. The chem-
istry o the local environment in which these interactions
occursuch as the hydrophobicity, hydrophilicity, and pKa
o amino acids near the binding sitemay also a ect the
a f nity o the drugreceptor interaction. The primary orces
that contribute to drugreceptor a f nity are described below
and in Table 1-1.
van der Waals orces , resulting rom the polarity induced
in a molecule by the shi ting o its electron density in re-
sponse to the close proximity o another molecule, provide
a weak attractive orce or drugs and their receptors. This
induced polarity is a ubiquitous component o all molecular
interactions. Hydrogen bonds have substantial strength and
are o ten important or drugreceptor association. This type
o bond is mediated by the interaction between positively
polarized hydrogen atoms (which are covalently attached
to more electronegative atoms such as nitrogen or oxygen)
and negatively polarized atoms (such as oxygen, nitrogen,
or sul ur that are covalently attached to less electronega-
tive atoms such as carbon or hydrogen). Ionic interactions ,
4 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Primary
Amino a cids
Secondary
Be ta ple a te d Alpha he lix
s he e t
Tertiary
Be ta ple a te d s he e t
Alpha he lix
Quaternary
FIGURE 1-1. Levels of protein structure. Protein structure can be divided
into our levels o complexity, re erred to as primary, secondary, tertiary,
and quaternary structure. Primary structure is determined by the sequence
o amino acids that make up the polypeptide chain. Secondary structure is
determined by the interaction o positively polarized hydrogen atoms with
negatively polarized atoms (such as oxygen) on the same polypeptide chain.
These interactions result in a number o characteristic secondary patterns
o protein con ormation, including the helix and pleated sheet. Tertiary
structure is determined by the interactions o amino acids that are relatively
ar apart on the protein backbone. These interactions, which include ionic
bonds and covalent disulf de linkages (among others), give proteins their
characteristic three-dimensional structure. Quaternary structure is deter-
mined by the binding interactions among two or more independent protein
subunits.
which occur between atoms with opposite charges, are
stronger than hydrogen bonds but less strong than covalent
bonds. Covalent bonding results rom the sharing o a pair o
electrons between two atoms on di erent molecules. Cova-
lent interactions are so strong that, in most cases, they are
essentially irreversible. Table 1-1 indicates the mechanism
o interaction and relative strength o each o these types o
bonds. As noted above, the environment in which drugs and
receptors interact also a ects the avorability o binding.
The hydrophobic effect re ers to the mechanism by which the
unique properties o the ubiquitous solvent water cause the
interaction o a hydrophobic molecule with a hydrophobic
binding site to be enhanced.
Rarely is drugreceptor binding caused by a single type
of interaction; rather, it is a combination of these binding
interactions that provides drugs and receptors with the
forces necessary to form a stable drugreceptor complex.
In general, multiple weak orces comprise the majority o
drugreceptor interactions. For example, imatinib orms
many van der Waals interactions and hydrogen bonds with
the ATP-binding site o the BCR-Abl tyrosine kinase. The
sum total o these relatively weak orces creates a strong
(high a f nity) interaction between this drug and its recep-
tor (Fig. 1-2). Ionic and hydrophobic interactions exert
orce at a greater distance than van der Waals interactions
and hydrogen bonds; or this reason, the ormer interac-
tions are o ten critical to initiate the association o a drug
and receptor.
Although relatively rare, covalent interactions between
a drug and its receptor are a special case. The ormation
o a covalent bond is o ten essentially irreversible, and in
such cases, the drug and receptor orm an inactive complex.
To regain activity, the cell must synthesize a new receptor
molecule to replace the inactivated protein; and the drug
molecule, which is also part o the inactive complex, is
generally not available to inhibit other receptor molecules.
Drugs that modi y their target receptors (o ten enzymes)
through this mechanism are sometimes called suicide sub-
strates . Aspirin is an example o such a drug; it irrevers-
ibly acetylates cyclooxygenases to reduce the production
o prostaglandins (anti-in ammatory e ect) and thrombox-
anes (antiplatelet e ect) (see Chapter 43, Pharmacology o
Eicosanoids).
The molecular structure o a drug dictates the physical
and chemical properties that contribute to its specif c bind-
ing to the receptor. Important actors include hydrophobicity,
ionization state (pKa), con ormation, and stereochemistry o
the drug molecule. All o these actors combine to determine
the complementarity o the drug to the binding site. Recep-
tor binding pockets are highly specif c, and small changes
in the drug can have a large e ect on the a f nity o the
drugreceptor interaction. For example, the stereochemistry
o the drug has a great impact on the strength o the bind-
ing interaction. Warfarin is synthesized and administered as
a racemic mixture (a mixture containing 50% o the right-
handed molecule and 50% o the le t-handed molecule);
however, the S enantiomer is our times more potent than
the R because o a stronger interaction o the S orm with its
binding site on vitamin K epoxide reductase. Stereochem-
istry can also a ect toxicity in cases where one enantiomer
o a drug causes the desired therapeutic e ect and the other
enantiomer causes an undesired toxic e ect, perhaps due to
an interaction with a second receptor or to metabolism to a
toxic species. Although it is sometimes di f cult or pharma-
ceutical companies to synthesize and puri y individual en-
antiomers on a large scale, a number o currently marketed
drugs are produced as individual enantiomers in cases where
one enantiomer has higher e f cacy and/or lower toxicity
than its mirror image.
 C h a p t e r 1 DrugReceptor Interactions 5

TABLE 1-1 Relative Strength o Bonds between Receptors and Drugs

BOND TYPE MECHANISM BOND STRENGTH
van der Waals Shi ting electron density in areas o a molecule, or in a molecule as a whole, results in the generation o
transient positive or negative charges. These areas interact with transient areas o opposite charge
on another molecule.

Hydrogen Hydrogen atoms bound to nitrogen or oxygen become more positively polarized, allowing them to bond
to more negatively polarized atoms such as oxygen, nitrogen, or sul ur.

Ionic Atoms with an excess o electrons (imparting an overall negative charge on the atom) are attracted to
atoms with a def ciency o electrons (imparting an overall positive charge on the atom).

Covalent Two bonding atoms share electrons.

Impact o Drug Binding on the Receptor The principle o induced f t suggests that drugreceptor
binding can have pro ound e ects on the con ormation o
How does drug binding produce a biochemical and/or physi-
the receptor. By inducing con ormational changes in the re-
ologic change in the organism? In the case o receptors with
ceptor, many drugs not only improve the quality o the bind-
enzymatic activity, the binding site o the drug is o ten the
ing interaction but also alter the action o the receptor. The
active site at which an enzymatic trans ormation is cata-
change in shape induced by the drug is sometimes identi-
lyzed, and the catalytic activity o the enzyme is inhibited
cal to that caused by the binding o an endogenous ligand.
by drugs that prevent substrate binding to the site or that
For example, exogenously administered insulin analogues
covalently modi y the site. In cases where the binding site is
all stimulate the insulin receptor to the same extent, despite
not the active site o the enzyme, drugs can cause a change
their slightly di erent amino acid sequences. In other cases,
by preventing the binding o endogenous ligands to their
drug binding alters the shape o the receptor so as to make it
receptor binding pockets. In many drugreceptor interac-
more or less unctional than normal. For example, imatinib
tions, however, the binding o a drug to its receptor results
binding to the BCR-Abl tyrosine kinase causes the protein to
in a change in the con ormation o the receptor. Altering the
assume an enzymatically inactive con ormation, thus inhib-
shape o the receptor can a ect its unction, including en-
iting the kinase activity o the receptor.
hancing the a f nity o the drug or the receptor. Such an
Another way to describe the induced f t principle is to
interaction is o ten re erred to as induced f t, because the re-
consider that many receptors exist in multiple con orma-
ceptors con ormation changes so as to improve the quality
tional statessuch as inactive (or closed), active (or open),
o the binding interaction.
and desensitized (or inactivated)and that the binding o a

A B Glu 286
C
Me t 290 Imatinib

Ile 313

Imatinib P he 382
Ala 269
Gly 383
As p 381
As n 368 Activa tion loop
of kina s e
Thr 315

P he 382 Lys 271

As p 363

Le u 248 P he 317
As p 381 Arg 367 Tyr 393
Tyr 253 Va l 256

Me t 318
Gly 321

Le u 370

FIGURE 1-2. Structural basis o specif c enzyme inhibition: imatinib interaction with the BCR-Abl kinase. A. The kinase portion o the BCR-Abl tyrosine
kinase is shown in a ribbon ormat (gray). An analogue o imatinib, a specif c inhibitor o the BCR-Abl tyrosine kinase, is shown as a space-f lling model (blue ).
B. Detailed diagram o the intermolecular interactions between the drug (shaded in purple ) and amino acid residues in the BCR-Abl protein. Hydrogen bonds
are indicated by dashed lines, while van der Waals interactions (indicated by halos around the amino acid name and its position in the protein sequence)
are shown or nine amino acids with hydrophobic side chains. C. The interaction o the drug (blue ) with the BCR-Abl protein (gray) inhibits phosphorylation
o a critical activation loop (green-highlighted ribbon format), thus preventing catalytic activity.
6 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
drug to the receptor stabilizes one or more o these con or-
mations. Quantitative models that incorporate these concepts
o drugreceptor interactions are discussed in Chapter 2.
Membrane E ects on DrugReceptor
Interactions
The structure o the receptor also determines where the pro-
tein is located in relationship to cellular boundaries such as
the plasma membrane. Proteins that have large hydrophobic
domains are able to reside in the plasma membrane because
o the membranes high lipid content. Many receptors that
span the plasma membrane have lipophilic domains that are
located in the membrane and hydrophilic domains that re-
side in the intracellular and extracellular spaces. Other drug
receptors, including a number o transcription regulators
(also called transcription actors ), have only hydrophilic do-
mains and reside in the cytoplasm, nucleus, or both.
Just as the structure o the receptor determines its loca-
tion in relationship to the plasma membrane, the structure o
a drug a ects its ability to gain access to the receptor. For
example, many drugs that are highly water-soluble are un-
able to pass through the plasma membrane and bind to target
molecules in the cytoplasm. Certain hydrophilic drugs are
able to pass through transmembrane channels (or use other
transport mechanisms) and gain ready access to cytoplasmic
receptors. Drugs that are highly lipophilic, such as many
steroid hormones, are o ten able to pass through the hydro-
phobic lipid environment o the plasma membrane without
special channels or transporters and thereby gain access to
intracellular targets.
Drug-induced alterations in receptor shape can allow
drugs bound to cell sur ace receptors to a ect unctions
inside cells. Many cell sur ace receptors have extracellular
domains that are linked to intracellular e ector molecules by
receptor domains that span the plasma membrane and extend
into the cytoplasm. In some cases, changing the shape o
the extracellular domain can alter the con ormation o the
membrane-spanning and/or intracellular domains o the
receptor, resulting in a change in receptor unction. In other
cases, drugs can cross-link the extracellular domains o two
receptor molecules, orming a dimeric receptor complex that
activates e ector molecules inside the cell.
All o these actorsdrug and receptor structure, the
chemical orces in uencing drugreceptor interaction, drug
solubility in water and in the plasma membrane, and the
unction o the receptor in its cellular environmentcon er
substantial specif city on the interactions between drugs
and their target receptors. This book discusses numerous
examples o drugs that can gain access and bind to receptors,
induce con ormational changes in the receptors, and thereby
produce biochemical and physiologic e ects. Specif city o
drugreceptor binding suggests that, armed with the knowl-
edge o the structure o a receptor, one could theoretically
design a drug that interrupts or enhances receptor activity.
This process, known as rational drug design, could poten-
tially increase the e f cacy and reduce the toxicity o drugs
by optimizing their structure so that they bind more selec-
tively to their targets. Rational drug design was f rst used to
develop highly selective agents such as the antiviral prote-
ase inhibitor ritonavir and the antineoplastic tyrosine kinase
inhibitor imatinib. Indeed, urther rounds o rational drug
design have led to the development o second-generation
protease inhibitors and antineoplastics with high a f nity or
the mutated drug targets that can evolve in patients who de-
velop resistance to f rst-generation drugs. The rational drug
design approach is discussed in greater detail in Chapter 51,
Drug Discovery and Preclinical Development.
MOLECULAR AND CELLULAR
DETERMINANTS OF DRUG SELECTIVITY
The ideal drug would interact only with a molecular target
that causes the desired therapeutic e ect but not with molec-
ular targets that cause unwanted adverse e ects. Although
no such drug has yet been discovered (i.e., all drugs cur-
rently in clinical use have the potential to cause adverse
e ects as well as therapeutic e ects; see Chapter 6, Drug
Toxicity), pharmacologists can take advantage o several de-
terminants o drug selectivity in an attempt to reach this goal.
Selectivity o drug action can be con erred by at least two
classes o mechanisms, including (1) the cell-type specif c-
ity o receptor subtypes and (2) the cell-type specif city o
receptore ector coupling.
Although many potential receptors or drugs are widely
distributed among diverse cell types, some receptors are
more limited in their distribution. Systemic administration o
drugs that interact with such localized receptors can result in
a highly selective therapeutic e ect. For example, drugs that
target ubiquitous processes such as DNA synthesis are likely
to cause signif cant toxic side e ects; this is the case with
many currently available chemotherapeutics or the treat-
ment o cancer. Other drugs that target cell-type restricted
processes such as acid generation in the stomach may have
ewer adverse e ects. Imatinib, or example, is an extremely
selective drug because the BCR-Abl protein is not expressed
in normal (noncancerous) cells. In general, the more re-
stricted the cell-type distribution o the receptor targeted by
a particular drug, the more selective the drug is likely to be.
Similarly, even though many di erent cell types may ex-
press the same molecular target or a drug, the e ect o that
drug may di er in the various cell types because o di er-
ential receptore ector coupling mechanisms or di erential
requirements or the drug target in the various cell types.
For example, although voltage-gated calcium channels are
ubiquitously expressed in the heart, cardiac pacemaker cells
are relatively more sensitive to the e ects o calcium chan-
nel blocking agents than are cardiac ventricular muscle cells.
This di erential e ect is attributable to the act that action po-
tential propagation depends mainly on the action o calcium
channels in cardiac pacemaker cells, whereas sodium chan-
nels are more important than calcium channels in the action
potentials o ventricular muscle cells. In general, the more
the receptore ector coupling mechanisms di er among the
various cell types that express a particular molecular target
or a drug, the more selective the drug is likely to be.
MAJ OR TYPES OF DRUG RECEPTORS
Given the great diversity o drug molecules, it might seem
likely that the interactions between drugs and their molecular
targets would be equally diverse. This is only partly true. In act,
most o the currently understood drugreceptor interactions
can be classif ed into six major groups. These groups com-
prise the interactions between drugs and (1) transmembrane
 C h a p t e r 1 DrugReceptor Interactions 7

A B C D

GDP

FIGURE 1-3. Major types of interactions between drugs and receptors. Most drugreceptor interactions can be divided into six groups, our o which are
shown here. A. Drugs can bind to ion channels spanning the plasma membrane, causing an alteration in the channels conductance. B. Heptahelical recep-
tors spanning the plasma membrane are unctionally coupled to intracellular G proteins. Drugs can in uence the actions o these receptors by binding to
the extracellular sur ace or transmembrane region o the receptor. C. Drugs can bind to the extracellular domain o a transmembrane receptor and cause a
change in signaling within the cell by activating or inhibiting an enzymatic intracellular domain (rectangular box) o the same receptor molecule. D. Drugs can
di use through the plasma membrane and bind to cytoplasmic or nuclear receptors. This is o ten the pathway used by lipophilic drugs (e.g., drugs that bind
to steroid hormone receptors). Additionally, drugs can bind to enzymes and other targets in the extracellular space and to cell sur ace adhesion receptors
without the need to cross the plasma membrane (not shown).

ion channels; (2) transmembrane receptors coupled to intra-
cellular G proteins; (3) transmembrane receptors with linked
enzymatic domains; (4) intracellular receptors, including en-
zymes, signal transduction molecules, transcription actors,
structural proteins, and nucleic acids; (5) extracellular targets;
and (6) cell sur ace adhesion receptors (Fig. 1-3). Table 1-2
provides a summary o each major interaction type.
Knowing whether and to what extent a drug activates or
inhibits its target provides valuable in ormation about the in-
teraction. Although pharmacodynamics (the e ects o drugs
on the human body) is covered in detail in the next chapter, it
is use ul to state brief y the major pharmacodynamic relation-
ships between drugs and their targets be ore examining the mo-
lecular mechanisms o drugreceptor interactions. Agonists are
molecules that, upon binding to their targets, cause a change
in the activity of those targets. Full agonists bind to and acti-
vate their targets to the maximal extent possible. For example,
acetylcholine binds to the nicotinic acetylcholine receptor and
induces a con ormational change in the receptor-associated ion
channel rom a nonconducting to a ully conducting state. Par-
tial agonists produce a submaximal response upon binding to
their targets. Inverse agonists cause constitutively active targets
to become inactive. Antagonists inhibit the ability of their tar-
gets to be activated (or inactivated) by physiologic or pharma-
cologic agonists. Drugs that directly block the binding site o
a physiologic agonist are called competitive antagonists ; drugs
that bind to other sites on the target molecule, and thereby pre-
vent the con ormational change required or receptor activation
(or inactivation), may be either noncompetitive or uncompetitive
antagonists (see Chapter 2). As the mechanism o each drug
receptor interaction is outlined in the next several sections, it
will be use ul to consider at a structural level how these di er-
ent pharmacodynamic e ects could be produced.
Transmembrane Ion Channels
Many cellular unctions require the passage o ions and
other hydrophilic molecules across the plasma membrane.

TABLE 1-2 Six Major Types of DrugReceptor Interactions

RECEPTOR TYPE SITE OF DRUGRECEPTOR INTERACTION SITE OF RESULTANT ACTION EXAMPLES
Transmembrane ion Extracellular, intrachannel, or intracellular Cytoplasm Amlodipine, diazepam,
channel lidocaine, omeprazole

Transmembrane linked to Extracellular or intramembrane Cytoplasm Albuterol, loratadine,

intracellular G protein losartan, metoprolol

Transmembrane with Extracellular or intracellular Cytoplasm Erlotinib, insulin, nesiritide,

linked enzymatic sunitinib
domain

Intracellular Cytoplasm or nucleus Cytoplasm or nucleus Atorvastatin, doxycycline,

levothyroxine, paclitaxel

Extracellular target Extracellular Extracellular Dabigatran, donepezil,

etanercept, lisinopril

Adhesion Extracellular Extracellular Eptif batide, natalizumab

8 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

Specialized transmembrane channels regulate these pro- plasma membrane (Fig. 1-4). Two o the subunits have been
cesses. The unctions o ion channels are diverse, including designated ; each contains a single extracellular binding
undamental roles in neurotransmission, cardiac conduction, site or ACh. In the ree (nonliganded) state o the recep-
muscle contraction, and secretion. Because o this, drugs tar- tor, the channel is occluded by amino acid side chains and
geting ion channels can have a substantial impact on major does not allow the passage o ions. Binding o two molecules
body unctions. o acetylcholine to the receptor induces a con ormational
Three major mechanisms are used to regulate the activ- change that opens the channel and allows ion conductance.
ity o transmembrane ion channels. In some channels, the Although the nicotinic ACh receptor appears to assume
conductance is controlled by ligand binding to the channel. only two states, open or closed, many ion channels assume
In other channels, the conductance is regulated by changes in other states as well. For example, some ion channels are able
voltage across the plasma membrane. In still other channels, to become refractory or inactivated. In this state, the chan-
the conductance is controlled by ligand binding to plasma nels permeability cannot be altered or a certain period o
membrane receptors that are linked to the channel in some time, known as the channels re ractory period. The volt-
way. The f rst group o channels is re erred to as ligand- age-gated sodium channel undergoes a cycle o activation,
gated, the second as voltage-gated, and the third as second channel opening, channel closing, and channel inactiva-
messenger-regulated. Table 1-3 summarizes the mechanism tion. During the inactivation (re ractory) period, the channel
o activation and unction o each channel type.
Channels are generally highly selective or the ions they
conduct. For example, action potential propagation in neu- A
rons o the central and peripheral nervous systems occurs as
a result o the synchronous stimulation o voltage-gated ion

channels that permit the selective passage o Na ions into
the cell. When the membrane potential in such a neuron be-
comes su f ciently positive, the voltage-gated Na channels
open, allowing a large in ux o extracellular sodium ions
that urther depolarizes the cell. The role o ion-selective Liga nd binding s ite s
channels in action potential generation and propagation is
discussed in Chapter 8, Principles o Cellular Excitability
and Electrochemical Transmission. B
Most ion channels share some structural similarity, re-
gardless o their ion selectivity, the magnitude o their
conductance, or their mechanism o activation (gating) or
inactivation. Ion channels are pore- orming macromolecules
consisting o one or more protein subunits that pass through
the plasma membrane. The ligand-binding domain can be ex-
tracellular, within the channel, or intracellular, whereas the O
domain that interacts with other receptors or modulators is Re ce ptor ga te clos e d
+
most o ten intracellular. The structures o several ion chan- N
nels have been determined to atomic resolution; the nico- O
tinic acetylcholine (ACh) receptor provides an example o Ace tylcholine
the structure o an important ligand-gated ion channel. This
receptor consists o f ve subunits, each o which crosses the
Na +

TABLE 1-3 Three Major Types of Transmembrane Ion

Channels
MECHANISM OF
CHANNEL TYPE ACTIVATION FUNCTION
Ligand-gated Binding o ligand to Altered ion
channel conductance
Na +
Voltage-gated Change in Altered ion Re ce ptor ga te ope n
transmembrane conductance
voltage gradient
FIGURE 1-4. Ligand-gated nicotinic acetylcholine receptor. A. The plasma
Second messenger- Binding o ligand to Second membrane acetylcholine (ACh) receptor is composed o f ve subunitstwo
regulated transmembrane messenger subunits, a subunit, a subunit, and a subunit. B. The subunit has
receptor with regulates ion been removed to show an internal schematic view o the receptor, demon-
G protein-coupled conductance strating that it orms a transmembrane channel. In the absence o ACh, the
cytosolic domain, o channel receptor gate is closed, and cations (most importantly, sodium ions [Na ])
leading to second are unable to traverse the channel. C. When ACh is bound to both subunits,
messenger generation the channel opens, and sodium can pass down its concentration gradient
into the cell.
 C h a p t e r 1 DrugReceptor Interactions 9

cannot be reactivated or a number o milliseconds, even i
the membrane potential returns to a voltage that normally
stimulates the channel to open. Some drugs bind with di er-
ent a f nities to di erent states o the same ion channel. This
state-dependent binding is important in the mechanism o
action o some local anesthetic and antiarrhythmic drugs, as
discussed in Chapters 12 (Local Anesthetic Pharmacology)
and 24 (Pharmacology o Cardiac Rhythm), respectively.
Two important classes o drugs that act by altering the
conductance o ion channels are the local anesthetics and the
benzodiazepines. Local anesthetics block the conductance
o sodium ions through voltage-gated sodium channels in
neurons that transmit pain in ormation rom the periphery to
the central nervous system, thereby preventing action poten-
tial propagation and, hence, pain perception (nociception).
Benzodiazepines also act on the nervous system, but by a
di erent mechanism. These drugs inhibit neurotransmission
in the central nervous system by potentiating the ability o
the neurotransmitter gamma-aminobutyric acid (GABA) to
increase the conductance o chloride ions across neuronal
membranes, thereby driving the membrane potential urther
away rom its threshold or activation.
Transmembrane G Protein-Coupled Receptors
G protein-coupled receptors are the most abundant class o
receptors in the human body. These receptors are exposed at
the extracellular sur ace o the plasma membrane, traverse
the membrane, and possess intracellular regions that acti-
vate a unique class o signaling molecules called G proteins .
(G proteins are so named because they bind the guanine nu-
cleotides GTP and GDP.) G protein-coupled signaling mech-
anisms are involved in many important processes, including
vision, ol action, and neurotransmission.
G protein-coupled receptors have seven transmembrane
regions within a single polypeptide chain. Each transmem-
brane region consists o a single helix, and the heli-
ces are arranged in a characteristic structural moti that is
similar in all members o this receptor class. The extracel-
lular domain o this class o proteins usually contains the
ligand-binding region, although some G protein-coupled
receptors bind ligands within the transmembrane domain
o the receptor. G proteins have and subunits that are
noncovalently linked in the resting state. Stimulation o a
G protein-coupled receptor causes its cytoplasmic domain to
bind and activate a nearby G protein, whereupon the sub-
unit o the G protein exchanges GDP or GTP. The -GTP
subunit then dissociates rom the subunit, and the or
subunit di uses along the inner lea et o the plasma mem-
brane to interact with a number o di erent e ectors. These
e ectors include adenylyl cyclase, phospholipase C, various
ion channels, and other classes o proteins. Signals medi-
ated by G proteins are usually terminated by the hydrolysis
o GTP to GDP, which is catalyzed by the inherent GTPase
activity o the subunit (Fig. 1-5).
One major role o the G proteins is to activate the production
o second messengers ; that is, signaling molecules that convey
the input provided by the f rst messengerusually an endog-
enous ligand or an exogenous drugto cytoplasmic e ectors
(Fig. 1-6). The activation o cyclases such as adenylyl cyclase ,
which catalyzes the production o the second messenger cyclic
adenosine-3,5-monophosphate (cAMP), and guanylyl cyclase ,
which catalyzes the production o cyclic guanosine-3,5-
monophosphate (cGMP), constitutes the most common path-
way linked to G proteins. In addition, G proteins can activate the
enzyme phospholipase C (PLC), which, among other unctions,
plays a key role in regulating the concentration o intracellular

Re ce ptor
Effe ctor
A

1 Agonis t unbinding 1 Agonis t binding

2 GTP hydrolys is 2 GTP -GDP e xcha nge

3 He te rotrime ric 3 G prote in a ctiva tion
G prote in re cons titute d GDP

Agonis t
Effe ctor a ctiva te d GTP

C B

1 -GTP diffus ion to e ffe ctor

2 Effe ctor a ctiva tion

GTP GTP

GDP

FIGURE 1-5. Receptor-mediated activation of a G protein and the resultant effector interaction. A. In the resting state, the and subunits o a G protein
are associated with one another, and GDP is bound to the subunit. B. Binding o an extracellular ligand (agonist) to a G protein-coupled receptor causes
the exchange o GTP or GDP on the subunit. C. The subunit dissociates rom the subunit, which di uses to interact with e ector proteins. Interac-
tion o the GTP-associated subunit with an e ector activates the e ector. In some cases (not shown), the subunit can also activate e ector proteins.
Depending on the receptor subtype and the specif c G iso orm, G can also inhibit the activity o an e ector molecule. The subunit possesses intrinsic
GTPase activity, which leads to hydrolysis o GTP to GDP. This leads to reassociation o the subunit with the subunit, and the cycle can begin again.
10 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

A Agonis t
TABLE 1-4 The Major G Protein Families and Examples
Re ce ptor Ade nylyl cycla s e of Their Actions
G PROTEIN ACTIONS
G-stimulatory (Gs ) Activates Ca 2 channels, activates adenylyl
cyclase
s
G-inhibitory (Gi) Activates K channels, inhibits adenylyl cyclase
GTP
ATP cAMP Go Inhibits Ca 2 channels

Gq Activates phospholipase C
PKA
G12/13 Diverse ion transporter interactions

P rote in phos phoryla tion

B be grouped into f ve major amiliesG-stimulatory (Gs),

P LC G-inhibitory (Gi), Go, Gq, and G12/13. Examples o the e ects
o these iso orms are shown in Table 1-4. The di erential
unctioning o these G proteins, some o which may couple
PIP2 DAG
in di erent ways to the same receptor in di erent cell types,
P KC is likely to be important or the potential selectivity o uture
(a ctive )
q drugs. The subunits o G proteins can also act as sec-

GTP ond messenger molecules, although their actions are not as
P KC
completely characterized.
IP3
One important class in the G protein-coupled receptor
Ca 2+ amily is the -adrenergic receptor group. The most thor-
oughly studied o these receptors have been designated 1,
Ca 2 + 2, and 3. As discussed in more detail in Chapter 11, Ad-

P rote in phos phoryla tion

renergic Pharmacology, 1 receptors play a role in control-
ling heart rate; 2 receptors are involved in the relaxation o
smooth muscle; and 3 receptors play a role in the mobiliza-
FIGURE 1-6. Activation of adenylyl cyclase (AC) and phospholipase C tion o energy by at cells. Each o these receptors is stimu-
(PLC) by G proteins. G proteins can interact with several di erent types o lated by the binding o endogenous catecholamines, such as
e ector molecules. The subtype o G protein that is activated o ten deter- epinephrine and norepinephrine , to the extracellular domain
mines which e ector the G protein will activate. Two o the most common G o the receptor. Epinephrine binding induces a con orma-
subunits are G s and G q, which stimulate adenylyl cyclase and phospholi- tional change in the receptor and thereby activates G pro-
pase C, respectively. A. When stimulated by G s , adenylyl cyclase converts teins associated with the cytoplasmic domain o the receptor.
ATP to cyclic AMP (cAMP). cAMP then activates protein kinase A (PKA), The activated (GTP-bound) orm o the G protein activates
which phosphorylates a number o specif c intracellular proteins. B. When
adenylyl cyclase, resulting in increased intracellular cAMP
stimulated by G q, phospholipase C (PLC) cleaves the membrane phospho-
lipid phosphatidylinositol-4,5-bisphosphate (PIP2) into diacylglycerol (DAG)
levels and downstream cellular e ects. Table 1-5 indicates
and inositol-1,4,5-trisphosphate (IP3). DAG di uses in the membrane to acti-
vate protein kinase C (PKC), which then phosphorylates specif c cellular pro-
teins. IP3 stimulates release o Ca 2 rom the endoplasmic reticulum into the
TABLE 1-5 Tissue Localization and Action of
cytosol. Calcium release also stimulates protein phosphorylation events that
lead to changes in protein activation. Although not shown, the subunits
-Adrenergic Receptors
o G proteins can also a ect certain cellular signal transduction cascades.
TISSUE
RECEPTOR LOCALIZATION ACTION
calcium. Upon activation by a G protein, PLC cleaves the mem- 1 Sinoatrial (SA) node Increases heart rate
brane phospholipid phosphatidylinositol-4,5-bisphosphate o heart
(PIP2) to the second messengers diacylglycerol (DAG) and Cardiac muscle Increases contractility
inositol-1,4,5-trisphosphate (IP3). IP3 triggers the release o Adipose tissue Increases lipolysis
Ca2 rom intracellular stores, thereby dramatically increasing
Bronchial smooth Dilates bronchioles
the cytosolic Ca2 concentration and activating downstream 2
muscle
molecular and cellular events. DAG activates protein kinase Gastrointestinal Constricts sphincters and
C, which then mediates other molecular and cellular events smooth muscle relaxes gut wall
including smooth muscle contraction and transmembrane ion Uterus Relaxes uterine wall
transport. All o these events are dynamically regulated, so that Bladder Relaxes bladder
the di erent steps in the pathways are activated and inactivated Liver Increases gluconeogenesis
with characteristic kinetics. and glycolysis
A large number o G protein iso orms have been identi- Pancreas Increases insulin release
f ed, each with unique e ects on its targets. Based on the Adipose tissue Increases lipolysis
3
primary sequence o the G subunit, these iso orms can
 C h a p t e r 1 DrugReceptor Interactions 11

FIGURE 1-7. Major types of transmembrane receptors with linked

enzymatic domains. There are f ve major categories o transmembrane re-
A ceptors with linked enzymatic domains. A. The largest group is composed
o receptor tyrosine kinases . A ter ligand-induced activation, these recep-
tors dimerize and transphosphorylate tyrosine residues in the receptor and,
o ten, on target cytosolic proteins. Examples o receptor tyrosine kinases
include the insulin receptor and many growth actor receptors. B. Some
Tyr Tyr
receptors can act as tyrosine phosphatases. These receptors dephos-
P Tyr Tyr P
phorylate tyrosine residues either on other transmembrane receptors or on
cytosolic proteins. Many cells o the immune system have receptor tyro-
Tyros ine kina s e Cytopla s mic sine phosphatases. C. Some tyrosine kinase-associated receptors lack a
a ctivity prote in def nitive enzymatic domain, but binding o ligand to the receptor triggers
Tyr P Tyr
activation o receptor-associated protein 1 (termed nonreceptor tyrosine
kinases ) that then phosphorylate tyrosine residues on certain cytosolic
proteins. D. Receptor serine/threonine kinases phosphorylate serine and
B threonine residues on certain target cytosolic proteins. Members o the
TGF- super amily o receptors are in this category. E. Receptor guanylyl
cyclases contain a cytosolic domain that catalyzes the ormation o cGMP
rom GTP. The receptor or B-type natriuretic peptide is one o the receptor
guanylyl cyclases that has been well characterized.

Tyros ine phos pha ta s e some o the diverse tissue localizations and actions o the
a ctivity
P Tyr Tyr
-adrenergic receptors.

Transmembrane Receptors with Linked

C
Enzymatic Domains
The third major class o cellular drug targets consists o
transmembrane receptors that transduce an extracellular li-
Activa te d kina s e gand-binding interaction into an intracellular action through
the activation o a linked enzymatic domain. The enzymatic
Ina ctive
kina s e Tyros ine kina s e domain may be part o the receptor itsel or part o a cyto-
a ctivity solic protein that is recruited to the receptor in response to
Tyr P Tyr receptor activation. Such receptors play roles in a diverse set
o physiologic processes, including cell metabolism, growth,
and di erentiation. Receptors that have a linked enzymatic
D domain can be grouped into f ve major classes based on their
cytoplasmic mechanism o action (Fig. 1-7). All o these
receptors are singlemembrane-spanning proteins, in con-
trast to the sevenmembrane-spanning moti present in G
protein-coupled receptors. Many receptors with enzymatic
S e r/Thr P S e r/Thr cytosolic domains orm dimers or multisubunit complexes
to transduce their signals.
Many receptors with linked enzymatic domains modi y
S e rine /thre onine
kina s e a ctivity proteins by adding or removing phosphate groups to or rom
S e r/Thr P S e r/Thr
specif c amino acid residues. Phosphorylation is a ubiq-
uitous mechanism of protein signaling. The large negative
charge o phosphate groups can dramatically alter the three-
E dimensional structure o a protein and thereby change that
proteins activity. In addition, phosphorylation is easily re-
versible, thus allowing this signaling mechanism to act spe-
cif cally in time and space.

Receptor Tyrosine Kinases

Gua nylyl cycla s e
The largest group o transmembrane receptors with enzy-
a ctivity matic cytosolic domains is the receptor tyrosine kinase am-
GTP cGMP
ily. These receptors transduce signals rom many hormones
and growth actors by phosphorylating tyrosine residues on
the cytoplasmic tail o the receptor. This leads to recruitment
and subsequent tyrosine phosphorylation o cytosolic signal-
ing molecules. When aberrantly expressed or overexpressed,
growth actor-responsive receptor tyrosine kinases (such as
epidermal growth actor receptor [EGFR], HER2/neu, and
vascular endothelial growth actor receptor [VEGFR]) are
12 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
associated with a wide array o cancers; these receptor tyro-
sine kinases are the targets o several monoclonal antibody
and small-molecule inhibitor drugs (see Chapter 40, Phar-
macology o Cancer: Signal Transduction).
The insulin receptor is a well-characterized receptor
tyrosine kinase. This receptor consists o two extracellular
subunits that are covalently linked to two membrane-
spanning subunits. Binding o insulin to the subunits
results in a change in con ormation o the adjacent subunits,
causing the subunits to move closer to one another on the
intracellular side o the membrane. The proximity o the
two subunits promotes a transphosphorylation reaction,
in which one subunit phosphorylates the other (autophos-
phorylation). The phosphorylated tyrosine residues then act
to recruit other cytosolic proteins, known as insulin receptor
substrate (IRS) proteins. Type 2 diabetes mellitus may, in
some cases, be associated with de ects in post-insulin recep-
tor signaling; thus, understanding the insulin receptor signal-
ing pathways is relevant or the potential design o rational
therapeutics. The mechanism o insulin receptor signaling is
discussed in more detail in Chapter 31, Pharmacology o the
Endocrine Pancreas and Glucose Homeostasis.
Receptor Tyrosine Phosphatases
Just as receptor tyrosine kinases phosphorylate the tyro-
sine residues o cytoplasmic proteins, receptor tyrosine
phosphatases remove phosphate groups rom specif c tyro-
sine residues. In some cases, this may be an example o re-
ceptor convergence (discussed later), where the di erential
e ects o two receptor types can negate one another. How-
ever, receptor tyrosine phosphatases possess novel signaling
mechanisms as well. Many receptor tyrosine phosphatases
are ound in immune cells, where they regulate cell activa-
tion. These receptors are discussed urther in Chapter 46,
Pharmacology o Immunosuppression.
Tyrosine Kinase-Associated Receptors
Tyrosine kinase-associated receptors constitute a diverse
amily o proteins that, although lacking inherent cata-
lytic activity, recruit active cytosolic signaling proteins in a
ligand-dependent manner. These cytosolic proteins are also
called (somewhat con usingly) nonreceptor tyrosine kinases .
Ligand activation o cell sur ace tyrosine kinase-associated
receptors causes the receptors to cluster together. This clus-
tering event recruits cytoplasmic proteins that are then acti-
vated to phosphorylate other proteins on tyrosine residues.
Thus, the downstream e ect is much like that o receptor
tyrosine kinases, except that tyrosine kinase-associated re-
ceptors rely on a nonreceptor kinase to phosphorylate target
proteins. Important examples o tyrosine kinase-associated
receptors include cytokine receptors and a number o other
receptors in the immune system. These receptors are dis-
cussed in detail in Chapter 46.
Receptor Serine/Threonine Kinases
Some transmembrane receptors are capable o catalyzing the
phosphorylation o serine or threonine residues on cytoplas-
mic protein substrates. Ligands or such receptors are typi-
cally members o the trans orming growth actor (TGF- )
super amily. Many receptor serine/threonine kinases are
important mediators o cell growth and di erentiation that
have been implicated in cancer progression and metastasis.
While there are many approved drugs that target cytosolic
serine/threonine kinases (see Intracellular Receptors below),
drugs selective or receptor serine/threonine kinases are
mainly in development.
Receptor Guanylyl Cyclases
As illustrated in Figure 1-6, the stimulation o G protein-
coupled receptors may cause activation and release o
G subunits, which, in turn, alter the activity o adenylyl and
guanylyl cyclases. In contrast, receptor guanylyl cyclases
have no intermediate G protein. Instead, ligand binding
stimulates intrinsic receptor guanylyl cyclase activity, in
which GTP is converted to cGMP. This is the smallest am-
ily o transmembrane receptors. B-type natriuretic peptide,
a hormone secreted by the ventricles in response to volume
overload, acts via a receptor guanylyl cyclase. Nesiritide ,
a recombinant version o the native peptide ligand, is ap-
proved or the treatment o decompensated heart ailure (al-
though it does not reliably improve outcomes), as discussed
in Chapter 21, Pharmacology o Volume Regulation.
Intracellular Receptors
The plasma membrane provides a unique barrier or drugs
that have intracellular receptors. Many such drugs are small
or lipophilic and are thus able to cross the membrane by
di usion. Others require specialized protein transporters or
acilitated di usion or active transport into the cell.
Intracellular Enzymes and Signal Transduction
Molecules
Enzymes are common intracellular drug targets. Many drugs
that target intracellular enzymes exert their e ect by altering
the enzymes production o critical signaling or metabolic
molecules. Vitamin K epoxide reductase, a cytosolic enzyme
involved in the post-translational modif cation o glutamate res-
idues in certain coagulation actors, is the target o the antico-
agulant drug warfarin. HMG-CoA reductase, the rate-limiting
enzyme in cholesterol synthesis, is the target o atorvastatin and
the other lipid-lowering statins. Many inhibitors o cytosolic
signal transduction molecules are approved or in development.
For example, inhibitors o the serine/threonine kinase mTOR
(such as everolimus ) are used to prevent rejection o trans-
planted organs, to treat certain cancers, and to prevent resteno-
sis in drug-eluting coronary stents.
Many other intracellular kinases play important roles in
cellular growth and di erentiation, and it is not surprising
that gain-o - unction mutations in these proteins can lead
to uncontrolled cell growth and cancer. Recall rom the in-
troductory case that chronic myeloid leukemia is associated
with the Philadelphia chromosome, which results rom a
reciprocal translocation between the long arms o chromo-
somes 9 and 22. The mutant chromosome codes or a con-
stitutively active tyrosine kinase re erred to as the BCR-Abl
protein. (BCR and Abl are short or break-point cluster
region and Abelson, respectively, the two chromosomal
regions that undergo translocation with high requency in
this orm o leukemia.) The constitutive activity o this kinase
results in phosphorylation o a number o cytosolic proteins,
leading to dysregulated myeloid cell growth and chronic
myeloid leukemia. Imatinib is a selective therapy or chronic
myeloid leukemia because it selectively targets the BCR-Abl
protein; the drug inhibits BCR-Abl activity by neutralizing
its ability to phosphorylate substrates. Imatinib was the f rst
example o a drug targeted selectively to tyrosine kinases,

and its success has led to the development o a number o
drugs that act by similar mechanisms. Such drugs include
second-generation drugs such as dasatinib and nilotinib
that are used to treat CML patients with imatinib-resistant
BCR-Abl iso orms, as well as the inhibitors o growth
actor-responsive receptor tyrosine kinases discussed above.
Indeed, the kinase targets o antineoplastic drugs are diverse.
For instance, sorafenib targets both receptor tyrosine kinases
and intracellular serine/threonine kinases, and vemurafenib
is a recently approved late-stage melanoma treatment that
targets a specif c mutant o the serine/threonine kinase
B-RAF. As a f nal example, idelalisib is a recently approved
phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) in-
hibitor used to treat certain leukemias and lymphomas (see
Chapter 40).
Transcription Factors
The transcription regulatory actors are important intracel-
lular receptors that are targeted by lipophilic drugs. All pro-
teins in the body are encoded by DNA. The transcription
o DNA into RNA and the translation o RNA into protein
are controlled by a diverse set o molecules. Transcription o
many genes is regulated, in part, by the interaction between
lipid-soluble signaling molecules and transcription regu-
latory actors. Because o the undamental role played by
control o transcription in many biological processes, tran-
scription regulators (also called transcription factors ) are the
targets o some important drugs. Steroid hormones are a class
o lipophilic drugs that di use readily through the plasma
membrane and act by binding to transcription actors in the
cytoplasm or nucleus (Fig. 1-8).
Just as the shape o a transcription actor governs the
drugs to which it binds, the shape also determines where on
the genome the transcription actor attaches and which co-
activator or corepressor molecules bind to it. By activating or
inhibiting transcription, thereby altering the intracellular or
extracellular concentrations o specif c gene products, drugs
that target transcription actors can have pro ound e ects
on cellular unction. The cellular responses to such drugs,
and the e ects that result rom these cellular responses in
tissues and organ systems, provide links between the mo-
lecular drugreceptor interaction and the e ects o the drug
on the organism as a whole. Because gene transcription is a
relatively slow and long-lasting process (minutes to hours),
drugs that target transcription actors o ten require a longer
period o time or the onset o action to take place, and have
longer lasting e ects, than do drugs that alter more transient
processes such as ion conductance (seconds to minutes).
Structural Proteins
Structural proteins are another important class o intracellu-
lar drug targets. For example, the antimitotic vinca alkaloids
bind to tubulin monomers and prevent the polymerization o
this molecule into microtubules. Inhibition o microtubule
ormation arrests the a ected cells in metaphase, making the
vinca alkaloids use ul antineoplastic drugs.
Nucleic Acids
Nucleic acids are a ourth subset o intracellular drug tar-
gets. Some small-molecule drugs bind directly to RNA or
ribosomes; these include important antibiotics (such as
doxycycline and azithromycin) that block translation in target
microorganisms. DNA- and RNA-binding chemotherapeutic
C h a p t e r 1 DrugReceptor Interactions 13
S te roid hormone
Hormone
re ce ptor
A Cha pe rone
Nucle us
B
DNA
C
FIGURE 1-8. Lipophilic molecule binding to an intracellular transcription
factor. A. Small lipophilic molecules can diffuse through the plasma mem-
brane and bind to intracellular transcription factors. In this example, steroid
hormone binding to a cytosolic hormone receptor is shown, although some
receptors of this class may be located in the nucleus before ligand binding.
B. Ligand binding triggers a conformational change in the receptor (and
often, as shown here, dissociation of a chaperone repressor protein) that
leads to transport of the ligandreceptor complex into the nucleus. In the
nucleus, the ligandreceptor complex typically dimerizes. In the example
shown, the active form of the receptor is a homodimer (two identical recep-
tors binding to one another), but heterodimers (such as the thyroid hormone
receptor and the retinoid Xreceptor) may also form. C. The dimerized ligand
receptor complex binds to DNA and may then recruit coactivators or core-
pressors (not shown). These complexes alter the rate of gene transcription,
leading to a change (either up or down) in cellular protein expression.
agents (such as doxorubicin) are mainstays o treatment or
many cancers. Drugs composed o nucleic acids can also tar-
get nucleic acids. Antisense therapeutics (such as the recently
approved drug mipomersen) bind target mRNA to block tran-
scription o specif c proteins. With continued development
o such antisense approaches and o related RNA inter er-
ence (RNAi) therapeutics, such targeting could someday en-
able physicians to routinely modi y the expression levels o
specif c gene transcripts. To date, technical challenges in de-
livering such therapeutics to their targets have limited their
utility to specialized applications.
Extracellular Targets
Many important drug receptors are enzymes with active sites
located outside the plasma membrane. The extracellular
environment consists o a milieu o proteins and signaling
molecules. Many o these proteins serve a structural role,
and others are used to communicate in ormation between
cells. Enzymes that modi y the molecules mediating these
important signals can in uence physiologic processes such
as vasoconstriction and neurotransmission. One example o
this class o receptors is the angiotensin converting enzyme
(ACE), which converts angiotensin I to the potent vasocon-
strictor angiotensin II. ACE inhibitors are drugs that inhibit
14 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

this enzymatic conversion and thereby lower blood pressure
(among other e ects; see Chapter 21). Another example is
acetylcholinesterase , which degrades acetylcholine a ter
this neurotransmitter is released rom cholinergic neurons.
Acetylcholinesterase inhibitors enhance neurotransmis-
sion at cholinergic synapses by preventing neurotransmit-
ter degradation at these sites (see Chapter 10, Cholinergic
Pharmacology).
Some extracellular targets are not enzymes. For example,
several proteins, including monoclonal antibodies, are used
to target soluble cytokines and block them rom interacting
with their endogenous receptors. One set o such drugs is the
anti-TNF- agents, including etanercept, in iximab, adalim-
umab, and others, which are commonly used to treat autoim-
mune diseases such as rheumatoid arthritis (see Chapter 46).
Cell Sur ace Adhesion Receptors
Cells o ten interact directly with other cells to per orm spe-
cif c unctions or to communicate in ormation. The orma-
tion o tissues and the migration o immune cells to a site
o in ammation are examples o physiologic processes that
require cellcell adhesive interactions. A region o contact
between two cells is termed an adhesion, and cellcell adhe-
sive interactions are mediated by pairs o adhesion receptors
on the sur aces o the individual cells. In many cases, several
such receptorcounter-receptor pairs combine to secure a
f rm adhesion, and intracellular regulators control the activ-
ity o the adhesion receptors by changing their a f nity or
by controlling their expression and localization on the cell
sur ace. Adhesion receptors also mediate adhesion o cells to
the extracellular matrix. Several adhesion receptors involved
in the in ammatory response are attractive targets or selec-
tive inhibitors. Inhibitors o a specif c class o adhesion re-
ceptors, known as integrins , have entered the clinic in recent
years, and these drugs are used in the treatment o a range
o conditions including thrombosis (abciximab, eptif batide ),
in ammatory bowel disease (vedolizumab), and multiple
sclerosis (natalizumab) (see Chapter 23, Pharmacology o
Hemostasis and Thrombosis, and Chapter 46).
PROCESSING OF SIGNALS
RESULTING FROM DRUGRECEPTOR
INTERACTIONS
Many cells in the body are continuously inundated with mul-
tiple inputs, some stimulatory and some inhibitory. How do
cells integrate these signals to produce a coherent response?
G proteins and other second messengers appear to provide
important points o integration. As noted above, relatively
ew second messengers have been identif ed, and it is un-
likely that many more remain to be discovered. Thus, second
messengers are an attractive candidate mechanism or pro-
viding cells with a set o common points upon which numer-
ous outside stimuli could converge to generate a coordinated
cellular e ect (Fig. 1-9).
Ion concentrations provide another point o integra-
tion or cellular e ects because the cellular concentration
o a particular ion is the result o the integrated activity o
multiple ionic currents that both increase and decrease the
concentration o the ion within the cell. For example, the
contractile state o a smooth muscle cell is a unction o
the intracellular calcium ion concentration, which is de-
termined by several di erent Ca2 conductances. These
conductances include calcium ion leaks into the cell and
calcium currents into and out o the cytoplasm through
specialized channels in the plasma membrane and smooth
endoplasmic reticulum.
Because the magnitude o cellular response is o ten
considerably greater than the magnitude o the stimulus
that caused the response, cells appear to have the ability
to ampli y the e ects o receptor binding. G proteins pro-
vide an excellent example o signal amplif cation. Ligand
binding to a G protein-coupled receptor activates a single
G protein molecule. This G protein molecule can then bind
to and activate many e ector molecules, such as adenylyl
cyclase, which can then generate an even greater number
o second messenger molecules (in this example, cAMP).
Another example o signal amplif cation is trigger Ca2
or calcium-induced calcium release, in which a small in ux

Liga nd 1 Ade nylyl cycla s e Liga nd 2

Re ce ptor Re ce ptor

s s s i i i

GDP GTP GTP GTP GTP GDP
ATP cAMP cAMP ATP

Ne t re s ult = inte gra te d e ffe ct

FIGURE 1-9. Signaling convergence o two receptors. A limited number of mechanisms are used to transduce intracellular signal cascades. In some
cases, this allows for convergence, where two different receptors have opposite effects that tend to negate one another in the cell. In a simple example, two
different G protein-coupled receptors could be stimulated by different ligands. The receptor shown on the left is coupled to G s , a G protein that stimulates
adenylyl cyclase to catalyze the formation of cAMP. The receptor shown on the right is coupled to G i, a G protein that inhibits adenylyl cyclase. When both
of these receptors are activated simultaneously, they can attenuate or even neutralize each other, as shown. Sometimes, signaling through a pathway may
alternate as the two receptors are sequentially activated.

o Ca2 through voltage-gated Ca2 channels in the plasma
membrane triggers the release o larger amounts o Ca2
rom intracellular stores into the cytoplasm.
CELLULAR REGULATION OF DRUG
RECEPTOR INTERACTIONS
Drug-induced activation or inhibition o a receptor o ten
has a lasting impact on the receptors subsequent respon-
siveness to drug binding. Mechanisms that mediate such
e ects are important because they prevent overstimulation
that could lead to cellular damage or adversely a ect the
organism as a whole. Many drugs show diminishing e -
ects over time; this phenomenon is called tachyphylaxis .
In pharmacologic terms, the receptor and the cell become
desensitized to the action o the drug. Mechanisms o de-
sensitization can be divided into two types: homologous ,
in which the e ects o agonists at only one type o re-
ceptor are diminished, and heterologous , in which the e -
ects o agonists at two or more types o receptors are
coordinately diminished. Heterologous desensitization is
thought to be caused by drug-induced alteration in a com-
mon point o convergence in the signaling pathways acti-
vated by the involved receptors, such as a shared e ector
molecule.
Many receptors exhibit desensitization. For example, the
cellular response to repeated stimulation o -adrenergic
receptors by epinephrine diminishes steadily over time
(Fig. 1-10). -Adrenergic receptor desensitization is medi-
ated by epinephrine-induced phosphorylation o the cyto-
plasmic tail o the receptor. This phosphorylation promotes
the binding o -arrestin to the receptor; in turn, -arrestin
inhibits the receptors ability to stimulate the G protein Gs.
With lower levels o activated Gs present, adenylyl cyclase
produces less cAMP. In this manner, repeated cycles o
ligandreceptor binding result in smaller and smaller cel-
lular e ects. Other molecular mechanisms have even more
pro ound e ects, completely turning o the receptor to
stimulation by ligand. The latter phenomenon, re erred to
as inactivation, may also result rom phosphorylation o the
receptor; in this case, the phosphorylation completely blocks
the signaling activity o the receptor or causes removal o the
receptor rom the cell sur ace.
Another mechanism that can a ect the cellular response
caused by drugreceptor binding is called refractoriness.
Receptors that assume a refractory state ollowing activa-
tion require a period o time to pass be ore they can be
stimulated again. As noted above, voltage-gated sodium
channels, which mediate the f ring o neuronal action po-
tentials, are subject to re ractory periods. A ter channel
opening induced by membrane depolarization, the voltage-
gated sodium channel spontaneously closes and cannot
be reopened or some period o time (called the refractory
period). This inherent property o the channel determines
the maximum rate at which neurons can be stimulated and
transmit in ormation.
The e ect o drugreceptor binding can also be in uenced
by drug-induced changes in the number o receptors on or
in a cell. One example o a molecular mechanism by which
receptor number can be altered is called down-regulation.
In this phenomenon, prolonged receptor stimulation by li-
gand induces the cell to endocytose and sequester receptors
C h a p t e r 1 DrugReceptor Interactions 15
P
A P hos phoryla tion by
P
P P
-a rre s tin P
P KA a nd/or ARK P P
P binding
-a rre s tin
Agonis t
G prote in binding
pre ve nte d
B S e que s tra tion
C De gra da tion
Endos ome
Lys os ome
FIGURE 1-10. -Adrenergic receptor regulation. Agonist-bound
-adrenergic receptors activate G proteins, which then stimulate adeny-
lyl cyclase activity (not shown). A. Repeated or persistent stimulation of
the receptor by agonist results in phosphorylation of amino acids at the
C-terminus of the receptor by protein kinase A (PKA) and/or -adrenergic
receptor kinase ( ARK). -Arrestin then binds to the phosphorylated domain
of the receptor and blocks Gs binding, thereby decreasing adenylyl cyclase
(effector) activity. B. Binding of -arrestin also leads to receptor sequestra-
tion into endosomal compartments via clathrin-mediated endocytosis (not
shown), effectively neutralizing -adrenergic receptor signaling activity.
The receptor can then be recycled and reinserted into the plasma mem-
brane. C. Prolonged receptor occupation by an agonist can lead to receptor
down-regulation and eventual receptor degradation. Cells can also reduce
the number of receptors by inhibiting the transcription or translation of the
gene coding for the receptor (not shown).
in endocytic vesicles. This sequestration prevents the re-
ceptors rom coming into contact with ligands, resulting
in cellular desensitization. When the stimulus that caused
the receptor sequestration subsides, the receptors can be
recycled to the cell sur ace and thereby rendered unctional
again (Fig. 1-10). Cells also have the ability to alter the
rates o synthesis or degradation o receptors and thereby
to regulate the number o receptors available or drug
binding. Receptor sequestration and alterations in recep-
tor synthesis and degradation occur on a longer time scale
than does phosphorylation and have longer lasting e ects
as well. Table 1-6 provides a summary o the mechanisms
by which the e ects o drugreceptor interactions can be
regulated.
16 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
TABLE 1-6 Mechanisms of Receptor Regulation
MECHANISM DEFINITION
Tachyphylaxis Repeated administration of the same dose of a
drug results in a diminishing effect of the drug
over time
Desensitization Decreased ability of a receptor to respond to
stimulation by a drug or ligand
Homologous Decreased response at a single type of
receptor
Heterologous Decreased response at two or more types of
receptor
Inactivation Loss of ability of a receptor to respond to
stimulation by a drug or ligand
Refractory After a receptor is stimulated, a period of time
is required before the next drugreceptor
interaction can produce an effect
Down-regulation Repeated or persistent drugreceptor interaction
results in removal of the receptor from sites
where subsequent drugreceptor interactions
could take place
DRUGS THAT DO NOT FIT THE DRUG
RECEPTOR MODEL
Although most drugs interact with one o the basic recep-
tor types outlined above, others act by nonreceptor-mediated
mechanisms. Two examples are the osmotic diuretics and
the antacids.
Diuretics control uid balance in the body by altering the
relative rates o water and ion absorption and secretion in
the kidney. Many o these drugs act on ion channels. One
class o diuretics, however, alters water and ion balance not
by binding to ion channels or G protein-coupled receptors
but by changing the osmolarity in the nephron directly. The
sugar mannitol, which is used mainly to treat increased in-
tracranial pressure, is secreted into the lumen o the nephron
and increases the osmolarity o the urine to such a degree
that water is drawn rom the peritubular blood into the
lumen. This uid shi t serves to increase the volume o urine
while decreasing the blood volume.
Another class o drugs that does not f t the drugreceptor
model is the antacids, which are used to treat gastroesopha-
geal re ux disease and peptic ulcer disease. Unlike antiul-
cer agents that bind to receptors involved in the physiologic
generation o gastric acid, antacids act nonspecif cally by
absorbing or chemically neutralizing stomach acid. Ex-
amples o these agents include bases such as NaHCO3 and
Mg(OH)2.
CONCLUSION AND FUTURE
DIRECTIONS
Although the molecular details o drugreceptor interactions
vary widely among drugs o di erent classes and receptors
o di erent types, the undamental mechanisms o action
described in this chapter serve as paradigms or the principles
o pharmacodynamics. The ability to classi y drugs based on
their receptors and mechanisms o action makes it possible
to simpli y the study o pharmacology, because the molecu-
lar mechanism o action o a drug can usually be linked to its
cellular, tissue, organ, and system levels o action. In turn, it
becomes easier to understand how a given drug mediates its
therapeutic e ects and its unwanted or adverse e ects in a
particular patient. The major aim o modern drug develop-
ment is to identi y drugs that are highly selective by tailoring
drug molecules to unique targets responsible or disease. As
knowledge o drug development and the genetic and patho-
physiologic basis o disease progresses, physicians and sci-
entists will learn to combine the molecular specif city o a
drug with the genetic and pathophysiologic specif city o the
drug target to provide more and more selective therapies.
Acknowledgment
We thank Jose B. Simon, Christopher W. Cairo, and Zachary
S. Morris or their valuable contributions to this chapter in
the First, Second, and Third Editions o Principles o Phar-
macology: The Pathophysiologic Basis o Drug Therapy.
Suggested Reading
Alexander SP, Mathie A, Peters JA. Guide to Receptors and Channels
(GRAC), 5th ed. Br J Pharmacol 2011;164(suppl 1):S1S324. (Brie over-
views o molecular targets or drugs, organized by types o receptors.)
Katritch V, Cherezov V, Stevens RC. Structure- unction o the G protein-
coupled receptor super amily. Annu Rev Pharmacol Toxicol 2013;53:
531556. (Reviews recent structural insights into G protein-coupled
receptors.)
Kole R, Krainer AR, Altman S. RNA therapeutics: beyond RNA inter-
erence and antisense oligonucleotides. Nat Rev Drug Discov 2012;11:
125140. (Highlights early successes, therapeutic mechanisms, and re-
maining challenges in the development o RNA-based therapies.)
Lagerstrm MC, Schith HB. Structural diversity o G protein-coupled
receptors and signif cance or drug discovery. Nat Rev Drug Discov
2008;7:339357. (Discusses the f ve amilies o G protein-coupled recep-
tors, with an eye toward uture drug development.)
Pratt WB, Taylor P, eds. Principles o drug action: the basis o pharmacol-
ogy. 3rd ed. New York: Churchill Livingstone; 1990. (Contains a detailed
discussion o drugreceptor interactions.)
Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu
MM. Molecular signatures o G protein-coupled receptors. Nature 2013;
494:185194. (Comparative analysis o structures, ligand binding, and
con ormational changes o G protein-coupled receptors.)
Zhang J, Yang PL, Gray NS. Targeting cancer with small molecule kinase
inhibitors. Nat Rev Cancer 2009;9:2839. (Discusses dysregulation o
protein kinases in cancer and targeting o these molecules by drugs such
as imatinib.)
 Agon
n is t
C ompee titive
a n ta g o n is t
C D
2
Pharmacodynamics
Q u e n t in J . Ba c a a n d David E. Go la n

Agonis
nINTRODUCTION
iiss t b iinding
n dingg Compe
C omp mpe p e ttiti
& CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 18
itivveeNoncncom
aompetiti
nntta vege Rooni nnis
ecep
ec epto
ep
itsorrtAntagonistss . . . . . . . . N o n c o m p e tit
. . . . . . . . . 22
DRUGRECEPTOR BI N ING. . . . . . . . . . . . . . . . . . . bindin
BIND bindd in g Partial
binding Nonreceptor Antagonists . . . . . . . . . . . . . . . . . . . .
b
bind i n d in g
DOSERESPONSE RELA ATITIONSHIPS . . . . . . . . . . . . . . . . . . . . . . . . 18 Agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Graded DoseRespponnse s e Relat
elatiionships . . . . . . . . . . . . . . . . . . . 18 Invee rs
rsee Agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242
Quan
Qu anta
tall DoseResponse Re Relalationships . . . . . . . . . . . . . . . . . . . 19 Spare Recept ptor
orss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
DRUGRECEPTOR INTERACTIONS . . . . . . . . . . . . . . . . . . . . . . . . . 20 CONCEPTS IN THERAPEUTICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
A i t . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Agonists Therapeutic Index and Therapeutic Wi Window
ndow
d w . . . . . . . . . . . . . . 25
Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 26
Competitive Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . 21 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

INTRODUCTION Consider the simpsimplest

plest case,, in whic
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o a drug on the body. These e ects are typically described kon
in quantitative terms. The previous chapter considered the L R
LR Equation 2-1
molecular interactions by which pharmacologic agents exert koff

their e ects. The integration o these molecular actions into

an e ect on the organism as a whole is the subject addressed
in this chapter. It is important to describe the e ects o a drug
quantitatively in order to determine appropriate dose ranges
or patients, as well as to compare the potency, e f cacy,
and sa ety o one drug to that o another.
DRUGRECEPTOR BINDING
The study o pharmacodynamics is based on the concept o
drugreceptor binding. When either a drug or an endogenous
ligand (such as a hormone or neurotransmitter) binds to its
receptor, a response may result rom that binding interac-
tion. When a su f cient number o receptors are bound (or
occupied) on or in a cell, the cumulative e ect o receptor
occupancy may become apparent in that cell. At some point,
all o the receptors may be occupied, and a maximal response
may be observed (an exception is the case o spare receptors;
see below). When the response occurs in many cells, the e ect
can be seen at the level o the organ or even the patient. But
this all starts with the binding o drug or ligand to a recep-
tor ( or the purpose o discussion, drug and ligand will
be used interchangeably or the remainder o this chapter).
A model that accurately describes the binding o drug to re-
ceptor would there ore be use ul in predicting the e ect o the
drug at the molecular, cellular, tissue (organ), and organism
(patient) levels. This section describes one such model.
where L is ligand (drug), R is ree receptor, and LR is bound
drugreceptor complex. At equilibrium, the raction o re-
ceptors in each state is dependent on the dissociation con-
stant, Kd, where Kd ko /kon. Kd is an intrinsic property o
any given drugreceptor pair. Although Kd varies with tem-
perature, the temperature o the human body is relatively
constant, and it can there ore be assumed that Kd is a con-
stant or each drugreceptor combination.
According to the law o mass action, the relationship be-
tween ree and bound receptor can be described as ollows:
[L][R] [L][R]
Kd , rearranged to [LR] Equation 2-2
[LR] Kd
where [L] is ree ligand concentration, [R] is ree receptor con-
centration, and [LR] is ligandreceptor complex concentration.
Because Kd is a constant, some important properties o the
drugreceptor interaction can be deduced rom this equation.
First, as ligand concentration is increased, the concentration
o bound receptors increases. Second, and not so obvious, is
that as ree receptor concentration is increased (as may happen,
or example, in disease states or upon repeated exposure to a
drug), bound receptor concentration also increases. There ore,
an increase in the effect of a drug can result from an increase in
the concentration of either the ligand or the receptor.
The remainder o the discussion in this chapter, how-
ever, assumes that the total concentration o receptors is a

17
18 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Ad m ira l X is a 66-ye a r-o ld re tire d s u b -
m a rin e ca p ta in w ith a 70 p a ckye a r
s m o kin g h is to ry (tw o p a cks a d a y o r
35 ye a rs ) a n d a a m ily h is to ry o co ro -
n a ry a rte ry d is e a s e . He ta ke s d a ily a to r-
va s ta tin to re d u ce h is ch o le s te ro l le ve l a n d a s p irin to
re d u ce h is ris k o co ro n a ry a rte ry o cclu s io n .
On e d a y, w h ile w o rkin g in h is w o o d s h o p , Ad m i-
ra l X b e g in s to e e l tig h tn e s s in h is ch e s t. Th e e e lin g
ra p id ly b e co m e s p a in u l, a n d th e p a in ra d ia te s d o w n
h is le t a rm . He ca lls 911, a n d a n a m b u la n ce tra n s -
p o rts h im to th e lo ca l e m e rg e n cy d e p a rtm e n t. A te r
e va lu a tio n , it is d e te rm in e d th a t Ad m ira l X is h a vin g
a n a n te rio r m yo ca rd ia l in a rctio n . Be ca u s e Ad m ira l X
ca n n o t b e tra n s e rre d to a h o s p ita l w ith a ca rd ia c
ca th e te riza tio n la b o ra to ry w ith in 120 m in u te s o
f rs t m e d ica l co n ta ct, a n d h e h a s n o re la tive co n -
tra in d ica tio n s to th ro m b o lytic th e ra p y (s u ch a s u n -
co n tro lle d hyp e rte n s io n , h is to ry o s tro ke , o r re ce n t
s u rg e ry), th e p h ys icia n in itia te s th e ra p y w ith b o th
a th ro m b o lytic a g e n t, tis s u e -typ e p la s m in o g e n a cti-
va to r (tPA), a n d a n a n tico a g u la n t, h e p a rin . Be ca u s e
o th e ir lo w th e ra p e u tic in d ice s , im p ro p e r d o s in g o
constant, so that [LR] [R] [Ro]. This allows Equation
2-2 to be arranged as ollows:
[L][R]
[Ro] [R] [LR] [R]
Kd
[L]
[R] 1 Equation 2-3
Kd
Solving or [R] and substituting Equation 2-3 into Equation
2-2 yields:
[Ro] [L]
[LR] , rearranged to
[L] Kd
[LR] [L]
Equation 2-4
[Ro] [L] Kd
Note that the le t side o this equation, [LR]/[Ro], represents
the raction o all available receptors that are bound to ligand.
Figure 2-1 shows two plots o Equation 2-4 or the bind-
ing o two hypothetical drugs to the same receptor. These
plots are known as drugreceptor binding curves . Figure 2-1A
shows a linear plot, and Figure 2-1B shows the same plot on
a semilogarithmic scale. Because drug responses occur over
a wide range o doses (concentrations), the semilog plot is
o ten used to display drugreceptor binding data. The two
drugreceptor interactions are characterized by di erent val-
ues o Kd. In this case, KdA KdB.
Notice rom Figure 2-1 that maximal drugreceptor bind-
ing occurs when [LR] is equal to [Ro], or [LR]/[Ro] 1. Also
notice that, according to Equation 2-4, when [L] Kd, then
[LR]/[Ro] Kd/2Kd . Thus, Kd can be def ned as the con-
centration o ligand at which 50% o the available receptors
are occupied.
b o th o th e s e d ru g s ca n h a ve d ire co n s e q u e n ce s
(h e m o rrh a g e a n d d e a th ). Th e re o re , Ad m ira l X is
clo s e ly m o n ito re d , a n d th e p h a rm a co lo g ic e e ct o
th e h e p a rin is m e a s u re d p e rio d ica lly b y te s tin g th e
p a rtia l th ro m b o p la s tin tim e (PTT). Ad m ira l Xs s ym p -
to m s re s o lve ove r th e n e xt s e ve ra l h o u rs , a lth o u g h
h e re m a in s in th e h o s p ita l o r m o n ito rin g . He is d is -
ch a rg e d a te r 4 d a ys in th e h o s p ita l; h is d is ch a rg e
m e d ica tio n s in clu d e a to rva s ta tin , a s p irin , a te n o lo l,
lis in o p ril, a n d clo p id o g re l o r s e co n d a ry p re ve n tio n
o m yo ca rd ia l in a rctio n .
Questions
1 . How does the molecular interaction o a drug with its re-
ceptor determine the potency and e f cacy o the drug?
2 . Why does the act that a drug has a low therapeutic
index mean that the physician must use greater care
in its administration?
3 . What properties o certain drugs, such as aspirin,
allow them to be taken without monitoring o plasma
drug levels, whereas other drugs, such as heparin, re-
quire such monitoring?
DOSERESPONSE RELATIONSHIPS
The pharmacodynamics o a drug can be quantif ed by the
relationship between the dose (concentration) o the drug
and the organisms (patients) response to that drug. One
might intuitively expect the doseresponse relationship to
be related closely to the drugreceptor binding relationship,
and this turns out to be the case or many drugreceptor
combinations. Thus, a use ul assumption at this stage o dis-
cussion is that the response to a drug is proportional to the
concentration o receptors that are bound (occupied) by the
drug. This assumption can be quantif ed by the ollowing
relationship:
response [DR] [D]
Equation 2-5
max response [Ro] [D] Kd
where [D] is the concentration o ree drug, [DR] is the
concentration o drugreceptor complexes, [Ro] is the con-
centration o total receptors, and Kd is the equilibrium disso-
ciation constant or the drugreceptor interaction. (Note that
the right side o Equation 2-5 is equivalent to Equation 2-4,
with [D] substituted or [L].) The generalizability o this as-
sumption is examined below.
There are two major types o doseresponse relationships
graded and quantal. The di erence between the two types is
that graded doseresponse relationships describe the e ect
o various doses o a drug on an individual, whereas quantal
relationships show the e ect o various doses o a drug on a
population o individuals.
Graded DoseResponse Relationships
Figure 2-2 shows graded doseresponse curves or two hy-
pothetical drugs that elicit the same biological response.

A Line a r
1.0
Drug A
Drug B
[LR]
0.5
[R o ]
0 0
KdA KdB
[L]
B S e miloga rithmic
1.0
Drug A
Drug B
[LR]
0.5
[R o ]
0 0
KdA KdB
[L]
FIGURE 2-1. Ligandreceptor binding curves. A. Linear graphs o drug
receptor binding or two drugs with di erent values o Kd. B. Semilogarithmic
graphs o the same drugreceptor binding. Kd is the equilibrium dissocia-
tion constant or a given drugreceptor interactiona lower Kd indicates
a tighter drugreceptor interaction (higher a f nity). Because o this rela-
tionship, Drug A, which has the lower Kd, will bind a higher proportion o
total receptors than Drug B at any given drug concentration. Notice that Kd
corresponds to the ligand concentration [L] at which 50% o the receptors
are bound (occupied) by ligand. [L] is the concentration o ree (unbound)
ligand (drug), [LR ] is the concentration o ligandreceptor complexes, and
[Ro] is the total concentration o occupied and unoccupied receptors. Thus,
[LR]/[Ro] is the fractional occupancy o receptors, or the raction o total
receptors that are occupied (bound) by ligand.
The curves are presented on both linear and semilogarithmic
scales. The curves are similar in shape to those in Figure 2-1,
consistent with the assumption that response is proportional
to receptor occupancy.
Two important parameterspotency and e f cacycan
be deduced rom the graded doseresponse curve. The po-
tency (EC50) o a drug is the concentration at which the drug
elicits 50% of its maximal response. The e f cacy (E max) is
the maximal response produced by the drug. In accordance
with the assumption stated above, e f cacy can be thought o
as the state at which receptor-mediated signaling is maximal
and, there ore, additional drug will produce no additional
response. This usually occurs when all the receptors are oc-
cupied by the drug. Some drugs, however, are capable o elic-
iting a maximal response when less than 100% o the drugs
receptors are occupied; the remaining receptors can be called
spare receptors . This concept is discussed urther in the text
C h a p t e r 2 Pharmacodynamics 19
A Line a r
1.0
Drug A
Drug B
E
0.5
E MAX
EC 50 (A) EC 50 (B)
[L]
B S e miloga rithmic
1.0
Drug A
Drug B
E
0.5
E MAX
EC 50 (A) EC 50 (B)
[L]
FIGURE 2-2. Graded doseresponse curves. Graded doseresponse
curves demonstrate the e ect o a drug as a unction o its concentration.
A. Linear graphs o graded doseresponse curves or two drugs. B. Semilog-
arithmic graphs o the same doseresponse curves. Note the close resem-
blance to Figure 2-1: the raction o occupied receptors [LR]/[Ro] has been
replaced by the ractional e ect E/Emax, where E is a quantif able response to
a drug (e.g., an increase in blood pressure). EC50 is the potency o the drug, or
the concentration at which the drug elicits 50% o its maximal e ect. In the
f gure, Drug A is more potent than Drug B because it elicits a hal -maximal
e ect at a lower concentration than Drug B. Drugs A and B exhibit the same
e f cacy (the maximal response to the drug). Note that potency and e f cacy
are not intrinsically relateda drug can be extremely potent but have little
e f cacy, and vice versa. [L] is drug concentration, E is e ect, Emax is e f cacy,
and EC50 is potency.
that ollows. Note again that the graded doseresponse curve
o Figure 2-2 bears a close resemblance to the drugreceptor
binding curve o Figure 2-1, with EC50 replacing Kd and Emax
replacing Ro.
Quantal DoseResponse Relationships
The quantal doseresponse relationship plots the fraction
of the population that responds to a given dose of drug
as a function of the drug dose. Quantal doseresponse
relationships describe the concentrations o a drug that pro-
duce a given e ect in a population. Figure 2-3 shows an
example o quantal doseresponse curves. Because o di er-
ences in biological response among individuals, the e ects
o a drug are seen over a range o doses. The responses are
def ned as either present or not present (i.e., quantal, not
graded). Endpoints such as sleep/no sleep or alive at
20 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

Cumula tive % e xhibiting Agonists

The ra pe utic e ffe ct Toxic e ffe ct Le tha l e ffe ct
An agonist is a molecule that binds to a receptor and stabi-
100 lizes the receptor in a particular conformation (usually, the
g
active conformation). When bound by an agonist, a typical
n
i
receptor is more likely to be in its active con ormation than
d
n
% Requiring dose to achieve
o
its inactive con ormation. Depending on the receptor, ago-
p
Therapeutic Toxic effect Lethal effect
s
nists may be drugs or endogenous ligands. A use ul model
e
effect
r
50 or understanding the relationship between agonist binding
s
l
a
and receptor activation is shown in Equation 2-6:
u
d
vi
R
i
D D R*
d
n
I
Equation 2-6
%
0
DR DR*
ED50 TD50 LD50

Dos e
FIGURE 2-3. Quantal doseresponse curves. Quantal doseresponse
curves demonstrate the average e ect o a drug, as a unction o its con-
centration, in a population o individuals. Individuals are typically observed
or the presence or absence o a response (e.g., sleep or no sleep), and this
result is then used to plot the percentage o individuals who respond to each
dose o drug. Quantal doseresponse relationships are use ul or predicting
the e ects o a drug when it is administered to a population o individuals
and or determining population-based toxic doses and lethal doses. These
doses are called the ED50 (dose at which 50% o subjects exhibit a therapeu-
tic response to a drug), TD50 (dose at which 50% o subjects experience a
toxic response), and LD50 (dose at which 50% o subjects die). Note that ED50
is the dose at which 50% o subjects respond to a drug, whereas EC50 (as
described in the previous f gure) is the dose at which a drug elicits a hal -
maximal e ect in an individual subject.
12 months/not alive at 12 months are examples o quantal
responses; in contrast, graded doseresponse relationships
are generated using scalar responses such as change in blood
pressure or heart rate. The goal is to generalize a result to a
population rather than to examine the graded e ect o di -
erent drug doses on a single individual. Types o responses
that can be examined using the quantal doseresponse re-
lationship include e ectiveness (therapeutic e ect), toxicity
(adverse e ect), and lethality (lethal e ect). The doses that
produce these responses in 50% o a population are known
as the median effective dose (ED50), median toxic dose (TD50),
and median lethal dose (LD50), respectively.
DRUGRECEPTOR INTERACTIONS
Many receptors or drugs can be modeled as having two con-
ormational states that are in reversible equilibrium with one
another. These two states are called the active state and the
inactive state . Many drugs unction as ligands or such recep-
tors and a ect the probability that the receptor exists pre er-
entially in one con ormation or the other. The pharmacologic
properties o drugs are o ten based on their e ects on the
state o their cognate receptors. A drug that, upon binding to
its receptor, avors the active receptor con ormation is called
an agonist; a drug that prevents agonist-induced activation
o the receptor is re erred to as an antagonist. Some drugs
do not f t neatly into this simple def nition o agonist and an-
tagonist; these include partial agonists and inverse agonists .
The ollowing sections describe these pharmacologic clas-
sif cations in more detail.
where D and R are unbound ( ree) drug and receptor concen-
trations, respectively, DR is the concentration o the agonist
receptor complex, and R* indicates the active con ormation
o the receptor. For most receptors and agonists, R* and DR
are unstable species that exist only brie y and are quantita-
tively insignif cant compared to R and DR*. There ore, in
most cases, Equation 2-6 simplif es to
D R
DR** Equation 2-7
Note that Equation 2-7 is identical to Equation 2-1, which
was used or the analysis o drugreceptor binding. This
suggests that, or most receptors, agonist binding is propor-
tional to receptor activation. Some receptors, however, do
have limited stability in the R* and/or DR con ormations;
in these cases, Equation 2-6 must be revisited (see below).
Equation 2-6 can also be used to illustrate quantitatively
the concepts o potency and e f cacy. Recall that potency is
the agonist concentration required to elicit a hal -maximal
e ect, and e f cacy is the maximal e ect o the agonist.
Assuming that a receptor is not active unless bound to a drug
(i.e., R* is insignif cant compared to DR*), Equation 2-8
provides a quantitative description o potency and e f cacy:
kon k
D R DR DR* Equation 2-8
koff k
Potency Efficacy
Here, k is the rate constant or receptor activation, and k
is the rate constant or receptor deactivation. This equation
demonstrates the relationship between potency (Kd ko /kon)
and agonist binding (D R DR), as well as the relation-
ship between e f cacy (k /k ) and the con ormational change
DR*). These
required or activation o the receptor (DR
relationships are intuitive when we consider that more potent
drugs are those that have a higher a f nity or their receptors
(lower Kd), and more e f cacious drugs are those that cause a
higher raction o receptors to be activated.
Antagonists
An antagonist is a molecule that inhibits the action of an ago-
nist but has no effect in the absence of the agonist. Figure 2-4
shows one approach to classi ying the various types o an-
tagonists. Antagonists can be divided into receptor and non-
receptor antagonists. A receptor antagonist binds to either
the active site (agonist binding site) or an allosteric site on a
receptor. Binding o an antagonist to the active site prevents
the binding o the agonist to the receptor, whereas binding
 C h a p t e r 2 Pharmacodynamics 21

Anta gonis ts

Re ce ptor Nonre ce ptor

a nta gonis ts a nta gonis ts

Active s ite Allos te ric

binding binding

Re ve rs ible Irre ve rs ible Re ve rs ible Irre ve rs ible

Compe titive Noncompe titive Noncompe titive Che mica l P hys iologic
a nta gonis t a ctive s ite a llos te ric a nta gonis t a nta gonis t
a nta gonis t a nta gonis t

FIGURE 2-4. Antagonist classif cation. Antagonists can be categorized based on whether they bind to a site on the receptor or agonist (receptor antago-
nists) or interrupt agonistreceptor signaling by other means (nonreceptor antagonists). Receptor antagonists can bind either to the agonist (active) site
or to an allosteric site on the receptor; in either case, they do not a ect basal receptor activity (i.e., the activity o the receptor in the absence o agonist).
Agonist (active) site receptor antagonists prevent the agonist rom binding to the receptor. I the antagonist competes with the ligand or agonist site binding,
it is termed a competitive antagonist; high concentrations o agonist are able to overcome competitive antagonism. Noncompetitive active site antagonists
bind covalently or with very high a f nity to the agonist site, so that even high concentrations o agonist are unable to activate the receptor. Allosteric recep-
tor antagonists bind to the receptor at a site other than the agonist site. They do not compete directly with agonist or receptor binding, but rather alter the
Kd or agonist binding or inhibit the receptor rom responding to agonist binding. High concentrations o agonist are generally unable to reverse the e ect
o an allosteric antagonist. Nonreceptor antagonists all into two categories. Chemical antagonists sequester agonist and thus prevent the agonist rom
interacting with the receptor. Physiologic antagonists induce a physiologic response opposite to that o an agonist, but by a molecular mechanism that does
not involve the receptor or agonist.

o an antagonist to an allosteric site either alters the Kd or
agonist binding or prevents the con ormational change re-
quired or receptor activation. Receptor antagonists can also
be divided into reversible and irreversible antagonists ; that
is, antagonists that bind to their receptors reversibly and
those that bind irreversibly. Figure 2-5 illustrates the general
e ects o these antagonist types on agonist binding; more
detail is provided in the ollowing sections.
A nonreceptor antagonist does not bind to the same re-
ceptor as an agonist, but it nonetheless inhibits the ability o
an agonist to initiate a response. At the molecular level, this
inhibition can occur by inhibiting the agonist directly (e.g.,
using antibodies), by inhibiting a downstream molecule in
the activation pathway, or by activating a pathway that op-
poses the action o the agonist. Nonreceptor antagonists can
be divided into chemical antagonists and physiologic antag-
onists. Chemical antagonists inactivate an agonist be ore it
has the opportunity to act (e.g., by chemical neutralization);
physiologic antagonists cause a physiologic e ect opposite
to that induced by the agonist.
Competitive Receptor Antagonists
A competitive antagonist binds reversibly to the active site
of a receptor. Unlike an agonist, which also binds to the ac-
tive site o the receptor, a competitive antagonist does not
stabilize the con ormation required or receptor activation.
There ore, the antagonist blocks an agonist rom binding to
its receptor, while maintaining the receptor in the inactive
con ormation. Equation 2-9 is a modif cation o Equation 2-7
that incorporates the e ect o a competitive antagonist (A).
AR
A D R
DR* Equation 2-9
In this equation, a raction o the ree receptor molecules (R)
are unable to orm a drug (agonist)receptor complex (DR*),
because receptor binding to the antagonist results in the

Agonis t
Agonis t Agonis t
Agonis t Allos te ric Compe titive
binding s ite a nta gonis t a nta gonis t
binding s ite Noncompe titive
A B C D a nta gonis t

Unbound re ce ptor Agonis t binding Compe titive a nta gonis t Noncompe titive a nta gonis t
binding binding

FIGURE 2-5. Types o receptor antagonists. A schematic illustrating the di erences between agonist (active) site and allosteric antagonists. A. The un-
bound inactive receptor. B. The receptor activated by agonist. Note the con ormational change induced in the receptor by agonist binding, or example, the
opening o a transmembrane ion channel. C. Agonist site antagonists bind to the receptors agonist site but do not activate the receptor; these agents block
agonist binding to the receptor. D. Allosteric antagonists bind to an allosteric site (di erent rom the agonist site) and thereby prevent receptor activation,
even when the agonist is bound to the receptor.
22 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

ormation o an antagonistreceptor complex (AR) instead.

In e ect, the ormation o the AR complex sets up a second A Compe titive a nta gonis t
equilibrium reaction that competes with the equilibrium or
agonistreceptor binding. Note that AR is incapable o un- 100
Agonis t a lone
dergoing a con ormational change to the active (R*) state o
the receptor.

e
s
n
Quantitative analysis yields the ollowing equation or

o
Agonis t + Anta gonis t

p
agonist (D) binding to the receptor in the presence o a com-

s
50

e
petitive antagonist (A):

R
%
[DR] [D]
Equation 2-10
[A] Anta gonis t a lone
[Ro] [D] Kd 1 0
KA

Equation 2-10 is similar to Equation 2-4, except that the e - B Noncompe titive a nta gonis t
ective Kd has been increased by a actor o (1 [A]/KA),
where KA is the dissociation constant or binding o the an-
tagonist to the receptor (i.e., KA [A][R]/[AR]). Because 100
Agonis t a lone
an increase in Kd is equivalent to a decrease in potency, the

e
presence o a competitive antagonist (A) reduces the potency

s
n
Agonis t + Anta gonis t
o an agonist (D) by a actor o (1 [A]/KA). Although the

o
p
s
potency o an agonist decreases as the concentration o com- 50

e
R
petitive antagonist increases, the e f cacy o the agonist is un-

a ected. This occurs because the agonist concentration [D]
can be increased to counteract (outcompete) the antago-
nist, thereby washing out or reversing the e ect o the
antagonist. Figure 2-6A shows the e ect o a competitive
antagonist on the agonist doseresponse relationship. Note
that the competitive antagonist has the e ect o shi ting the
agonist doseresponse curve to the right, causing a decrease
in agonist potency while maintaining agonist e f cacy.
Atorvastatin, the drug used in the case at the beginning o
this chapter to lower Admiral Xs cholesterol, is an example
o a competitive antagonist. Atorvastatin is a member o the
HMG-CoA reductase inhibitor (statin) class o lipid-lowering
drugs. HMG-CoA reductase is an enzyme that catalyzes the
reduction o HMG-CoA, which is the rate-limiting step in
cholesterol biosynthesis. The similarity between the chemi-
cal structures o statins and HMG-CoA allows the statin
molecule to bind to the active site o HMG-CoA reductase
and thereby to prevent HMG-CoA rom binding. This inhi-
bition is reversible because no covalent bonds are ormed
between the statin and the enzyme. Inhibition o HMG-CoA
reductase decreases endogenous cholesterol synthesis and
lowers the patients cholesterol levels. For a more detailed
discussion o the mechanism o action o atorvastatin and
other HMG-CoA reductase inhibitors, see Chapter 20, Phar-
macology o Cholesterol and Lipoprotein Metabolism.
Noncompetitive Receptor Antagonists
Noncompetitive antagonists can bind to either the active site
or an allosteric site o a receptor (Fig. 2-4). A noncompetitive
antagonist that binds to the active site o a receptor can bind
either covalently or with very high a f nity; in either case, the
binding is e ectively irreversible. Because an irreversibly
bound active site antagonist cannot be outcompeted, even
at high agonist concentrations, such an antagonist exhibits
noncompetitive antagonism.
A noncompetitive allosteric antagonist acts by prevent-
ing the receptor rom being activated, even when the agonist
is bound to the active site. An allosteric antagonist exhibits
noncompetitive antagonism regardless o the reversibility o
its binding, because such an antagonist acts not by competing
%
Anta gonis t a lone
0
Agonis t or a nta gonis t conce ntra tion
FIGURE 2-6. Antagonist effects on the agonist doseresponse
relationship. Competitive and noncompetitive antagonists have di erent
e ects on potency (the concentration o agonist that elicits a hal -maximal
response) and e f cacy (the maximal response to an agonist). A. A competi-
tive antagonist reduces the potency o an agonist, without a ecting agonist
e f cacy. B. A noncompetitive antagonist reduces the e f cacy o an agonist.
As shown here, most allosteric noncompetitive antagonists do not a ect
agonist potency.
with the agonist or binding to the active site, but rather by
preventing receptor activation. The reversibility o antago-
nist binding is nonetheless important, because the e ect o
an irreversible antagonist does not diminish when the ree
(unbound) drug is eliminated rom the body, whereas the
e ect o a reversible antagonist can be washed out over
time as it dissociates rom the receptor (see Equation 2-9).
A receptor that is bound by a noncompetitive antago-
nist can no longer be activated by the binding o an agonist.
There ore, the maximal response (e f cacy) o the agonist is
reduced. A characteristic di erence between competitive and
noncompetitive antagonists is that competitive antagonists
reduce agonist potency, whereas noncompetitive antagonists
reduce agonist e f cacy. This di erence can be explained by
considering that a competitive antagonist continuously com-
petes or receptor binding, e ectively reducing the recep-
tors a f nity or an agonist without limiting the number o
available receptors. In contrast, a noncompetitive antagonist
removes unctional receptors rom the system, thereby lim-
iting the number o available receptors. Figures 2-6A and
2-6B compare the e ects o competitive and noncompetitive
antagonists on the agonist doseresponse relationship.
Aspirin is one example o a noncompetitive antagonist.
This agent irreversibly acetylates cyclooxygenase, the enzyme
 C h a p t e r 2 Pharmacodynamics 23

responsible or generating thromboxane A2 in platelets. In the

absence o thromboxane A2 generation, platelet aggregation A
is inhibited. Because the inhibition is irreversible and plate-
100
lets are not capable o synthesizing new cyclooxygenase
molecules, the e ects o a single dose o aspirin last or 7 to
10 days (the time required or the bone marrow to generate Butyl
new platelets), even though the ree drug is cleared rom the He xyl
He ptyl
body much more rapidly.

n
o
i
t
Nonreceptor Antagonists

c
a
50

r
Nonreceptor antagonists can be divided into chemical an-

t
n
Octyl

o
tagonists and physiologic antagonists. A chemical antagonist

C
inactivates the agonist o interest by modi ying or sequester-

%
ing it, so that the agonist is no longer capable o binding
to and activating the receptor. Protamine is an example o a
chemical antagonist; this basic protein binds stoichiometri-
cally to the acidic heparin class o anticoagulants and thereby
0
inactivates these agents (see Chapter 23, Pharmacology o 10 -7 10 -6 10 -5 10 -4 10 -3
Hemostasis and Thrombosis). Because o this chemical an-
tagonism, protamine can be used to terminate the e ects o [D] (Mola r)
B
heparin rapidly.
A physiologic antagonist either blocks a receptor that me-
100
diates the physiologic response o the receptor or agonist or
activates a receptor that mediates a response physiologically Morphine
opposite to that o the receptor or agonist. For example, in
a
the treatment o hyperthyroidism, -adrenergic antagonists i
s
e
are used as physiologic antagonists to counteract the tachy-
g
l
50
a
cardic e ect o excess thyroid hormone. Excess thyroid hor-
n
Bupre norphine
A
mone produces tachycardia, at least in part, via up-regulation
%
o cardiac -adrenoceptors, and blocking -adrenergic stim-
ulation relieves the tachycardia (see Chapter 11, Adrenergic
Pharmacology, and Chapter 28, Pharmacology o the Thy- 0
roid Gland). 0.01 0.1 ED50 (B) ED50 (M) 10

Partial Agonists
A partial agonist is a molecule that binds to a receptor at its
active site but produces only a partial response, even when
all of the receptors are occupied (bound) by the agonist.
Figure 2-7A shows a amily o doseresponse curves or
several ull and partial agonists. Each agonist acts by bind-
ing to the same site on the muscarinic acetylcholine (ACh)
receptor. Note that butyl trimethylammonium (TMA) is not
only more potent than longer chain derivatives at stimulating
muscle contraction but also more e f cacious than some o
the derivatives (e.g., the heptyl and octyl orms) at produc-
ing a greater maximal response. For this reason, butyl TMA
is a full agonist at the muscarinic ACh receptor, whereas the
octyl derivative is a partial agonist at this receptor.
Because partial agonists and ull agonists bind to the
same site on a receptor, a partial agonist can reduce the re-
sponse produced by a ull agonist. In this way, the partial
agonist can act as a competitive antagonist. For this reason,
partial agonists are sometimes called partial antagonists or
even mixed agonist-antagonists.
It is interesting to consider how an agonist could pro-
duce a less-than-maximal response i a receptor can exist
in only the active or the inactive state. This is an area o
current investigation, or which several hypotheses have
been proposed. Recall that Equation 2-6 was simplif ed to
Equation 2-7 based on the assumption that R and DR* are
much more stable than R* and DR. But what would happen
i a drug (call it a partial agonist) could stabilize DR as well
[D] (mg/kg)
FIGURE 2-7. Full and partial agonist doseresponse curves. There are
many instances in which drugs that all act at the agonist site on the same
receptor produce di erent maximal e ects. A. Various alkyl derivatives o
trimethylammonium all stimulate muscarinic acetylcholine (ACh) recep-
tors to cause muscle contraction in the gut, but they produce di erent
maximal responses, even when all receptors are occupied. In this example,
the butyl and hexyl trimethylammonium derivatives are ull agonists
although they have di erent potencies, they are both capable o eliciting
a maximal response. Agonists that produce only a partial response, such
as the heptyl and octyl derivatives, are called partial agonists . Note that
the doseresponse curves o these partial agonists plateau at values less
than those o ull agonists. ACh acts as a ull agonist in this system (not
shown). B. Partial agonists may be more or less potent than ull agonists. In
this case, buprenorphine (ED50 0.3 mg/kg) is more potent than morphine
(ED50 1.0 mg/kg), although it cannot achieve the same maximal response
as the ull agonist. Buprenorphine is used clinically in the treatment o opioid
addiction, where it is desirable to use a partial agonist that is less e f cacious
than an addicting opioid such as heroin or morphine. Low concentrations
o the partial agonist buprenorphine bind tightly to the opioid receptor and
competitively inhibit the binding o the more e f cacious opioids. Very high
doses o buprenorphine show a paradoxically diminished analgesic e ect
that may be due to lower a f nity interactions o the drug with nonmu-opioid
receptors (not shown).
24 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
as DR*? In that case, addition o the partial agonist would
result in stabilization o some receptors in the DR orm and
some receptors in the DR* orm. At ull receptor occupancy,
some receptors would be in the active state and some in the
inactive state, and the e f cacy o the drug would be reduced
compared to that o a ull agonist (which stabilizes only
DR*). In this ormulation, a ull agonist binds pre erentially
to the active state o the receptor, a partial agonist binds with
comparable a f nity to both the active and inactive states o
the receptor, and an inverse agonist binds pre erentially to
the inactive state o the receptor (see below).
A second hypothesis or the action o partial agonists
is that a receptor may have multiple DR* con ormations,
each with a di erent intrinsic activity. Depending on the
particular con ormations o the receptor that are bound by
the agonist, a raction o the maximum possible e ect may
be observed even when a partial agonist is bound to 100%
o the receptors. This may be the case with the so-called
selective estrogen receptor modulators (SERMs) such as ral-
oxifene and tamoxifen (see Chapter 30, Pharmacology o
Reproduction). Raloxi ene acts as a partial agonist at estro-
gen receptors in bone and an antagonist at estrogen recep-
tors in breast. The crystal structure o raloxi ene bound to
the estrogen receptor, when compared to that o estrogen
bound to the estrogen receptor, reveals that the side chain o
raloxi ene inhibits an helix o the estrogen receptor rom
aligning in the active site (see Fig. 30-8). This may result
in inhibition o some downstream e ects o the estrogen
receptor, while maintaining other e ects. At a physiologic
level, this would be observed as partial agonist activity in
bone (see Fig. 30-7).
A variation o the second hypothesis is that a receptor
may have multiple DR* con ormations that di erentially
activate signal transduction pathways in cells. Drugs that
activate some but not all o these pathways are called bi-
ased agonists . Biased agonism has been demonstrated or
experimental compounds interacting with G protein-coupled
receptors and may be relevant or some partial agonists in
clinical use.
A study o partial agonists acting on ligand-gated ion
channels has suggested yet another model, in which the
receptor requires a priming con ormational change that
must occur be ore activation o the receptor is possible. In
this model, although a partial agonist may bind to the re-
ceptor with high a f nity, it is less e f cient than a ull ago-
nist at inducing the primed con ormation o the receptor.
Because this primed con ormation is a prerequisite or
activation o the receptor, a partial agonist causes the recep-
tor to spend less time in the open con ormation than a ull
agonist does, and the partial agonist has lower e f cacy than
the ull agonist.
The relative potency o ull agonists and partial agonists
may be clinically relevant (Fig. 2-7B). A partial agonist with
high a f nity or its receptor (such as buprenorphine) may be
more potent but less e f cacious than a ull agonist with lower
a f nity or the same receptor (such as morphine). This char-
acteristic is leveraged clinically when the partial agonist bu-
prenorphine is used to treat opioid addiction. Buprenorphine,
with its high a f nity or the mu-opioid receptor, can be
administered to outcompete other opioids taken by a patient
and can there ore help to prevent relapse o opioid addic-
tion. Buprenorphine must be care ully administered to a pa-
tient who is currently addicted to ull-agonist opioids such as
heroin or morphine, because it can outcompete these opioids
and cause withdrawal symptoms.
Inverse Agonists
The action o inverse agonists can be understood by consid-
ering Equation 2-6 again. As noted above, in some cases,
receptors can have inherent stability in the R* state. In these
cases, there is intrinsic activity (tone) o the receptor sys-
tem, even in the absence o an endogenous ligand or an ex-
ogenously administered agonist. An inverse agonist acts by
abrogating this intrinsic (constitutive) activity of the free
(unoccupied) receptor. Inverse agonists may unction by
binding to and stabilizing the receptor in the DR (inactive)
orm. This has the e ect o deactivating receptors that had
existed in the R* orm in the absence o drug. The physi-
ologic importance o receptors that have inherent stability in
the R* state is currently under investigation; receptors with
mutations that render them constitutively active may become
attractive targets or inverse agonist approaches.
Consider the similarities and di erences between the ac-
tions o inverse agonists and competitive antagonists. Both
types o drug act to reduce the activity o a receptor. In the
presence o a ull agonist, both competitive antagonists
and inverse agonists act to reduce agonist potency. Recall,
however, that a competitive antagonist has no e ect in the
absence o an agonist, whereas an inverse agonist deacti-
vates receptors that are constitutively active in the absence
o an agonist. Using Equations 2-6 through 2-9 as models,
these concepts can be summarized by stating that full ago-
nists stabilize DR*, partial agonists stabilize both DR and
DR* (or alternate forms of DR* or primed forms of DR),
inverse agonists stabilize DR, and competitive antagonists
stabilize R (or AR) by preventing full, partial, and inverse
agonists from binding to the receptor.
Spare Receptors
Recall that the initial discussion o drugreceptor binding
assumed that 100% receptor occupancy is required or an ag-
onist to exert its maximal e ect. Now, consider the possibil-
ity that a maximal response could be achieved with less than
100% receptor occupancy. Figure 2-8 shows an example o a
drugreceptor binding curve and a doseresponse curve that
illustrate this situation. In this example, a maximal e ect is
achieved at a lower dose o agonist than that required or re-
ceptor saturation, that is, the EC50 is less than the Kd or this
system. This type o discrepancy between the drugreceptor
binding curve and the doseresponse curve signif es the
presence o spare receptors . At least two molecular mecha-
nisms are thought to be responsible or the spare receptor
phenomenon. First, the receptor could remain activated a ter
the agonist departs, allowing one agonist molecule to acti-
vate several receptors. Second, the cell signaling pathways
described in Chapter 1, DrugReceptor Interactions, could
allow or signif cant amplif cation o a relatively small sig-
nal, and activation o only a ew receptors could be su f -
cient to produce a maximal response. The latter is true, or
example, with many G protein-coupled receptors; activation
o a single G s molecule can stimulate adenylyl cyclase to
catalyze the ormation o dozens o molecules o cAMP.
The presence o spare receptors alters the e ect o a
noncompetitive antagonist on the system. At low antagonist

A Drug-re ce ptor binding curve
1.0
[DR]
0.5
[R o ]
0
Kd
B Dos e -re s pons e curve
1.0
E receptors, however, potency is decreased but e f cacy is una ected at low
0.5
E MAX
0
EC 50 Kd
[D]
FIGURE 2-8. Comparison between a drugreceptor binding curve and a
doseresponse curve in the presence of spare receptors. In the absence
o spare receptors, there o ten exists a close correlation between a drug
receptor binding curve and a doseresponse curvethe binding o additional
drug to the receptor causes an incremental increase in response, and EC50
is approximately equal to Kd. In situations with spare receptors, however, a
hal -maximal response is elicited when less than hal o all receptors are oc-
cupied (the term spare implies that occupation o every receptor with drug
is not necessary to elicit a ull response). A. Drugreceptor binding curve.
B. Doseresponse curve or the same drug, in the presence o spare receptors.
Note that the maximal response occurs at a lower agonist concentration than
does maximal binding, and EC50 Kd. These two relationships conf rm the
presence o spare receptors. D is drug, R is receptor, and [DR]/[Ro] is rac-
tional receptor occupancy. E is response (e ect), Emax is maximal response
(e f cacy), and E/Emax is ractional response. EC50 is potency, and Kd is the equi-
librium dissociation constant or drugreceptor binding.
concentrations, the noncompetitive antagonist binds recep-
tors that are not required to produce a maximal response;
there ore, the e f cacy o the agonist is not decreased. The
potency o the agonist is a ected, however, because potency
is proportional to the raction o available receptors that must
be occupied to produce a 50% response. A noncompetitive
antagonist reduces the number o available receptors, thereby
increasing the raction o receptors that must be bound at any
agonist concentration to produce the same response. At high
antagonist concentrations, the noncompetitive antagonist
binds not only the spare receptors but also receptors that
are required to produce a maximal response, and the e f cacy
and potency o the agonist are both decreased. Figure 2-9
illustrates this concept.
C h a p t e r 2 Pharmacodynamics 25
1.0
Agonis t only
E
0.5
E MAX
Agonis t + incre a s ing
noncompe titive a nta gonis t
0
[D]
FIGURE 2-9. Effect of a noncompetitive antagonist on the agonist dose
response curve in the presence of spare receptors. In a system without
spare receptors, a noncompetitive antagonist causes e f cacy to decrease
at all concentrations o the antagonist (see Fig. 2-6B). In a system with spare
concentrations o the antagonist, because a su f cient number o unoccu-
pied receptors is available to generate a maximal response. As increas-
ing concentrations o antagonist bind noncompetitively to more and more
receptors, the antagonist eventually occupies all o the spare receptors,
and e f cacy is also reduced.
CONCEPTS IN THERAPEUTICS
Therapeutic Index and Therapeutic Window
The therapeutic window is the range o doses (concentra-
tions) o a drug that elicits a therapeutic response, without
unacceptable adverse e ects (toxicity), in a population o
patients. For drugs that have a small therapeutic window,
plasma drug levels must be monitored closely to maintain
e ective dosing without exceeding the level that could
produce toxicity. The next chapter discusses some o the
techniques used in clinical therapeutics to maintain plasma
concentrations o drugs within the therapeutic window.
The therapeutic window can be quantif ed by the thera-
peutic index (TI) (sometimes called the therapeutic ratio),
commonly def ned as
TD50
Therapeutic Index (TI) Equation 2-11
ED50
where TD50 is the dose o drug that causes a toxic response
in 50% o the population, and ED50 is the dose o drug that
is therapeutically e ective in 50% o the population. The
TI provides a single number that quantif es the relative
sa ety margin o a drug in a population o people. A large
TI represents a large (or wide) therapeutic window (e.g., a
thousand- old di erence between the therapeutic and toxic
doses), and a small TI represents a small (or narrow) thera-
peutic window (e.g., a two old di erence between the thera-
peutic and toxic doses).
In the case at the beginning o this chapter, the potential
or toxicity associated with the use o heparin and tPA is in-
dicated by the low TIs o these drugs. For example, the dose
o heparin that can cause major bleeding in a patient is o ten
26 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
TABLE 2-1 Summary of Agonist and Antagonist Action
CLASSES OF AGONISTS
AGONIST CLASS
Full agonist
Partial agonist
Inverse agonist
CLASSES OF ANTAGONISTS
EFFECTS ON
ANTAGONIST CLASS AGONIST POTENCY
Competitive antagonist Yes
Noncompetitive active site antagonist No
Noncompetitive allosteric antagonist No
less than twice the dose needed or a therapeutic e ect; hep-
arin can there ore be def ned as having a therapeutic index o
less than two. For this reason, patients treated with heparin
must have their PTT, a marker o the coagulation cascade,
monitored every ew hours. Aspirins high TI is indicative
o its relative sa ety. Note that the pharmacologic e ect o
heparin was monitored periodically in the case, whereas as-
pirin could be administered without the need to monitor its
plasma drug level.
CONCLUSION AND FUTURE
DIRECTIONS
Pharmacodynamics is the quantitative study o the e ects
o drugs on the body. Several tools have been developed to
compare the e f cacy and potency o drugs, including the
graded and quantal doseresponse relationships. The ormer
is used to examine the e ects o various drug doses on an
individual, whereas the latter is used to examine the e ects
o various drug doses on a population. The therapeutic win-
dow and therapeutic index are used to compare the concen-
trations o drugs that produce therapeutic e ects and toxic
(adverse) e ects.
In the study o pharmacodynamics, drugs can be divided
into two broad classesagonists and antagonists. Most ag-
onists cause a receptor to maintain its con ormation in the
active state, whereas antagonists prevent activation o the
receptor by agonists. Antagonists are urther divided accord-
ing to the molecular location o their e ect (i.e., receptor
or nonreceptor), the site at which they bind to the receptor
(i.e., active site or allosteric site), and the mode o their bind-
ing to the receptor (i.e., reversible or irreversible). Table 2-1
provides a summary o the various types o agonists and
antagonists presented in this chapter.
ACTION
Activates receptor with maximal e f cacy
Activates receptor but not with maximal e f cacy
Inactivates constitutively active receptor
EFFECTS ON
AGONIST EFFICACY ACTION
No Binds reversibly to active site o receptor;
competes with agonist binding to this site
Yes Binds irreversibly to active site o receptor;
prevents agonist binding to this site
Yes Binds reversibly or irreversibly to site other
than active site o receptor; prevents
con ormational change required or receptor
activation by agonist
Elucidation o the molecular basis or receptor activation
by ull agonists and partial agonists is likely to lead to new
opportunities or drug discovery. For example, it has been
shown that persistent activation o some G protein-coupled
receptors (GPCRs) requires the binding o both an agonist
and a G protein to the GPCR. This knowledge may be use ul
in designing new drugs that modulate the unction o specif c
GPCRs with greater selectivity.
Acknowledgment
We thank Harris S. Rose or his valuable contributions to
this chapter in the First and Second Editions o Principles o
Pharmacology: The Pathophysiologic Basis o Drug Therapy.
Suggested Reading
Cowan A, Doxey JC, Harry EJ. The animal pharmacology o buprenor-
phine, an oripavine analgesic agent. Br J Pharmacol 1977;60:547554.
(Provides an experimental demonstration o the variation in potency and
e f cacy o ull and partial agonists.)
Kenakin T, Williams M. Def ning and characterizing drug/compound unc-
tion. Biochem Pharmacol 2014;87:4063. (Summarizes how the complex
drugreceptor interactions o partial agonists, inverse agonists, biased
agonists, and allosteric antagonists help to in orm drug discovery.)
Lape R, Colquhoun D, Sivilotti LG. On the nature o partial agonism in the
nicotinic receptor super amily. Nature 2008;454:722727. (Suggests a mech-
anistic model or the e ect o partial agonists on ligand-gated ion channels.)
Le P. The two-state model o receptor activation. Trends Pharmacol Sci
1995;16:8997. (Provides the theoretical grounding or Equation 2-6; dis-
cusses quantitative treatment o drugreceptor interactions.)
Pratt WB, Taylor P, eds. Principles o drug action: the basis o pharmacology.
3rd ed. New York: Churchill Livingstone; 1990. (Contains an in-depth dis-
cussion o pharmacodynamics.)
Sprang SR. Cell signaling: binding the receptor at both ends. Nature
2011;469:172173. (Summarizes the f nding that persistent activation o
some GPCRs requires binding o both agonist and G protein molecules to
the receptor.)
 Free e Bo u n d
F re e Bo

3
Pharmacokinetics
Q u e n t in J . Ba c a a n d David E. Go la n

INTRODUCTIO ON & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2728 METABOLISM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

PHYSIOLOGIC C BARRIERS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 M ta
Me t bo
Oxidation/Reduction Reactions b o lite
bolit
lite s
lit . . . . . . . . . . . . . . . . . 34
Biological Membran
M nes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Conjugation/Hydrolysis Reactions . . . . . . . . . . . . . . . . . . . . . . . 344
Traversininng the Membrane . . . . 28 ((a ctive
ctiv
ti e a ndnd
EXCRETION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
Memb
Me mbrraane Diffus P rote
t iin
in-boun
bbound
nd . . . . 28 Rena
Re nall Ex
Excr
cret
ettioon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Central Nervous
r System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Bililiaa ry Excretion
Bi reti
et
inaa ctive
ina cctiv
tivee ) . . . . . . . . . . . . . . . . . . . . . . . . . 37
ABSORPTION
Administratio
drug
dr
d rug
ug
N. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ioon Routes and Rationale . . . . . . . . . . . . . . . . . . . . . 30
CLINICAL APPLICA
Clearance
APP ATI TIONONS S OF PHARMACOKINETICS . . . . . . . . . . 37
nc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
Enterall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 Metabolism and Excretion Kineticss . . . . . . . . . . . . . . . . . . . . 37
Met
Parenterall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Half-Life
lf- . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Mucous Membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Factors Altering Half-Lifee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Transdermall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Therapeutic Dosing and Frequency . . . . . . . . . . . . . . . . . . . . . . 39
T
Local, Regional, and Systemic Factors Affecting Absorption. . . . 31 Loading Dosee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
DIST
STRI
RIBU
BUTITION
ON . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Maintenance Dosee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 41
Plasma Protein Binding. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Modeling the Kinetics of Drug Distribution . . . . . . . . . . . . . . . . 33

INTRODUCTION
Even the most promising o pharmacologic therapies will
ail in clinical trials i the drug is unable to reach its tar-
get organ at a concentration su f cient to have a therapeu-
tic e ect. Many o the characteristics that render the human
body resistant to harm by oreign invaders and toxic sub-
stances also limit the ability o modern drugs to combat
pathologic processes within a patient. An appreciation o
the many actors that a ect a drugs ability to act within a
patient and the dynamic nature o these actors over time is
vitally important to the clinical practice o medicine.
All drugs must meet certain minimal requirements to
achieve clinical e ectiveness. A success ul drug must be
able to cross the physiologic barriers that limit the access o
oreign substances to the body. Drug absorption may occur
by a number o mechanisms that are designed either to ex-
ploit or to breach these barriers. A ter absorption, the drug
uses distribution systems within the body, such as the blood
and lymphatic vessels, to reach its target organ in an appro-
priate concentration. The drugs ability to act on its target is
also limited by several processes within the patient. These
processes all broadly into two categories: metabolism, in
which the body typically inactivates the drug through en-
zymatic degradation (primarily in the liver), and excretion,
in which the drug is eliminated rom the body (primarily
by the kidneys and liver, and in the eces). This chapter
presents a broad overview o the pharmacokinetic processes
o absorption, distribution, metabolism, and excretion (o ten
abbreviated as ADME; Fig. 3-1), with a conceptual emphasis
on basic principles that, when applied to an un amiliar situ-
ation, should enable the student or physician to understand
the pharmacokinetic basis o drug therapy.
PHYSIOLOGIC BARRIERS
A drug must overcome physical, chemical, and biological
barriers to reach its molecular and cellular sites o action.
The epithelial lining o the gastrointestinal tract and other
mucous membranes is one sort o barrier; additional bar-
riers are encountered a ter the drug enters the blood and
lymphatics. Most drugs must distribute rom the blood into
local tissues, a process that may be impeded by structures
such as the bloodbrain barrier. Typically, drugs leave the
intravascular compartment at the level o the postcapillary
venules, where there are gaps between the endothelial cells
through which the drug can pass. Drug distribution occurs
mainly through passive di usion, the rate o which is a -
ected by local ionic and cellular conditions. This section
describes the major physical, chemical, and biological barri-
ers to drug transport in the body and the properties o drugs
that a ect their ability to overcome these barriers.
27
28 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Mr. W is a 66-ye a r-o ld te ch n o lo g y co n -
s u lta n t w h o m a ke s re q u e n t trip s a s
p a rt o h is jo b in th e te le co m m u n ica -
tio n s in d u s try. His o n ly m e d ica l p ro b -
le m is ch ro n ic a tria l f b rilla tio n , a n d h is
o n ly ch ro n ic m e d ica tio n is warfarin. On th e la s t n ig h t
o a co n s u ltin g trip a b ro a d , h e a tte n d s a la rg e d in n e r
e a tu rin g ke b a b s a n d o th e r o o d s h e d o e s n o t o te n
e a t. Th e n e xt d a y, h e d e ve lo p s p ro u s e , wa te ry, o u l-
s m e llin g d ia rrh e a . A p hys icia n m a ke s a d ia g n o s is o
tra ve le r s d ia rrh e a a n d p re s crib e s a 7-d a y co u rs e o
trimethoprim-sulfamethoxazole.
Mr. W e e ls e n tire ly w e ll 2 d a ys in to th e co u rs e
o a n tib io tics , a n d 4 d a ys la te r (w h ile s till ta kin g h is
a n tib io tics ), h e m e e ts w ith s o m e clie n ts a t a n o th e r
la vis h d in n e r. Mr. W a n d h is g u e s ts b e co m e in toxi-
ca te d a t th e d in n e r, a n d Mr. W s tu m b le s a n d a lls
o n th e cu rb a s h e is le a vin g th e re s ta u ra n t. Th e n e xt
d a y, Mr. W h a s a m a rke d ly s w o lle n rig h t kn e e th a t
Biological Membranes
All human cells are limited by a lipid bilayer membrane. The
membrane lipids consist mainly o phospholipids, sterols
(especially cholesterol), and glycolipids. The amphiphilic
nature o the membrane lipids and the aqueous intracellular
and extracellular environments cause the membrane to as-
sume a structure with a hydrophobic core and two hydro-
philic sur aces. In addition to lipid components, biological
membranes contain proteins that may span the membrane
(transmembrane proteins) or be exposed only at the extra-
cellular or intracellular membrane sur ace. The membranes
Re ce ptors Tis s ue
Fre e Bound re s e rvoirs
Fre e Bound
S ys te mic
circula tion
Abs orption Free drug Excre tion
Me ta bolite s
(a ctive a nd
P rote in-bound
drug
ina ctive )
Me ta bolis m
FIGURE 3-1. Drug absorption, distribution, metabolism, and excretion
(ADME). The basic principles o pharmacokinetics a ect the amount o ree
drug that ultimately reaches the target site. To elicit an e ect on its target,
a drug must be absorbed and then distributed to its target be ore being
metabolized and excreted. At all times, ree drug in the systemic circulation
is in equilibrium with tissue reservoirs, plasma proteins, and the target site
(which usually consists o receptors); only the raction o drug that binds to
specif c receptors will have a pharmacologic e ect. Note that metabolism
o drug can result in both inactive and active metabolites; active metabolites
may also exert a pharmacologic e ect, either on the target receptors or
sometimes on other receptors.
re q u ire s e va lu a tio n in a lo ca l e m e rg e n cy d e p a rt-
m e n t. Phys ica l e xa m in a tio n a n d im a g in g s tu d ie s a re
co n s is te n t w ith a m o d e ra te -s ize d h e m a rth ro s is o
th e rig h t kn e e . La b o ra to ry s tu d ie s s h o w a m a rke d ly
e le va te d in te rn a tio n a l n o rm a lize d ra tio (INR), w h ich
is a s ta n d a rd ize d m e a s u re o p ro th ro m b in tim e a n d ,
in th is clin ica l s e ttin g , a s u rro ga te m a rke r o r p la s m a
wa r a rin le ve l. Th e e m e rg e n cy p hys icia n a d vis e s Mr.
W th a t h is wa r a rin le ve l is in th e s u p ra th e ra p e u tic
(toxic) ra n g e a n d th a t th is e e ct is like ly d u e to a d -
ve rs e d ru g d ru g in te ra ctio n s invo lvin g h is wa r a rin ,
h is a n tib io tics , a n d h is re ce n t a lco h o l in toxica tio n .
Questions
1 . How does a patient with well-established therapeutic
levels o a chronic medication suddenly develop clini-
cal mani estations o drug toxicity?
2 . Could this situation have been avoided? I so, how?
semipermeable lipid bilayer structure provides a barrier to
the transport o molecules and has important implications
or drug therapy.
Traversing the Membrane
The hydrophobic core of a biological membrane presents the
major barrier to drug transport. Small nonpolar molecules,
such as steroid hormones, are able to di use easily through
membranes. However, passive di usion is ine ective or the
transport o many large polar molecules and drugs. Some
transmembrane proteins in the human solute carrier (SLC)
super amilywhich includes 52 amilies o proteins such
as organic anion transporters, organic cation transporters,
peptide transporters, and nucleoside transportersallow
transport o polar drugs and molecules across the membrane.
Transmembrane carrier proteins may be specif c or a drug
and related endogenous molecules; upon binding o the
drug to the extracellular sur ace o the protein, the protein
undergoes a con ormational change that may be energy-
independent (facilitated diffusion) or require energy (active
transport). This con ormational change allows the bound
drug access to the interior o the cell, where the drug mol-
ecule is released rom the protein. Alternatively, some drugs
bind to specif c cell sur ace receptors and trigger endocyto-
sis , a process in which the cell membrane involutes around
the molecule to orm a vesicle rom which the drug is subse-
quently released into the cell interior.
Membrane Diffusion
In the absence o other actors, a drug will enter a cell until
the intracellular and extracellular concentrations o the drug
are equal. The rate o di usion depends on the concentra-
tion gradient o the drug across the membrane and on the
thickness, area, and permeability o the membrane. Ficks
law o di usion states that the net drug ux across the mem-
brane is:
(C2 C1) (Area Permeability)
Flux Equation 3-1
Thicknessmembrane

[1,000] [1]
HA A- + H+
S toma ch pH~1
Ga s tric Mucos a l Ba rrie r
P la s ma pH~7
HA A- + H+
[1,000] [1,000,000]
FIGURE 3-2. pH trapping across lipid bilayers. In the example shown, con-
sider a hypothetical drug with pKa 4. Although this drug is a weak acid,
in the highly acidic environment of the stomach, it is largely protonated. If
the stomach pH is approximately 1, then for every 1,001 molecules of drug,
1,000 molecules are protonated (and neutral) and only 1 is deprotonated
(and negatively charged). The protonated, neutral form of the drug is able
to diffuse across the gastric mucosal barrier into the blood. Because the
blood plasma has a pH of approximately 7 (it is actually 7.4), and the drug
has a pKa of 4, the vast majority of drug now exists in the deprotonated
(negatively charged) form: for every 1,001 molecules of drug, only 1 molecule
is protonated (and neutral), while 1,000 molecules are deprotonated (and
negatively charged). The negatively charged form of the drug is no longer
able to diffuse across the lipid bilayers of the gastric mucosa, and the drug
is effectively trapped in the plasma.
where C1 and C2 are the intracellular and extracellular con-
centrations o the drug, respectively. This def nition applies
to an ideal situation where there is an absence o complicat-
ing actors such as ionic, pH, and charge gradients across the
membrane. In vivo, however, these additional actors a ect
the ability o a drug to enter cells. For example, a higher
concentration o drug outside the cell would ordinarily avor
net drug entry into the cell, but i both the cell interior and
the drug are negatively charged, then net drug entry into the
cell may be impeded. In contrast, a negatively charged cell
interior could avor entry o a positively charged drug.
Net di usion o acidic and basic drugs across lipid bilayer
membranes may also be a ected by a charge-based phenom-
enon known as pH trapping, which depends on the drugs acid
dissociation constant (pKa) and the pH gradient across the
membrane. For weakly acidic drugs, such as phenobarbital
and aspirin, the protonated, electrically neutral orm o the
drug is predominant in the highly acidic environment o the
stomach. The uncharged orm o the drug can pass through
the lipid bilayers o the gastric and duodenal mucosa, speed-
ing the drugs absorption (Fig. 3-2). The weakly acidic drug is
then e ectively trapped as it is deprotonated to its electrically
charged orm in the more basic environment o the plasma.
In quantitative terms, the pKa o a drug represents the pH
value at which one-hal o the drug is present in its ionic
orm. The HendersonHasselbalch equation describes the
relationship between the pKa o an acidic or basic Drug A and
the pH o the biological medium containing the drug:
[HA]
pKa pH logg Equation 3-2
[A ]
C h a p t e r 3 Pharmacokinetics 29
where HA is the protonated orm o Drug A. For example,
consider the hypothetical case o a weakly acidic drug with a
pKa o 4. In the stomach, which has a pH o approximately 1,
Equation 3-2 becomes:
[HA]
pKadrug pHstomach log ,
[A ]
which simplifies to:
[HA]
3 log ,
[A ]
and finally:
[HA]
1,000 .
[A ]
The protonated orm o the drug is present at 1,000 times
the concentration o the deprotonated orm, and 99.9% o
the drug is in the neutral orm. Conversely, in the plasma,
where the pH is approximately 7.4, more than 99.9% o the
drug is in the deprotonated orm (see Fig. 3-2).
Central Nervous System
The central nervous system (CNS) presents special chal-
lenges to pharmacologic therapy. Unlike most other anatomic
regions, the CNS is particularly well insulated rom oreign
substances. The bloodbrain barrier uses specialized tight
junctions to prevent the passive di usion o most drugs rom
the systemic to the cerebral circulation. There ore, drugs de-
signed to act in the CNS must either be su f ciently small and
hydrophobic to traverse biological membranes easily or use
existing transport proteins in the bloodbrain barrier to pen-
etrate central structures. Hydrophilic drugs that ail to target
acilitated or active transport proteins in the bloodbrain bar-
rier cannot penetrate the CNS. The bloodbrain barrier can
be bypassed using intrathecal drug delivery, in which drugs
are delivered directly into the cerebrospinal uid (CSF).
Although this approach can be used, or example, to treat
in ectious meningitis or to provide spinal anesthesia or a ce-
sarean delivery, the intrathecal route is impractical or drugs
that must be taken regularly by a patient.
ABSORPTION
The human body presents ormidable obstacles to invasion by
microorganisms. The integument has a keratinized outer layer
and de ensins in the epithelium. Mucous membranes are pro-
tected by mucociliary clearance in the trachea, lysozyme se-
cretion rom lacrimal ducts, acid in the stomach, and base in
the duodenum. These nonspecif c de ense mechanisms present
barriers to drug absorption and may limit the drugs bioavail-
ability at target organs. Bioavailability, or the raction o admin-
istered drug that reaches the systemic circulation, may depend
on the route by which the drug is administered, the chemical
orm o the drug, and a number o patient-specif c actors such
as gastrointestinal and hepatic transporters and enzymes.
Bioavailability is def ned quantitatively as:
Quantity of drug
reaching systemic
circulation
Bioavailability Equation 3-3
Quantity of drug
administered
30 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

This def nition o bioavailability is based on the act that

most drugs reach their molecular and cellular sites of action
directly from the systemic circulation. Intravenously admin-
istered drugs are injected directly into the systemic circula-
Ora l, s ubcuta ne ous ,
tion; or these drugs, the quantity administered is equivalent
n
Intra ve nous or intra mus cula r:
o
to the amount reaching the systemic circulation, and the bio-
i
t
100% bioa va ila bility
a
r
availability is, by def nition, 1.0. In contrast, incomplete gas-
t
n
trointestinal absorption and f rst-pass hepatic metabolism
e
c
n
(see below) typically cause the bioavailability o an orally
o
c
administered drug to be less than 1.0 (Fig. 3-3).
g
u
r
d
a
Ora l, s ubcuta ne ous ,
Administration Routes and Rationale
m
or intra mus cula r:
s
a
50% bioa va ila bility New drugs are designed and tested in a dosage orm that is
l
P
administered by a specif c route. Routes o administration
are o ten chosen to take advantage o transport molecules
Time and other mechanisms that permit the drug to enter body
tissues. This section discusses the advantages and disadvan-
tages o drug administration by enteral (oral), parenteral,
FIGURE 3-3. Bioavailability after administration of a single dose of mucous membrane, and transdermal routes (Table 3-1).
drug. An intravenously administered drug is immediately available in the
circulation. In this example, the drug is then distributed to other body com- Enteral
partments (see Fig. 3-7) and eliminated by f rst-order kinetics (see Fig. 3-6). Enteral drug administration, or the administration o a drug
In contrast, other routes o administration (e.g., oral, subcutaneous, and
by mouth, is the simplest o drug routes. The enteral route
intramuscular) demonstrate slower entry o drug into the blood. In addi-
tion, nonintravenous routes o administration must take into account bio-
o administration exploits existing weaknesses in human
availability or example, many orally administered drugs are incompletely barrier de enses, but it exposes the drug to harsh acidic
absorbed or undergo f rst-pass metabolism in the liver. I a drug has 100% (stomach) and basic (duodenum) environments that could
bioavailability, the total amount o drug reaching the systemic circulation will limit its absorption. This route provides many advantages
be the same or all routes o drug administration, but nonintravenous routes or the patient: oral drugs are easily and conveniently sel -
will require a longer period o time to reach a peak concentration o drug in administered, and these dosage orms are less likely than
the plasma. I the bioavailability o an oral, subcutaneous, or intramuscular other methods to introduce systemic in ection as a compli-
dosage orm is less than 100%, then the dose o the drug would have to cation o treatment.
be increased in order or the total amount o drug reaching the systemic An orally administered drug must be stable during its
circulation to be the same as that o an intravenous dose. Note that the
absorption across the gastrointestinal tract epithelium. Gas-
total amount o drug reaching the systemic circulation can be quantif ed by
integrating the area under the curve (AUC) o the plasma drug concentration
trointestinal epithelial cell junctions make paracellular trans-
versus time plot. Thus, although di erent routes o administration (e.g., oral, port across an intact epithelium di f cult. Instead, ingested
subcutaneous, and intramuscular) can have di erent rates o drug absorp- substances (such as drugs) must usually traverse the cell
tion and there ore di er in the kinetics o plasma drug concentration over membrane at both apical and basal sur aces be ore entering
time (Fig. 3-4), i these routes exhibit the same level o bioavailability, then the blood. The e f ciency o this process is determined by
they will have the same AUC. drug size and hydrophobicity and sometimes by the presence

TABLE 3-1 Routes of Drug Administration

ROUTE ADVANTAGES DISADVANTAGES
Enteral (e.g., aspirin) Simple, inexpensive, convenient, painless, no Drug exposed to harsh gastrointestinal (GI)
in ection environments and f rst-pass metabolism,
requires GI absorption, slow delivery to site o
pharmacologic action

Parenteral (e.g., morphine) Rapid delivery to site o pharmacologic action, Irreversible, in ection, pain, ear, skilled personnel
high bioavailability, not subject to f rst-pass required
metabolism or harsh GI environments

Mucous membrane (e.g., nitroglycerin)
Rapid delivery to site o pharmacologic action,
not subject to f rst-pass metabolism or harsh
GI environments, o ten painless, simple,
convenient, low in ection, direct delivery to
a ected tissues possible
Few drugs have chemical characteristics or
ormulations that allow them to be administered
via this route

Transdermal (e.g., nicotine) Simple, convenient, painless, excellent or Requires highly lipophilic drug, slow delivery to site
continuous or prolonged administration, not o pharmacologic action, may be irritating
subject to f rst-pass metabolism or harsh GI
environments

o carriers through which the drug may enter and/or exit the
cell. In general, hydrophobic and neutral drugs cross cell
membranes more e f ciently than hydrophilic or charged
drugs, unless the membrane contains a carrier molecule that
acilitates the transport o hydrophilic substances.
Upon traversing the gastrointestinal epithelium, drugs are
carried by the portal system to the liver be ore entering the
systemic circulation. While the portal circulation protects
the body rom the systemic e ects o ingested toxins by de-
livering these substances to the liver or detoxif cation, this
system may complicate drug delivery. All orally adminis-
tered drugs are subjected to f rst-pass metabolism in the liver.
In this process, liver enzymes may inactivate a raction o the
ingested drug. Any drug that exhibits signif cant f rst-pass
metabolism must be administered in a quantity su f cient to
ensure that an e ective concentration o active drug exits the
liver into the systemic circulation, rom which it can reach
the target organ. Drugs administered by nonenteral routes
are not subjected to f rst-pass liver metabolism.
Parenteral
Parenteral administration, in which a drug is introduced
directly into the systemic circulation, cerebrospinal uid,
vascularized tissue, or some other tissue space, immediately
overcomes barriers that can limit the e ectiveness o orally
administered drugs (Table 3-2). Tissue administration re-
sults in a rate o onset o drug action that di ers among the
various body tissues, depending on the rate o blood ow to
the tissue. Subcutaneous (SC) administration o a drug into
poorly vascularized adipose tissue results in a slower onset
o action than injection into well-vascularized intramuscu-
lar (IM) spaces. Drugs that are soluble only in oil-based
solutions are o ten administered intramuscularly. Direct in-
troduction o a drug into the venous (intravenous [IV]) or
arterial (intra-arterial [IA]) circulation or into the cerebro-
spinal uid (intrathecal [IT]) results in the drug reaching its
target organ the astest. Unlike subcutaneous and intramus-
cular injections, intravenous injection is not typically limited
in the amount o drug that can be delivered. Continuous in-
travenous in usions can allow tight control over peak and
steady-state plasma concentrations during drug delivery.
Parenteral administration may be associated with sev-
eral potential disadvantages, including an increased risk o
TABLE 3-2 Routes o Parenteral Drug Administration
PARENTERAL
ROUTE ADVANTAGES DISADVANTAGES
Subcutaneous Slow onset, may be Slow onset, small
(e.g., lidocaine) used to administer volumes
oil-based drugs
Intramuscular (e.g., Intermediate onset, Can affect lab tests
haloperidol) may be used to (creatine kinase),
administer oil- intramuscular
based drugs hemorrhage, painful
Intravenous (e.g., Rapid onset, Peak-related drug
morphine) controlled drug toxicity
delivery
Intrathecal (e.g., Bypasses blood Infection, highly skilled
methotrexate) brain barrier personnel required
C h a p t e r 3 Pharmacokinetics 31
in ection and the requirement or administration by a health
care pro essional. The onset o action o parenterally admin-
istered drugs is o ten rapid, potentially resulting in increased
toxicity when such drugs are administered too rapidly or
in incorrect doses. These disadvantages must be weighed
against the advantages o parenteral administration (such as
speed o onset and control o the delivered dose) and the
urgency o the indication or pharmacologic therapy.
Mucous Membrane
Administration o drugs across mucous membranes can po-
tentially provide rapid absorption, low incidence o in ec-
tion, convenience o administration, and avoidance o harsh
gastrointestinal environments and f rst-pass metabolism.
Sublingual, ocular, pulmonary, nasal, rectal, urinary, and
reproductive tract epithelia have all been used to deliver
drugs in the orm o liquid drops, rapidly dissolving tablets,
aerosols, and suppositories (among other dosage orms).
The mucous membranes are highly vascular, permitting the
drug to enter the systemic circulation rapidly and to reach
its target organ with minimal delay. Drugs may also be ad-
ministered directly into the target organ, resulting in virtu-
ally instantaneous onset o action. This is advantageous in
critical conditions such as acute asthma, where drugs such as
-adrenergic agonists are administered via aerosol directly
into the airways.
Transdermal
A limited number o drugs have su f ciently high lipophilic-
ity that passive di usion across the skin is a viable route o
administration. Transcutaneously administered drugs are ab-
sorbed rom the skin and subcutaneous tissues directly into
the blood. This route o administration is ideal or a drug
that must be slowly and continuously administered over ex-
tended periods. There is no associated risk o in ection, and
drug administration is simple and convenient. The success
o transdermal nicotine, estrogen, and scopolamine patches
demonstrates the utility o this route o administration (see
Chapter 55, Drug Delivery Modalities, or more details on
transdermal drug delivery).
Local, Regional, and Systemic Factors
A ecting Absorption
The rate and extent o absorption o a drug are a ected by
local, regional, and systemic actors. In general, a large or
rapidly administered dose creates a high local concentration
o a drug. A large concentration gradient between the site o
administration and the surrounding tissue drives the distri-
bution o the drug into the nearby tissue and/or vasculature.
Any actor that decreases the concentration gradient at the
site o administration will diminish the driving orce o the
gradient and may reduce the amount o drug that is dis-
tributed into the local tissues. Regional blood ow has the
greatest e ect in this regard; in a highly per used region,
drug molecules crossing into that compartment are rapidly
removed. This e ect maintains the drug concentration at
a low level in the compartment, allowing the driving orce
or entry o new drug molecules into the compartment to
remain high (see Equation 3-1). For example, volatile gen-
eral anesthetics are administered via inhalation. The lungs
are highly per used, and the anesthetic is removed rapidly
rom the lungs into the systemic circulation. Anesthetic does
not accumulate in the local circulation, and a concentration
32 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

TABLE 3-3 Drug Distribution to Different

Body Compartments
A
COMPARTMENT EXAMPLES
n
o
i
B Total body water Small water-soluble molecules (e.g., ethanol)
t
a
r
t
n
Extracellular water Larger water-soluble molecules (e.g., mannitol)
e
c
C
n
o
Blood plasma Highly plasma protein-bound molecules, very
c
g
large molecules, highly charged molecules
u
r
(e.g., heparin)
d
a
m
Adipose tissue Highly lipid-soluble molecules (e.g., propo ol)
s
a
l
P
Bone and teeth Certain ions (e.g., uoride, strontium)

Time
FIGURE 3-4. Effect of rate of absorption on peak plasma concentration of
drug and on duration of drug action. The duration o action and peak plasma
concentration o a drug can be a ected markedly by the drugs absorption
rate. In this example, three drugs with identical bioavailability, volume o dis-
tribution, and clearance are administered in identical doses. The drugs dem-
onstrate di erent rates o absorptionDrug A is absorbed quickly, Drug C is
absorbed slowly, and Drug Bs absorption rate is between those o Drugs A
and C. Drug A reaches the highest peak plasma concentration, since all o
the drug is absorbed be ore signif cant elimination can take place. Drug C
is absorbed slowly and never achieves a high plasma concentration, but it
persists in the plasma or longer than Drugs A or B because absorption con-
tinues during the elimination phase. It should be noted that the hypothetical
Drugs A, B, and C could all be the same drug administered by three di erent
routes. For example, curve A could represent intravenous glucocorticoid
administration, curve B could be an intramuscular injection, and curve C
could be a transdermal ormulation o the same drug.
gradient promoting di usion o anesthetic into the blood is
maintained (see Chapter 17, General Anesthetic Pharmacol-
ogy, or more details). In an individual with greater body
mass, both the increased sur ace area or absorption and the
larger tissue volumes available or distribution tend to re-
move a drug rom the site o administration aster and in-
crease the rate and extent o drug absorption. The rate o
drug absorption a ects both the local concentration o a
drug (including its plasma concentration) and its duration o
action (Fig. 3-4).
tissue concentration, the e ect o the drug in the target tissue
o ten correlates well with the plasma drug concentration.
Organs and tissues vary widely in their capacity to take up
di erent types o drugs (Table 3-3) and in the proportion o
systemic blood ow they receive (Table 3-4). In turn, these
actors a ect the concentration o the drug in the plasma and
determine the amount o drug that must be administered to
achieve the desired plasma drug concentration. The ability
o nonvascular tissues and plasma proteins to take up and/or
bind the drug must be accounted or in designing dosing
regimens to achieve and maintain therapeutic drug levels.
Volume of Distribution
The volume of distribution (Vd) describes the extent to which
a drug partitions between the plasma and tissue compart-
ments. In quantitative terms, Vd represents the uid volume
that would be required to contain the total amount o ab-
sorbed drug in the body at a concentration equivalent to that
in the plasma at steady state:
Dose
Vd Equation 3-4
[Drug]plasma
The volume o distribution is an extrapolated volume
based on the concentration o drug in the plasma, not a
physical volume. Thus, Vd is low or drugs that are retained
TABLE 3-4 Total and Weight-Normalized Tissue Blood
Flow in an Adult

DISTRIBUTION NORMALIZED
ORGAN BLOOD FLOW ORGAN BLOOD FLOW
Absorption o a drug is a prerequisite or establishing ad- PERFUSED (mL/min) MASS (kg) (mL/min/kg)
equate plasma drug levels, but the drug must also reach its
target organ(s) in therapeutic concentrations to have the de- Liver 1,700 2.5 680
sired e ect on a pathophysiologic process. Drug distribu- Kidneys 1,000 0.3 3,333
tion is achieved primarily through the circulatory system; a
minor component is contributed by the lymphatic system. Brain 800 1.3 615
Once a drug has been absorbed into the systemic circulation,
it is then capable o reaching any target organ (with the pos- Heart 250 0.3 833
sible exception o sanctuary compartments such as the cen- Adipose 250 10.0 25
tral nervous system and testes). The concentration o drug in
the plasma is typically used to def ne and monitor therapeu- Other (muscle, 1,400 55.6 25
tic drug levels, because the concentration o drug in the tar- etc.)
get organ is o ten di f cult to measure. Even in cases where Total 5,400 70.0
the plasma concentration o a drug is very di erent rom the
 C h a p t e r 3 Pharmacokinetics 33

primarily within the vascular compartment and high or

drugs that are highly distributed into adipose and other non- A S ite of
pha rma cologic
vascular compartments. For very highly distributed drugs, a ction
the volume o distribution is o ten much greater than the Va s cula r s pa ce
volume o total body water, re ecting the low concentration
o drug in the vascular compartment at steady state. Some
drugs have very large volumes o distribution; examples
include amiodarone (4,620 liters [L] or a 70-kg person),
azithromycin (2,170 L), chloroquine (9,240 L), and digoxin
(645 L), among others.
The capacity o the blood and the various organs and
tissues to take up and retain a drug depends on both the Cle a ring
orga n
volume (mass) o the tissue and the concentrations o spe-
cif c and nonspecif c binding sites or the drug within that
tissue. A drug that is taken up in large quantities by tissues
such as adipose will pre erentially distribute out o the sys-
temic circulation and into these tissues at steady state. In
many cases, these tissues must be saturated be ore plasma S ite of
B
levels o such drugs can increase su f ciently to a ect the pha rma cologic
a ction
drugs target organ. Thus, or drugs o equal potency, a
Va s cula r s pa ce
drug that is more highly distributed among body tissues
generally requires a higher initial dose to establish a thera-
peutic plasma concentration than does a drug that is less
highly distributed.

Plasma Protein Binding

The capacity o adipose tissue to absorb a drug increases the
tendency o the drug to di use rom the blood into nonvas-
cular compartments, but this tendency can be counteracted
to some extent by plasma protein binding o the drug. Albu-
min is the most abundant plasma protein ( 4 g/dL) and is
the protein responsible or most drug binding. Many drugs
bind with low a f nity to albumin through both hydropho-
bic and electrostatic orces. Plasma protein binding tends to
reduce the availability o a drug or di usion or transport
into the drugs target organ because, in general, only the ree
or unbound orm o the drug is capable o di usion across
membranes (Fig. 3-5). Plasma protein binding may also re-
duce the transport o drugs into nonvascular compartments
such as adipose tissue. Because a highly protein-bound drug
tends to remain within the vasculature, such a drug o ten has
a relatively low volume o distribution (typically, 7 to 8 L or
a 70-kg person).
Theoretically, plasma protein binding could be important
as a mechanism or some drugdrug interactions. Coadmin-
istration o two or more drugs that bind to plasma protein
could result in a higher-than-expected plasma concentration
o the ree orm o either or both drugs as the coadministered
drugs compete or the same binding sites. The increased ree
drug concentration could potentially cause increased thera-
peutic and/or toxic e ects o the drug. In such cases, the
dosing regimen o one or both o the drugs would need to
be adjusted to keep the ree drug concentration in the thera-
peutic range. In practice, however, it has been di f cult to
demonstrate clinically signif cant drugdrug interactions
caused by competitive binding o drugs to plasma proteins,
possibly because o the increased clearance o the ree drugs
as they are displaced rom their plasma protein binding sites
(see below). An important exception is the contraindication
to the use o the antibiotic ceftriaxone in neonates with hy-
perbilirubinemia, since ce triaxone displaces bilirubin rom
its binding sites on albumin and thereby exacerbates the hy-
perbilirubinemia.
Cle a ring
orga n
Drug A bound
Drug A to a lbumin
Albumin
Drug B bound
Drug B to a lbumin
FIGURE 3-5. Protein binding and drug trapping. A drug that is bound to
albumin or other plasma proteins cannot di use rom the vascular space
into surrounding tissues. A. Drugs that do not bind plasma proteins ap-
preciably (shown here as Drug A) di use readily into tissues. This results
in both a high level o binding to the site o pharmacologic action (usually
receptors) and a high rate o elimination (represented by f ux through a
clearing organ). Examples o such drugs include acetaminophen, acyclovir,
nicotine, and ranitidine. B. In contrast, or drugs that exhibit high levels o
binding to plasma proteins (shown here as Drug B), a higher total plasma
drug concentration is required to ensure an adequate concentration o ree
(unbound) drug in the circulation, since only a small raction o the drug
can di use into the extravascular space. Examples o such drugs include
amiodarone, f uoxetine, naproxen, and war arin. It should be emphasized
that plasma protein binding is only one of many variables that determine
drug distribution. Drug molecule size, lipophilicity, and rate o metabolism
are other important parameters that must be taken into account when con-
sidering the pharmacokinetics o a particular drug.
Modeling the Kinetics of Drug Distribution
Most drugs are distributed rapidly rom the systemic circula-
tion (intravascular compartment) to other compartments in
the body. This distribution phase results in a sharp decrease
in the plasma drug concentration shortly a ter intravenous
34 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Dis tribution pha s e
n
o
i
t
a
r
t
n
e
c
n
Elimina tion pha s e
o
c
g
u
r
d
a
m
s
a
l
P
Time
FIGURE 3-6. Drug distribution and elimination after intravenous
administration. Immediately a ter intravenous administration o a drug, the
plasma drug concentration declines rapidly as the drug distributes rom the
vascular compartment to other body compartments. This rapid decline is
ollowed by a slower decline as the drug is metabolized and excreted rom
the body. Both drug distribution and elimination display f rst-order kinetics,
as demonstrated by linear kinetics on a semilogarithmic plot.
administration o a drug bolus. Even a ter the drug equili-
brates among its tissue reservoirs, the plasma drug concen-
tration continues to decline because o drug elimination rom
the body. However, the plasma drug concentration decreases
more slowly during the elimination phase, in part due to
a reservoir o drug in the tissues that can di use back
into the blood to replace the drug that has been eliminated
(Figs. 3-6 and 3-7).
The tendency or a drug to be taken up by adipose and
muscle tissue during the distribution phase determines a set
o dynamic equilibria among drug concentrations in the vari-
ous body compartments. As shown in Figure 3-8, the rapid
decline o plasma drug concentration a ter administration o
an intravenous bolus o drug can be approximated by using a
our-compartment model consisting o the blood and vessel-
rich, muscle-rich, and adipose-rich tissues. The vessel-rich
group is the f rst extravascular compartment in which the
concentration o drug increases, because the high blood ow
received by this group kinetically avors drug entry into this
compartment. However, the muscle-rich group and adipose-
rich group o ten have a higher capacity or taking up drug
than the vessel-rich group, with the adipose-rich group ac-
cumulating the greatest amount o drug at the slowest rate.
The capacity o a compartment or a drug and the rate o
blood ow to the compartment also a ect the rate at which
the drug exits rom the compartment. Drugs tend to exit f rst
rom the vessel-rich group, ollowed by the muscle group
and then the adipose group. A complex and dynamic pat-
tern o changing blood concentrations may develop, and the
pattern is specif c or each drug. The pattern may also be
patient-specif c, depending on actors such as the size, age,
and f tness level o the patient. For example, an older pa-
tient typically has less skeletal muscle mass than a younger
patient, decreasing the contribution o muscle uptake to
changes in the plasma concentration o drug. An opposite
e ect may be seen in an elite athlete, who would be expected
to have both greater muscle mass and greater proportional
muscle blood ow. As a third example, an obese person typi-
cally exhibits higher capacity or drug uptake into adipose
tissue.
More complicated approaches to modeling the kinetics o
drug distribution throughout the body can include an exhaus-
tive number o compartments. Some approaches model each
organ or vascular bed individually to describe more precisely
the drug concentration at specif c target sites over time.
METABOLISM
Several organs are capable o metabolizing drugs to some
extent, using enzymatic reactions that are discussed in
Chapter 4, Drug Metabolism. The kidneys, gastrointestinal
tract, lungs, skin, and other organs all contribute to systemic
drug metabolism. However, the liver contains the greatest
diversity and quantity o metabolic enzymes, and the ma-
jority o drug metabolism occurs there. The ability o the
liver to modi y drugs depends on the amount o drug that
enters the hepatocytes. Highly hydrophobic drugs can gener-
ally enter cells readily (including liver cells), and the liver
pre erentially metabolizes hydrophobic drugs. However,
the liver contains a multitude o transporters in the human
solute carrier (SLC) super amily that allow entry o some
hydrophilic drugs into hepatocytes as well. Hepatic enzymes
chemically modi y a variety o substituents on drug mole-
cules, thereby either rendering the drugs inactive or acili-
tating their elimination. These modif cations are collectively
re erred to as biotransformation. Biotrans ormation reactions
are classif ed into two types, termed oxidation/reduction
reactions and conjugation/hydrolysis reactions . (Although
biotrans ormation reactions are o ten called phase I and
phase II reactions, in this book we typically use the more pre-
cise terms oxidation/reduction and conjugation/hydrolysis;
see Chapter 4.)
Oxidation/Reduction Reactions
Oxidation/reduction reactions modi y the chemical structure
o a drug; typically, a polar group is added or uncovered. The
most common pathway, the microsomal cytochrome P450
enzyme system in the liver, mediates a large number o oxida-
tive reactions. Some drugs may be administered in inactive
(prodrug) orm and are altered metabolically by oxidation/
reduction reactions to the active (drug) orm in the liver. This
prodrug strategy can acilitate oral bioavailability, decrease
gastrointestinal toxicity, and/or prolong the elimination hal -
li e o a drug.
Conjugation/Hydrolysis Reactions
Conjugation/hydrolysis reactions hydrolyze a drug or conju-
gate a drug to a large, polar molecule in order to inactivate
the drug or, more commonly, to enhance the drugs solubil-
ity and excretion in the urine or bile. Occasionally, hydro-
lysis or conjugation can result in the metabolic activation
o prodrugs. The most commonly added groups include
glucuronate, sul ate, glutathione, and acetate.
As described in more detail in the next chapter, the e ects
o oxidation/reduction and conjugation/hydrolysis reactions
on a particular drug also depend on the presence o other
drugs that are being taken concomitantly by the patient.
Certain classes o drugs, such as barbiturates, are power ul
 C h a p t e r 3 Pharmacokinetics 35

n
g
o
u
i
A

t
r
a
d
r
t
a
n
m
e
c
s
n
a
o
l
P
c
Extra va s cula r Blood Time
volume

n
g
o
u
i
B

t
r
a
d
r
t
a
n
m
e
c
s
n
a
o
l
P
c
Blood Time
n
g
o
u
i
C
t
r
a
d
r
t
a
n
m
e
c
s
n
a
o
l
P
c
Extra va s cula r Blood Time
volume

FIGURE 3-7. Schematic model of drug distribution and elimination. A two-compartment pharmacokinetic model can be used to describe drug distribution
and elimination a ter administration o a single intravenous dose. The drug concentration rises rapidly as the drug is added to the f rst compartment. A. In the
absence o elimination, the initial rise in drug concentration is ollowed by a rapid decline to a new plateau as the drug equilibrates (distributes) between the
two compartments. B. I the distribution o the drug is conf ned to the blood volume, then the plasma drug concentration declines more slowly as the drug
is eliminated rom the body. In both cases, as the concentration o drug in the plasma decreases, the orces driving (A) drug distribution and (B) elimination
decrease, and the absolute amount o drug distributed or eliminated per unit time decreases. There ore, the kinetics o both distribution and elimination
appear as straight lines on a semilogarithmic plot; this is the def nition o f rst-order kinetics. Note that the hal -time or drug elimination is generally longer
than the hal -time or drug distribution. C. When drug distribution and elimination are occurring simultaneously, the decline o plasma drug concentration
with time is represented by the sum o the two processes. Note that the curve in (C) is the sum o the two f rst-order processes shown in (A) and (B). In the
schematics on the le t o the f gure, the volume in the Blood compartment represents plasma drug concentration, the volume in the Extravascular volume
compartment represents tissue drug concentration, the dropper above the Blood compartment represents absorption o drug into the systemic circulation,
and the drops below the Blood compartment represent elimination o drug by metabolism and excretion.

inducers o enzymes that mediate oxidation/reduction reac-
tions; other drugs are capable o inhibiting these enzymes
(see Table 4-3). An understanding o these drugdrug inter-
actions is an essential prerequisite to the appropriate dosing
o drug combinations.
Physicians and researchers have begun to elucidate the
important role o genetic di erences among individuals in
the various transporters and enzymes responsible or drug ab-
sorption, distribution, excretion, and especially metabolism.
For example, an individuals complement o cytochrome
P450 enzymes in the liver and their specif c genetic poly-
morphisms determine the rate and extent to which that in-
dividual can metabolize numerous therapeutic agents. This
topic is discussed in detail in Chapter 7, Pharmacogenomics.
EXCRETION
Oxidation/reduction and conjugation/hydrolysis reactions
enhance the hydrophilicity o a hydrophobic drug and its
metabolites, enabling such drugs to be excreted along a f nal
36 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

blood ow, increasing glomerular f ltration rate, and de-

1.0 creasing plasma protein binding cause a drug to be excreted
more rapidly. Renal excretion plays the primary role in the
t
n
Blood Mus cle
e
clearance o many drugs; examples include vancomycin,
m
0.8
t
r
atenolol, and ampicillin. Drugs such as these can accumulate
a
p
m
VRG to toxic levels in patients with compromised renal function
o
0.6
c
and in elderly patients (who often manifest some degree of
n
i
Adipos e renal compromise). For example, in individuals with normal
e
s
0.4
kidney unction, the typical dosing interval or vancomycin
o
d
is 12 hours. In severe kidney disease, however, therapeutic
f
o
n
0.2 levels o the drug may persist or 7 days a ter a single intra-
o
i
t
venous dose.
c
a
r
Urinary drug concentration rises in the proximal tubule
F
0.1
0.1 1.0 10 100 1000 because o passive di usion o uncharged drug molecules,
Time (minute s )
acilitated di usion o charged or uncharged molecules, and
active secretion o anionic and cationic molecules rom the
blood into the urinary space. The secretory mechanisms are
FIGURE 3-8. Four-compartment model o drug distribution. A ter adminis- generally not specif c or the drugs; rather, drug secretion
tration o an intravenous bolus, the drug is delivered to various tissues via the takes advantage o molecular similarities between the drug
systemic circulation. The raction o the administered dose is initially highest and naturally occurring substances such as organic anions
in the vascular compartment (blood), but the blood raction subsequently
(transported by OAT amily and other proteins) and cations
alls rapidly as the drug is distributed to the other tissue compartments. The
most vessel-rich tissues (i.e., the tissues that are supplied by the highest
(transported by OCT amily and other proteins). Penicillin
raction o the cardiac output) are generally the f rst to accumulate drug. is an example o a drug that is eliminated largely by ac-
However, the tissue compartments also vary in their capacity or taking tive transport in the proximal tubule. The extent o plasma
up drug. Because the mass o the muscle group is larger than that o the protein binding appears to have a relatively small e ect on
vessel-rich group (VRG), the muscle group has a larger uptake capacity. But
because the muscles are less well per used than the vessel-rich group, this
e ect is mani ested only a ter the drug has begun to distribute to the VRG.
The most poorly per used group is the adipose-rich group, but this group has P roxima l
P e ritubula r
the highest capacity to accumulate drug. The peak level o drug in the adi- ca pilla ry tubule
pose group is not as high as that in the muscle-rich group, because a signif -
cant amount o drug has been eliminated by metabolism or excretion be ore
Tubular Glomerular
the adipose group begins to accumulate drug. A ter the administration o Secretion Filtration Affe re nt
drug has been completed, the reverse pattern is seenthe drug leaves f rst a rte riole
rom the vessel-rich group and then rom the muscle and adipose groups, 2 1
respectively. This pattern emphasizes that adipose tissue can provide a sig-
nif cant reservoir o drug even a ter drug administration is discontinued. The
drug in this example is thiopental, a barbiturate that can be used to induce
general anesthesia. Drug
in blood

common pathway with drugs that are intrinsically hydro-
philic. Most drugs and drug metabolites are eliminated rom
the body through renal and biliary excretion. Renal excretion
is the most common mechanism o drug excretion, and it
relies on the hydrophilic character o a drug or metabolite.
Only a relatively small number o drugs are excreted pri-
marily in the bile or through respiratory and dermal routes.
Many orally administered drugs are incompletely absorbed
rom the upper gastrointestinal tract, and residual drug is
eliminated by ecal excretion.
Renal Excretion
Renal blood ow comprises about 25% o total systemic
blood ow, ensuring that the kidneys are continuously ex-
posed to any drug ound in the blood. The rate o drug elimi-
nation through the kidneys depends on the balance o drug
f ltration, secretion, and reabsorption rates (Fig. 3-9). The
a erent arteriole introduces both ree (unbound) drug and
plasma protein-bound drug into the glomerulus. Typically,
however, only the ree drug orm is f ltered into the renal tu-
bule. There ore, renal blood ow, glomerular f ltration rate,
and drug binding to plasma protein all a ect the amount
o drug that enters the tubule at the glomerulus. Enhancing
3
Tubular
Reabsorption
Effe re nt
4 a rte riole
Urine
FIGURE 3-9. Drug f ltration, secretion, and reabsorption in the kidney.
Drugs may be (1) f ltered at the renal glomerulus, (2) secreted into the proxi-
mal tubule, (3) reabsorbed rom the tubular lumen and transported back into
the blood, and (4) excreted in the urine. The relative balance o f ltration,
secretion, and reabsorption rates determines the kinetics o drug elimination
by the kidney. Enhancing blood ow, increasing glomerular f ltration rate,
and decreasing plasma protein binding all cause a drug to be excreted more
rapidly, because all these changes result in increased f ltration o drug at the
glomerulus. Some drugs, such as penicillin, are actively secreted into the
proximal tubule. Although reabsorption can decrease the elimination rate o
a drug, many drugs exhibit pH trapping in the distal tubule and are there ore
e f ciently excreted in the urine. For drugs that are dependent on the kidney
or elimination, compromised renal unction can result in higher plasma drug
concentrations, and the dose and requency o drug administration must be
altered accordingly.

drug secretion into the proximal tubule, because the highly
e f cient transporters that mediate active tubular secretion
rapidly remove ree (unbound) drug rom the peritubular
capillaries and thereby alter the equilibrium between ree
and protein-bound drug at these sites.
The urinary concentration o a drug may all as the drug
is reabsorbed in the proximal and distal tubules. Reabsorp-
tion is limited primarily by pH trapping, as described above.
The renal tubular uid is typically acidic in and beyond the
proximal tubule, which tends to avor trapping o the ionic
orm o weak bases. Because this region o the tubule con-
tains transporter proteins that are di erent rom those in
preceding segments o the nephron, ionic drug orms resist
acilitated di usional reabsorption, and their excretion is
thereby enhanced. Drug reabsorption in the tubule can be
enhanced or inhibited by chemical adjustment o the urinary
pH. Changing the rate o urine ow through the tubules can
also modi y the rate o drug reabsorption. An increased rate
o urine output tends to dilute the drug concentration in the
tubule and to decrease the amount o time during which a-
cilitated di usion can occur; both o these e ects tend to de-
crease drug reabsorption. For example, aspirin is a weak acid
that is excreted by the kidney. Aspirin overdose is treated
by administering sodium bicarbonate to alkalinize the urine
(and thus trap aspirin in the tubule) and by increasing the
urine ow rate (and thus dilute the tubular concentration o
the drug). Both o these clinical maneuvers result in aster
elimination o the drug.
Biliary Excretion
Drug reabsorption also plays an important role in biliary
excretion. Some drugs are secreted rom the liver into the
bile by members o the ATP binding cassette (ABC) super am-
ily o transporters, which includes seven amilies o proteins
such as the multidrug resistance (MDR) amily. Because the
bile duct enters the gastrointestinal tract in the duodenum,
such drugs must pass through the length o the small and
large intestine be ore being eliminated. In many cases, these
drugs undergo enterohepatic circulation, in which they are
reabsorbed in the small intestine and subsequently retained
in the portal and then the systemic circulation. Drugs such
as steroid hormones, digoxin, and some cancer chemothera-
peutic agents are largely excreted in the bile.
CLINICAL APPLICATIONS OF
PHARMACOKINETICS
The dynamic interactions among drug absorption, distribu-
tion, metabolism, and excretion determine the plasma con-
centration o a drug and dictate the ability o the drug to
reach its target organ in an e ective concentration. O ten,
the desired duration o drug therapy exceeds that achievable
by a single dose, and multiple doses are needed to provide a
relatively constant plasma concentration o drug within the
limits o e f cacy and toxicity. The results o clinical trials
o drugs under development, as well as clinical experience
using US Food and Drug Administration (FDA)-approved
drugs, suggest standard doses o a drug in the average patient.
However, pharmacokinetic and other di erences among pa-
tients (such as disease status and pharmacogenomic prof le)
must also be considered in designing a dosing regimen or a
drug or drug combination in the individual patient.
C h a p t e r 3 Pharmacokinetics 37
Clearance
The clearance o a drug is the pharmacokinetic parameter
that most signif cantly limits the time course o action o the
drug at its molecular, cellular, and organ targets. Clearance
can be conceptualized in two complementary ways. First, it
is def ned as the rate o elimination o the drug rom the
body relative to the concentration o the drug in plasma.
Alternatively, clearance is the rate at which plasma would
have to be cleared o the drug to account or the observed
kinetics o change o the total amount o drug in the body,
assuming that all the drug in the body is present at the same
concentration as that in the plasma. There ore, clearance is
expressed in units o volume/time, as ollows:
Metabolism Excretion
Clearance Equation 3-5
[Drug]plasma
where metabolism and excretion are expressed as rates
(amount/time).
Although metabolism and excretion are distinct physio-
logic processes, the pharmacologic endpoint is equivalent
a reduction in circulating levels o active drug. As such,
metabolism and excretion are o ten re erred to collectively
as clearance mechanisms, and the principles o clearance
can be applied to both:
Clearancetotal Clearancerenal Clearancehepatic
ClearanceOther Equation 3-6
Metabolism and Excretion Kinetics
The rate o drug metabolism and excretion by an organ is
limited by the rate o blood ow to that organ. The majority
o drugs demonstrate f rst-order kinetics when used in stan-
dard therapeutic doses; that is, the amount o drug that is
metabolized or excreted in a given unit o time is directly
proportional to the concentration o drug in the systemic
circulation at that time. Because the clearance mechanisms
or most drugs are not saturated under ordinary circum-
stances, increases in plasma drug concentration are matched
by increases in the rate o drug metabolism and excretion
(see Equation 3-5). The f rst-order elimination rate (where
elimination includes both metabolism and excretion) ollows
Michaelis-Menten kinetics:
Vmax C
E Equation 3-7
Km C
where Vmax is the maximum rate o drug elimination, Km is
the drug concentration at which the rate o elimination is
Vmax, C is the concentration o drug in the plasma, and
E is the elimination rate (Fig. 3-10). Because elimination
is usually a f rst-order process, a semilogarithmic plot o
plasma drug concentration versus time typically shows a
straight line during the elimination phase (see Fig. 3-6).
A small number o drugs (e.g., phenytoin and ethanol)
demonstrate saturation kinetics , in which the clearance
mechanisms become saturated at or near the therapeutic con-
centration o the drug. Once saturation occurs, the clearance
rate ails to increase with increasing plasma drug concen-
trations (zero-order kinetics ). This can result in dangerously
elevated plasma concentrations o the drug, which can cause
toxic (or even lethal) e ects.
38 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

where Vd is the volume o distribution and 0.693 is an

approximation o ln 2.
Thus, all o the actors outlined above that a ect the
volume o distribution and clearance o a drug also a ect the
Vma x hal -li e o the drug. A decrease in drug clearance or increase
e
t
in volume o distribution tends to prolong the elimination
a
r
hal -li e and thereby enhance the e ect o the drug on the
n
o
target organ. The hal -li e must be care ully considered in
i
t
a
n
designing any dosing regimen, as the e ects rom a drug
i
m
with a long hal -li e may last or a number o days. For ex-
i
Vma x
l
e
ample, the hal -li e o chloroquine is more than 1 week and
g
2
u
that o amiodarone is more than 1 month.
r
D
Factors Altering Half-Life
Physiologic and pathologic changes in the volume o distri-
Km
bution must be considered when determining the appropriate
drug dose and dosing interval (Table 3-5). As patients age,
P la s ma drug conce ntra tion
their skeletal muscle mass decreases, which could decrease
the volume o distribution. In contrast, an obese person has
FIGURE 3-10. Michaelis-Menten kinetics. Drug elimination typically an increase in the capacity or drug uptake by adipose tissue,
ollows Michaelis-Menten (f rst-order) kinetics. The rate o drug elimination and a drug that distributes into at may need to be given in a
increases as the plasma drug concentration increases, until the elimination higher dose in order to reach therapeutic plasma drug levels.
mechanisms become saturated and reach a maximal elimination rate (Vmax)
As a third example, i drug dosing is based on total body
at high plasma concentrations. The Michaelis-Menten constant, Km, is the
drug concentration at which the drug elimination rate is Vmax.
weight but the adipose group does not take up the drug, then
potentially toxic drug levels could be reached in an obese
individual. Finally, some drugs may partition pre erentially
into pathologic uid spaces such as ascites or a pleural
e usion, causing long-term toxicity i the drug dosage is not
The extent to which an organ contributes to drug clear-
adjusted accordingly.
ance is quantif ed by its extraction ratio, which compares the
Physiologic and pathologic processes may also a ect
drug levels in plasma immediately be ore entering and just
drug clearance. For example, the cytochrome P450 enzymes
a ter exiting the organ:
responsible or drug metabolism in the liver can be induced,
Cin Cout increasing the rate o drug inactivation, or inhibited, decreas-
Extraction Equation 3-8
Cin ing the rate o drug inactivation. Specif c P450 enzymes are
induced by some drugs (such as carbamazepine , phenytoin,
where C is the concentration. An organ that contributes prednisone , and rifampin) and inhibited by others (such as
substantially to drug clearance is expected to have a higher
extraction ratio (closer to 1) than an organ that does not par-
ticipate substantially in drug clearance (closer to zero). For
example, the liver extraction ratio is high or drugs that have TABLE 3-5 Factors Affecting Drug Half-Life
substantial f rst-pass metabolism.
FACTORS AFFECTING MOST COMMON
HALF-LIFE EFFECT ON HALF-LIFE
Half-Life
By decreasing the concentration o active drug in the blood, Effects on Volume of Distribution
drug metabolism and excretion shorten the time during
Aging (decreased muscle mass Decreased
which a drug is capable o acting on a target organ. The decreased distribution)
elimination half-life o a drug is def ned as the amount
of time over which the drug concentration in the plasma Obesity (increased adipose mass Increased
decreases to one-half of its original value. Knowledge o increased distribution)
a drugs elimination hal -li e allows the clinician to es-
Pathologic uid (increased distribution) Increased
timate the requency o dosing required to maintain the
plasma concentration o the drug in the therapeutic range Effects on Clearance
(see below). There are many potentially con ounding ac-
tors in any clinical situation, and it is use ul to consider here Cytochrome P450 induction (increased Decreased
the simplest o cases. Because most drugs are eliminated metabolism)
by f rst-order kinetics, the body can o ten be modeled as a Cytochrome P450 inhibition (decreased Increased
single compartment with a volume that is equivalent to the metabolism)
volume o distribution. In this model, the elimination hal -
li e (t1/2) depends only on the volume o distribution and Cardiac ailure (decreased clearance) Increased
clearance o the drug:
Hepatic ailure (decreased clearance) Increased
0.693 Vd
t1/2 Equation 3-9 Renal ailure (decreased clearance) Increased
Clearance
 C h a p t e r 3 Pharmacokinetics 39

cimetidine , ciprof oxacin, diltiazem, and f uoxetine ); see
Table 4-3 or a list o notable inducers and inhibitors o spe-
cif c enzymes. Organ ailure is another critical actor in de-
termining appropriate dosing regimens. Hepatic ailure may
both alter liver enzyme unction and decrease biliary excre-
tion. Decreased cardiac output reduces the amount o blood
that reaches clearance organs. Renal ailure decreases drug
excretion because o decreased drug f ltration and secretion
into the renal tubules. In summary, hepatic, cardiac, and
renal ailure can each lead to a decreased ability to inacti-
vate or eliminate a drug and thereby increase the elimina-
tion hal -li e o the drug.
Therapeutic Dosing and Frequency
The basic principles o pharmacokineticsabsorption, dis-
tribution, metabolism, and excretioninf uence the design
o an optimal dosing regimen or a drug. Absorption deter-
mines the potential route(s) o administration and helps to
determine optimal drug dose. For two drugs with the same
potency, the more highly absorbed drugas evidenced by
a higher bioavailabilitygenerally requires a lower dose
than the more poorly absorbed drug. In contrast, a more
highly distributed drugas evidenced by a higher volume o
distributiongenerally necessitates higher drug dosing. The
elimination rate o a drug in uences its hal -li e and thereby
determines the requency o dosing required to maintain
therapeutic plasma drug levels.
In general, therapeutic dosing o a drug seeks to main-
tain the peak (highest) plasma drug concentration below the
toxic concentration and the trough (lowest) drug concen-
tration above the minimally e ective level (Fig. 3-11). This
can be accomplished most e f ciently using continuous drug
delivery by intravenous (continuous in usion), subcutane-
ous (continuous pump or implant), transcutaneous (dermal
patch), oral (sustained-release tablet), and other routes o
administration, as described in more detail in Chapter 55. In
many cases, however, the dosing regimen must also consider

A Therapeutic Dosing B Therapeutic Dosing with Loading Dose

n
n
Toxic ra nge Toxic ra nge
o
o
2.0
i
i
2.0
t
t
a
a
r
r
t
t
n
n
e
e
1.5 1.5
c
c
n
n
o
o
c
c
1.0 1.0
g
g
The ra pe utic ra nge The ra pe utic ra nge
u
u
r
r
d
d
a
a
0.5 0.5
m
m
s
s
a
a
S ubthe ra pe utic ra nge S ubthe ra pe utic ra nge
l
l
P
P
0 0
0 3 6 9 12 0 3 6 9 12

1s t dos e Da ys 1s t dos e Da ys

C Toxic Dosing D Subtherapeutic Dosing

n
n
Toxic ra nge
o
o
Toxic ra nge
i
i
2.8 2.0
t
t
a
a
r
r
t
t
n
n
e
e
2.1 1.5
c
c
n
n
o
o
c
c
The ra pe utic ra nge
g
g
1.4 1.0
u
u
r
r
d
d
The ra pe utic ra nge
a
a
0.7 0.5
m
m
s
s
a
a
S ubthe ra pe utic ra nge S ubthe ra pe utic ra nge
l
l
P
P
0
0 3 6 9 12 0
0 3 6 9 12

1s t dos e Da ys 1s t dos e Da ys

FIGURE 3-11. Therapeutic, subtherapeutic, and toxic drug dosing. From a clinical perspective, drug concentrations in plasma can be divided into sub-
therapeutic, therapeutic, and supratherapeutic or toxic ranges. The goal o most drug-dosing regimens is to maintain the drug at concentrations within the
therapeutic range (re erred to as the therapeutic window). A. The f rst several doses o a drug are typically subtherapeutic as the drug equilibrates to its
steady-state concentration (approximately our elimination hal -lives are required to achieve steady state). Appropriate drug dosing and dosing requency
result in steady-state drug levels that are therapeutic, and the maximal and minimal concentrations o the drug remain within the therapeutic window.
B. I the initial (loading) dose is larger than the maintenance dose, the drug reaches therapeutic concentrations more rapidly. The magnitude o the loading
dose is determined by the volume o distribution o the drug. C. Excessive maintenance doses or dosing requency result in drug accumulation and toxicity.
D. Insu f cient maintenance doses or dosing requency result in subtherapeutic steady-state drug concentrations. In all our panels, the drug is administered
once daily, distributed very rapidly to the various body compartments, and eliminated with f rst-order kinetics.
40 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

drug concentration increases, because the elimination rate is

Continuous infus ion
proportional to the plasma drug concentration. Steady state is
Infre que nt la rge dos e s
reached when the two rates (kin and kout) are equal. Because kin
Fre que nt s ma ll dos e s
is a constant, the approach to steady state is governed by kout,
The ra pe utic ra nge the composite rate for all drug clearance mechanisms. (kout
)
L
/
8 can also be called ke, the composite rate or drug elimination.)
g
m
In most dosing regimens, drug levels accumulate a ter each
(
n
successive dose, and the steady state is reached only when
o
i
t
6 the amount o drug entering the system is equal to the amount
a
r
t
being removed rom the system (see Fig. 3-11). Clinically,
n
e
this principle must be remembered when the dosing regimen
c
n
4
o
is altered, because approximately our elimination hal -lives
c
g
must pass be ore the new steady state is reached.
u
r
The concept o context-sensitive half-life describes the
d
2
a
dynamic hal -li e o elimination o drug rom its target site
m
rom the beginning o dosing to the time at which steady
s
a
l
state is reached. This concept is important clinically, particu-
P
0
0 larly or continuous in usions o drugs such as opioid an-
Time
algesics or intravenous anesthetics such as propo ol. O ten,
FIGURE 3-12. Fluctuations in steady-state drug concentration depend on these drugs are administered as continuous in usions or pe-
dosing frequency. The same average steady-state plasma drug concen- riods o time that are insu f ciently long to reach steady state.
tration can be achieved using a variety o di erent drug doses and dosing In these cases, the hal -li e o elimination o drug rom a tar-
intervals. In the example shown, the same total amount o a drug is adminis- get site depends on the duration o drug administration. This
tered by three di erent dosing regimens: continuous in usion, requent small concept can be used clinically to predict (1) the response
doses, and in requent large doses. The smooth curve represents the e ect o patients to drugs that are not at steady state and (2) the
o a continuous in usion o drug. Discontinuous dosing results in uctua- amount o time required or the drug e ects to clear a ter
tions above and below the continuous-in usion curve. Note that all three discontinuation o the drug in usion.
dosing regimens have the same time-averaged plasma drug concentra- The steady-state plasma drug concentration can be al-
tion at steady state (4 mg/L) and the same area under the curve, but the
tered by the addition o a new drug to a patients treatment
discontinuous regimens result in peaks and troughs above and below the
target drug concentration. I these peaks and troughs all above or below regimen. In the case o Mr. W, the addition o trimethoprim-
the boundaries o the therapeutic window (as in the in requent large-dose sul amethoxazole inhibited the metabolism o war arin, de-
regimen), then clinical outcome can be adversely a ected. For this reason, creasing the clearance rate o the latter drug and causing its
requent small-dose regimens are generally more e f cacious and better tol- steady-state concentration to reach supratherapeutic levels.
erated than in requent large-dose regimens. However, this concern must be This e ect was exacerbated by Mr. Ws acute intoxication
balanced against the convenience o (and improved patient adherence with) with ethanol, which also inhibited war arin metabolism. As-
less requent (e.g., once daily) dosing regimens. suming that Mr. Ws weight is approximately 70 kg, he is
taking 5 mg o war arin every 24 hours, and the bioavail-
ability o war arin is 0.93, then his initial steady-state plasma
patient convenience. Frequent small doses (usually oral) can war arin concentration can be calculated as ollows:
be administered to achieve minimal variation in steady-state
plasma drug concentration, but this strategy subjects the pa- 0.93 5 mg
Csteady state 1.01 mg/L
tient to the inconvenience o requent drug administration. 24 h 0.192 L/ h
Less requent dosing requires the use o higher doses and
leads to greater uctuations in peak and trough drug levels; where the clearance value o 0.192 L/hour is determined
this type o regimen is more convenient or the patient but rom the hal -li e and volume o distribution o the drug (see
also more likely to cause problems due to excessive (toxic) Equations 3-9 and 3-10). When his war arin clearance was
or insu f cient (subtherapeutic) drug levels (Fig. 3-12). decreased by the addition o trimethoprim-sul amethoxazole
Optimal dosing regimens typically maintain the steady- and ethanol, the steady-state plasma concentration o war a-
state plasma drug concentration within the therapeutic win- rin increased to toxic levels. This situation could have been
dow or that drug. Because steady state is reached when the avoided by measuring Mr. Ws INR several days a ter the ad-
rate o drug input is equal to its output, the steady-state drug dition o trimethoprim-sul amethoxazole (and adjusting his
concentration is a ected by drug bioavailability, clearance, war arin dose, i necessary) and by cautioning him to temper
dose, and dosing interval (the requency o administration): his alcohol consumption while taking war arin (one to two
drinks on an occasional basis).
Bioavailability Dose
Csteady state Equation 3-10
Intervaldosing Clearance Loading Dose
A ter administration o a drug by any route, the plasma con-
where C is the plasma concentration o the drug. centration o the drug initially increases. Distribution o drug
Immediately a ter the initiation o drug therapy, the rate o rom the vascular (blood) compartment to body tissues then
drug entry into the body (kin) is much greater than the elimina- causes the plasma drug concentration to decrease. The rate
tion rate (kout); there ore, the drug concentration in the blood and extent o this decrease are signif cant or drugs with high
increases. Assuming that elimination ollows f rst-order ki- volumes o distribution. I the administered dose o drug
netics, the rate o elimination also increases as the plasma ails to take account o the volume o distribution, instead
 C h a p t e r 3 Pharmacokinetics 41

accounting only or the blood volume, then therapeutic drug

levels will not be reached promptly. Initial (loading) doses o Toxic ra nge
drug are o ten administered to compensate or drug distribu-

n
o
i
tion into the tissues. Such doses may be much higher than

t
a
r
would be required i the drug were retained in the vascular

t
n
e
compartment. Loading doses may be used to achieve thera- The ra pe utic ra nge

c
n
peutic levels o drug (i.e., levels at the desired steady-state

o
c
concentration) with only one or two doses o drug:

g
u
r
d
Doseloading Vd Csteady state Equation 3-11

a
m
s
where Vd is the volume o distribution and C is the desired

steady-state plasma concentration o the drug.
In the absence o a loading dose, approximately our
elimination hal -lives are required or the tissue distribution
and plasma concentration o a drug to reach steady state.
Use o a loading dose circumvents this process by providing
a su f cient amount o drug to attain an appropriate (thera-
peutic) drug concentration in the blood and tissues a ter only
one or two doses o drug. For example, lidocaine has a vol-
ume o distribution o 77 L in a 70-kg person. Assuming that
a steady-state plasma concentration o 3.5 mg/L is needed to
control ventricular arrhythmias, the appropriate loading dose
o lidocaine in this person can be calculated as:
Doseloading 77 L 3.5 mg/ L 269.5 mg
a
l
P
S ubthe ra pe utic ra nge
Time
FIGURE 3-13. Saturation kinetics and drug toxicity. Drug elimination
typically ollows f rst-order Michaelis-Menten kinetics, increasing as the
plasma drug concentration increases. At optimal dosing, the steady-state
plasma drug concentration remains within the therapeutic range (bottom
curve). However, excessive drug dosing may saturate the bodys capacity to
eliminate the drug, or example, by overwhelming the hepatic cytochrome
P450 enzyme system (top curve). In this case, the elimination rate o the
drug does not increase with increasing plasma drug concentration (i.e.,
elimination ollows zero-order rather than f rst-order kinetics). Continued
administration o the drug results in drug accumulation, and the plasma drug
concentration may reach toxic levels.

Maintenance Dose
Once steady-state drug concentrations are achieved in the
plasma and the tissues, subsequent doses need to replace
only the amount o drug that is lost through metabolism and CONCLUSION AND FUTURE
excretion. The maintenance dose rate o a drug is depen- DIRECTIONS
dent on the drug clearance, according to the principle that This chapter has provided an overview o the pharmacoki-
rate in rate out at steady state: netic processes o absorption, distribution, metabolism, and
Dosemaintenance Clearance Csteady state Equation 3-12 excretion (ADME). An understanding o the actors that de-
termine a drugs ability to act in an individual patient and the
Administration o a dose rate greater than the calculated changing nature o these actors over time is vitally impor-
maintenance dose rate would provide a drug input greater tant to the sa e and e f cacious use o drug therapy. The key
than the drug clearance, and the drug could accumulate to equations governing the relationships among dosing, clear-
toxic levels within the tissues. In Mr. W, the calculated main- ance, and plasma drug concentration (Table 3-6) are impor-
tenance dose or war arin is: tant to consider when making therapeutic decisions about
drug regimens.
Dosemaintenance 0.192 L /h 1.01 mg/ L
0.194 mg/h 4.65 mg/day
TABLE 3-6 Summary of Key Pharmacokinetic
The appropriate maintenance dose or Mr. W is there ore Relationships
4.65 mg/day. Because war arin is only 93% bioavailable,
Mr. W should take 5 mg/day to maintain an adequate steady- Loading dose
state plasma concentration. (Note also that, because war arin Initial concentration =
Volume of
has a low therapeutic index and toxic levels o the drug can distribution
lead to potentially atal hemorrhage, the biological activity
o war arin should be monitored care ully by periodic mea-
surement o the INR.) Fraction absorbed
For a small number o drugs, the bodys capacity to Maintenance dose
Steady-state concentration =
eliminate the drug (e.g., through hepatic metabolism) may Dosing interval
become saturated at therapeutic or only slightly suprathera- Clearance
peutic plasma drug concentrations. In these cases, the ki-
netics o drug elimination may change rom f rst-order to
0.693 Volume
zero-order (also called saturation kinetics ; see above). Con- of distribution
tinued administration o drug results in rapid drug accumula- Elimination half -life =
tion in the plasma, and drug concentrations may reach toxic Clearance
levels (Fig. 3-13).
42 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
At present, the clinical applicability o pharmacokinetics
is mainly based on drug e ects that have been observed in
a population o individuals. There are nearly inf nite major
and minor variations among individuals, however, and these
variations in uence the e ects o drug therapy. For example,
clear di erences in pharmacokinetics are present among
persons o di erent ages, genders, body mass, f tness levels,
ethnicities, genomic makeup, and disease states. For some
drugs, advances in therapeutic drug monitoring have enabled
the real-time determination o plasma drug concentrations.
A more extraordinary revolution in pharmacokinetics is o -
ered by pharmacogenomics . Future drug therapy may in-
volve the administration o drugs that have been engineered
specif cally or the patient who is receiving them. Knowl-
edge o a patients genomic makeup could enable drug thera-
pies to exploit strengths and compensate or weaknesses in a
host o patient-specif c variables. For example, genetic tests
or variants o the P450 enzymes that metabolize war arin
are now available, and clinical trials are underway to study
whether pharmacogenetic testing can better predict dosing
requirements to maintain therapeutic levels o this drug. This
topic is discussed in Chapter 7.
Finally, it should be noted that the use o proteins and
other macromolecules as drugs presents unique pharmaco-
kinetic opportunities and challenges compared to the use o
small molecules as drugs. Some o the challenges include
protein absorption and stability, protein distribution to sites
o therapeutic action, and protein clearance by enzymatic
degradation and other mechanisms. The study o the mech-
anisms involved in determining the pharmacokinetics o
protein therapeutics is in its in ancy compared to the consid-
erable knowledge that exists regarding the pharmacokinetics
o small molecules and provides opportunities or discovery
and optimization o macromolecular therapies. This topic is
discussed in more detail in Chapter 54, Protein Therapeutics.
Acknowledgment
We thank John C. LaMattina or his valuable contributions
to this chapter in the First and Second Editions o Princi-
ples o Pharmacology: The Pathophysiologic Basis o Drug
Therapy.
Suggested Reading
Ezan E. Pharmacokinetic studies o protein drugs: past, present and uture.
Adv Drug Deliv Rev 2013;65:10651073. (Overview o the opportunities
and challenges presented by the pharmacokinetics o protein therapeutics.)
Godin DV. Pharmacokinetics: disposition and metabolism o drugs. In:
Munson PL, ed. Principles o pharmacology. New York: Chapman & Hall;
1995. (A solid introductory text, this chapter illustrates the various aspects
o pharmacokinetics with many examples o specif c drugs.)
Hediger MA, Clmenon B, Burrier RE, Bru ord EA. The ABCs o mem-
brane transporters in health and disease (SLC series): introduction. Mol As-
pects Med 2013;34:95107. (Reviews and introduces a special issue on the
52 amilies o proteins in the human solute carrier super amily.)
Klaasen CD, Aleksunes LM. Xenobiotic, bile acid, and cholesterol trans-
porters: unction and regulation. Pharmacol Rev 2010;62:196. (Reviews
the unction, regulation, and substrates o ABC-super amily, SLC-super-
amily, and other transporters that mediate the cellular uptake and e ux o
drugs and other molecules.)
Pratt WB, Taylor P, eds. Principles o drug action: the basis o pharmacol-
ogy. 3rd ed. New York: Churchill Livingstone; 1990, Chapters 3 and 4. (This
text provides a comprehensive treatment o pharmacokinetics and pharma-
cokinetic principles.)
Rees DC, Johnson E, Lewinson O. ABC transporters: the power to change.
Nat Rev Mol Cell Biol 2009;10:218227. (Reviews the molecular mecha-
nisms o ABC-super amily transporters.)
 H2 O
O2 -
1
4
5 -Fe 3+
P 4 50

(paa re
(p re nt
R -H
n t dr
H
drug
ug))
ug ( xi
(o xidi
R-OH
R- O
d iizz e d d rug
g) 4
Drug Metabolism
R-OH H H
B F. Pe t e r Gu e n g e rich
(oxiidiz
diz e d d rug
g) 0 R-H (pa re nt drug))
H2 O

H2 O
Fe 3+ H2 O
INTRODUCTION ON & CA
CASE
CAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
CAS 4 44 44 INDIVIDUA
NDIVID
VID
IDUAL L FAC
FACT
FA
ACCTORS
C AFFE ECT
CTIN ING DRUG METABOLISM. . . . . . 50
6
T0E OF DRUG
SITES RUG
UG METTA
ABOLISM LISM. . . . . . . . . . . . . . . . . . . . He . . . me
. . . . . . 43 1 PPharmacogenomics
macog . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
PATHWAYS
ATT OFR-
O RDRUG
R-HH ME
RUG META T BOLISM . . . . . . . . . . . . . . . . . . . . . . . 44 hnn y . . . . . . . . . . . R-H
Race and Ethnicity
thn R. . .H. . . . . . . . . . . . . . . . . . . . . . . 533
R-
Oxidatio
Oxidati ion/Reduction
Reductio Rea eact ctio
ionns . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Agee a nd
n Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 5
3
3+
FConju
Fe + Diet and Enviro
iron F 33+
onnnment
mFe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
juugati
tion/Hydrolysis Reac actit ons . . . . . . . . . . . . . . . . . . . . . . . 47
Metabolic Drug ug Interact
Interacti
Interactio i ns . . . . . . . . . . . . . .Flavoprote
tions . . . . . .p. . . .t . .in. . 53 ADP +
NA
Dru
D rugg Transport . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Induction and Inhibhibit
itio
ionn. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Diseases Affecting Drug Metabolism
M . . . . . . . . ((re
. .e. .duce
. . . . .d)
. ). . . 54
54
H2 O Active and Toxic Metabolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 CONCLUSION AND FUTURE DIRECTIONS D CTIOe -S . . . . . . . . . . . . . . . . . . 544
Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544
5
2 Flavoprote in NADP H
2H+ i(on
on/h
xidi
/hidiz
yddzroly
reoly
dl ) to
d)
INTRODUCTION
NT
T
0-
we use oxidation/reductionn and conjugation/hydrolysis n/hydr
describe
desc
de scri
ribe
be tthese
hese
hese pprocesses
roce
rocess
sses
es m
more
oree ac
oor accurately.
accu
cura
rattelly. Th
The chapt
chapter
h ter con-
Our
Ou tissuesues are exposed on a daily basis to xenobiotics cludes with a discussion o th tthe actors
ctors
ors that
tthaa can lead to di er-
or
oreign
orei R
bsttHaanc
ign ssubstances
nces
c tthat
hatt are nott nat
naturally
t rall
ll oound
ndd iinn tthe
he bbody.
odd ences iin ddrug metabolism R-H
b li among iindividuals.
di iidd l
Most drugs are xenobiotics that are used to modulate bodily
unctions or therapeutic ends. Drugs and other environmen- SITES OF DRUG METABOLISM
tal chemicals that enter the body are modif ed by a vast array
o enzymes. The biochemical trans ormations per ormed by The liver is the main organ o drug metabolism. This act
these enzymes can alter the compound to render it benef - f gures prominently in the phenomenon known as the f rst-
cial, harm ul, or simply ine ective. The processes by which pass e ect. Orally administered drugs are o ten absorbed
biochemical reactions alter drugs within the body are collec- in the gastrointestinal (GI) tract and transported directly to
tively called drug metabolism or drug biotrans ormation. the liver via the portal circulation (Fig. 4-1). In this manner,
The previous chapter introduced the importance o renal the liver has the opportunity to metabolize drugs be ore they
clearance in the pharmacokinetics o drugs. Although the reach the systemic circulation and, there ore, be ore they
biochemical reactions that alter drugs to renally excretable reach their target organs. The f rst-pass e ect must be taken
orms are an essential part o drug metabolism, drug me- into account when designing dosing regimens because, i
tabolism encompasses more than this one unction. Drug hepatic metabolism is extensive, the amount o drug that
biotrans ormation can alter drugs in our important ways: reaches the target tissue is much less than the amount (dose)
that is administered orally (see Chapter 3, Pharmacokinet-
An active drug may be converted to an inactive drug.
ics). Certain drugs are inactivated so e f ciently upon their
An active drug may be converted to an active or toxic
f rst pass through the liver that they cannot be administered
metabolite.
orally and must be given parenterally. One such drug is the
An inactive prodrug may be converted to an active drug.
antiarrhythmic lidocaine, which has a bioavailability o only
An unexcretable drug may be converted to an excretable
3% when taken orally (see Chapter 12, Local Anesthetic
metabolite (e.g., to enhance renal or biliary clearance).
Pharmacology).
This chapter presents the major processes o drug metab- Although the liver is quantitatively the most important
olism. Following the case is an overview o the sites o drug organ in metabolizing drugs, every tissue in the body is ca-
metabolism, ocusing principally on the liver. The two major pable o drug metabolism to some degree. Particularly active
types o biotrans ormation are then discussed; these are o ten sites include the skin, the lungs, the gastrointestinal tract,
termed phase I and phase II reactions , although the terminol- and the kidneys. The gastrointestinal tract deserves special
ogy is imprecise and it incorrectly implies a temporal order mention because this organ, like the liver, can contribute
o the reactions. (In addition, phase III is sometimes used to the f rst-pass e ect by metabolizing orally administered
to describe the process o drug transport.) In this chapter, drugs be ore they reach the systemic circulation.

43
44 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Ms . B is a 32-ye a r-old Ca u ca s ia n w om a n
w h o co m p la in s o s o re th ro a t a n d d i -
f cu lty s wa llo w in g o r th e p a s t 5 d a ys .
Ph ys ica l e xa m in a tio n re ve a ls cre a m y
w h ite le s io n s o n th e to n g u e th a t a re
id e n tif e d a s o ra l th ru s h , a u n ga l in e ctio n . He r h is -
to ry in clu d e s s e xu a l a ctivity w ith m u ltip le p a rtn e rs ,
in co n s is te n t u s e o co n d o m s , a n d co n tin u o u s u s e
o o ra l co n tra ce p tive s o r th e p a s t 14 ye a rs . Th e p re -
s e n ta tio n s u g g e s ts a d ia g n o s is o HIV-1 in e ctio n ,
w h ich is co n f rm e d b y p o lym e ra s e ch a in re a ctio n
(PCR) a n a lys is . Ms . B h a s a lo w CD4 T-ce ll co u n t
a n d is im m e d ia te ly s ta rte d o n a s ta n d a rd a n ti-HIV
re g im e n th a t in clu d e s th e p ro te a s e in h ib ito r s a q u i-
n a vir. He r o ra l th ru s h re s o lve s w ith a to p ica l a n ti-
u n ga l a g e n t. De s p ite a g g re s s ive th e ra p y, h e r CD4
ce ll co u n t co n tin u e s to d e cre a s e , a n d s h e p re s e n ts
PO
S ubcuta ne ous
Tra ns de rma l
GI IV
P orta l ve in Conta ins
firs t-pa s s
Live r me ta bolite s
S ys te mic circula tion
Othe r
orga ns
to h e r p hys icia n s e ve ra l m o n th s la te r w ith a tig u e
a n d a p e rs is te n t co u g h . Fu rth e r inve s tiga tio n le a d s
to a d ia g n o s is o tu b e rcu lo s is .
Questions
1 . One o the f rst-line drugs in the treatment o tubercu-
losis is ri ampin, which decreases the e ectiveness o
HIV protease inhibitors. What is the mechanism o this
drugdrug interaction?
2 . Isoniazid is another drug commonly used in the treat-
ment o tuberculosis. Why does Ms. Bs ethnic back-
ground give her physician reason or concern when
considering the use o this drug?
3 . What dietary interactions should be taken into consid-
eration when prescribing medications to treat Ms. Bs
HIV in ection?
PATHWAYS OF DRUG METABOLISM
Drugs and other xenobiotics undergo biotrans ormation be-
ore excretion rom the body. Many pharmaceuticals are li-
pophilic, enabling the drug to di use across cell membranes,
such as those o the intestinal mucosa or o the target tissue.
Un ortunately, the same chemical property that enhances
bioavailability o drugs may also make renal excretion di -
f cult, because clearance by the kidney requires that these
drugs be made more hydrophilic so that they can dissolve in
the aqueous urine. Thus, biotrans ormation reactions o ten
enhance the hydrophilicity o compounds to render them
more susceptible to renal excretion.
Biotrans ormation reactions have been classically di-
vided into two main types: oxidation/reduction (phase I) and
conjugation/hydrolysis (phase II). Oxidation reactions typi-
cally trans orm the drug into more hydrophilic metabolites
by adding or exposing polar unctional groups such as hy-
droxyl (-OH) or amine (-NH2) groups (Table 4-1). Such me-
tabolites are o ten pharmacologically inactive and, without
urther modif cation, may be excreted. Some products o
oxidation and reduction reactions, however, require urther
modif cations prior to excretion. Conjugation (phase II) reac-
tions modi y compounds through attachment o hydrophilic
groups, such as glucuronic acid, to create more polar conju-
gates (Table 4-2). It is important to note that these conjugation
reactions occur independently o oxidation/reduction reac-
tions, and the enzymes involved in oxidation/reduction and
conjugation/hydrolysis reactions o ten compete or substrates.
FIGURE 4-1. Portal circulation and the f rst-pass e ect. Drugs adminis-
tered by mouth (per os, or PO) are absorbed in the GI tract and then de-
livered, via the portal vein, to the liver. This pathway allows the liver to
metabolize drugs be ore they reach the systemic circulation, a process
responsible or the f rst-pass e ect. In contrast, drugs that are adminis-
tered intravenously (IV), transdermally, or subcutaneously enter the sys-
temic circulation directly and can reach their target organs be ore hepatic
modif cation. The f rst-pass e ect has important implications or bioavail-
ability; the oral ormulation o a drug that undergoes extensive f rst-pass
metabolism must be administered in a much larger dose than the equivalent
IV ormulation o the same drug.
 C h a p t e r 4 Drug Metabolism 45

TABLE 4-1 Oxidation and Reduction Reactions

REACTION CLASS STRUCTURAL FORMULA REPRESENTATIVE DRUGS

I. Cytochrome P450-Dependent Oxidations

1. Aliphatic Hydroxylation OH Barbiturates
Digitoxin
R Cyclosporine
R
OH
R
O

2. Aromatic Hydroxylation HO Propranolol

Phenytoin
R R

3. N-Dealkylation O Methamphetamine
R1 + Lidocaine
N R2 R1
H NH2 H R2

4. O-Dealkylation O Codeine
O R2 OH +
R R H R2

5. S-Oxidation O Phenothiazine
Cimetidine
S S
R1 R2 R1 R2

6. N-Oxidation H Quinidine
NH2 N
R R OH

7. Desulfuration S O Thiopental

R1 R2 R1 R2

8. Epoxide Formation O Carbamazepine

R1
R2 R1 R2

II. Cytochrome P450-Independent Oxidations

1. Alcohol Dehydrogenation/ O O Ethanol
Aldehyde Dehydrogenation Pyridoxine
R OH
R H R OH

2. Oxidative Deamination O Histamine

+ NH3 Norepinephrine
R NH2
R H

3. Decarboxylation OH Levodopa
R R OH
+ CO 2
O

III. Reductions
1. Nitro Reduction O2N H2 N Nitrofurantoin
R Chloramphenicol
R

2. Dehalogenation R X R H Halothane
Chloramphenicol

3. Carbonyl Reduction O OH Methadone

Naloxone
R1 R2 R1 R2
46 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

TABLE 4-2 Hydrolysis and Conjugation Reactions

REACTION CLASS STRUCTURAL FORMULA REPRESENTATIVE DRUGS

I. Hydrolysis
1. Ester Hydrolysis O O Procaine
R2 Aspirin
R2 + HO
R1 O R1 OH Succinylcholine

2. Amide Hydrolysis O O Procainamide

+ R2 Lidocaine
R2 H2 N
R1 N R1 OH Indomethacin
H

3. Epoxide Hydrolysis OH Carbamazepine (epoxide metabolite)

O
R1
R2
R1 R2
OH

II. Conjugation
1. Glucuronidation COOH Diazepam
COOH
O Digoxin
O OH
+ OH R Ezetimibe
OH UDP O
R O OH
OH OH
OH

2. Acetylation O O Isoniazid
OH + CoA R Sulfonamides
R
S O

3. Glycine Conjugation O O O Salicylic acid

H
+ H2 N R N
R OH OH OH
O

4. Sulfate Conjugation H Estrone

NH2 O N
R + HO 3 S ADP R S O3H Methyldopa

OH O O
R
+ HO 3 S ADP R S O3H

5. Glutathione Conjugation (and O NH2 Ethacrynic acid

H
processing to mercapturic acids) N Dichloroacetic acid
X + HOOC N COOH
R H Acetaminophen (metabolite)
O Chlorambucil
HS

O NH2
H
N
HOOC N COOH
H
O
S
R
H
HOOC N

R O
S

6. N-Methylation H
Methadone
N N Norepinephrine
R1 R2 R1 R2

7. O-Methylation HO R O R Catecholamines

HO HO

8. S-Methylation SH S Thiopurines
R R

Oxidation/Reduction Reactions
Oxidation reactions involve membrane-associated enzymes
expressed in the endoplasmic reticulum (ER) o hepatocytes
and, to a lesser extent, o cells in other tissues. The enzymes
that catalyze these phase I reactions are typically oxidases;
the majority o these enzymes are heme protein mono-
oxygenases o the cytochrome P450 class. Cytochrome P450
enzymes (sometimes abbreviated CYP) are also known as
microsomal mixed-function oxidases and are involved in the
metabolism o approximately 75% o all drugs used today.
(The term P450 re ers to the 450-nm absorption peak char-
acteristic o these heme proteins when they bind carbon
monoxide.)
The net result o a cytochrome P450-dependent oxidation
reaction is:
Drug O2 NADPH H the cytosol and the endoplasmic reticulum o hepatocytes (and
Drug-OH H2O NADP Equation 4-1
The reaction proceeds when the drug binds to the oxidized
(Fe3 ) cytochrome P450 to orm a complex, which is then
reduced in two sequential oxidation/reduction steps as out-
lined in Figure 4-2A. Nicotinamide adenine dinucleotide
phosphate (NADPH) donates the electrons in both o these
steps via a avoprotein reductase. In the f rst step, the do-
nated electron reduces the cytochrome P450drug complex.
In the second step, the electron reduces molecular oxygen
to orm an activated oxygencytochrome P450drug com-
plex. Finally, as the complex becomes more active through
rearrangement, the reactive oxygen atom is trans erred to
the drug, resulting in the ormation o the oxidized drug
product and recycling oxidized cytochrome P450 in the
process. The mechanism o these reactions is illustrated in
Figure 4-2B.
Most liver cytochrome P450 oxidases exhibit broad sub-
strate specif city (Table 4-1). This is due in part to the acti-
vated oxygen o the complex, which is a power ul oxidizing
agent that can react with a variety o substrates. The names o
the cytochrome P450 enzymes are sometimes designated by
P450 ollowed by the number o the P450 enzyme amily,
capital letter o the sub amily, and an additional number to
identi y the specif c enzyme (e.g., P450 3A4). Many o the
P450 enzymes have partially overlapping specif cities that
together allow the liver to recognize and metabolize a wide
array o xenobiotics.
Together, P450-mediated reactions account or more than
95% o oxidative biotrans ormations. Other pathways may
also oxidize lipophilic molecules. A pertinent example o a
non-P450 oxidative pathway is the alcohol dehydrogenase
pathway that oxidizes alcohols to their aldehyde derivatives
as part o the overall process o excretion. These enzymes
are also the basis or the toxicity o methanol. Methanol is
oxidized by alcohol dehydrogenase to ormaldehyde, which
can do considerable damage to some tissues. The optic nerve
is particularly sensitive to ormaldehyde, and methanol tox-
icity can cause blindness.
Another important non-P450 enzyme is monoamine
oxidase (MAO). This enzyme is responsible or the oxida-
tion o amine-containing endogenous compounds such as
catecholamines and tyramine (see Chapter 11, Adrenergic
Pharmacology) and some xenobiotics, including drugs.
C h a p t e r 4 Drug Metabolism 47
Conjugation/Hydrolysis Reactions
Conjugation and hydrolysis reactions provide a second set o
mechanisms or modi ying compounds or excretion (Fig. 4-3).
Although hydrolysis o ester- and amide-containing drugs is
sometimes included among the phase I reactions (in the older
terminology), the biochemistry o hydrolysis is more closely
related to conjugation than to oxidation/reduction. Substrates
or these reactions include both metabolites o oxidation re-
actions (e.g., epoxides) and compounds that already contain
chemical groups appropriate or conjugation, such as hydroxyl
(-OH), amine (-NH2), or carboxyl (-COOH) moieties. These
substrates are coupled by trans er enzymes to endogenous me-
tabolites (e.g., glucuronic acid and its derivatives, sul uric acid,
acetic acid, amino acids, and the tripeptide glutathione) in reac-
tions that o ten involve high-energy intermediates (Table 4-2).
The conjugation and hydrolysis enzymes are located in both
other tissues). In most cases, the conjugation process makes
the drug more polar. Virtually all o the conjugated products
are pharmacologically inactive, with some important excep-
tions (e.g., morphine glucuronide).
Some conjugation reactions are important clinically in
the case o neonates, who have not yet ully developed the
capacity to carry out this set o reactions. UDP-glucuronyl
trans erase (UDPGT) is responsible or conjugating bili-
rubin in the liver and acilitating its excretion. A relative
def ciency o this enzyme at the time o birth puts in ants
at risk or neonatal jaundice, which results rom increased
serum levels o unconjugated bilirubin. Neonatal jaundice is
a problem because neonates have not only underdeveloped
activity o this enzyme but also an undeveloped bloodbrain
barrier. Unconjugated bilirubin is water-insoluble and very
lipophilic; it binds readily to the unprotected neonatal brain
and is capable o causing signif cant damage to the central
nervous system. This pathologic condition is known as bili-
rubin encephalopathy or kernicterus . Neonatal hyperbiliru-
binemia (unconjugated) can be treated with phototherapy
with 450-nm light, which converts circulating bilirubin to an
isomer that is more rapidly excreted. Another e ective treat-
ment is the administration o small doses o the barbiturate
phenobarbital, which power ully up-regulates the expression
o the enzyme UDPGT and thereby reduces serum levels o
unconjugated bilirubin. This example illustrates a recurring
theme: understanding drug metabolism can help predict both
adverse and potentially advantageous drugdrug interactions.
It is important to note that conjugation and hydrolysis reac-
tions do not necessarily constitute the last step o biotrans or-
mation. Since the conjugation o these highly polar moieties
occurs intracellularly, they o ten require active transport
across cellular membranes to be excreted (active transport o
the parent drug can also occur). Moreover, some conjugation
products may be subjected to urther metabolism.
Drug Transport
Although many drugs are su f ciently lipophilic to cross
cell membranes passively, it is now appreciated that many
drugs need to be transported actively into cells. This act
has signif cant consequences or oral bioavailability (trans-
port into enterocytes or active excretion into the intestinal
lumen), hepatic metabolism (transport into hepatocytes or
enzymatic metabolism and or excretion into bile), and renal
48 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

A NADP + NADP H

Fla voprote in Fla voprote in

(re duce d) (oxidize d)

2
+e -

RH P 450-Fe2+

+e -
RH P 450-Fe 3+ 3
O2

RH P 450-Fe 2+
H2 O
O2-
1
4
P 450-Fe3+

R-H R-OH
(pa re nt drug) (oxidize d drug)

R-OH H H
B
(oxidize d drug) 0 R-H (pa re nt drug)
H2 O

H2 O
Fe3+ H2 O

0 6
He me 1
R-H R-H

Fe3+ Fe3+
Fla voprote in NADP +
(re duce d)
H2 O e-

5
2 Fla voprote in NADP H
+ (oxidize d)
2H
0-
0
R-H R-H

Fe2+ Fe2+

0 0-
4 0 0
R-H R-H O2
3
e- Fe2+ Fe3+
(from NADP H)

FIGURE 4-2. Cytochrome P450-mediated drug oxidation. Many drug metabolism reactions involve a system o hepatic P450 microsomal enzymes that
catalyze the oxidation o drugs. A. An overview o the reaction involves a set o oxidation/reduction steps in which an iron moiety in the P450 enzyme acts as
an electron carrier to trans er electrons rom NADPH to molecular oxygen. The reduced oxygen is then trans erred to the drug, resulting in an additional -OH
group on the now-oxidized drug ( or this reason, P450 enzymes are sometimes re erred to colloquially as oxygen guns or even natures blowtorch). The
addition o the -OH group results in increased drug hydrophilicity and an increased rate o drug excretion. B. The detailed mechanism o the P450 reaction can
be divided into six steps: (1) drug complexes with oxidized cytochrome P450; (2) NADPH donates an electron to the avoprotein reductase, which reduces the
P450-drug complex; (3 and 4) oxygen joins the complex, and NADPH donates another electron, creating the activated oxygenP450 substrate complex; (5) iron
is oxidized, with the loss o water; and (6) the oxidized drug product is ormed. There are multiple P450 enzymes; each has a somewhat di erent specif city
or substrates (such as drugs). Five o the human P450s (1A2, 2C9, 2C19, 2D6, and 3A4) account or approximately 90% o the oxidative metabolism o drugs.

D-glucurona te
D the transporter OATP1B1, which transports the drug into
D-a ce ta te
Drug or
pha s e I D-glycine
Excre tion
drug me ta bolite D-s ulfa te
OH NH2
D-gluta thione
D D
D-me thyl
FIGURE 4-3. Conjugation reactions. In these reactions, a drug (represented
by D) or drug metabolite (represented by D-OH and D-NH2) is conjugated to
an endogenous moiety. Glucuronic acid, a sugar, is the most common group
that is conjugated to drugs, but conjugations of acetate, glycine, sulfate,
glutathione, and methyl groups are also common. The addition of one of
these moieties makes the resulting drug metabolite more hydrophilic and
often enhances drug excretion. (Methylation, an important exception, does
not increase drug hydrophilicity.) Transport mechanisms also play a major
role in the elimination of drugs and their metabolites.
clearance (transport into proximal tubular cells and excre-
tion into the tubular lumen). Several important molecules
mediate these processes. The multidrug resistance protein 1
(MDR1), or P-glycoprotein, which is a member o the ABC
amily o e ux transporters, actively transports compounds
back into the intestinal lumen. This process limits the oral
bioavailability o several important drugs, including digoxin
and HIV-1 protease inhibitors. The metabolism o drugs
rom the portal circulation (i.e., the f rst-pass e ect) o ten
requires the transport o compounds into hepatocytes via the
organic anion transporting polypeptide (OATP) and the organic
cation transporter (OCT) amily o proteins. These transport-
ers are particularly relevant or the metabolism o several
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) re-
ductase inhibitors (statins), which are used in the treatment
o hypercholesterolemia. For example, metabolism o the
A D
Extra ce llula r
Cytopla s m
A C
P 450 e nzyme
Nucle us
Coa ctiva tor
A transcription of the P450 enzyme. Induction can also occur via the consti-
RxR
P XR P 450 tra ns cription
C h a p t e r 4 Drug Metabolism 49
HMG-CoA reductase inhibitor pravastatin is dependent on
hepatocytes. Drug uptake into hepatocytes via OATP1B1
is thought to be the rate-limiting step in the clearance o
pravastatin rom the bloodstream. The uptake o pravastatin
on its f rst pass through the liver also provides a potential ad-
vantage by keeping the drug out o the systemic circulation,
rom which it could be taken up by muscle cells and thereby
cause toxic e ects such as rhabdomyolysis. The organic anion
transporter (OAT) amily o transporters is responsible or
renal secretion o many clinically important anionic drugs,
such as -lactam antibiotics, nonsteroidal anti-in ammatory
drugs (NSAIDs), and antiviral nucleoside analogs.
Induction and Inhibition
The use o phenobarbital to prevent neonatal jaundice dem-
onstrates that drug metabolism can be in uenced by the
expression levels o drug-metabolizing enzymes. Although
some P450 enzymes are constitutively active, others can be
induced or inhibited by various compounds. Induction or in-
hibition can be incidental (a side e ect o a drug) or deliber-
ate (the desired e ect o therapy).
The primary mechanism o P450 enzyme induction is
an increase in the expression o the enzyme chie y through
increased transcription, although augmented translation and
decreased degradation can also have minor roles. The in-
duction o P450 enzymes by a wide array o drugs re ects
the biology o xenobiotic receptors that act as the bodys
surveillance system to metabolize potentially toxic com-
pounds. Drugs, environmental pollutants, industrial chemi-
cals, and even oodstu s can enter hepatocytes and bind to
several di erent xenobiotic receptors, such as the pregnane
X receptor (PXR), constitutively active/androstane recep-
tor (CAR), and aryl hydrocarbon receptor (AhR) (Fig. 4-4).
D D
OH
D D D D D D
I
P 450 P 450 P 450
FIGURE 4-4. Conceptualization of P450 induction and inhibition. Drugs can
both induce the expression and inhibit the activity of P450 enzymes. Some
drugs can induce the synthesis of P450 enzymes (left panel). In this example,
Drug A activates the pregnane Xreceptor (PXR), which heterodimerizes with
the retinoid Xreceptor (RXR) to form a complex with coactivators and initiate
tutively active/androstane receptor (CAR) or the aryl hydrocarbon receptor
(AhR) (not shown). Drug D enters the cell and is hydroxylated by a P450
enzyme (right panel). The P450 enzyme can be inhibited by a second drug
acting as a competitive inhibitor (Drug C) or an irreversible inhibitor (Drug I).
The mechanism by which a drug inhibits P450 enzymes is not necessarily
predictable from the drugs chemical structure; the mechanism can only be
determined experimentally. In addition, metabolites of Drugs A, C, and I can
play a role in enzyme induction and inhibition (not shown).
50 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
These molecules are nuclear hormone receptors; when a
xenobiotic compound binds to and activates the receptor,
the complex is translocated to the nucleus, where it binds
to the enhancer regions o various biotrans ormation en-
zymes, promoting increased expression o P450 enzymes
via transcription. By a similar mechanism, nuclear hormone
receptor activation can also increase the expression o drug
transporters that aid in clearing the compounds rom the
body, such as MDR1 and OATP1.
There are multiple consequences o P450 enzyme in-
duction. First, a drug can increase its own metabolism. For
example, carbamazepine , an antiepileptic drug, not only in-
duces P450 3A4 but also is metabolized by P450 3A4. Hence,
carbamazepine increases its own metabolism by inducing
P450 3A4. Second, a drug can increase the metabolism o a
co-administered drug. For example, P450 3A4 is responsi-
ble or metabolizing almost 50% o all clinically prescribed
drugs. Should such a drug be co-administered with carbam-
azepine, its metabolism would also be increased. This situ-
ation can be problematic, because the increased P450 3A4
activity can reduce drug concentrations below their thera-
peutic levels i standard doses o the drugs are administered.
In Ms. Bs case, the administration o rifampin in conjunction
with her HIV therapy could be detrimental, because ri ampin
induces P450 3A4 and thereby increases the metabolism o
protease inhibitors such as saquinavir, thus reducing the
therapeutic e ectiveness o the protease inhibitor. Third,
induction o P450s or some o the other biotrans ormation
enzymes can result in the production o toxic levels o re-
active drug metabolites, resulting in tissue damage or other
adverse e ects.
Just as certain compounds can induce P450 enzymes,
other compounds can inhibit these enzymes. An important
consequence of enzyme inhibition is the decreased metabo-
lism of drugs that are metabolized by the inhibited enzyme.
Such inhibition can both allow drug levels to reach toxic
concentrations and prolong the presence o active drug in
the body.
Enzyme inhibition can be achieved in several di erent
ways (Fig. 4-4). For example, ketoconazole , a widely used
anti ungal drug, has a nitrogen moiety that binds to the
heme iron in the active site o P450 enzymes; this binding
prevents the metabolism o co-administered drugs by com-
petitive inhibition. An example o irreversible inhibition is
secobarbital, a barbiturate, which alkylates and permanently
inactivates the P450 complex. On occasion, the inhibition
o P450 enzymes can be used to therapeutic advantage. For
example, the protease inhibitor ritonavir is highly e ective
against HIV but has signif cant gastrointestinal adverse
e ects that limit its use as a chronic treatment. However,
because ritonavir is a potent inhibitor o P450 3A4, it can be
used clinically in doses that are below the threshold or gas-
trointestinal adverse e ects but high enough to inhibit P450
3A4. Inhibition o P450 3A4 boosts the e ective concen-
trations o other HIV protease inhibitors that are metabolized
by this P450 enzyme. For example, lopinavir cannot achieve
therapeutic levels as a single agent because o extensive f rst-
pass metabolism, but co-administration with ritonavir allows
lopinavir to reach therapeutic concentrations.
Drug transporters can also be induced or inhibited by
other drugs. For example, macrolide antibiotics can inhibit
MDR1, and this inhibition can lead to increased serum lev-
els o drugs, such as digoxin, that are excreted by MDR1.
MDR1 is also transcriptionally regulated by PXR. Conse-
quently, drugs that induce up-regulation o P450 enzymes
via the PXR pathway (e.g., P450 3A4) concomitantly in-
crease transcription o the MDR1 drug transporter.
A detailed list o compounds that can inhibit or induce
the common P450 enzymes can be ound in Table 4-3. This
list is not meant to be exhaustive, but only to highlight com-
mon medications that are metabolized by the same P450
enzymes. New drugs are extensively tested or drug interac-
tions, both in the laboratory (in vitro) and in clinical trials, as
required by the US Food and Drug Administration.
Active and Toxic Metabolites
Knowing the routes by which therapeutic agents are metabo-
lized can a ect the choice o drug to prescribe in a particular
clinical situation. This is true both when the metabolite is
active, in which case the administered agent may be acting
as a prodrug, and when the agent has toxic metabolites (see
Chapter 6, Drug Toxicity).
Prodrugs are inactive compounds that are metabolized by
the body into their active, therapeutic forms. One example
o a prodrug is the selective estrogen receptor modulator
tamoxifen; this drug has little activity until it is hydroxylated
to become 4-hydroxytamoxi en, a metabolite that is 30- to
100- old more active than the parent compound. Another ex-
ample is the angiotensin II receptor antagonist losartan; the
potency o this drug is increased ten old upon oxidation o
its alcohol group to a carboxylic acid by P450 2C9.
The strategy o selective prodrug activation can be used
or therapeutic benef t in cancer chemotherapy. One example
o this strategy is the use o mitomycin C, a naturally occur-
ring compound that is activated to a power ul DNA alkylat-
ing agent a ter it is reduced by several enzymes including a
cytochrome P450 reductase. Mitomycin C selectively kills
hypoxic cancer cells in the core o solid tumors because
(1) these cells have increased levels o the cytochrome P450
reductase that activates mitomycin C and (2) reoxidation o
the drug is inhibited under hypoxic conditions.
Other examples o toxic metabolites, including the im-
portant case o acetaminophen, are discussed in Chapter 6.
INDIVIDUAL FACTORS AFFECTING
DRUG METABOLISM
For a number o reasons, the rates o biotrans ormation reac-
tions may vary greatly rom one person to another. The most
important o these actors are discussed below.
Pharmacogenomics
The e ects o genetic variability on drug metabolism are an
important part o the new science o pharmacogenomics (see
Chapter 7, Pharmacogenomics). Certain populations exhibit
polymorphisms or mutations in one or more enzymes o drug
metabolism, changing the rates o some o these reactions
and eliminating others altogether. These pharmacogenetic
di erences must be taken into account in therapeutic decision
making and drug dosing. Current research uses new tech-
nology (e.g., SNP analysis, gene microchips) to understand
how genetic di erences in the enzymes o drug metabolism
a ect patient responses to various drugs. Such approaches
are already employed extensively in pharmaceutical devel-
opment and are beginning to be applied in clinical practice.
 C h a p t e r 4 Drug Metabolism 51

TABLE 4-3 Some Pharmacologic Substrates, Inhibitors, and Inducers o Cytochrome P450 Enzymes
P450 ENZYME SUBSTRATES INHIBITORS INDUCERS

P450 3A4 Anti-HIV agents Anti ungal agents (azoles) Antiepileptics

Indinavir Itraconazole Carbamazepine
Nelf navir Ketoconazole Oxcarbazepine
Ritonavir Anti-HIV agents Phenobarbital
Saquinavir Delavirdine Phenytoin
Benzodiazepines Indinavir Anti-HIV agents
Alprazolam Ritonavir E avirenz
Midazolam Saquinavir Nevirapine
Triazolam Calcium channel blockers Ri amycins
Calcium channel blockers Diltiazem Ri abutin
Diltiazem Verapamil Ri ampin
Felodipine Macrolide antibiotics Ri apentine
Ni edipine Clarithromycin Others
Verapamil Erythromycin St. J ohns wort
Immunosuppressants Troleandomycin (not azithromycin)
Cyclosporine Others
Tacrolimus Cimetidine
Macrolide antibiotics Grape ruit juice
Clarithromycin Mi epristone
Erythromycin Ne azodone
Statins Nor oxacin
Atorvastatin
Lovastatin
Others
Finasteride
Loratadine
Losartan
Quinidine
Sildenaf l
Tadalaf l

P450 2D6 5-HT reuptake inhibitors 5-HT reuptake inhibitors None identif ed
Fluoxetine Fluoxetine
Paroxetine Paroxetine
Antiarrhythmic agents Antiarrhythmic agents
Flecainide Amiodarone
Mexiletine Quinidine
Propa enone Antidepressants
Antidepressants Clomipramine
Amitriptyline Antipsychotics
Clomipramine Haloperidol
Desipramine
Imipramine
Nortriptyline
Antipsychotics
Haloperidol
Perphenazine
Risperidone
Venla axine
Beta-adrenergic antagonists
Alprenolol
Bu uralol
Carvedilol
Metoprolol
Penbutolol
Propranolol
Timolol
Opioids
Codeine
Dextromethorphan

continues
52 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

TABLE 4-3 Some Pharmacologic Substrates, Inhibitors, and Inducers o Cytochrome P450 Enzymes (continued)
P450 ENZYME SUBSTRATES INHIBITORS INDUCERS

P450 2C19 Antidepressants Proton pump inhibitors Norethindrone

Clomipramine Omeprazole Prednisone
Imipramine Others Ri ampin
Proton pump inhibitors Fluoxetine
Lansoprazole Ritonavir
Omeprazole Sertraline
Pantoprazole
Others
Clopidogrel
Propranolol
R-War arin

P450 2C9 Angiotensin II receptor antagonists Anti ungal agents (azoles) Ri ampin
Irbesartan Fluconazole Secobarbital
Losartan Miconazole
Nonsteroidal anti-inf ammatory drugs Others
(NSAIDs) Amiodarone
Ibupro en Phenylbutazone
Supro en
Others
S-War arin
Tamoxi en

P450 2E1 General anesthetics Disulf ram Ethanol

En urane Isoniazid
Halothane
Iso urane
Methoxy urane
Sevo urane
Others
Acetaminophen
Ethanol

P450 1A2 Antidepressants Quinolones Char-grilled meat

Amitriptyline Cipro oxacin Cruci erous vegetables
Clomipramine Enoxacin Insulin
Clozapine Nor oxacin Omeprazole
Imipramine O oxacin Tobacco smoke
Others Others
R-War arin Fluvoxamine
Tacrine

For example, most pharmaceutical companies avoid devel-
opment o a drug that is metabolized primarily by a highly
polymorphic enzyme, because such polymorphisms may
lead to wide interindividual variability in drug response.
One clinically important example o pharmacogenetic
variability involves the plasma enzyme cholinesterase. One
in every 2,000 Caucasians carries a genetic alteration in cho-
linesterase, which metabolizes the muscle relaxant succinyl-
choline (among other unctions). This altered orm o the
enzyme has an approximately 1,000- old reduced a f nity
or succinylcholine, resulting in slowed elimination and pro-
longed circulation o the active drug. Should a su f ciently
high plasma concentration o succinylcholine be reached,
respiratory paralysis and death can occur unless the patient is
supported with artif cial respiration until the drug is cleared.
A similar situation can occur with isoniazid, one o the
drugs considered or treatment o Ms. Bs tuberculosis.
Genetic variability, in the orm o a widespread autosomal
recessive trait that results in decreased synthesis o an en-
zyme, causes the metabolism o this drug to be slowed in
certain subsets o the US population. The enzyme at issue is
N-acetyltrans erase, which inactivates isoniazid by an acety-
lation (conjugation) reaction. The slow acetylator pheno-
type is expressed by 45% o whites and blacks in the United
States and by some Europeans living in high northern lati-
tudes. The ast acetylator phenotype is ound in more than
90% o Asians and in Inuits in the United States. Blood lev-
els o isoniazid are elevated our old to six old in slow acet-
ylators relative to ast acetylators. Moreover, because the
ree drug acts as an inhibitor o P450 enzymes, slow acety-
lators are more susceptible to adverse drug interactions. I
Ms. B expresses the slow acetylator phenotype and her dose
o isoniazid is not decreased accordingly, then the addition
o isoniazid to her drug regimen could potentially have a
toxic e ect.
A third example involves clopidogrel, an antiplatelet drug
that promotes blood vessel patency a ter strokes or coronary
angioplasty. The loss o e f cacy o this medication may
lead to re-stenosis or thrombosis o a vessel or stent, o ten
with severe consequences. Clopidogrel is a prodrug that is

metabolized to its active orm via P450 enzymes, including
P450 2C19. Polymorphisms o P450 2C19 have recently
been associated with both decreased antiplatelet e ect and
increased cardiovascular morbidity. In addition, because
many proton pump inhibitors are also metabolized by P450
2C19, co-administration o clopidogrel with one o these
commonly prescribed medications may lead to a decrease in
the plasma levels o active clopidogrel.
Race and Ethnicity
Some genetic aspects o race and/or ethnicity a ect drug
metabolism. In particular, di erences in drug action among
races/ethnicities have been attributed to polymorphisms in
specif c genes. For example, P450 2D6 is unctionally inac-
tive in 8% o Caucasian individuals but in only 1% o Asians.
Moreover, A rican Americans have a high requency o a
P450 2D6 allele that encodes an enzyme o reduced activity.
These observations are clinically relevant, in that P450 2D6
is responsible or the oxidative metabolism o about 20% o
drugsincluding many beta-antagonists and tricyclic anti-
depressantsand or the conversion o codeine to morphine.
In some cases, a polymorphism in the target gene is the
basis or racial di erences in drug action. The activity o the
enzyme vitamin K epoxide reductase (VKORC1), which is
the target o the anticoagulant warfarin, is a ected by single
nucleotide polymorphisms (SNPs) that render an individual
either more or less sensitive to war arin and that dictate ad-
ministration o lower or higher doses o the drug, respectively.
In one study, Asian American populations were ound to be
enriched in haplotypes (inherited combinations o individual
base/SNP di erences) associated with increased sensitivity
to war arin, while A rican American populations exhibited
haplotypes associated with increased resistance to war arin.
Perhaps the most prominent example o a race-based thera-
peutic is the combination o f xed-dose isosorbide dinitrate
and hydralazine (also known as BiDil). This combination o
vasodilators was reported to cause a 43% decrease in mor-
tality in A rican Americans with heart ailure. Although the
biochemical basis o this e ect is not known, these clinical
data demonstrate that race may be a key consideration in
choosing drug treatments and doses.
Age and Gender
Drug metabolism can also di er among individuals as a re-
sult o age and gender di erences. Many reactions o bio-
trans ormation are slowed in both young children and the
elderly. At birth, neonates are capable o carrying out many
but not all oxidative reactions; however, most o these drug-
metabolizing enzyme systems mature gradually over the f rst
2 weeks o li e and throughout childhood. Recall that neonatal
jaundice results rom a def ciency o the bilirubin-conjugating
enzyme UDPGT. Another example o a conjugating enzyme
def ciency that puts in ants at risk or toxicity is the so-called
gray baby syndrome . Haemophilus inf uenzae in ections in in-
ants were once treated with the antibiotic chloramphenicol;
excretion o this drug requires an oxidative trans ormation
ollowed by a conjugation reaction. The oxidation metabolite
o chloramphenicol is toxic; i this metabolite ails to undergo
conjugation, it can build up in the plasma and may reach toxic
concentrations. Toxic levels o the metabolite can cause neo-
nates to experience shock and circulatory collapse, leading to
the pallor and cyanosis that give the syndrome its name.
C h a p t e r 4 Drug Metabolism 53
In the elderly, a general decrease in metabolic capacity
is observed. As a result, particular care must be taken in
prescribing drugs or this segment o the population. The
elderlys decline in metabolic capacity has been attributed to
age-related decreases in liver mass, hepatic blood ow, and
possibly hepatic enzyme activity. Another therapeutic con-
sideration is that the elderly are requently taking multiple
medications, with a consequent increase in the risk o drug
drug interactions.
There is some evidence or gender di erences in drug me-
tabolism, although the mechanisms are not well understood
and data rom experimental animals have not been particu-
larly illuminating. Decreased oxidation o ethanol, estrogens,
benzodiazepines, and salicylates has been reported anecdot-
ally in women relative to men and may be related to andro-
genic hormone levels.
Diet and Environment
Both diet and environment can alter drug metabolism by
inducing or inhibiting enzymes o the P450 system. An inter-
esting example is grape ruit juice. The psoralen derivatives
and avonoids in grape ruit juice inhibit both P450 3A4 and
MDR1 in the small intestine. Inhibition o P450 3A4 signif -
cantly decreases the f rst-pass metabolism o co-administered
drugs that are also metabolized by this enzyme, and inhibi-
tion o MDR1 signif cantly increases the absorption o co-
administered drugs that are substrates or export (e ux) by
this enzyme. The grapefruit juice effect is important when
grape ruit juice is ingested together with drugs that are acted
upon by these enzymes. Such drugs include some protease
inhibitors, macrolide antibiotics, HMG-CoA reductase in-
hibitors (statins), and calcium channel blockers. Saquinavir
is one o the protease inhibitors that is both metabolized by
P450 3A4 and exported by MDR1. In the case that opens
this chapter, Ms. B should be alerted to the act that the
simultaneous ingestion o grape ruit juice and saquinavir
could inadvertently lead to toxic serum levels o the protease
inhibitor.
Herbal medications can also have signif cant e ects on
the P450 system. One such example is St. J ohns wort, a pop-
ular herbal preparation used or mood stabilization. Many
observational studies have noted that St. Johns wort can in-
duce P450 expression and thereby decrease the e f cacy o
other drugs. Compounds rom herbs and spices may also in-
hibit P450s. One example is piperine (the essential chemical
in black pepper), which has been shown to inhibit P450 3A4
and the MDR protein in animal models; the clinical impor-
tance o this e ect remains uncertain.
Because many endogenous substances used in the con-
jugation reactions are ultimately derived rom the diet (and
also require energy or the production o the appropriate
co actors), nutrition can a ect drug metabolism by altering
the pool o such substances available to the conjugating en-
zymes. Pollutant exposures can produce similarly dramatic
e ects on drug metabolism; one common example is the
AhR-mediated P450 enzyme induction by polycyclic aro-
matic hydrocarbons in cigarette smoke.
Metabolic Drug Interactions
Drugs can potentially a ect oral bioavailability, plasma
protein binding, hepatic metabolism, and renal excretion o
co-administered drugs. Among the categories o drugdrug
54 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
interactions, the e ects on biotrans ormation have special
clinical importance. The concept o P450 enzyme induc-
tion and inhibition has already been introduced. A com-
mon clinical situation that must take this type o drugdrug
interaction into consideration is the prescription o certain
antibiotics to women who are already using hormonal con-
traception. For example, enzyme induction by the antibiotic
rifampin can cause estrogen-based hormonal contraception
to be ine ective at standard doses because P450 3A4 is
induced by ri ampin and this is the main enzyme involved
in the metabolism o the common estrogenic component
17 -ethynylestradiol. In this situation, other means o birth
control should be recommended during the course o ri-
ampin therapy. Ms. B should be made aware o this interac-
tion i ri ampin is added to her therapeutic regimen. Another
phenomenon associated with enzyme induction is tolerance ,
which can occur when a drug induces its own metabolism
and thus reduces its e f cacy over time (see the discussion
o carbamazepine above and the discussion o tolerance in
Chapter 19, Pharmacology o Drugs o Abuse).
Because drugs are o ten prescribed in combination with
other pharmaceuticals, care ul attention should be paid to
drugs that are metabolized by the same hepatic enzymes.
The concomitant administration o two or more drugs that
are metabolized by the same enzyme will generally result in
higher serum levels o the drugs. The mechanisms o drug
drug interaction can involve competitive substrate inhibition,
allosteric inhibition, or irreversible enzyme inactivation; in
any case, drug levels can increase acutely, possibly leading
to deleterious results. For example, erythromycin is metabo-
lized by P450 3A4, but the resulting nitrosoalkane metabolite
can orm a complex with P450 3A4 and inhibit the enzyme.
This inhibition can lead to potentially atal drugdrug in-
teractions. A notable example is the interaction between
erythromycin and cisapride , a drug that stimulates GI tract
motility. Toxic concentrations o cisapride can inhibit hERG
potassium channels in the heart and thereby induce poten-
tially atal cardiac arrhythmias; or this reason, cisapride was
withdrawn rom the market in 2000. Be ore its withdrawal,
cisapride was o ten well tolerated as a single agent. How-
ever, because cisapride is metabolized by P450 3A4, when
the activity o P450 3A4 was compromised due to the con-
comitant administration o erythromycin or another inhibitor
o P450 3A4, serum cisapride concentrations could increase
to levels associated with arrhythmia induction.
In other cases, drug interactions may be benef cial. For
example, as noted above, the ingestion o methanol (a com-
ponent o wood alcohol) can result in blindness or death be-
cause its metabolites ( ormaldehyde, an embalming agent,
and ormic acid, a component o ant venom) are highly
toxic. One treatment or methanol poisoning is the admin-
istration o ethanol, which competes with methanol or oxi-
dation by alcohol dehydrogenase (and, to a lesser extent,
by P450 2E1). The resulting delay in oxidation allows the
methanol to be cleared renally be ore its toxic byproducts
can orm in the liver.
Diseases Affecting Drug Metabolism
Many disease states can a ect the rate and extent o drug
metabolism in the body. Because the liver is the main site
o biotrans ormation, many liver diseases signif cantly com-
promise drug metabolism. Hepatitis, cirrhosis, cancer, he-
mochromatosis, and atty inf ltration o the liver each impair
cytochrome P450s and other hepatic enzymes that are cru-
cial to drug metabolism. As a result o this slowed metabo-
lism, the levels o the active orms o many drugs may be
signif cantly higher than intended and thereby cause toxic
e ects. Thus, the doses o many drugs may need to be low-
ered or individuals with hepatic disease.
Concomitant cardiac disease can also a ect drug metabo-
lism. The rate o metabolism o many drugs, such as the anti-
arrhythmic lidocaine and the opioid morphine, is dependent
on drug delivery to the liver via the bloodstream. Because
blood ow is commonly compromised in cardiac disease,
there must be heightened awareness o the potential or su-
pratherapeutic levels o drugs in patients with heart ailure.
In addition, some antihypertensive agents selectively reduce
blood ow to the liver and can thereby increase the hal -
li e o a drug such as lidocaine, leading to potentially toxic
levels.
Thyroid hormone regulates the basal metabolic rate o the
body, which, in turn, a ects drug metabolism. Hyperthyroid-
ism can increase the rate o metabolism o some drugs, whereas
hypothyroidism can do the opposite. Other conditions, such as
pulmonary disease, endocrine dys unction, and diabetes, are
also thought to a ect drug metabolism, but the mechanisms
or these e ects are not yet completely understood.
CONCLUSION AND FUTURE
DIRECTIONS
This chapter has reviewed a number o issues relating to
drug metabolism, including the sites o biotrans ormation,
the transport and enzymatic metabolism o drugs at those
sites, and individual actors that can a ect those reactions.
The case o Ms. B illustrates the clinical implications o
drug metabolism, including the possible in uences o eth-
nicity and drugdrug interactions on pharmacologic therapy.
Understanding drug metabolism, and particularly the inter-
actions o drugs within the body, allows the principles o
biotrans ormation to be applied in the design and use o ther-
apeutics. As pharmacogenomics and rational drug design
lead pharmacology research into the uture, increased under-
standing o biotrans ormation will also render the pharmaco-
logic treatment o disease more individualized, e f cacious,
and sa e. This topic is discussed in Chapter 7.
Acknowledgment
We thank Cullen Taniguchi or his valuable contributions
to this chapter in the Second and Third Editions o Princi-
ples of Pharmacology: The Pathophysiologic Basis of Drug
Therapy.
Suggested Reading
Burchard EG, Ziv E, Coyle N, et al. The importance o race and ethnic back-
ground in biomedical research and practice. N Engl J Med 2003;348:1170
1175. (Current understanding regarding ethnic variability in response to
drug administration.)
Gong IY, Kim RB. Impact o genetic variation in OATP transporters to
drug disposition and response. Drug Metab Pharmacokinet 2013;28:4 18.
(Review of the crucial role played by drug transporters in drug metabolism.)
Johansson I, Ingelman-Sundberg M. Genetic polymorphism and toxicology
with emphasis on cytochrome P450. Toxicol Sci 2011;120:113. (Review of
toxicity issues with some drugs and the role of P450 variations.)
Katsanis SH, Javitt G, Hudson K. Public health. A case study o personal-
ized medicine. Science 2008;320:5354. (A discussion of aspects of the use
of personalized medicine, including roles of P450 genes.)

Kirchheiner J, Seeringer A. Clinical implications of pharmacogenetics
of cytochrome P450 drug metabolizing enzymes. Biochim Biophys Acta
2007;1770:489494. (Discussion o clinical issues with several drugs and P450s.)
Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 polymorphisms
and response to clopidogrel. N Engl J Med 2009;360:354362. (Example o
P450 genetic polymorphisms and clinical e f cacy o clopidogrel.)
Rendic S, Guengerich FP. Survey of human oxidoreductases and cyto-
chrome P450 enzymes involved in the metabolism of xenobiotic and natu-
ral chemicals. Chem Res Toxicol 2015;28:3842. (Analysis o ractions o
drugs metabolized by di erent cytochrome P450 enzymes.)
Seden K, Dickinson L, Khoo S, Back D. Grapefruit-drug interactions.
Drugs 2010;70:23732407. (Review o P450 interactions with grape ruit.)
Shi S, Klotz U. Drug interactions with herbal medicines. Clin Pharmacoki-
net 2012;51:77104. (Review o P450 interactions with herbal medicines.)
C h a p t e r 4 Drug Metabolism 55
Wienkers L, Pearson P, eds. Handbook o drug metabolism. 2nd ed. New
York: Marcel Dekker; 2009. (Collection o articles on aspects o drug
metabolism.)
Wilke RA, Lin DW, Roden DM, et al. Identifying genetic risk factors for
serious adverse reactions: current progress and challenges. Nat Rev Drug
Discov 2007;6:904916. (Review o current status o use o genetics or
predicting adverse reactions.)
Wilkinson GR. Drug metabolism and variability among patients in drug
response. N Engl J Med 2005;352:22112221. (An excellent basic review o
the P450 system and drugdrug interactions.)
Zhang D, Zhu M, Humphreys WG, eds. Drug metabolism in drug design
and development: basic concepts and practice. Hoboken, NJ: John Wiley
& Sons; 2007. (Drug metabolism as it pertains to development o new
pharmaceuticals.)
 E NT2
T2
OATP
OA
ATP
MRP 3 OA
O A
AT
TP 1A2,
TP 1A2 MDR1
MD
M R11 (P -gp)
ENT1, ENT
E T2 OATP
A 2B1
BCRP

MRP
P4

5
O T -
OS
OS T MRP 5
OC
O C T1

B
d

lo
o

o
lo

d
B
Drug Transporters E NT2
ENT2 OA
ATP 22B1
NTCP
OS T -OS T

Ba ra n A. Ers oy a n d Ke it h A. Ho ffm
A as te r

B
OAT3

d
lo
OATP
OA
A 1B3

o
lo
o
d

B
OA
O AT2 MRP 6
OATP
A 1B1
O AT1
OA
ENT1,, ENT2
OCT
O
OCT2
OC
INTRODUCTION & CASE CA
A
ASSE
S E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
565
6
657
6 E f ux Tra
ransporters . .OA . . . . . . . . . . . . . . . . . . . MDR1
. .A.T7
OAT7 . . . . . . . . . . . . . 62
2
OA
O ATP
P ATP-Binding
4C1
4C (P -gp)
g )
UPTAKE AND EFFLUX UX
X TR
TRARAN
RANS
AN
ANS
NS SP P
PO ORTE
O
ORTER R S . . . . . . . . . . . . . . 58
58 Cassette (ABC) (AB BC)
BC
BC)CT Transp
Tra
Trran
ra nnsp
nspo
nssppo
p rter Family amily ly . . . . . . . . . 62
6
M
MDR
MDR1
MD DR R1 1 (P
(P -gp)gp) O AT2
OAT2
OA AT2
Uptake TransENT1
nsport rters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Sollute
te Cararri
r er (SLC) Family
Faa ily
Fami y . . . . . .BS . . .EP
. . . . . . . . . . . . . . . . . . 64
MATE1
MA ATE1 MA
MATE1, ATE2
TE2-K OCT1 VES
Organic Anion-Transporting
OCTN2 2 nsp
nns or
ortrtin
rting
iing
nngg Po
Poly
P
Polypeptide
Polyp
olyly CLINICAL PERSPECTIVES V SO ON ND DRU
RU UG T
UG TRANS
TR S
SP P
POR
PORTER
O
OR
ORT R
RTERS
TERS
TE ERRS . . . . . . . . 64
MRP 2, MRP 4
(OATP) Family. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599 DrugDrug Interactio tioons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 6M
MAT
MA
AT
TE1

ile
Organic Anion Transporte ter
e r (O
er O
OA A
ATT) FaF
Fam
am mil
mi
mily
illy
y . . . . . . . . . . . . . . . . 59
5 Drug Inter erence nce
cee wit
with
w th En
th Endogen
Endo
E nd
ndogenou BCRP
enousouss MPMetabol
eeta
etabo
etabolite
tab
ta boolit
olilit
liit Traa cckingck
cki
kiing
kkin
king g . . . 66

B
Orga
Or gani
nicc Ca
Catition
on Transporter (OCT) OCT
O CT
C T) F Family
Fam
aam
m y . . . . . . . . . . . . . . . 59
mily Pharmacogenom
ogggeno
e omomi
miics
ccss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Bile Acid TransporteP EPe rs
T11 , P EP T2 . . . . . . . . . . . . . . . . . . . . . . . 59 IN
T1, INTE
TEGR
GRAT
ATION N OF D DR RUG M
DRUG MRP
MR
T P4
TRANSPORTER ER RS SCI
SC C
CIEN NC
NCE MRP
M P2
Peptide Transpporterr (PEP(PEPT) T) Famamil ilyy . . . . . . . . . . . . . . . . . . . . . 61 INTO DRUG DIS DISCOVERY
ISCOV
ISC
SCOVE
SC ERY AND DEVELOPMENT
DEVELO LOP
OPM
OPPM T . . . . . . . . . . . . . . . 67 67
U

URA
URAT1
UR AT1 T1 MRP
M 3
ri

Concentrative and Equilibrative Nucleo oside

ssid
iid
ide
d
de TIO . . . . .EN ENT1
. . .T1
n

CONCLUSION AND NDD FUTURE DIRECTIONS

DIREC
DIRECT CTI
CT . . . . . . . . . . . 67
e

Transs po
port
rter
er (CN
CNT T an
andd ENENT T) Families
OAT4
OA AT44. . . . . . . . . . . . . . . . . 61
Suggested Reading
Glucose Transporterss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Kidne y pro ximal
Kid i l ttubule
b l c e ll
INTRODUCTION
Membrane transporters are proteins that acilitate the trans-
port o soluble small molecules across lipid bilayers. These
transporters regulate the tissue and plasma distribution
as well as the excretion o drugs and endogenous compounds
and there ore a ect their pharmacokinetic prof le (i.e., ab-
sorption, distribution, metabolism, and excretion). Trans-
porters are generally classif ed as uptake or e f ux proteins
depending on the direction in which they move substrates
across the membranes o cells. They include several protein
amilies that exhibit broad substrate specif city and tissue
distribution. The unction o transporters depends on the tis-
sue in which they are expressed as well as their subcellular
localization to the apical or basolateral membrane (Fig. 5-1).
Whereas transporters expressed in organs o elimination
(e.g., liver or kidney) can acilitate the clearance o drugs
and/or metabolites rom the systemic circulation, e ux
transporters in non-eliminating organs such as the central
nervous system and placenta primarily unction to minimize
the exposure o the brain and the developing etus, respec-
tively, to potentially harm ul exogenous substrates. In some
cases, intestinal e ux transporters expressed at the apical
membrane o the enterocyte can limit the oral bioavailabil-
ity o drugs; in other cases, uptake transporters expressed at
this membrane can aid in the systemic absorption o com-
pounds, thereby enhancing their oral bioavailability. Trans-
porter unction in the liver o ten acilitates drug clearance,
but e f cient active uptake into the liver a ter an oral dose can
also a ect drug bioavailability by contributing to f rst-pass
hepatic metabolism and elimination. Because drugs can both
56
ngg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
He pato
He t c yte
t
inhibit and induce transporters, concurrent administration o
multiple drugs may alter the pharmacokinetics and pharma-
codynamics o the other compounds depending on trans-
porter a f nity, specif city, and alternate mechanisms o drug
disposition. There ore, identi ying the specif c transporter(s)
or which a novel drug is a substrate (or inhibitor) may not
only help to devise optimization and ormulation strategies
that improve drug bioavailability and e f cacy, but may also
prevent adverse e ects by anticipating and limiting drug
drug interactions. There are over 400 transporters in the
human genome. This chapter provides an overview o this
e ective but complex system by ocusing on a select number
o well-characterized transporters involved in drug disposi-
tion and in the ux o endogenous substrates and on those
that may become the sites o drugdrug interactions.
The Human Genome Organisation (HUGO) Gene No-
menclature Committee (HGNC) has approved standard acro-
nyms or both solute carrier (SLC) and ATP-binding cassette
(ABC) amilies o transporters. However, many drug trans-
porters, especially those discussed in greater detail in this
chapter, were initially cloned and named based on their phar-
macologic attributes such as substrate specif city and asso-
ciation with drug resistance. For instance, the ABCB1 gene
was originally named and is more commonly re erred to as
P-glycoprotein (P-gp) because it was initially identif ed as a
glycoprotein that controls cell membrane permeability (P).
Ensuing studies have also led to its characterization as a
multidrug resistance (MDR) protein encoded by the MDR1
gene. There ore, P-gp, MDR1, and ABCB1 are all synonyms
or the same transporter. In this chapter, the transporters are
re erred to using popular names, with HGNC nomenclature
 C h a p t e r 5 Drug Transporters 57

Mr. H is a 47-ye a r-o ld m ild ly ove rw e ig h t s ta rtin g th e n e w m e d ica tio n p re s crib e d to h e lp co n -

m a n w h o co m e s to th e wa lk-in clin ic
co m p la in in g o m u s cle p a in a n d w e a k-
n e s s in h is a rm s a n d le g s . He h a s b e e n
ta kin g a s ta tin m e d ica tio n o r th e p a s t
4 ye a rs a n d h a s b e e n a b le to m a n a g e h is ch o le s te ro l
le ve ls e e ctive ly w ith th is m e d ica tio n a n d d ie t m o d i-
f ca tio n s . Wh e n a s ke d a b o u t a ny re ce n t ch a n g e s to
h is m e d ica tio n s o r d ie t, h e in d ica te s th a t h is p rim a ry
ca re p hys icia n s ta rte d h im 3 w e e ks a g o o n m e d ica l
th e ra p y to h e lp co n tro l h is trig lyce rid e le ve ls . In a d -
d itio n to th e re ce n t m u s cle p a in , Mr. H h a s n o tice d
a m ild ra s h o n h is to rs o ove r th e p a s t 3 w e e ks s in ce
tro l h is trig lyce rid e s .
Questions
1 . Without knowing the speci c medications that Mr. H is
taking, which drugdrug interactions do you suspect
might be contributing to his new symptoms?
2 . Consultation with Mr. Hs primary care physician re-
veals that Mr. H is also taking a xed-dose combina-
tion o lopinavir/ritonavir to manage his HIV in ection.
How might this complicate the drugdrug interaction
suspected in question 1?

Intestinal epithelial cell Brain capillary endothelial cell

e
in

ENT1, ENT2
st
te
In

MDR1 (P -gp)
MCT1 BCRP
AS BT

B
MRP 2

ra
in
P EP T1, P EP T2
ENT2
OATP
MRP 3 OATP 1A2, MDR1 (P -gp)
ENT1, ENT2 OATP 2B1
BCRP

MRP 4
OS T -
OS T MRP 5
OCT1
B
d

lo
o

o
lo

d
B

OS T -OS T
NTCP
ENT2 OATP 2B1
B

OAT3
d
lo

OATP 1B3
o
lo
o
d

OAT2 MRP 6
OATP 1B1
OAT1
ENT1, ENT2
OCT2 MDR1
OAT7 (P -gp)
OATP 4C1
MDR1 (P -gp) OAT2
ENT1 BS EP
MATE1, MATE2-K OCT1
OCTN2
MRP 2, MRP 4
MATE1
ile

BCRP
B

P EP T1, P EP T2 MRP 4
MRP 2
U

URAT1 MRP 3
ri

ENT1
n
e

OAT4

Kidney proximal tubule cell Hepatocyte

FIGURE 5-1. Major transporters of drugs and endogenous compounds in the intestine, kidney, liver, and bloodbrain barrier. Uptake transporters are
shown in blue and e f ux transporters are shown in red. Bidirectional transport is denoted by double arrows. See text or abbreviations.
58 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

and other acronyms stated in parentheses. Additional de- Extra ce llula r s pa ce

tails on nomenclature and synonyms/previous names can be
ound at http://www.genenames.org/gene amilies/ABC and
http://www.genenames.org/gene amilies/SLC. P rote in cha nne l

UPTAKE AND EFFLUX TRANSPORTERS Ce ll

me mbra ne
Drugs and endogenous compounds cross cellular membrane
barriers by simple di usion, passive transport, or active Ca rrie r prote ins
transport. Simple di usion (also called passive diffusion)
can occur when small, partially water-soluble solutes such as
certain polar lipids pass reely through a membrane bilayer, Intra ce llula r s pa ce
driven by their concentration gradient across the membrane
(Fig. 5-2). However, many molecules require the assis- FIGURE 5-3. Passive transport. In this process, protein channels or carrier
tance o membrane transporters to move across membranes. proteins acilitate the transport o substrates down their concentration gradient.
Solute carriers acilitate the passive transport o substrates
down their concentration gradient (Fig. 5-3). In contrast,
exception o OST -OST (which transports bile acids; see
the transport o substrates against their concentration gra-
below), all known uptake transporters lack ATPase activity
dient requires active transporters (Fig. 5-4). Primary active
and belong to the solute carrier (SLC) amily. Secondary or
transport utilizes the energy o hydrolysis o adenosine tri-
tertiary active transport mechanisms are required or cel-
phosphate (ATP); the substrate f rst binds to the transporter,
lular absorption o many drugs, nutrients, and endogenous
and substrate transport across the membrane is completed
metabolites. The next section outlines the transporters that
upon ATP-mediated activation o the transporter (Fig. 5-4A).
have essential roles in the uptake o drugs and endogenous
Secondary active transport depends on the creation o an in-
ward sodium gradient by the ATP-mediated activation o the
A
Na /K -ATPase pump. The inward sodium gradient drives
the coupled transport (co-transport) through a solute carrier Extra ce llula r s pa ce
Na + Na +
o sodium (down its electrochemical gradient) and o a sec- Na +/K+
ond solute (against its concentration gradient) (Fig. 5-4B). ATP a s e
This mechanism is called secondary active transport because
the transport through the solute carrier does not directly re- Ce ll
quire ATP hydrolysis but is coupled to a primary ATPase. me mbra ne
Tertiary active transport also requires an ATPase-dependent P P
sodium gradient. However, in this case, sodium in ux a- P
cilitates the di usion and intracellular accumulation o an ATP K+ ADP

anion such as bicarbonate via a secondary active transporter. K+

Intra ce llula r s pa ce
In the f nal step o tertiary active transport, the solute car-
rier exports the intracellular anion in exchange or the up- B
take o an extracellular organic anion (Fig. 5-4B). With the K+ Na+ Na+ HCO 3 - HCO 3 - OA-

Extra ce llula r
s pa ce Na +/K+ S ymporte r Antiporte r
ATP a s e

ATP ADP

K+ Na + Na + HCO3- HCO3- OA-

P rima ry S e conda ry Te rtia ry
Ce ll
me mbra ne
FIGURE 5-4. Active transport. The transport o substrates against their con-
centration gradient requires active transporters. A. Primary active transport.
In this process, the energy o hydrolysis o adenosine triphosphate (ATP) is
used to transport solutes against their concentration gradients; or example,
the Na /K -ATPase pump drives sodium (outward) and potassium (inward)
Intra ce llula r against their concentration gradients. B. Secondary and tertiary active
s pa ce transport. In secondary active transport, the creation o an inward sodium
gradient by the ATPase-mediated activation o the Na /K -ATPase drives
the coupled transport (co-transport) through a solute carrier (symporter) o
Time sodium (down its concentration gradient) and a second solute (against its
concentration gradient). Here, the second solute is bicarbonate (HCO3 ). In
FIGURE 5-2. Simple diffusion. In this process, small, partially water- tertiary active transport, a second solute carrier (antiporter) acilitates the
soluble solutes pass reely through a membrane bilayer, driven by their export o the second solute (here, HCO3 ) in exchange or the uptake o an
concentration gradient across the membrane. This process is also called extracellular organic anion (OA ). Font size ref ects the relative concentra-
passive diffusion. tion o the solute in the extracellular space and the intracellular space.

compounds in key tissues that are involved in the absorp-
tion, distribution, and elimination o drugs. These tissues in-
clude the intestine, liver, kidney, and endothelial cells o the
bloodbrain barrier.
Uptake Transporters
Organic Anion-Transporting Polypeptide
(OATP) Family
OATPs (SLCO, ormer SLC21) are expressed in all epithe-
lial cells. These transporters acilitate the uptake o large
hydrophobic and amphiphilic organic compounds, such as
bile acids, thyroid hormones, conjugated steroids, and eico-
sanoids (Table 5-1). Although OATPs are primarily respon-
sible or the transport o anionic compounds, some members
o the OATP amily transport bulky type II organic cations
such as rocuronium. The accumulation o substrates such
as bile acids within the liver is a concentrating process,
and OATPs move substrates into cells by a tertiary active
transport mechanism. O the 11 amily members, 5 have
been implicated in the transport o xenobiotics. OATP1B1,
OATP1B3, and OATP2B1 mediate the uptake o drugs (e.g.,
statins ) across the sinusoidal membrane o hepatocytes,
whereupon the drugs can be metabolized by enzymes such
as cytochrome P450s (CYPs) and/or secreted into the bile
or back into the systemic circulation (Fig. 5-1). Inhibition
o hepatic OATPs has been implicated as a potential mecha-
nism o drugdrug interactions. The potential or these in-
teractions has resulted in revised dosing guidelines or some
statins when they are administered with drugs that inhibit
OATPs (e.g., cyclosporine , gemf brozil, lopinavir/ritonavir).
OATP1A2 is ubiquitously expressed and contributes primar-
ily to drug absorption rom the intestinal lumen into intesti-
nal epithelial cells. OATP4C1 acilitates the uptake o drugs
such as digoxin rom the circulation into kidney proximal tu-
bule cells, rom which the drugs are eliminated via the urine
(Fig. 5-1).
In the introductory case, Mr. H was most likely started
on a drug that inhibited the hepatic uptake o his statin, and
thereby increased the systemic bioavailability o the statin,
via a transporter-related drugdrug interaction. Fibrates
such as gemf brozil are commonly used to reduce triglycer-
ide levels when statins and diet modif cation prove insu f -
cient. Concurrent administration o statins with gemf brozil
can cause myopathy, however, in part due to inhibition o
OATP1B1-mediated hepatic uptake o statins by gemf bro-
zil. This drugdrug interaction results in increased blood
levels o the statin and consequent systemic toxicity. Mr. H
was also taking a f xed dose o lopinavir/ritonavir, which is
an inhibitor o OATP1B1- and OATP1B3-mediated drug up-
take into the liver; this combination o HIV protease inhibi-
tors may have urther contributed to drugdrug interactions
and exacerbated systemic adverse e ects o Mr. Hs statin
a ter initiation o treatment or hypertriglyceridemia.
Organic Anion Transporter (OAT) Family
OATs, which belong to the SLC22A amily, mediate the
cellular uptake o small organic anions such as conjugated
steroids, biogenic amines, and cGMP as well as a broad
range o xenobiotics such as antivirals, antibiotics, ACE
inhibitors, and anticancer drugs (Table 5-1). Despite their
classif cation as uptake transporters, OAT iso orms 14 and
7 have essential roles in drug clearance by acilitating the
C h a p t e r 5 Drug Transporters 59
uptake o drugs rom the systemic circulation into the liver
and kidneys, where they can be metabolized and excreted
(Fig. 5-1). Uptake o anions into cells against their elec-
trochemical gradient requires OATs to unction as tertiary
active transporters. OAT1, OAT3, and OAT4 exchange in-
tracellular 2-oxoglutarate, and OAT7 exports intracellular
short-chain atty acids such as butyrate in exchange or their
extracellular substrates. OAT1, OAT2, and OAT3 clear many
organic anions rom the systemic circulation into the kid-
ney proximal tubule, rom which the anions are eliminated
in the urine. OAT2 and OAT7 are expressed mainly on the
sinusoidal membrane o hepatocytes. Unlike OAT1, OAT2,
and OAT3, OAT4 and the urate anion exchanger 1 (URAT1)
are expressed on the apical (brush border) membrane o the
kidney proximal tubule, where they mediate the reabsorption
o uric acid rom urine. There ore, drugs that inhibit OAT4
and URAT1 may decrease blood uric acid levels and thereby
provide therapeutic benef t (e.g., in the treatment o gout by
the URAT1 inhibitor probenecid; see Chapter 49, Integra-
tive In ammation Pharmacology: Gout) and may potentially
cause enhanced elimination o OAT4 substrates.
Organic Cation Transporter (OCT) Family
Like OATs, OCTs belong to the SLC22A amily and con-
tribute to the renal clearance o xenobiotics such as antiviral
drugs. OCTs also mediate the transport o a diverse group
o small organic cations such as catecholamines, hormones,
and neurotransmitters (Table 5-1). Transport o cations by
OCTs occurs down the electrochemical gradient o the sol-
ute and does not depend on ATP hydrolysis or ion exchange;
instead, the transport is thought to be driven by di erences
in membrane potential. OCT iso orms can have overlapping
substrates, and the transport o solutes can be bidirectional
depending on the electrochemical gradient. There is strong
evidence or the roles o OCT1, OCT2, and OCT3 in drug
disposition (Table 5-1; Fig. 5-1). OCT1 is highly expressed
in the sinusoidal (basolateral) membrane o hepatocytes.
OCT2 is expressed mostly in the kidney proximal tubule and
it contributes to the uptake o metabolites rom the blood
into the tubule. In contrast, OCT3 exhibits broad tissue dis-
tribution; its highest expression is in the intestine, liver, and
kidney, where it acilitates intestinal absorption and hepatic
and renal secretion o drugs, respectively. All three trans-
porters mediate the uptake o a wide array o therapeutic
agents, including sedatives, antidepressants, -blockers,
and antidiabetic drugs such as met ormin. OCTs are also an
important site o drugdrug interactions. In certain cases,
OCT-mediated renal uptake can contribute to the adverse
e ects o nephrotoxic drugs, which can be prevented by the
concomitant administration o an OCT inhibitor.
Bile Acid Transporters
A signif cant raction o bile acids are recycled via three
main transporter mechanisms in the liver and gastrointesti-
nal (GI) tract. Na /taurocholate co-transporting polypeptide
(NTCP, SLC10A1) is exclusively expressed at the sinusoi-
dal membrane o hepatocytes and is a key mechanism in the
transport o conjugated and unconjugated bile acids rom the
circulation into the liver (Fig. 5-1). Whereas OATPs are re-
sponsible or the sodium-independent uptake o bile acids,
NTCP is responsible or sodium-dependent secondary ac-
tive bile acid transport that is coupled to the activation o
Na /K -ATPase. In addition to bile acids, NTCP mediates
60 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

TABLE 5-1 Uptake Transporters

ORGAN/LOCATION ENDOGENOUS
TRANSPORTER (SEE FIG. 5-1) SUBSTRATES DRUG SUBSTRATES INHIBITORS
OATP1B1 (SLCO1B1) Hepatocytes Steroid hormones, Repaglinide, valsartan, olmesartan, Saquinavir, ritonavir,
(sinusoidal) thyroid hormones, cerivastatin, pitavastatin, lopinavir, ri ampicin,
bilirubin glucuronide, rosuvastatin, temocaprilat, enalapril cyclosporine, gem brozil,
bilirubin, bile acids, clarithromycin
prostaglandin E2

OATP1B3 (SLCO1B3) Hepatocytes Steroid hormones, Pitavastatin, rosuvastatin, Ri ampicin, cyclosporine,

(sinusoidal) bile acids exo enadine, valsartan, ritonavir, lopinavir,
telmisartan, olmesartan, enalapril, erythromycin
erythromycin, valsartan

OATP1A2 (SLCO1A2) Brain, kidney, Bile salts, cholic
liver, intestine, acid, DHEAS,
endothelium prostaglandin E2,
taurocholate, bilirubin,
conjugated steroids,
peptides
Aliskiren, erythromycin, exo enadine,
imatinib, levof oxacin, lopinavir,
methotrexate, rosuvastatin,
pitavastatin, ouabain, saquinavir,
sul obromophthalein, unoprostone,
acebutolol, atenolol, atrasentan,
celiprolol, sotalol, talinolol,
tebipenem, digoxin
Naringin, hesperidin,
quercetin, ritonavir,
lopinavir, saquinavir,
ri ampicin, ri amycin,
verapamil, apigenin

OATP2B1 (SLCO2B1) Hepatocytes Bile acids, steroid Glyburide, rosuvastatin, exo enadine, Ri ampin, cyclosporine,
(sinusoidal), hormones, bosentan, ri ampicin naringin, hesperidin,
placenta, heart, taurocholate quercetin
brain, kidney, lung,
small intestine,
endothelium

OAT1 (SLC22A6) Kidney proximal Uric acid, olate,
tubule, placenta cyclic nucleotides,
prostaglandins E2
and F2
Ade ovir, cido ovir, zidovudine, Probenecid, novobiocin
lamivudine, zalcitabine, acyclovir,
teno ovir, ciprof oxacin,
cephaloridine, methotrexate,
pravastatin

OAT3 (SLC22A8) Kidney proximal Uric acid, bile acids, Nonsteroidal anti-inf ammatory Probenecid, novobiocin
tubule, choroid prostaglandins drugs (NSAIDs), exo enadine,
plexus, blood methotrexate, ce tizoxime, ce aclor
brain barrier

OCT1 (SLC22A1) Hepatocytes Choline, acetylcholine, Met ormin, oxaliplatin, acyclovir, Quinine, quinidine,
(sinusoidal), monoamine ganciclovir disopyramide, cimetidine,
intestine (apical), neurotransmitters atropine, prazosin
neurons

OCT2 (SLC22A2) Kidney proximal Choline, acetylcholine,
tubule, neurons monoamine
neurotransmitters,
creatinine, bile acids
Met ormin, pindolol, procainamide,
ranitidine, amantadine, amiloride,
oxaliplatin, varenicline, cisplatin,
debrisoquine, propranolol,
guanidine, D-tubocurarine,
pancuronium
Cimetidine, pilsicainide,
cetirizine, testosterone,
quinidine, ri ampicin,
naringin, ritonavir

OCT3 (SLC22A3) Liver, kidney, Creatinine, guanidine, Atropine, prazosin, diphenhydramine, Cimetidine, quinidine,
placenta, small neurotransmitters, ranitidine, amantadine, ketamine, ri ampicin, prazosin,
intestine hormones memantine, phencyclidine, phenoxybenzamine,
nicotine, clonidine, dizocilpine, corticosterone,
met ormin, cimetidine, verapamil, progesterone, -estradiol
procainamide, D-amphetamine

PEPT1 (SLC15A1) Kidney proximal Dipeptides and Cephalexin, ce adroxil, bestatin, Glycylproline,
tubule, intestinal tripeptides enalapril, captopril, valacyclovir, 4 -aminomethylbenzoic acid
enterocytes -lactam antibiotics, ACE inhibitors

PEPT2 (SLC15A2) Kidney proximal Dipeptides, tripeptides Cephalexin, ce adroxil, ubenimex, Zo enopril, osinopril,
tubule, choroid valacyclovir, enalapril, captopril, ce adroxil, captopril,
plexus, lung -lactam antibiotics, ACE inhibitors losartan

ORGAN/LOCATION ENDOGENOUS
TRANSPORTER (SEE FIG. 5-1) SUBSTRATES
NTCP (SLC10A1) Hepatocytes Taurocholate, bile salts,
(sinusoidal) steroids, thyroid
hormones
ASBT (SLC10A2) Intestine Taurocholate, bile acids
OST -OST Intestine (apical), Bile acids
hepatocytes
(sinusoidal)
Data compiled rom: Giacomini KM, Huang SM, Tweedie DJ , et al.; International Transporter Consortium. Membrane transporters in drug development. Nat Rev Drug Discov
2010;9:215236. Knowledge Center, Solvo Biotechnology; http://www.solvobiotech.com/knowledge-center. Knig J , Mller F, Fromm MF. Transporter and drugdrug interactions:
important determinants o drug disposition and e ects. Pharmacol Rev 2013;65:944966. US Food and Drug Administration. Drug development and drug interactions: table o
substrates, inhibitors, and inducers. http://www. da.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm.
partial uptake o some statins (e.g., rosuvastatin; Table 5-1).
The apical sodium-dependent bile acid transporter (ASBT,
SLC10A2) is expressed at the apical membrane o the ep-
ithelial cells o the distal small intestine and mediates the
uptake o bile acids rom the intestinal lumen (Fig. 5-1,
Table 5-1). OST -OST is the only uptake transporter that
does not belong to the SLC amily. It comprises a heterodi-
mer o two di erent subunits and can unction as either an
e ux transporter or an uptake transporter depending on
the electrochemical gradient o its substrates. However, the
major unction o the transporter is to contribute to the en-
terohepatic recirculation o bile acids: OST -OST medi-
ates the e ux o bile acids and conjugated steroids rom
intestinal epithelia into the circulation, rom which the bile
acids are taken up by hepatocytes (Fig. 5-1, Table 5-1).
Peptide Transporter (PEPT) Family
PEPT amily transporters (SLC15A) are proton-driven sym-
porters that are highly expressed in the intestine and kidney.
PEPT1 has a key role in the absorption o dietary nitrogen,
in the orm o dipeptides and tripeptides, rom the lumen o
the small intestine into enterocytes. Peptide-like metabolites
or drugs such as -lactam antibiotics and ACE inhibitors ex-
hibit high bioavailability due largely to PEPT1-mediated ab-
sorption (Table 5-1). Both PEPT1 and PEPT2 are expressed
in the kidney, where they mediate reuptake o small peptides
at the apical membrane o the kidney proximal tubule and
regulate systemic nitrogen balance (Fig. 5-1).
Concentrative and Equilibrative Nucleoside
Transporter (CNT and ENT) Families
CNT (SLC28) amily members CNT1, CNT2, and CNT3
mediate sodium-dependent uptake o nucleosides by epithe-
lial cells. CNT1 and CNT2 specif cally transport pyrimidine
and purine nucleosides, respectively, whereas CNT3 is
capable o transporting both classes o nucleosides. In con-
trast, ENT (SLC29) amily members provide bidirectional
transport o purine and pyrimidine nucleosides. The direction
o ENT-mediated transport depends on the concentration
C h a p t e r 5 Drug Transporters 61
DRUG SUBSTRATES INHIBITORS
Rosuvastatin Cyclosporine, gemf brozil,
propranolol, urosemide,
ketoconazole, ri amycin,
glibenclamide, ritonavir,
bosentan, e avirenz,
saquinavir
Dimeric bile acid analogues Dihydropyridine, calcium
channel blockers, statins
Digoxin, rosuvastatin Ri amycin SV
gradient o the nucleosides and unctions to equilibrate ex-
tracellular and intracellular nucleoside levels. Whereas intra-
cellular nucleoside accumulation contributes to nucleotide
synthesis, CNT- and ENT-mediated nucleoside uptake may
also limit the activation o extracellular nucleoside signal-
ing events, such as the activation o adenosine receptors.
In addition to endogenous nucleosides, CNTs and ENTs
transport nucleoside analogues such as cytotoxic anticancer
(e.g., gemcitabine ) and antiviral (e.g., zidovudine ) drugs.
There ore, actors or compounds that reduce the expression
or activity o these transporters on target tissues may reduce
the e f cacy o nucleoside anticancer and antiviral drugs.
Glucose Transporters
The glucose transporter amily (GLUT, SLC2) regulates
the distribution o glucose between the plasma and tissues.
Among the several amily members, GLUT14 iso orms are
the most studied and most relevant to glucose metabolism.
GLUT1 has broad tissue expression and is responsible or
sustaining basal cellular glucose levels with a slow uptake
rate. GLUT2 is expressed in the organs that participate in
the regulation o plasma glucose levels, such as kidney,
liver, intestine, and pancreas. GLUT2 mediates the uptake
o dietary glucose in the intestine. Because it has relatively
low a f nity or glucose, GLUT2 acts as a sensor or glucose
levels within the pancreatic beta cells that secrete insulin
in response to increases in plasma glucose. GLUT2 exhib-
its bidirectional transport capability, allowing or the in ux
or e ux o glucose across the cell membrane. The e ux
transporter activity o GLUT2 at the sinusoidal membrane
o hepatocytes is essential or the transport o glucose pro-
duced in the liver into the plasma in order to maintain plasma
glucose homeostasis during starvation or asting. GLUT3 is
enriched in neurons; it exhibits high relative a f nity or glu-
cose in order to provide a constant in ux o glucose rom the
circulation into neuronal cells, even at low plasma glucose
concentrations. GLUT4 mediates insulin-sensitive glucose
uptake and storage in the adipose tissue and striated muscle.
Under conditions o low plasma insulin concentrations, such
62 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
as asting, GLUT4 is sequestered in intracellular vesicles
and does not transport glucose. Insulin stimulation causes
GLUT4 to translocate to the plasma membrane, where it ini-
tiates glucose uptake (see Fig. 31-4).
Sodium glucose transport protein (SGLT, SLC5) amily
members 1 and 2 are symporters that transport glucose
against its concentration gradient via a secondary active
mechanism. SGLT1 at the intestinal brush border and
SGLT1 and SGLT2 at the kidney proximal tubule brush
border mediate glucose absorption rom the intestinal lumen
and the renal f ltrate, respectively. In turn, GLUT2 e ux
activity at the apical membrane o these tissues acilitates
glucose transport rom the cells into the circulation. SGLT2
is responsible or more than 90% o glucose reuptake rom
the renal f ltrate, and inhibition o SGLT2 reduces plasma
glucose levels. SGLT2 has been targeted or pharmacologic
intervention in the management o diabetes. Dapaglif ozin
selectively inhibits SGLT2 over SGLT1; this selective inhi-
bition acilitates reduction o plasma glucose levels without
impairing SGLT1-mediated intestinal glucose absorption,
potentially limiting adverse e ects such as diarrhea that may
be associated with elevated intestinal glucose levels.
E f ux Transporters
Oral drug administration generally provides the most con-
venient and a ordable route or the systemic delivery o
therapeutic agents; high, reproducible oral bioavailability
minimizes variability in drug exposure across patient popula-
tions. A ter oral administration, drugs typically are absorbed
rom the intestinal lumen, delivered into the mesenteric
blood supply, and then circulated through the hepatic portal
system via the portal vein be ore entering the systemic circu-
lation (see Chapter 3, Pharmacokinetics). E ux transport-
ers can a ect oral bioavailability (1) by limiting the amount
o drug that is absorbed across the enterocyte and/or (2) by
transporting drug rom the liver into the bile and thereby
contributing to a f rst-pass e ect. Whereas e ux transport-
ers expressed on the canalicular membrane o the hepatocyte
acilitate the excretion o xenobiotics into the bile, e ux
transporters expressed on the sinusoidal (basolateral) mem-
brane can promote the ux o drug and metabolites back
into the systemic circulation (Fig. 5-1). Compounds elimi-
nated into the bile across the canalicular membrane o the
hepatocyte are concentrated in the gall bladder and released
into the small intestine, where both parent drug and possibly
metabolites can be absorbed across the intestine (a process
known as enterohepatic recirculation) or eliminated into the
eces. However, the same f rst-pass mechanisms (i.e., ab-
sorption, e ux, metabolism, and biliary excretion) that lim-
ited the compounds ability to reach the systemic circulation
and the peripheral tissues still exist. The oral bioavailability
o compounds that undergo extensive enterohepatic recircu-
lation may appear extremely low; however, in cases where
the target tissue is either the liver (e.g., statins) or intestine,
these compounds may have desired pharmacologic e ects
despite limited systemic exposure. For drugs that are high-
a f nity substrates or intestinal and hepatic transporters, al-
ternative routes o administration (such as intravenous and
subcutaneous) can circumvent the f rst-pass e ect and pos-
sibly increase the systemic exposure. However, even when
drug delivery is used to avoid a f rst-pass e ect, the drugs
that reach the systemic circulation must nevertheless transit
through the hepatobiliary system and may still be cleared
rapidly due to e f cient drug e ux processes. Compounds
in the systemic circulation can also be eliminated in the kid-
ney via active e ux into the urine. Because the transport
o compounds rom within the intracellular space is o ten
against a concentration gradient, the process requires active
transport; the majority o e ux pumps belong to the ATP-
binding cassette (ABC) amily o active transporters. This
section outlines the e ux transporters that have major roles
in drug disposition as well as those that acilitate the trans-
port o endogenous compounds.
ATP-Binding Cassette (ABC) Transporter Family
ABC transporters constitute the largest transporter super-
amily. They are active transporters that mediate e ux o
various substratessuch as phospholipids, steroids, and
drugsout o cells against their concentration gradient. The
super amily is divided into seven amilies, o which only
members o the ABCB, ABCC, and ABCG amilies have es-
sential roles in drug disposition. ABCA and ABCD proteins
transport only endogenous substrates and regulate cellular
cholesterol and atty acid metabolism, and ABCE and ABCF
amily members lack transmembrane domains and are not
involved in the transport o drugs or endogenous compounds
across the membranes o cells.
P-Glycoprotein and Bile Salt Export Pump (ABCB Family)
The ABCB amily, also known as multidrug resistance/
transporters associated with antigen processing (MDR/
TAP), consists o 11 members and includes perhaps the
most studied drug transporter, P-glycoprotein (P-gp, also
known as MDR1 or ABCB1). P-gp was initially discovered
and characterized as a protein that mediates anticancer drug
resistance. Its expression is elevated in many cancer cells,
and P-gp contributes to multidrug resistance against anti-
neoplastic therapeutics. P-gp is also expressed in the apical
membrane o the small intestine, liver, kidney, endothelial
cells o the bloodbrain barrier, and placenta (Fig. 5-1), and
it both limits exposure o substrates to certain organs and
serves as a mechanism to eliminate xenobiotics rom the
body. P-gp has broad substrate specif city and it exhibits
high a f nity or cationic and amphiphilic compounds such
as phospholipids (Table 5-2).
Although P-gp may have evolved as a de ense mecha-
nism to protect organisms against exogenous toxins, other
ABCB amily members such as MDR3 are important or
phospholipid homeostasis in cell membranes. The bile salt
export pump (BSEP, ABCB11) is an ABCB e ux trans-
porter that is expressed at high levels on the hepatocyte
canalicular membrane (Fig. 5-1). BSEP acilitates transport
o bile salts and bile salt conjugates such as taurocholate
rom hepatocytes into the bile, and bile ow rate is largely
regulated by the activity o BSEP. BSEP has also been
shown to export statins such as pravastatin into the bile; by
this mechanism, such drugs may be cleared rom the liver
(Table 5-2). Although its interaction with pravastatin sug-
gests that BSEP may play a role in drug disposition, a more
immediate concern is that a xenobiotic can inhibit BSEP
and potentially contribute to cholestasis and intracellular
accumulation o bile acids in hepatocytes. Clinical studies
suggest that the endothelin receptor antagonist bosentan
inhibits BSEP and may thereby induce cholestasis due to
intracellular accumulation o cytotoxic bile salts.
 C h a p t e r 5 Drug Transporters 63

TABLE 5-2 E f ux Transporters

ORGAN/LOCATION ENDOGENOUS
TRANSPORTER (SEE FIG. 5-1) SUBSTRATES DRUG SUBSTRATES INHIBITORS
P-gp (MDR1, Intestine (apical), Steroids, phospholipids, Digoxin, loperamide, quinidine, Cyclosporine, quinidine,
ABCB1) kidney proximal bilirubin, bile acids vinblastine, talinolol, berberine, tariquidar, verapamil,
tubule, irinotecan, doxorubicin, ketoconazole, nel navir,
hepatocytes paclitaxel, exo enadine, seliciclib, ritonavir, tacrolimus,
(canalicular), telithromycin, clarithromycin valspodar, saquinavir,
bloodbrain barrier elacridar, reserpine

MDR3 (ABCB4) Liver (canalicular) Phosphatidylcholine Digoxin, paclitaxel, vinblastine Verapamil, cyclosporine

BSEP (ABCB11) Liver (canalicular) Bile acids, taurocholate Pravastatin, vinblastine Bosentan, cyclosporine,
ri ampin, glibenclamide,
glyburide

BCRP (ABCG2) Intestine, liver Uric acid, vitamins, dietary Daunorubicin, doxorubicin, topotecan, Elacridar, imatinib,
(canalicular), f avonoids, porphyrins, irinotecan, methotrexate, imatinib, novobiocin, estrone,
breast, placenta, estrone 3-sul ate rosuvastatin, sul asalazine, 17 -estradiol, ritonavir,
bloodbrain nucleoside analogues omeprazole
barrier, stem cells

MRP2 (ABCC2) Intestine, liver, kidney, Bilirubin, cholecystokinin, Glutathione and glucuronide Cyclosporine, delavirdine,
brain estrone 3-sul ate, conjugates, indinavir, cisplatin, e avirenz, emtricitabine,
glutathione and methotrexate, etoposide, benzbromarone
glucuronide conjugates mitoxantrone, valsartan, olmesartan

MRP3 (ABCC3) Intestine (brush Bile salts, estradiol- Etoposide, methotrexate, teniposide, Delavirdine, e avirenz,
border), liver 17 -glucuronide, exo enadine, glucuronide emtricitabine, lamivudine,
(sinusoidal), leukotriene C4 conjugates, acetaminophen, teno ovir, indomethacin,
kidney, placenta, vincristine urosemide, probenecid,
adrenal gland nevirapine

MRP4 (ABCC4) Prostate, kidney, Taurocholate, cAMP, Acyclovir, ritonavir, teno ovir, Indomethacin, MK571,
placenta, liver, cGMP, urate, DHEAS, topotecan, PMEA, methotrexate, diclo enac, celecoxib,
bloodbrain barrier prostaglandins E1 urosemide, ce tizoxime, ce azolin, sul npyrazone, quercetin
and E2 6-mercaptopurine

MATE1 (SLC47A1) Kidney proximal Creatinine, guanidine, Met ormin, cephalexin, acyclovir, Quinidine, cimetidine,
tubule, liver nucleosides ganciclovir, exo enadine, verapamil, procainamide
(canalicular), oxaliplatin
skeletal muscle

MATE2-K Kidney proximal Estrone sul ate, creatinine Met ormin, cimetidine, procainamide Cimetidine, quinidine,
(SLC47A2) tubule pramipexole

Data compiled rom same sources as in Table 5-1.

Multidrug Resistance-Associated Proteins (ABCC Family)
The ABCC amily, also known as the multidrug resistance-
associated protein (MRP/CFTR) family, consists o 9 mem-
bers that exhibit high specif city or organic anions such
as glutathione- and glucuronide-conjugated drugs. ABCC
amily members are localized to the apical and basolat-
eral membranes o hepatocytes, enterocytes, kidney proxi-
mal tubule, endothelial cells o the bloodbrain barrier, and
placenta (Fig. 5-1). Similar to P-gp, MRPs are abundantly
expressed in tumors and cause resistance to anticancer drugs.
MRP2 mediates hepatobiliary clearance o drugs including
methotrexate and statins. In addition to its expression on the
canalicular membrane o hepatocytes, MRP2 is expressed on
the apical membrane o the intestine and the kidney proximal
tubule. In contrast, MRP3 and MRP4 are expressed on the
basolateral membrane o the liver and are responsible or the
transport o compounds rom the liver back into the blood.
Several pathophysiologic consequences o hereditary MRP
def ciency have been reported, the most notable o which
is Dubin-J ohnson syndrome . In this syndrome, MRP2 de-
f ciency results in the clinical mani estation o conjugated
hyperbilirubinemia. MRPs transport not only exogenous mol-
ecules but also a wide array o endogenous compounds such
as leukotrienes, bilirubin glucuronides, prostaglandins, cAMP,
cGMP, and steroids (Table 5-2). Moreover, MRPs likely have
a role in the disposition and elimination o drug metabolites,
especially charged anionic glucuronide and sul ate conjugates.
The cystic f brosis transmembrane conductance regulator
(CFTR) is also a member o the ABCC amily. CFTR transports
chloride ions across the membrane o mucus-secreting epithe-
lial cells in the lung, digestive system, pancreas, reproductive
system, and other organs and tissues. Mutations in CFTR dis-
rupt chloride transport, which leads to impaired mucus orma-
tion and ow, and are the cause o cystic f brosis in humans.
64 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Breast Cancer Resistance Protein (ABCG Family)
Among the f ve ABCG amily members, breast cancer resis-
tance protein (BCRP, ABCG2) is the only one implicated in
the disposition o drugs and xenobiotics (Table 5-2). BCRP
is expressed in several tissues, including the intestinal tract,
bloodbrain barrier, liver canalicular membrane, kidney prox-
imal tubule, testis, and placenta (Fig. 5-1). The substrate spec-
if city o BCRP overlaps with that o P-gp; as such, BCRP can
enhance the xenobiotic barrier unction where these transport-
ers are co-expressed. Despite its name, BCRP has relatively
low levels o expression in breast cancers, but it has been
shown to con er drug resistance in several other tumor types
(e.g., leukemia, lung cancer, and melanoma). In addition to its
role in drug disposition, BCRP exports urea into the urinary
tract and mediates secretion o vitamins into breast milk.
Other ABCG amily members are involved in endogenous
unctions (see Chapter 20, Pharmacology o Cholesterol and
Lipoprotein Metabolism). ABCG5 and ABCG8 orm a het-
erodimer that controls biliary sterol and lipid secretion in
the canalicular membrane o the liver as well as clearance
o sterols in the small intestine. ABCG1 promotes e ux o
cholesterol rom macrophages to high-density lipoprotein
(HDL) particles.
ABCA and ABCD Families
ABCA and ABCD amily members mediate the transport
o endogenous substrates. For example, ABCA1 o the
ABCA amily mediates cellular lipid e ux by transporting
cholesterol and phospholipids out o hepatocytes and mac-
rophages, contributing to the biogenesis o HDL. ABCD
transporters are expressed on the membrane o peroxisomes
and regulate atty acid uptake by these organelles. This sug-
gests that some transporters may have evolved to regulate
tra f cking o endogenous compounds between plasma and
tissues and to eliminate toxic byproducts o cellular metabo-
lism, whereas a subset o transporters may have adapted to
also promote the elimination o nutrients, xenobiotics, and
their metabolites.
Solute Carrier (SLC) Family
Multi-Antimicrobial Extrusion Protein (MATE) Family
Multi-antimicrobial extrusion proteins, also known as mul-
tidrug and toxic compound extrusion proteins (MATEs), are
a amily o multidrug e ux transporters that exhibit a f n-
ity or organic cations. They unction as proton/drug anti-
porters that import a proton into the intracellular medium
as a counterion or the export o a drug molecule out o the
cell. MATE1 (SLC47A1) is expressed on the canalicular
membrane o hepatocytes and on kidney proximal tubule
cells, where it exports exogenous compounds into bile and
urine, respectively (Fig. 5-1). MATE2-K (SLC47A2) is ex-
pressed only in the kidney proximal tubule, where it medi-
ates clearance o exogenous substrates alongside MATE1
(Fig. 5-1). Both transporters exhibit selectivity or com-
pounds that are substrates or OCTs, such as metformin and
tetraethylammonium. Their endogenous substrates include
organic cations such as guanidine and creatinine (Table 5-2).
CLINICAL PERSPECTIVES ON DRUG
TRANSPORTERS
The pharmacokinetic, pharmacodynamic, and toxicologic
properties o drugs are characterized and optimized initially
through a comprehensive series o in silico predictions, in
vitro cell culture, and membrane preparation studies and then
through in vivo animal models and clinical trials. Membrane
uptake and e ux transporters can in uence the absorption,
distribution, and excretion o xenobiotics and may there ore
have substantial impact on the e f cacy and sa ety o drugs.
Drugs can act as substrates or transporters and may also alter
the activity o transporters through inhibition or induction o
transport processes, which could result in the impaired or en-
hanced transport o endogenous substrates. Moreover, much
as in the case o drug-metabolizing enzymes, the concomi-
tant administration o several drugs can lead to drugdrug
interactions i one agent alters the transport o the other. This
could potentially reduce the clearance o the co-administered
drug, a ect the drugs oral bioavailability, and lead to ad-
verse e ects or lack o e f cacy due to unexpected changes
in drug exposure. Understanding the specif c transporters
that govern the absorption, distribution, and clearance o
new therapeutic agents will help anticipate and minimize the
unexpected impact o these mechanisms on drug disposition
and potential drugdrug interactions.
There are apparent species di erences in drug transport-
ers as well as lack o direct orthologs or some human trans-
porters (e.g., OATP1B1 and OATP1B3), and several human
transporters have there ore been cloned and expressed in
cell lines. Transgenic mouse models expressing human
transporter genes have also been created to enable pre-
clinical studies designed to help predict clinical outcomes.
These models, together with known substrates and inhibi-
tors o drug transporters (Tables 5-1 and 5-2), can aid in
understanding the clinical relevance o these mechanisms
or drug disposition.
DrugDrug Interactions
Since the discovery o P-gp as a multidrug resistance gene
against anticancer drugs, many other hydrophobic and cat-
ionic drugs have been identif ed as its substrates (Table 5-2).
The cardiac glycoside digoxin is considered to be a proto-
typical P-gp substrate, and the potential drugdrug interac-
tions due to inhibition o P-gp by novel drug entities can
be determined by measuring the plasma levels o digoxin
upon co-administration o the novel drugs. Drugs that inhibit
P-gp, such as the antiarrhythmic agent quinidine and the an-
tiviral drug ritonavir, elevate intestinal uptake and reduce
biliary and renal clearance o digoxin in vivo and thereby
increase plasma levels o digoxin (Table 5-3). Because P-gp
is the primary transporter preventing the entry o exogenous
compounds into the central nervous system, substrates or
P-gp are o ten unable to cross the bloodbrain barrier. Inhi-
bition o P-gp at the bloodbrain barrier has been reported in
some preclinical studies, but the ability to inhibit P-gp at the
human bloodbrain barrier does not yet have proven clini-
cal relevance, likely because the compounds are unable to
achieve high enough unbound concentrations in the systemic
circulation to inhibit bloodbrain barrier P-gp in vivo.
Like P-gp, BCRP was initially characterized as a multi-
drug resistance gene expressed in neoplastic cell lines. In an-
imal studies, BCRP not only limits the e f cacy o anticancer
drugs such as topotecan but also substantially reduces the
intestinal uptake o non-cancer drugs such as atorvastatin.
Elacridar is a potent BCRP inhibitor that can be used to test
whether new drugs are cleared by BCRP or to increase the
bioavailability o known BCRP substrates. For example,
 C h a p t e r 5 Drug Transporters 65

TABLE 5-3 Clinically Observed DrugDrug Interactions Due to Transporters

PHARMACOKINETIC CHANGES
TRANSPORTER INHIBITOR OR *INDUCER AFFECTED DRUG DUE TO AFFECTED DRUG
OATP1B1 (SLCO1B1) Lopinavir/ritonavir Bosentan AUC 5-48-fold
Cyclosporine Pravastatin AUC 9.9-fold, Cmax 7.78-fold
Rifampin (single dose) Glyburide AUC 2.3-fold

OATP1B3 (SLCO1B3) Cyclosporine Pitavastatin AUC 4.6-fold, Cmax 6.6-fold

Cyclosporine Rosuvastatin AUC 7.1-fold
Lopinavir/ritonavir Rosuvastatin AUC 2.1-fold, Cmax 4.65-fold

OATP1A2 (SLCO1A2) Grapefruit juice Fexofenadine AUC 2.7-fold, Cmax 2.63-fold

Orange juice Fexofenadine AUC 3.3-fold, Cmax 3-fold
Apple juice Fexofenadine AUC 3.7-fold, Cmax 3.57-fold
Naringin Aliskiren AUC 1.6-fold, Cmax 2.44-fold

OATP2B1 (SLCO2B1) Orange juice Aliskiren AUC 2.6-fold

Apple juice Aliskiren AUC 2.6-fold

OAT1 (SLC22A6) Probenecid Cephradine AUC 3.6-fold

Probenecid Cidofovir AUC 1.5-fold, CLr 1.47-fold
Probenecid Acyclovir AUC 1.4-fold, CLr 1.47-fold

OAT3 (SLC22A8) Probenecid Furosemide AUC 2.9-fold

OCT2 (SLC22A2) Cimetidine Dofetilide AUC 1.5-fold, CLr 1.5-fold

Cimetidine Pindolol AUC 1.5-fold, CLr 1.5-fold
Cimetidine Metformin AUC 1.4-fold, CLr 1.37-fold
Cimetidine Varenicline AUC 1.3-fold
Cimetidine Pilsicainide AUC 1.3-fold, CLr 1.39-fold

P-gp (MDR1, ABCB1) Dronedarone Digoxin AUC 2.6-fold, Cmax 1.75-fold

Quinidine Digoxin AUC 1.7-fold, CLr 1.5-2-fold
Ritonavir Digoxin AUC 1.86-fold, CLr 1.54-fold
Ranolazine Digoxin AUC 1.6-fold, Cmax 1.46-fold
Clarithromycin Digoxin AUC 1.7-fold, Cmax 1.75-fold
*Rifampin Digoxin AUC 1.4-fold, Cmax 1.6-fold
*St. J ohns wort Digoxin AUC 1.4-fold, Cmax 1.56-fold
*Rifampin Talinolol AUC 1.5-fold, Cmax 1.6-fold
*St. J ohns wort Talinolol AUC 1.3-fold
*Tipranavir/ritonavir Loperamide AUC 2-fold
*Tipranavir/ritonavir Saquinavir/ritonavir AUC 5-fold

BCRP (ABCG2) Elacridar Topotecan AUC 2.4-fold, Cmax 3.8-fold

the oral administration o elacridar with topotecan sub-
stantially increases plasma concentrations o topotecan
(Table 5-3). Similar to the limited signif cance o P-gp inhi-
bition at the human bloodbrain barrier, BCRP inhibition at
the bloodbrain barrier is thought to have limited e ect on
drug distribution to the brain.
Among the uptake transporters, OAT1 and OAT3 are im-
plicated in the transport and clearance via the kidney proximal
tubule o a broad range o drugs such as antivirals, antibiotics,
statins, and anticancer drugs. Probenecid is a well-established
inhibitor o both transporters and, when co-administered with
urosemide or methotrexate, increases the bioavailability o
these OAT substrates. Probenecid is also used to prevent
renal injury by blocking OAT1-mediated renal uptake o the
nephrotoxic antiviral drug cidofovir (Table 5-3).
OCTs and MATEs o ten work in concert to acilitate drug
transport across the liver and kidney (Fig. 5-1, and see the
ollowing discussion). These two transporter amilies also
share the common inhibitors cimetidine (histamine receptor
antagonist), pyrimethamine (antiprotozoal and antimalarial
dihydro olate reductase inhibitor), and the chemotherapeutic
tyrosine kinase inhibitors imatinib and erlotinib (Tables 5-1
and 5-2). Although cimetidine has been largely supplanted
by proton pump inhibitors in the treatment o acid re ux,
it may prove use ul or the study o drugdrug interactions
in vivo. Both cimetidine and pyrimethamine exhibit higher
selectivity and increased potency or MATE compared to
OCT amily members; there ore, any drugdrug interaction
involving these drugs could depend on the dose o the co-
administered inhibitors. OCTs acilitate drug uptake rom
the blood into the liver and kidney, and MATEs contribute to
drug secretion rom these tissues into the bile and urine, re-
spectively. There ore, or example, low-dose cimetidine co-
administration, which would inhibit only MATE-mediated
excretion, may result in increased metformin localization to
the liver and kidneys. As a second example, high-dose cimeti-
dine co-administration inhibits not only MATE-mediated
drug excretion but also OCT2-mediated renal uptake o the
66 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

anticancer drug cisplatin rom the blood, thereby increasing

cisplatin plasma levels and protecting the kidneys against the TABLE 5-4 Adverse Drug Reactions Due to
nephrotoxic adverse e ects o this drug. TransporterDrug Interactions
Inhibition o drug uptake into the liver and kidney can TRANSPORTER DRUG ADVERSE REACTION
result in increased plasma levels and improved e f cacy o
the drug. This generalization does not hold, however, i the P-gp (MDR1, ABCB1) Cyclosporine Nephrotoxicity
site o action o the drug is the liver or kidney. For example, Tacrolimus Nephrotoxicity
the liver is the target tissue or statins such as atorvastatin, Loperamide Respiratory depression
pravastatin, and rosuvastatin, where these agents inhibit BSEP (ABCB11) Bosentan Cholestatic liver injury
HMG-CoA reductase to reduce cholesterol synthesis. The Cyclosporine Cholestatic liver injury
uptake o statins into hepatocytes is mediated by OATP1B1 Glibenclamide Cholestatic liver injury
and OATP1B3 (Fig. 5-1). Co-administered drugs that in- Rifampin Cholestatic liver injury
hibit these uptake transporters impair statin uptake by the Troglitazone Cholestatic liver injury
liver and increase statin plasma concentration (Table 5-3).
MRP2 (ABCC2) Irinotecan Diarrhea
This may not only lead to reduced e f cacy o the statin in
Methotrexate Nephrotoxicity
the liver but also increase the risk o adverse e ects such
as rhabdomyolysis; the combination o these e ects could BCRP (ABCG2) Irinotecan Myelosuppression
decrease the therapeutic index o the drug.
Foods as well as drugs can inter ere with transporter ac- OAT1 (SLC22A6) Adefovir Nephrotoxicity
tivity. Grape ruit juice was initially identif ed as an inhibitor Cidofovir Nephrotoxicity
Tenofovir Nephrotoxicity
o the drug-metabolizing enzyme CYP3A4. However, re-
cent studies show that grape ruit juice and other ruit juices OCTs Metformin Hyperlactacidemia,
such as orange juice and apple juice may also impair OATP- lactic acidosis
mediated uptake transport. Naringin, the active component o
grape ruit juice, inhibits OATP1A2 and OATP1B1 and leads OCT2 (SLC22A2) Cisplatin Nephrotoxicity
to reduced drug bioavailability in clinical studies. In addi- OATP1B1 (SLCO1B1) Mycophenolate Leukopenia, anemia,
tion, the hesperidin and quercetin constituents o orange juice mofetil thrombocytopenia,
and apple juice, respectively, may be responsible or inhibit- diarrhea, nausea,
ing OATP1A2 and OATP2B1. Although co-administration vomiting, infection
o certain ruit juices with drugs that are OATP substrates Simvastatin Myopathy
may reduce drug bioavailability, clinical e ects have been
Adapted from Table 4 of Knig J , Mller F, Fromm MF. Transporter and drugdrug
observed only when the drugs are taken together with large interactions: important determinants of drug disposition and effects. Pharmacol
volumes o these juices (Table 5-3). In vitro studies have Rev 2013;65:944966.
started to explore the potential or oods to alter the unc-
tion o other transporters, but these observations have yet
to translate into clinical outcomes. For example, grape ruit
juice has been shown to inhibit P-gp activity in vitro, but
clinical studies do not demonstrate inhibition o P-gp when stemming rom the inhibitory e ect o these drugs on trans-
grape ruit juice is co-administered with digoxin. porters. For example, inhibition o the bile salt transporter
Drugs are also capable o inducing the expression o BSEP could impair bile ormation and ow, resulting in ele-
transporters. Similar to the induction o P450 enzyme ex- vated hepatic bile acids and leading to cholestatic liver injury
pression, drug transporter expression can be regulated by (Table 5-4). URAT1 and OAT4 are essential or establishing
the nuclear pregnane X receptor (PXR), constitutive an- systemic uric acid balance, and inhibition o URAT1 has been
drostane receptor (CAR), arnesoid X receptor (FXR), and exploited as a treatment or gout. However, compounds such
vitamin D receptor. Relative to the e ect o transporter as losartan can inhibit both URAT1 and OAT4 and may there-
inhibition, the overall impact o transporter induction on ore cause undesirable adverse e ects such as the ormation
clinically relevant drug interactions is minimal, and most o kidney stones. The HIV protease inhibitor ritonavir blocks
drug interactions involving induction have been attributed GLUT4, and this could result in hyperglycemia in prediabetic
to the induction o P-gp in the intestine. St. J ohns wort and patients treated with ritonavir. Pharmacologic inhibition o
ri ampin are strong PXR agonists, and the co-administration SGLT2 results in osmotic diuresis due to the increased glu-
o digoxin with St. Johns wort or ri ampin results in reduced cose load in the urine and has been linked to increased urina-
digoxin plasma levels (Table 5-3). Similarly, ri ampin pre- tion and thirst in clinical studies. One such SGLT2 inhibitor,
administration reduces plasma concentrations o talinolol dapaglif ozin, may cause hypotension and light-headedness
and carvedilol, likely due to P-gp induction. In all o these due to excessive dehydration. Additional adverse e ects re-
cases, enhanced expression o P-gp would be expected to lated to transporterdrug interactions are listed in Table 5-4.
reduce the systemic exposure o the drug and thereby reduce
the e f cacy o the drug. Pharmacogenomics
Genotype-dependent alterations in drug-metabolizing en-
zymes (such as CYPs) are well documented. Similar to CYPs,
Drug Inter erence with Endogenous uptake and e ux transporters are subject to single nucleo-
Metabolite Tra cking tide polymorphisms (SNPs), which can result in altered
Several drugs have been implicated in the disruption o en- pharmacokinetics or certain drugs such as statins and
dogenous metabolite tra f cking and homeostasis, most likely antidiabetics. The OATP1B1 polymorphism N130D has

been shown to result in elevated serum bilirubin levels and
reduced hepatic uptake o OATP1B1 drug substrates, such as
statins. Patients who carry one or two copies o the V174A
variant o OATP1B1 exhibit 2- and 12- old increased risk
o developing myopathy, respectively, in the setting o daily
simvastatin treatment. The Q141K variant o BCRP is also
associated with altered statin pharmacokinetics; increased
plasma levels o the drug are due to reduced e ux activ-
ity at the intestinal lumen. The A270S variant o OCT2 has
been implicated in reduced renal uptake and clearance o the
antidiabetic drug metformin. Because such SNPs represent
common variants that occur in more than 1% o the popula-
tion, a large number o patients could potentially be a ected
by altered pharmacokinetics. There ore, genetic analysis o
specif c drug transporters could provide a valuable advance
toward personalized medicine.
INTEGRATION OF DRUG TRANSPORTER
SCIENCE INTO DRUG DISCOVERY AND
DEVELOPMENT
Progress in our understanding o mechanisms o drug trans-
port aids in designing drugs with optimal transport prop-
erties, predicting drugdrug and drugdisease interactions,
and determining optimal routes o administration (Box 5-1).
A new drug entity may be optimized or maximum potency
against its biological target by structural modif cation o
moieties on the molecule and pharmacologic testing o the
derivative compounds in cell culture or in silico systems.
However, the e f cacy o a potential drug candidate with ex-
quisite in vitro potency may be severely impeded in clinical
trials i it does not also have an optimal pharmacokinetic
prof le. For drug candidates that are substrates or one or
more o the major drug transporters, the transporter(s)
can in uence the pharmacokinetic prof le o the drug by
limiting or enhancing the ability o the drug to reach its bio-
logical target in vivo. There ore, in drug discovery, an un-
derstanding o whether a compound (or compound class) is
a substrate or inhibitor o a drug transporter can aid in early
optimization o the compounds chemical structure. For oral
administration, it is important to take into account the con-
tribution o intestinal drug e ux transporters (e.g., P-gp,
BCRP, and MRP2) relative to the contribution o passive
intestinal permeability, since these transporters can reduce
overall intestinal permeability and contribute to low oral
bioavailability.
Drug disposition can be improved not only by avoiding
e ux channels but also by optimizing or transport by up-
take channels. Because the target organ o statins is the liver,
optimal uptake rom the plasma into hepatocytes would be
expected to improve the pharmacodynamics o these HMG-
CoA reductase inhibitors. The substrate pre erence o CNTs/
ENTs and PEPTs or nucleosides and peptides, respectively,
has been exploited to enhance the absorption o drugs that
otherwise exhibit high clearance rates. The oral bioavailabil-
ity o ganciclovir is ten old less than its optimized peptide
conjugate (prodrug) valganciclovir, which is a substrate or
PEPT1. As a f nal example, the chemotherapeutic e f cacy
o a cytotoxic nucleoside analogue such as gemcitabine may
depend on its cellular uptake into tumors by ENT1. Patients
whose tumors exhibit low levels o ENT1 expression respond
poorly to treatment with gemcitabine.
C h a p t e r 5 Drug Transporters 67
The identif cation o transporters that may have pri-
mary roles in the uptake and elimination o new drug
entities is key to understanding the disposition as well
as the potential or drugdrug interactions o a novel
therapeutic agent. Advances in drug transporter research
have also contributed to awareness by regulatory agen-
cies that transport is an important consideration in the
evaluation o new drugs. The US Food and Drug Admin-
istration (FDA), European Medicines Agency (EMA),
and the Japanese Pharmaceuticals and Medical Devices
Agency (PMDA) have o ered updated clinical and non-
clinical guidelines on drug transporters to consider in
drug development. Increased awareness and recogni-
tion o transporter-dependent drugdrug interactions has
led to the inclusion o these interactions in drug labels,
along with the precautions that must be taken in the set-
ting o multidrug therapies. The International Transporter
Consortium (ITC) has proposed decision trees that could
guide and help interpret preclinical studies assessing the
potential role o specif c transporters in the disposition
o new drug entities and extrapolate whether additional
clinical studies or drugdrug interactions are warranted.
There is now general consensus around the importance
o testing the transport o new drugsespecially by the
well-established transporters P-gp, BCRP, OCT2, OAT1,
OAT3, OATP1B1, and OATP1B3in order to better pre-
dict clinical outcomes and drugdrug interactions.
CONCLUSION AND FUTURE
DIRECTIONS
Signif cant advances have been made in our understand-
ing o drugtransporter interactions in recent years, and
the majority o key transporters essential in drug disposi-
tion and drugdrug interactions have been identif ed. The
impact (or lack thereo ) o many o these transporters has
been tested and demonstrated clinically, and both drug de-
velopment strategies and regulatory guidelines continue to
be established and ref ned based on our evolving scientif c
understanding o drug transporters. As listed in Tables 5-1
and 5-2, transporter inhibitors that are currently available
or use in vitro and in vivo exhibit overlapping specif ci-
ties. This limits the use o nonspecif c inhibitors to screen
or interactions in cell culture and animal models. Discov-
ery o more selective inhibitors would help to establish
and standardize in vitro and in vivo techniques and should
lead to consistent characterization o drug disposition and
drugdrug interactions or novel therapeutics. These e -
orts should be assisted by computational approaches that
predict transportersubstrate interactions based on the
chemical structures o the molecules using molecular dock-
ing simulations as well as established crystal structures
o transporters. With the continued and expanding use o
polypharmacy to treat complex diseases, there is an urgent
need to understand the potential or transporter-mediated
drug interactions together with metabolic drug interac-
tions. Emerging in vitro and in vivo tools to study drug
disposition, such as 3-D tissue-engineered organ models,
coupled with our growing insights into the basic science o
drug transporters, should enable better predictions o the
clinical impact o transporter-related mechanisms on the
patient.
68 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

B O X 5 - 1 Dru g De ve lo p m e n t Ca s e

A pharmaceutical lab is developing a new drug or the treat-

ment o hypercholesterolemia. The approach is to inhibit a key In vitro Ora l
Compound pote ncy bioa va ila bility In vivo
enzyme involved in the cholesterol biosynthesis pathway. This obs e rva tions
(nM) (%F)
enzyme, HMG-CoA reductase, is localized to the liver and it
serves as the rate-controlling enzyme o the mevalonate path- A 35 3.1 Ele va te d
conjuga te d bilirubin
way, the metabolic pathway that produces cholesterol and other
isoprenoids. The main strategy or the program is to utilize the
B 41 28 No a dve rs e e ve nts
livers capacity or active uptake o xenobiotics in order to target
the liver selectively. Data rom recent studies with the companys
lead compounds have recently been presented. Figure A shows C 0.2 2.2 No a dve rs e e ve nts
the uptake o our compounds into suspended rat hepatocytes.
Each o the compounds was incubated with the cells at 37C or D 121 97 Incre a s e d s e rum
bile a cids
up to 30 seconds.
The project team decides to conduct ollow-up studies in rats.
These in vivo studies show signi cant di erences among the
compounds in bioavailability a ter oral administration (%F), acute FIGURE B. In vitro and in vivo data or Compounds A, B, C, and D a ter
hyperbilirubinemia with Compound A, and a transient increase in oral administration o 30 mg/kg in rats.
serum bile acids with Compound D (Figure B). Given the high in
vitro potency o the our compounds (Figure B), the pharmacolo- the cell through passive di usion or could be transported
gist on the project team is also keen to determine their in vivo by a low-a f nity, high-capacity transporter at a very slow
e cacy in rats. Results show that, when administered at 5 mg/kg uptake rate.
orally, the e cacy o the compounds is rank-ordered as ollows: 2. Why is the bioavailability o Compounds A and C low,
A (most e cacious) D B C (least e cacious). whereas the bioavailability o Compound D is high?
Compound A most likely undergoes enterohepatic re-
Questions and Discussion circulation, and only a limited amount o the drug makes it
1. Based on the data shown in Figure A, by which mechanism
into the systemic circulation. Compound C exhibits both low
is each compound likely entering the hepatocytes?
hepatic uptake and low bioavailability, so the majority o the
Compound A and Compound B could be taken up by mul-
compound might simply not be absorbed in the intestine and
tiple uptake transporters (e.g., OATPs, OATs, or OCTs) that
instead be eliminated in the eces. Compound D has minimal
are expressed on the sinusoidal membrane o hepatocytes.
uptake into hepatocytes and nearly complete oral bioavail-
Transporter-mediated uptake could be tested by measuring
ability. Complete absorption o Compound D across the intes-
the uptake o each compound into suspended hepatocytes
tine, with a minimal f rst-pass hepatic transport or metabolism
in the presence o selective transporter inhibitors or by
e ect, would explain the high oral bioavailability in rats.
measuring the uptake o the compounds in cell lines that
3. Assuming that Compound A is acidic and is charged at
express a specif c transporter compared to the uptake in a
physiologic pH, which speci c active-transport mecha-
control cell line. Compound C and Compound D likely enter
nisms (uptake and/or e f ux) are likely responsible or the
transport o Compound A rom the plasma into the bile?
3500 I Compound A is acidic and charged at physiologic pH
(anionic), then it is more likely to be transported into hepa-
3000 tocytes by uptake transporters that exhibit relatively high
)
g
a f nity or anionic substrates, such as OATP1B1. MRP2 may
m
2500
/
l
Compound A mediate its excretion into bile, since this e ux transporter
o
m
2000 also has relatively high a f nity or anionic substrates.
p
(
n
4. What are potential mechanisms by which Compounds A and
o
i
1500
t
a
D cause hyperbilirubinemia and cholestasis, respectively?
l
u
Compound B
m
1000 Impaired clearance o bilirubin via the hepatobiliary
u
c
route can result in hyperbilirubinemia. Compound A in-
c
A
500 creases conjugated bilirubin, suggesting that the com-
Compounds C a nd D
0
pound has minimal impact on the transport o bilirubin into
0 5 10 15 20 25 30 the hepatocyte and limited impact on the metabolism o bili-
Time (s e conds ) rubin to bilirubin glucuronide. Compound A likely inhibits a
mechanism involved in the excretion o conjugated bilirubin
FIGURE A. Accumulation o our lead HMG-CoA reductase inhibitors in into the bile, likely via MRP2. MRP2 inhibition studies in
suspended rat hepatocytes over 30 seconds.

B O X 5 - 1 Dru g De ve lo p m e n t Ca s e (co n tin u e d )
trans ected cell lines, combined with in vivo studies in rats
with cannulated bile ducts, would help to support this hy-
pothesis. Compound D does not appear to be a substrate
or hepatic transport based on the suspended hepatocyte
data; nonetheless, the compound could inhibit transporters
involved in bile acid disposition. Inhibition o either NTCP
at the sinusoidal membrane or BSEP at the canalicular
membrane o hepatocytes would explain the in vivo results.
Further studies o uptake inhibition o bile acids (e.g., tauro-
cholate) into suspended hepatocytes, or inhibition o BSEP
(measured by taurocholate transport) in BSEP-expressing
vesicles or in sandwich-cultured hepatocytes, would help to
determine the mechanism that is more likely to be involved.
5. The team is allowed to advance only one of the four lead
compounds into clinical trials. Which compound would be
the preferred agent for clinical-trial testing?
Compound A should be advanced into clinical studies.
This compound exhibits the highest e f cacy in vivo, likely
due to its e ective uptake into the liverwhich is the tar-
get site o action or the inhibition o HMG-CoA reductase.
Compound A is likely to be associated with a relatively low
level o systemic adverse e ects due to its enterohepatic
recirculation, and the observed hyperbilirubinemia in rats
could potentially be avoided by dose adjustment. Given the
likely involvement o hepatic transporters in Compound A
disposition, Compound A may need to be studied urther
in patients with hepatic impairment in order to understand
Suggested Reading
Brouwer KL, Keppler D, Hoffmaster KA, et al.; International Transporter
Consortium. In vitro methods to support transporter evaluation in drug dis-
covery and development. Clin Pharmacol Ther 2013;94:95112. (In vitro
methods or the identif cation o drug transporters involved in the disposi-
tion o new drug entities.)
Giacomini KM, Huang SM, Tweedie DJ, et al.; International Transporter
Consortium. Membrane transporters in drug development. Nat Rev Drug
Discov 2010;9:215236. (The initial white paper rom the International
Transporter Consortium.)
Giacomini KM, Huang SM. Transporters in drug development and clinical
pharmacology. Clin Pharmacol Ther 2013;94:39. (Reviews roles o drug
transporters in drug absorption, distribution, and elimination.)
Knig J, Mller F, Fromm MF. Transporter and drugdrug interactions: im-
portant determinants of drug disposition and effects. Pharmacol Rev 2013;65:
944966. (Reviews the role o transporters in drugdrug interactions.)
C h a p t e r 5 Drug Transporters 69
any potential impact on sa ety and e f cacy. Compound D
exhibits low hepatic uptake and high bioavailability, sug-
gesting that higher levels o systemic exposure would be
required to achieve a pharmacologic e ect comparable to
that o Compound A. The need or higher systemic exposure
would warrant a care ul assessment o o -target e ects
that could contribute to dose-limiting toxicities in the clinic.
Moreover, the observation o altered bile acid disposition in
rats suggests that urther investigation o the mechanism
o cholestasis would be warranted, as well as evaluation
o the potential or translation to humans i the compound
were to move urther into development. Compound B ex-
hibits good hepatic uptake and in vitro potency. Although
the lack o adverse e ects makes it a potential candidate
or advancement to clinical trials, its e f cacy in vivo is sig-
nif cantly lower than that o Compounds A and D. Higher
doses o Compound B may be permissible due to the appar-
ent lack o toxicity, but the physicochemical properties o
the compound will at some point limit the dose that can be
absorbed/administered. Compound C is the least promising
candidate due to its low hepatic uptake and low in vivo e -
f cacy. For all o the compounds, the potential or species
di erences in transporter activity should be considered
(both as substrates and inhibitors), and analogous studies
with human transporters should be conducted to better pre-
dict the likelihood that the results o the rodent studies will
translate aith ully to the clinic.
Morrissey KM, Wen CC, Johns SJ, Zhang L, Huang SM, Giacomini
KM. The UCSF-FDA TransPortal: a public drug transporter data-
base. Clin Pharmacol Ther 2012;92:545546. (http://dbts.ucs .edu/ da
transportal)
Nigam SK. What do drug transporters really do? Nat Rev Drug Discov
2015;14:2944. (Reviews endogenous unctions o drug transporters.)
Palmeira A, Sousa E, Vasconcelos MH, Pinto MM. Three decades of P-gp
inhibitors: skimming through several generations and scaffolds. Curr Med
Chem 2012;19:19462025. (Overview o P-gp activity modulators or the
reversal o multidrug resistance in cancer.)
Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the or-
ganic anion and cation transporters of the SLCO and SLC22A gene
superfamilies. Br J Pharmacol 2012;165:12601287. ( Extensive re-
view o the biology and pharmacology o organic anion and cation
transporters.)
 D D

Drrugg Drrugg
m ta bo
me bbolilis m m e ta bolis
me b m

6 D-X
X D-X

Drug Toxicity
M ich a e l W. Co n n e r, Ca t h e rin e Do ria n -Co n n e r,
Vis h a l S. Va id ya , La u ra C. Gre e n , a n d David E. Go la n
Uniinte
Un in nde d Inte nde d
Inte nde d re ce p
pttor ree ce pt
ptor
or Un inte
Unin te nd
ndee d
re cee pt
ptor
or re ce ptor
INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 700711 Drug-Indduc
uced Renal Toxicityy . . . . . . . . . . . . . . . . . . . . . . . . . . 80
"OnOn-ta
On-targ
MECHANISMS a rg e tt"DR
targ DRUGUG TOXIC ICITITY . . . . . . . . . . .g. .e. t"
Y"Off-targ . . . . . . . . . . . 71 "O
"On-
DO ugn-ta
ttarced
rg eNeurotoxicity
t" .Off
. . . . . tar
y . . . . ."Off-targ targ
. . . .g. .e. t"
t. . . . . . . . 81
adOn ve Taras ge e ff
fffe
fe c ts . . . . . . . . .adve
fects ad
. . . ve
. . . rs
r. .s. e. . .e. ffe
. . . .c. .ts
. . . . . . . . 72 dDrug-Induced
rs e e ffeSkel
ve rs
adve c tstall MuMusc sclelead Toxicity
adve d ve rrs.s. e. . .e .ff. . . c. .ts
ffe . . . . . 81
Off-Target Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Drug-Induced Cardiovascular Toxicity ty
y. . . . . . . . . . . . . . . . . . 81
Dos os e toot hi
Idiosyncratic high h . . . . . . . . . IIn
Toxicity .n. .co
corr
. . .rre
. .e. .ct
c. t. .re
. . ce
. . . .p
ptor
. . . . . . . 75 CDrug-Induced
Corre ct re ce ptor
ptor,, Toxxic
Pulmonary ciiityyIn
icit In co
corree cct ree ce pto ptorr82
Chro
Ch
CO h ro
roni
o nic
niic a cct
ctiv
ctitiv
tti
ivvUG TOXICITY . . is
a ttion . . .a. .ctiva
. . . . . .te . . .d. .or
. . . . . . . . . . 75 but
b ut incorre ctDttis
Carcinogenesis is s ueug Theis a ctiva ctiv
ct iva.a tete.d . oor . .r. . . . . 82
Terato
toge
gene
nesi
ne siss Du
si Duee to Dru r g Th Therapy . . . . . . . . . . . . 82
orrDrug ib o . . . . . . . . . . . . . . inhib
Overdose
inhibition inhi
in
inhibite
. . .hibi
. b te t. . .d. . . . . . . . . . . . . . . . 75 Dos
Doso s e too
t hi high h
PRINCIPLES FOR TREATING PATIENTS WITH
inhibite
inhhibite d
DrugDrugg In nte
tera ract
ctio
ions
ns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 755
e ffe
ffffePharmacokinetic
ccts
ts DrugDrug Interacttio ions
ns . . . . . . . . . . . . . . 75
ns RUChronic
Chro
Ch roni
nicc aTOXICITY
DRUG-INDUCED ccti
ctiva
tiv
va tio
tio
ion
o n . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
on
Phar
Ph arma
rmmacocodydynanamimicc DrugDrug Interactions ti . . . . . . . . . . . . . 75 TOWARD EARLYiDETECTION
or inhibition
inhibiti on AND PREDICTION OF
DrugHerb
g Interactionss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 DRUG TOXICITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
e ffe
ffe cts
Cellularr Mechanisms of Toxicity: Apoptosis i and Necrosis . . . 76 CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 85
Organ and a Tissue Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76 Suggested
Suggesttedd RReading
e adi
ding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Harmful Immune Responses and Immunotoxicityy . . . . . . . . 76
Drug-Induced Hepatotoxicityy . . . . . . . . . . . . . . . . . . . . . . . . . 79

INTRODUCTION
Like many medical interventions, the use o drugs or ther-
apeutic benef t is subject to the law o unintended conse-
quences. These consequencestermed side effects , adverse
effects , or toxic effects are a unction o the mechanisms
o drug action, the size o the drug dose, and the character-
istics and health status o the patient. As such, the principles
o pharmacology, presented in the preceding chapters, apply
to drug toxicology as well. Many subsequent chapters con-
tain Drug Summary Tables that list, among other properties,
the specif c adverse e ects that can be caused by each drug.
This chapter ocuses on the mechanisms underlying these
adverse e ects.
As a general matter, adverse e ects range rom those that
are common and relatively benign to those that pose serious
risk o organ damage or death. Even the ormer group o
adverse e ects, however, can cause considerable discom ort
and lead patients to avoid or reduce their use o medication.
Also, in general, the type and risk o adverse e ects depend
on the margin of safety between the dose required or e f cacy
and the dose that causes adverse e ects. When the margin
o sa ety is large, toxicity results primarily rom overdoses;
when this margin is small or nonexistent, adverse e ects
may be mani est at otherwise therapeutic doses. These prin-
ciples apply both to prescription medications and to over-
the-counter drugs such as acetaminophen and aspirin. Note
70
that sa ety margins are a unction not only o the drug but
also o the patient, in that genetic or other characteristics
such as polymorphisms in enzymes that detoxi y harm ul
metabolites, comorbidities, or reduced unctional reserve in
key organsrender patients more or less capable o de end-
ing against toxicity. This is one reason why, all other things
being equal, new medications should be initiated at the low-
est doses likely to be therapeutic.
Drug toxicity is critically important in drug develop-
ment (see Chapter 51, Drug Discovery and Preclinical De-
velopment, and Chapter 52, Clinical Drug Evaluation and
Regulatory Approval). Early in drug development, preclini-
cal and clinical studies are used to evaluate compound po-
tency, selectivity, pharmacokinetic and metabolic prof les,
and toxicity. Prior to marketing, the regulatory agencies re-
sponsible or drug approval review the test data and decide
whether the benef ts o the drug outweigh its risks. Once a
drug is marketed and many more patients are exposed, the
appearance o unexpected types or requencies o adverse
e ects may cause a reevaluation o the drug, such that its
use may be restricted to specif c patient populations or with-
drawn entirely (as in the cases, or example, o the nonste-
roidal anti-in ammatory drug rofecoxib and the antidiabetic
drug troglitazone ).
In this chapter, categories o drug toxicities that derive
rom inappropriate activation or inhibition o the intended
drug target (on-target adverse effects ) or unintended targets

Ms . G is a n 80-ye a r-o ld p ia n o te a ch e r
w ith p ro g re s s ive ly s e ve re rig h t le g p a in
ove r a p e rio d o 5 to 10 ye a rs . S h e h a s
co n tin u e d to te a ch in h e r s tu d io b u t a t
th e co s t o in cre a s in g p a in a n d a tig u e .
Im a g in g s tu d ie s re ve a l s e ve re o s te o a rth ritis o th e
rig h t h ip . S h e is s ch e d u le d o r e le ctive re p la ce m e n t
o th e rig h t h ip w ith a p ro s th e tic jo in t.
Th e to ta l h ip re p la ce m e n t is p e r o rm e d w ith o u t
im m e d ia te com p lica tio n s . Du rin g th e f rs t e w d a ys
a te r th e o p e ra tio n , Ms . G is g ive n lo w-m o le cu la r-
w e ig h t h e p a rin a n d wa r a rin a s p ro p hyla xis a ga in s t
d e e p ve in th ro m b o s is . S ix d a ys a te r th e o p e ra tio n ,
s h e d e ve lo p s e xcru cia tin g p a in in th e a re a o th e
o p e ra tio n . Rig h t la te ra l h ip a n d b u tto ck s w e llin g is
n o te d o n p hys ica l e xa m in a tio n . A co m p le te b lo o d
co u n t re ve a ls s ig n if ca n t b lo o d lo s s (d ro p in h e m a -
to crit ro m 35% to 25%), a n d s h e is ta ke n b a ck to th e
o p e ra tin g ro om o r e va cu a tion o a la rg e he m a to m a
a ro u n d th e p ro s th e tic jo in t. Alth o u g h th e h e m a to m a
does not appear to be gros sly in ected, cultures o the
h e m a to m a a re pos itive or S ta phylococcus a u re us .
Be ca u s e p ro s th e tic jo in t in e ctio n s a re d i f cu lt to
tre a t s u cce s s u lly w ith o u t re m ova l o th e p ro s th e s is ,
Ms . G is s ta rte d o n a n a g g re s s ive 12-w e e k co u rs e
o co m b in a tio n a n tib io tics in w h ich in tra ve n o u s
va n co m ycin a n d o ra l ri a m p in a re a d m in is te re d o r
2 w e e ks o llo w e d b y o ra l cip ro o xa cin a n d ri a m p in
o r 10 w e e ks . S h e to le ra te s th e f rs t 2 w e e ks o a n -
tib io tics w ith o u t co m p lica tio n s . Ho w e ve r, 36 h o u rs
a te r s w itch in g h e r a n tib io tic ro m va n co m ycin to
cip ro o xa cin , s h e d e ve lo p s a h ig h e ve r to 103F
(off-target adverse effects ) are discussed f rst. The pheno-
typic e ects o these drug toxicities are then discussed at
the physiologic, cellular, and molecular levels. General prin-
ciples and specif c examples are also illustrated in this chap-
ter and throughout the book. The development o rational
therapeutic strategies o ten requires an understanding o the
mechanisms o both drug action and drug toxicity.
MECHANISMS OF DRUG TOXICITY
Whether a drug will do more harm than good in an individ-
ual patient depends on many actors, including the patients
age, genetic makeup, and preexisting conditions; the dose
o the drug administered; and other drugs that the patient
may be taking. For example, the very old or very young may
be more susceptible to the toxic e ects o a drug because
o age-dependent di erences in pharmacokinetic prof les
or drug-metabolizing enzymes. As discussed in Chapter 4,
Drug Metabolism, genetic actors may determine individual
characteristics o drug metabolism, receptor activity, or repair
mechanisms. Adverse drug reactions may be more likely in
patients with preexisting conditions, such as liver or kidney
dys unction, and, o course, in patients allergic to specif c
C h a p t e r 6 Drug Toxicity 71
a n d e xtre m e w e a kn e s s . As p ira tio n o th e h ip re ve a ls
o n ly a s ca n t a m o u n t o s tra w-co lo re d (i.e ., n o n p u ru -
le n t) u id . Ms . G is th e re o re a d m itte d to th e h o s p i-
ta l o r clo s e o b s e rva tio n .
Tw e lve h o u rs a te r h e r a d m is s io n , Ms . G d e ve lo p s
a n e xte n s ive m a cu lo p a p u la r ra s h o ve r h e r ch e s t,
b a ck, a nd e xtre m itie s . He r cip ro oxa cin a n d ri a m p in
a re d is co n tin u e d , a n d va n co m ycin is re s ta rte d .
Gra d u a lly, ove r th e n e xt 72 h o u rs , h e r te m p e ra tu re
re tu rn s to n o rm a l a n d h e r ra s h b e g in s to a d e . Th e re
is n o g ro w th in th e cu ltu re o th e rig h t h ip a s p ira te .
Ms . G is co n tin u e d o n va n co m ycin a s a s in g le a g e n t
o r th e n e xt 4 w e e ks w ith o u t in cid e n t; ri a m p in is
re s ta rte d , a ga in w ith o u t in cid e n t; a n d th e 12-w e e k
a n tib io tic co u rs e is e ve n tu a lly co m p le te d u s in g a
co m b in a tio n o trim e th o p rim -s u l a m e th oxa zo le a n d
ri a m p in .
Fo u r m o n th s a te r h e r h ip s u rg e ry, Ms . G is b a ck
to te a ch in g h e r p ia n o s tu d e n ts a n d m a kin g s lo w b u t
s te a d y p ro g re s s in h e r re h a b ilita tio n p ro g ra m .
Questions
1 . How likely was it that Ms. Gs high ever, weakness, and
skin rash represented a drug reaction to ciprof oxacin?
2 . What was the rationale or co-administration o low-
molecular-weight heparin and war arin in the immedi-
ate postoperative period?
3 . Was there a cause-and-e ect relationship between
administration o the prophylactic anticoagulants and
Ms. Gs li e-threatening bleeding complication?
drugs. Concomitant medications can con ound both e f cacy
and toxicity o drugs, particularly when these medications
share or modulate the same metabolic pathways or transport-
ers. Drug interactions with health supplements are also an
important but o ten under-recognized cause o drug toxicity.
Drugdrug and drugherb interactions are discussed later in
this chapter. The clinical determination o a drugs toxicity
may not always be straight orward: as in the case o Ms. G,
or example, a patient being treated with an antibiotic to com-
bat an in ection can develop a high ever, skin rash, and sig-
nif cant morbidity due either to recurrence o the in ection or,
instead, to an adverse reaction to the antibiotic.
Although a spectrum o adverse e ects may be associated
with the use o any drug or drug class, it is help ul to con-
ceptualize the mechanisms o drug toxicity based on several
general paradigms:
On-target adverse e ects, which are the result o the
drug binding to its intended receptor, but at an inappro-
priate concentration, with suboptimal kinetics, or in the
incorrect tissue (Fig. 6-1)
O -target adverse e ects, which are caused by the
drug binding to a target or receptor or which it was not
intended (Fig. 6-1)
72 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

Intended Unintended
tissue tissue
D D

Drug Drug
metabolism metabolism

D-X D-X

Uninte nde d Inte nde d

Inte nde d re ce ptor re ce ptor Uninte nde d
re ce ptor re ce ptor

"On-target" "Off-target" "On-target" "Off-target"

adverse effects adverse effects adverse effects adverse effects
Dos e too high Incorre ct re ce ptor Corre ct re ce ptor, Incorre ct re ce ptor
Chronic a ctiva tion is a ctiva te d or but incorre ct tis s ue is a ctiva te d or
or inhibition inhibite d Dos e too high inhibite d
e ffe cts Chronic a ctiva tion
or inhibition
e ffe cts

Toxic cellular effects

FIGURE 6-1. On-target and off-target adverse drug effects. Drug D is intended to modulate the unction o a specif c receptor (intended receptor) in a
particular tissue (intended tissue). On-target adverse e ects in the intended tissue could be caused by a supratherapeutic dose o the drug or by chronic
activation or inhibition o the intended receptor by Drug D or its metabolite DX. The same on-target e ects could occur in a second tissue (unintended
tissue); in addition, the intended receptor could mediate an adverse e ect because the drug is acting in a tissue or which it was not designed. O -target
e ects occur when the drug and/or its metabolites modulate the unction o a target (unintended receptor) or which it was not intended.

Adverse e ects mediated by the immune system (Fig. 6-2)
Idiosyncratic responses or which the mechanism is not
known
These our mechanisms are discussed below. Note that
many drugs can have both on-target and o -target e ects,
and adverse e ects observed in patients can be due to mul-
tiple mechanisms.
On-Target Effects
An important concept in drug toxicity is that an adverse
e ect may be an exaggeration o the desired pharmaco-
logic action as a result o changes in exposure or sen-
sitivity to the drug (see Fig. 6-1). This can occur due
to deliberate or accidental overdoses, alterations in the
pharmacokinetics o the drug (e.g., due to liver or kidney
disease or to interactions with other drugs), or changes in
the pharmacodynamics o the drugreceptor interaction
that alter the pharmacologic response (e.g., an increase
in receptor number). All such changes can lead to an in-
crease in the e ective concentration o the drug and thus
to an increased biological response. Because on-target
e ects are mediated via the desired mechanism o ac-
tion o the drug, these e ects are o ten shared by every
member o the therapeutic class and are thus also known
as class effects .
An important set o on-target adverse e ects may occur
because the drug, or one o its metabolites, interacts with the
appropriate receptor but in tissues other than those a ected
by the disease condition being treated (Fig. 6-1). Many drug
targets are expressed in more than one cell type or tissue. For
example, the antihistamine diphenhydramine is an H1 receptor
antagonist used to ameliorate the e ects o histamine release
in allergic conditions. This drug also crosses the bloodbrain
barrier to antagonize H1 receptors in the central nervous sys-
tem, leading to somnolence. This adverse e ect led to the
design o second-generation H1 receptor antagonists that
do not cross the bloodbrain barrier and thus do not induce
drowsiness. Notably, the f rst o these second-generation H1
antagonists, terfenadine , produced an o -target e ect (inter-
action with cardiac potassium channels) that led to a di er-
ent and serious adverse e ectan increased risk o cardiac
death. This example is discussed later in this chapter.
Local anesthetics such as lidocaine and bupivacaine pro-
vide a second example o an on-target adverse e ect. These
drugs are intended to prevent axonal impulse transmission
by blocking sodium channels in neuronal membranes near
the site o injection. Blockade o sodium channels in the
central nervous system (CNS) ollowing overdose or inap-
propriate administration (e.g., intravascular administration)
can lead to tremors, seizures, and death. These on-target
e ects are discussed in greater detail in Chapter 12, Local
Anesthetic Pharmacology.
The antipsychotic agent haloperidol is thought to produce
its benef cial e ect through blockade o mesolimbic and
mesocortical D2 receptors. One consequence o blocking D2
 C h a p t e r 6 Drug Toxicity 73

A
Ha pte n Ma s t ce ll
1 2

Ha pte n-bound
P rote in prote in

B Comple me nt-me dia te d

RBC lys is
Cytotoxic
Antige n T ce ll
1 2 3

Antige n-bound RBC lys is

RBC RBC Antibodie s bind
RBC
RBC re mova l by
re ticuloe ndothe lia l s ys te m

C Ma cropha ge

Antige n
1 2 3

Antibodie s
Antige na ntibody Immune comple x
comple xe s de pos ition in tis s ue s

D
Ha pte n
1 2 3

Ha pte n-bound
P rote in prote in
Antige n Antige n pre s e nte d
pha gocytos is Activa te d
T ce ll

FIGURE 6-2. Mechanisms of hypersensitivity reactions. A. Type I hypersensitivity reactions occur when a hapten binds to a protein (1). The antigen
cross-links IgE antibodies on the sur ace o a mast cell, leading to mast cell degranulation (2). Mast cells release histamine and other inf ammatory mediators.
B. Type II hypersensitivity reactions occur when an antigen binds to the sur ace o a circulating blood cell, usually a red blood cell (RBC) (1). Antibodies to
the antigen then bind the sur ace o the RBC (2), attracting cytotoxic T cells (3), which release mediators that lyse the RBC. Binding o antibody to RBCs can
also directly activate complement-mediated RBC lysis and RBC removal by the reticuloendothelial system. C. Type III hypersensitivity reactions occur when
antibodies bind to a soluble toxin, acting as an antigen (1). The antigenantibody complexes are then deposited in the tissues (2), attracting macrophages
(3) and activating a complement-mediated reaction sequence (not shown). D. Type IV hypersensitivity reactions occur when a hapten binds to a protein
(1) and the hapten-bound protein is phagocytosed by a Langerhans cell (2). The Langerhans cell migrates to a regional lymph node, where it presents the
antigen to a T cell, thereby activating the T cell (3).

receptors in the pituitary gland is an increase in prolactin
secretion, leading in some cases to amenorrhea, galactor-
rhea, sexual dys unction, and osteoporosis. These on-target
e ects are discussed in Chapter 14, Pharmacology o Dopa-
minergic Neurotransmission.
Sometimes, on-target adverse e ects unmask impor-
tant unctions o the biological target. A prominent ex-
ample o this phenomenon occurs with administration o
hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors (so-called statins ), which are used to decrease
cholesterol levels. The intended target tissue o these drugs
is the liver, where they inhibit HMG-CoA reductase, the
rate-limiting enzyme o isoprenoid synthesis. A rare ad-
verse e ect o statin therapy is muscle toxicity, including
rhabdomyolysis and myositis; the act that this e ect oc-
curs highlights the physiologic role o HMG-CoA reductase
in regulating the post-translational modif cation o several
muscle proteins through a lipidation process called geranyl-
geranylation. Statins, as examples o drugs causing skeletal
muscle injury, are also re erenced later in this chapter.
Off-Target Effects
Very ew drugs are so selective that they interact with only
one molecular target. O -target adverse e ects occur when
a drug interacts with unintended targets (Fig. 6-1). A promi-
nent example o an o -target e ect is the interaction o nu-
merous compounds with cardiac IKr potassium channels.
(Because the human ether--go-go-related gene [hERG]
codes or one subunit o the human IKr channel, these chan-
nels are also called hERG channels.) Inhibition o potassium
currents carried by IKr channels can lead to delayed repolar-
ization o cardiac myocytes (see Chapter 24, Pharmacology
o Cardiac Rhythm). In turn, delayed repolarization can lead
74 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
to an increase in the heart-rate corrected QT interval (QTc),
cardiac arrhythmias including torsades de pointes, and sud-
den death. The antihistamine ter enadine was one o the
earliest examples o compounds ound to inter ere with car-
diac potassium channel currents, leading to potentially atal
arrhythmias. This drug was designed to avoid drowsiness,
an adverse e ect o the f rst-generation H1 antagonists (see
earlier discussion). The observation o increased deaths due
to cardiac arrhythmias in patients receiving ter enadine led
to both withdrawal o this compound rom the market and
vigorous e orts to understand how to prevent such events.
It is now known that, although many compounds inhibit the
hERG channel, compounds with a hal -maximal inhibitory
concentration (IC50) more than 30- old greater than the max-
imum plasma concentration at the recommended therapeu-
tic dose (Cmax, adjusted or protein binding) pose a low risk
o causing QTc prolongation and cardiac arrhythmia. The
active metabolite o ter enadine, exo enadine , inhibits the
hERG channel only weakly, and exo enadine is now mar-
keted as a sa er antihistamine.
Many compounds can inter ere with cardiac potassium
channels: accordingly, all new drug candidates are evaluated
or the potential to interact with these promiscuous channels.
In the hERG assay, the potential e ect o compounds on
human cardiac potassium currents is measured in an in vitro
system using cells trans ected with hERG. In addition to the
hERG assay, the potential or altering cardiac electrophysi-
ology is evaluated in a nonrodent animal model (see Chapter
51). As a condition o marketing approval, new drugs are
also evaluated or their ability to prolong QTc in humans;
this evaluation is generally per ormed in large, late-stage
clinical trials. Compounds that increase QTc by more than
a specif ed value at an exposure near that required or the
therapeutic e ect are considered to pose a risk or producing
arrhythmias. The positive control compound used in many
o these thorough QTc studies is moxif oxacin, an antibi-
otic that increases QTc at clinical doses (but con ers a low
risk o arrhythmogenesis). While the approach o relying
most heavily on hERG inhibition in vitro and on thorough
QTc clinical trials has prevented the recent introduction o
torsadogenic drugs, this approach has been criticized or
its low sensitivity, cost, and lack o assessment o the im-
pact o other ion channel e ects that mitigate or enhance
the e ects o compounds on QTc. Based on these concerns,
alternative approaches are being considered, including pre-
clinical evaluations that study a broader range o ion chan-
nel e ects and clinical studies at an earlier stage o drug
development.
Enantiomers (mirror-image isomers) o a drug can also
cause o -target e ects. As described in Chapter 1, Drug
Receptor Interactions, drug receptors are exquisitely sensi-
tive to the three-dimensional structure o the drug molecule;
there ore, receptors can o ten distinguish between enan-
tiomers o a drug. A tragic and well-known example o
this phenomenon occurred with the administration o ra-
cemic thalidomide (mixture o [R]- and [S]-enantiomers)
in the 1960s as a treatment or morning sickness in preg-
nant women. While the [R]-enantiomer o thalidomide
was an e ective sedative, the [S]-enantiomer was a potent
teratogen that caused severe birth de ects such as ame-
lia (absence o limbs) and various degrees o phocomelia
in an estimated 10,000 newborns in 46 countries (but not
in the United States, thanks to Frances Kelsey at the Food
and Drug Administration [FDA], who doubted the sa ety o
thalidomide and prevented its approval). The use o drugs
in pregnant patients is discussed later in this chapter (see
Teratogenesis Due to Drug Therapy and Box 6-1).
The potential or signif cant pharmacologic di erences
between drug enantiomers has led researchers and the FDA
to evaluate such compounds as separate chemical entities.
I a single enantiomeric preparation o a drug can be shown
to have improved pharmacologic properties over a racemic
version, then the purif ed enantiomer can be approved as a
new drug. For example, the racemic proton pump inhibitor
omeprazole and its [S]-enantiomer esomeprazole (as in [S]-
omeprazole) are marketed as separate drugs.
Another common o -target e ect is the unintended ac-
tivation o di erent receptor subtypes. For example, the
1-adrenergic receptor is expressed in the heart, and its ac-
tivation increases heart rate and myocardial contractility.
Closely related 2-adrenergic receptors are expressed in
smooth muscle cells in the airways and in the vasculature,
and activation o 2 receptors leads to smooth muscle relax-
ation and dilation o these tissues (see Chapter 11, Adrenergic
Pharmacology). The clinical uses o -adrenergic receptor
antagonists ( -blockers ) are o ten targeted to the 1 receptor
to control heart rate and reduce myocardial oxygen demand
in patients with angina or heart ailure. However, some 1
receptor antagonists are not entirely selective or the 1 re-
ceptor and can also antagonize the 2 receptor. -Adrenergic
receptor antagonists with nonselective e ects are there ore
contraindicated in patients with asthma, because such drugs
could cause bronchoconstriction by antagonizing 2 recep-
tors. Similarly, the use o inhaled 2 agonists in the treatment
o asthma, particularly at high doses, may lead to increased
heart rate.
A second o -target e ect due to unintended activation
o di erent receptor subtypes is the valvulopathy caused
by the anorectic agent enf uramine . This drugs primary
mechanism o action appears to involve release o serotonin
(5-hydroxytryptamine [5-HT]) and inhibition o 5-HT reup-
take in brain areas that regulate eeding behavior. However,
the compound also activates 5-HT2B receptors, leading to
proli eration o myof broblasts in the atrioventricular valves.
Pulmonary hypertension can develop and, in some cases,
lead to death. Because o this adverse e ect, en uramine
has been withdrawn rom the market (see Drug-Induced
Cardiovascular Toxicity).
The potential o -target e ects o some drugs can be
explored by using genetically modif ed laboratory mice or
rats in which the intended target receptor has been deleted
(sometimes only in specif c tissues). I the drug nonetheless
a ects the physiology o these rodents, then targets other
than the intended target must be involved.
O -target e ects o some drugs and drug metabolites
can be determined only empirically, underscoring the im-
portance o extensive drug testing both in preclinical experi-
ments and in clinical trials. Despite such testing, some rare
drug toxicities are discovered only when exposure occurs in
a much larger population than that required or clinical trials.
For example, f uoroquinolones , a class o broad-spectrum an-
tibiotics derived rom nalidixic acid, displayed minimal tox-
icities in preclinical studies and clinical trials. Wider clinical
use o these drugs, however, led to reports o anaphylaxis,
QTc prolongation, and potential cardiotoxicity, resulting
in the removal o two drugs o this class, temaf oxacin and

grepaf oxacin, rom the market. Use o another uoroqui-
nolone, trovaf oxacin, is signif cantly restricted due to he-
patic toxicity. In comparison, ciprof oxacin and levof oxacin
are generally well tolerated and are requently used in the
treatment o bacterial in ections. As seen in the introductory
case, however, even these agents can occasionally cause a
severe drug hypersensitivity reaction.
Idiosyncratic Toxicity
Idiosyncratic drug reactions are adverse e ects that appear
unpredictably, in a small raction o patients, or unknown
reasons. These e ects are not typically mani est in premar-
keting testing in either laboratory animals or patients. The
appearance o idiosyncratic injury leading to permanent
organ dys unction and/or death, even i rare, o ten prompts
withdrawal o the drug rom the market, precisely because
susceptible patient populations cannot be identif ed. The
systematic study o patient variations in response to di erent
drugs may help to elucidate the genetic or other mechanisms
that underlie idiosyncratic drug reactions.
CONTEXTS OF DRUG TOXICITY
Drug Overdose
The Swiss physician and alchemist Paracelsus noted nearly
500 years ago that all substances are poison; there is none
which is not a poison. The right dose di erentiates a poison
and a remedy. In some cases, such as a suicide or homicide,
the overdose o a drug is intentional. Most cases o overdose,
however, are accidents. Adverse drug events due to medi-
cation errors are estimated to a ect some 7 million people
each year, with associated costs o $21 billion annually. This
signif cant cost to both the patient and the health care system
has led to systematic e orts intended to minimize errors in
prescribing and dosing practices.
DrugDrug Interactions
As the population has aged and increasing numbers o pa-
tients have been prescribed multiple medications, the po-
tential or drugdrug interactions has grown. Numerous
adverse interactions have been identif ed, and the mecha-
nisms o ten involve pharmacokinetic or pharmacodynamic
e ects. Drugherb interactions are also an important subset
o drugdrug interactions.
Pharmacokinetic DrugDrug Interactions
Pharmacokinetic interactions arise when one drug changes
the absorption, distribution, metabolism, or excretion o
another drug, thereby altering the concentration o active
drug in the body. As discussed in Chapter 4, some drugs can
inhibit or induce hepatic P450 enzymes. I two drugs are
metabolized by the same P450 enzyme, competitive or irre-
versible inhibition o that P450 enzyme by one drug can re-
sult in an increase in the plasma concentration o the second
drug. On the other hand, induction o a specif c P450 enzyme
by one drug can lead to a decrease in the plasma concentra-
tions o other drugs that are metabolized by the same en-
zyme. The anti ungal drug ketoconazole is a potent inhibitor
o cytochrome P450 3A4 (CYP3A4). Co-administration o
drugs that are also metabolized by CYP3A4 may result in
reduced metabolism o these drugs and higher plasma drug
C h a p t e r 6 Drug Toxicity 75
levels. I the co-administered drug has a low therapeutic
index, toxicity may occur. Because o its potent inhibition
o CYP3A4, ketoconazole is o ten used in clinical studies
designed to assess the importance o pharmacokinetic drug
drug interactions.
In addition to altering the activity o P450 enzymes, drugs
can a ect the transport o other drugs into and out o tissues
(see Chapter 4 and Chapter 5, Drug Transporters). For ex-
ample, P-glycoprotein (P-gp), encoded by the multidrug re-
sistance 1 (MDR1) gene, is an e ux pump that transports
drugs into the intestinal lumen. Administration o a drug that
inhibits or is a substrate or P-gp can lead to an increase in
the plasma concentration o other drugs that are normally
pumped out o the body by this mechanism. Since P-gp also
plays a role in transport o drugs across the bloodbrain
barrier, compounds that inhibit P-gp can a ect drug trans-
port into the CNS. Other transporters, such as the organic
anion transporting polypeptide 1 (OATP1), mediate uptake o
drugs into hepatocytes or metabolism and transport o drugs
across the tubular epithelium o the kidney or excretion;
both o these mechanisms promote clearance o drugs rom
the body. Interactions o a drug or one o its metabolites with
these classes o transporters can lead to inappropriately high
plasma concentrations o other drugs that are handled by the
same transporter.
A pharmacokinetic interaction can sometimes be desirable.
For example, because penicillin is cleared via tubular secre-
tion in the kidney, the elimination hal -li e o this drug can be
increased i the drug is given concomitantly with probenecid,
an inhibitor o renal tubular transport. A second example is
the combination o imipenem, a broad-spectrum antibiotic,
with cilastatin, a selective inhibitor o a renal brush border
dipeptidase (dehydropeptidase I). Because imipenem is rap-
idly inactivated by dehydropeptidase I, co-administration
o imipenem with cilastatin is used to achieve therapeutic
plasma concentrations o the antibiotic.
A drug that binds to plasma proteins (such as albumin)
may displace a second drug rom the same proteins to in-
crease its ree plasma concentration and thereby increase
its bioavailability to target and nontarget tissues. This e ect
can be enhanced in a situation in which circulating albumin
levels are low, such as liver ailure or malnutrition (decreased
albumin synthesis) or nephrotic syndrome (increased albu-
min excretion).
Pharmacodynamic DrugDrug Interactions
Pharmacodynamic interactions arise when one drug changes
the response o target or nontarget tissues to another drug.
Toxic pharmacodynamic interactions can occur when two
drugs activate complementary pathways, leading to an exag-
gerated biological e ect. Such a drug interaction occurs upon
co-administration o sildena l ( or erectile dys unction) and
nitroglycerin ( or angina pectoris). Sildenaf l inhibits phos-
phodiesterase type 5 (PDE5) and thus prolongs the action o
cyclic GMP (cGMP), and nitroglycerin stimulates guanylyl
cyclase to increase cGMP levels in vascular smooth muscle.
Co-exposure to the two drugs increases cGMP to an even
greater degree, increasing the risk o severe hypotension (see
Chapter 22, Pharmacology o Vascular Tone).
A second example is the co-administration o antithrom-
botic drugs. A ter hip replacement surgery, patients are o ten
treated with prophylactic war arin or a number o weeks
to prevent the development o postoperative deep vein
76 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
thrombosis. Because plasma war arin concentrations may
not reach a therapeutic level or several days, patients are
sometimes co-administered low-molecular-weight heparin
and war arin during this time. As seen in the case o Ms. G,
however, signif cant bleeding may result i the e ects o the
heparin and war arin synergize to produce supratherapeutic
levels o anticoagulation. Newer antithrombotic drugs used
or prophylaxis a ter orthopedic surgery (e.g., apixaban,
rivaroxaban) may avoid this increased risk o bleeding be-
cause they reach therapeutic concentrations rapidly and do
not require co-administration with another antithrombotic
drug such as heparin.
DrugHerb Interactions
The sa ety and e f cacy o a drug may also be altered by co-
exposure with various nonpharmaceuticals, such as oods,
beverages, and herbal and other dietary supplements. Many
herbal products are complex mixtures o biologically active
compounds, and their sa ety and e ectiveness have rarely
been tested in controlled studies. The wide use o unregu-
lated herbal products among the public should lead clini-
cians to inquire about patient use o such products.
The literature contains some reports o therapeutic ail-
ure o drugs taken in conjunction with herbal products and
some reports o toxicity. For example, the herbal preparation
ginkgo biloba ( rom the tree o the same name) inhibits plate-
let aggregation. Concomitant use o ginkgo and nonsteroidal
anti-inf ammatory drugs (NSAIDs), which also inhibit platelet
aggregation, may increase the risk o bleeding. In combi-
nation with selective serotonin reuptake inhibitors , St. J ohns
wort may cause serotonin syndrome.
Cellular Mechanisms o Toxicity:
Apoptosis and Necrosis
Cells are equipped with various mechanisms to avoid or
repair damage: toxicity occurs i and when these de enses
are overwhelmed. In some cases, toxicity can be minimized
in the short term, but repeated insults (e.g., those leading to
f brosis) can eventually compromise organ unction.
The primary cellular responses to a potentially toxic drug
are illustrated in Figure 6-3A and 6-3B, using the hepatocyte
as an example. Depending on the severity o the toxic insult,
a cell may undergo apoptosis (programmed cell death) or
necrosis (uncontrolled cell death). Apoptosis allows the cell
to undergo ordered sel -destruction by the coordinated acti-
vation o a number o dedicated proteins. Apoptosis can be
benef cial when it eliminates damaged cells without damage
to surrounding tissue. Inhibition o apoptosis is common in
many cancer cells.
I the toxic insult is so severe that ordered cell death
cannot be accomplished, the cell may undergo necrosis .
Necrosis is characterized by enzymatic digestion o cellu-
lar contents, denaturation o cellular proteins, and disruption
o cellular membranes. While apoptotic cells undergo cell
death with minimal in ammation and disruption o adjacent
tissue, necrotic cells attract in ammatory cells that can dam-
age nearby healthy cells.
Organ and Tissue Toxicity
Most chapters in this book contain tables that list the serious
and common adverse e ects o the drugs discussed in that
chapter. Here, we consider common mechanisms o injury
and repair pertaining to the toxic e ects o drugs on the
major organ systems. This chapter cannot catalogue every
known or suspected injury to each organ or organ system,
since the range o drug-associated organ and tissue toxicity
is quite large. Instead, a ew specif c examples o injury are
provided to demonstrate the general eatures o drug toxicity.
Harmful Immune Responses and Immunotoxicity
Stimulation o the immune system plays a role in the toxic-
ity o several drugs and drug classes. Drugs can be respon-
sible or immune reactions (the classic type I through type IV
reactions), syndromes that mimic some eatures o immune
responses (red man syndrome), and skin rashes (eruptions)
including severe and li e-threatening conditions such as
Stevens-Johnson syndrome and toxic epidermal necrolysis.
Drugs can also compromise the normal unction o the im-
mune system (immunotoxicity), leading to secondary e ects
such as increased risk o in ection.
Some drugs may be recognized by the immune system as
oreign substances. Small-molecule drugs with a mass o less
than 600 daltons are not direct immunogens but can act as
haptens , such that the drug binds (o ten covalently) to a pro-
tein in the body and is then capable o triggering an immune
response. I a drug is su f ciently large (e.g., a therapeutic
peptide or protein), it may directly activate the immune sys-
tem. The two principal immune mechanisms by which drugs
can produce damage are hypersensitivity responses (allergic
responses) and autoimmune reactions .
The hypersensitivity responses are classically divided
into our types (Fig. 6-2). Table 6-1 provides in ormation
about the mediators and clinical mani estations o the our
types o hypersensitivity reactions. Prior exposure to a sub-
stance is required or each o the our types o reactions.
Type I hypersensitivity responses (immediate hypersen-
sitivity or anaphylaxis ) result rom the production o IgE
antibody a ter exposure to an antigen. The antigen may be
a oreign protein, such as the bacterially derived thrombo-
lytic drug streptokinase , or it may be an endogenous protein
modif ed by a hapten to become immunogenic. Penicillin
ragmentseither in the administered drug ormulation or
ormed in vivocan act as haptens and activate the immune
system. Subsequent exposure to the antigen causes mast
cells to degranulate, releasing in ammatory mediators such
as histamine, serotonin, and leukotrienes that promote bron-
choconstriction, vasodilatation, and in ammation. Type I
hypersensitivity responses mani est as a wheal-and-f are re-
action in the skin. Symptoms o hay ever such as conjunc-
tivitis and rhinitis may develop in the upper respiratory tract,
while asthmatic bronchoconstriction may occur in the lower
respiratory tract (see Chapter 48, Integrative In ammation
Pharmacology: Asthma).
Type II hypersensitivity responses (antibody-dependent
cytotoxic hypersensitivity) occur when a drug binds to cells,
usually red blood cells, and is recognized by an antibody,
usually IgG or IgM. The antibody triggers cell lysis by com-
plement f xation, phagocytosis by macrophages, or cytolysis
by cytotoxic T cells. Type II responses are rare adverse re-
sponses to several drugs, including penicillin and quinidine .
Type III hypersensitivity responses (immune complex-
mediated hypersensitivity) occur when antibodies, usually IgG
or IgM, are ormed against soluble antigens. The antigen
antibody complexes are deposited in tissues such as kidneys,
joints, and lung vascular endothelium. These complexes
 C h a p t e r 6 Drug Toxicity 77

A Drug

Quie s ce nt
Kupffe r ce ll
He pa tocyte

Cytotoxins
(IL-1, -TNF)
Mitochondria l uncoupling
ROS Activa te d
Cons umption of ATP
S tre s s e d Kupffe r ce ll
Cons umption of a ntioxida nts
he pa tocyte
Lipid a nd prote in oxida tion
IL-1
Dis turba nce of Ca 2+ home os ta s is ROS
EC-GF
ROS TGF-
RNI

ROS
TGF-

Apoptotic Endothe lia l ce lls Ito ce ll

he pa tocyte (a ctiva tion a nd prolife ra tion)

Fibros is

B
Drug
Circula ting
monocyte s

Quie s ce nt
Kupffe r ce ll
He pa tocyte Che mota ctic
a ctiva ting
fa ctors
(LTB4, LP O)

P la s ma me mbra ne ble bs
Injure d Incre a s e d ce llula r volume Cytotoxins
he pa tocyte Mitochondria l s we lling (RNI, ROS ) Activa te d
Dila te d e ndopla s mic re ticulum
Kupffe r ce ll

ROS
RNI IL-1 ROS

Endothe lia l ce lls

Ne crotic (a ctiva tion)
he pa tocyte

FIGURE 6-3. Subtoxic and toxic damage to hepatocytes in response to moderate and high doses of drug. A. Subtoxic damage. Moderate doses o a po-
tentially toxic drug activate Kup er cells and are metabolized by hepatocytes. The resulting hepatocyte stress may be exacerbated by the e ects o reactive
oxygen species (ROS) and reactive nitrogen intermediates (RNI) elaborated by activated endothelial cells. Hepatocyte apoptosis and Ito cell activation may
result, leading to f brosis. B. Toxic damage. High doses o a toxic drug are metabolized by hepatocytes to reactive metabolites that can induce cell injury.
Chemotactic activating actors released by the injured hepatocytes activate Kup er cells and endothelial cells, which elaborate toxic ROS and RNI. The end
result o this toxic cascade is hepatocyte necrosis. EC-GF, endothelial cell growth actor; IL-1, interleukin-1; IL-1 , interleukin-1 ; LPO, lipid peroxidation;
LTB4, leukotriene B4; TGF- , trans orming growth actor ; -TNF, tumor necrosis actor .
78 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
TABLE 6-1 Types o Hypersensitivity Reactions
CLASSIFICATION PRIMARY TRIGGERS
Type I or immediate- Antigen-binding IgE
type hypersensitivity on mast cells
(humoral)
Type II or antibody- IgG, IgM, and cell-bound
dependent cellular antigen
cytotoxicity (humoral)
Type III or immune- IgG, IgM, and soluble
complex disease antigen
(humoral)
Type IV or delayed-type Antigen in association with
hypersensitivity major histocompatibility
(cell-mediated) complex (MHC) protein
on the surface of
antigen-presenting cells
Adapted from Table 2 in Bugelski PJ . Genetic aspects of immune-mediated adverse drug effects. Nat Rev Drug Discov 2005;4:5969.
cause damage by initiating serum sickness , an in ammatory
response in which leukocytes and complement are activated
within the tissues. For example, type III hypersensitivity can
be caused by the administration o antivenins , horse serum
proteins obtained by inoculating a horse with the venom to
be neutralized. Examples o other drugs that may pose a risk
o serum sickness are bupropion and ce aclor.
Type IV hypersensitivity responses (cell-mediated or
delayed-type hypersensitivity) result rom the activation o
TH1, TH17, and cytotoxic T cells. This type o hypersensitivity
most commonly presents as contact dermatitis when a sub-
stance acts as a hapten and binds to host proteins. The f rst
exposure does not normally produce a response, but subse-
quent dermal exposure can activate Langerhans cells, which
migrate to local lymph nodes and activate T cells. The T cells
then return to the skin and initiate an immune response. Well-
known type IV hypersensitivity responses include reactions to
poison ivy and the development o latex allergies. Repeated
exposure to a drug that is recognized as oreign by the im-
mune system can trigger a massive immune response. This
cytokine storm can lead to ever, hypotension, and even
organ ailure. Thus, physicians should consider possible im-
mune reactions to all administered drugs, even those that have
appeared to be sa e in large populations. In the case presented
at the beginning o the chapter, Ms. Gs ever and rash were
likely caused by a T-cell-mediated hypersensitivity reaction to
cipro oxacin. Once this was recognized and the cipro oxacin
was stopped, her ever and rash resolved as well.
Autoimmunity results when a persons immune system at-
tacks her or his own cells (see Chapter 46, Pharmacology
o Immunosuppression). Several drugs and other chemi-
cals can initiate autoimmune reactions. Methyldopa can
cause hemolytic anemia by eliciting an autoimmune reac-
tion against the Rhesus antigens (Rh actors) on red blood
cells. Several other drugs, such as hydralazine , isoniazid, and
procainamide , can cause a lupus-like syndrome by inducing
antibodies to myeloperoxidase (hydralazine and isoniazid)
or DNA (procainamide).
EXAMPLES OF SIGNS EXAMPLES
PRIMARY MEDIATORS AND SYMPTOMS OF DRUGS
Histamine, serotonin Hives and urticaria, Penicillin
bronchoconstriction,
hypotension, shock
Activated complement; Hemolysis Cefotetan
neutrophils, macrophages,
natural killer cells
Activated complement; Cutaneous vasculitis Mitomycin C
neutrophils, macrophages,
natural killer cells; reactive
oxygen species, chemokines
Cytotoxic T lymphocytes, Macular rash, organ Sulfamethoxazole
macrophages, cytokines failure
Red man syndrome occurs in a small percentage o patients
receiving intravenous drugs such as the antibiotic vancomycin.
The reaction is caused by the direct e ect o the drugs on
mast cells, causing these cells to degranulate. Unlike in type I
hypersensitivity reactions, the mast cell degranulation in red
man syndrome is independent o pre ormed IgE or comple-
ment. Red man syndrome is associated with the emergence o
cutaneous wheals and urticaria (similar to type I reactions);
however, it is o ten a relatively localized phenomenon a ect-
ing the neck, arms, and upper trunk. Only rarely does red man
syndrome progress to severe toxicity such as angioedema and
hypotension. Red man syndrome has also been called an
anaphylactoid reaction because o its resemblance to ana-
phylaxis (type I reaction). Because red man syndrome is initi-
ated by the direct action o a drug on mast cells, it typically
develops during the drug in usion (vancomycin in usions, or
example, are o ten administered over a period o 60 minutes).
The syndrome usually diminishes in severity or resolves a ter
reducing the in usion rate or discontinuing the in usion; it can
be reduced by the prophylactic use o antihistamines; and it
may diminish in severity with repeated intravenous adminis-
trations. In addition to vancomycin, ciprof oxacin, amphoteri-
cin B, and ri ampin can cause this reaction. Red man syndrome
is also associated with certain excipients used in intravenous
ormulations; one such excipient is Cremophor (also known
as Kolliphor ), an excipient or paclitaxel, cyclosporine , and
several other drugs.
Many drugs can elicit the development o skin rashes ,
which are usually diagnosed as erythema multi orme. The
more severe (sometimes li e-threatening) conditions known as
Stevens-Johnson syndrome and toxic epidermal necrolysis have
been reported with barbiturates, sul onamides, antiepileptics
(phenytoin, carbamazepine ), nonsteroidal anti-in ammatory
drugs (ibupro en, celecoxib, valdecoxib), allopurinol, and other
drugs. The pathogenesis o Stevens-Johnson syndrome is not
completely understood, but the morphologic appearance o
mucous membrane and skin in ammation, with the devel-
opment o blisters and separation o the epidermis rom the

dermis, is consistent with an immune etiology. A temporal re-
lationship may exist between the administration o a drug and
the development o skin lesions, but some cases o Stevens-
Johnson syndrome are idiopathic or related to in ection. Thus,
not every case o Stevens-Johnson syndrome can be attributed
to drug exposure.
Immunotoxicity, or injury to the immune system, can
occur either as an adverse e ect o therapy or as the specif c
intent o therapy. Cytotoxic agents used in cancer chemo-
therapy are designed to kill proli erating neoplastic cells but
also routinely damage proli erating normal cells in the bone
marrow, lymphoid tissues, gastrointestinal tract, and hair ol-
licles at concentrations o drug that are required or e f cacy.
For these agents, there is generally little sa ety margin or
damage to normal tissues, and success ul therapy depends
on a greater sensitivity o the cancer cells compared to nor-
mal tissues (see Chapter 33, Principles o Antimicrobial and
Antineoplastic Pharmacology). An increased risk o in ec-
tion o ten accompanies therapy with agents that are cytotoxic
to white blood cells. The margin between adverse e ects and
therapeutic e ects may be increased by the use o agents that
stimulate leukocyte production (e.g., f lgrastim).
Targeting o the immune system may be appropriate
when the disease is caused or exacerbated by a deleteri-
ous immune response (see Chapter 46). For example, in-
haled corticosteroids may be used to control symptoms
in patients with requent, severe exacerbations o chronic
obstructive pulmonary disease (see Chapter 48). By in-
hibiting immune responses to pathogenic microorgan-
isms, however, such treatment is also associated with an
increased risk o pneumonia.
Some immunotherapies target specif c cell types in the
immune system and are associated with an increased risk o
serious in ection. Rituximab is a monoclonal antibody (mAb)
that targets CD20-positive B cells, which are involved in
the pathogenesis o non-Hodgkins lymphoma (malignant
CD20-positive B cells) and rheumatoid arthritis (antibody-
producing CD20-positive B cells). Two potentially serious
adverse e ects that have been observed with the use o
rituximab are progressive multi ocal leukoencephalopathy
(PML), an in ection caused by a polyomavirus, the JC virus
(JCV), and hepatitis B reactivation with the potential or ul-
minant hepatitis. These in ectious agents are generally pres-
ent in latent orm in patients prior to treatment with rituximab,
but the loss o immunocompetence as a result o treatment
allows expression o these serious in ections. Similarly,
e alizumab is a monoclonal antibody that targets CD11a, the
subunit o leukocyte unction-associated antigen-1 (LFA-
1), which is expressed on all leukocytes. By decreasing the
cell sur ace expression o CD11a and inhibiting the binding
o LFA-1 to intercellular adhesion molecule-1 (ICAM-1),
e alizumab inhibits leukocyte adhesion and is an e ective
immunotherapy or psoriasis. However, because CD11a is
also expressed on the sur ace o B cells, monocytes, neutro-
phils, natural killer cells, and other leukocytes, e alizumab
can a ect the activation, adhesion, migration, and destruc-
tion o these cells as well. Like rituximab, e alizumab has
been associated with PML; this serious adverse e ect led to
its withdrawal rom the market in 2009. A similar increase
in the requency o PML has been ound in patients receiv-
ing natalizumab or multiple sclerosis. Natalizumab binds to
the 4 subunit o 4 1 and 4 7 integrins expressed on the
sur ace o all leukocytes except neutrophils; by inhibiting
C h a p t e r 6 Drug Toxicity 79
the 4-mediated adhesion o leukocytes to their target cells,
leukocyte recruitment and activation are prevented.
Cytotoxic antineoplastic agents o ten decrease the pro-
li eration not only o the target cancer cells but also o pro-
li erating cells o normal tissues (see earlier discussion).
Targeted antineoplastic therapies may reduce the impact on
normal proli erating cell populations (see Chapter 33), but
immunosuppression and in ection remain risks. In recent
years, numerous tyrosine kinase inhibitors have been devel-
oped or the treatment o malignant tumors. The mechanism
o action o these compounds is competitive inhibition with
ATP at the ATP-binding site o the kinases. The role o ty-
rosine kinases in cancer is presented in detail in Chapter 40,
Pharmacology o Cancer: Signal Transduction. Sunitinib is
an example o an anticancer tyrosine kinase inhibitor. This
agent is approved or use in gastrointestinal stromal tumors,
advanced renal cell carcinoma, and well-di erentiated pan-
creatic neuroendocrine tumors. Although sunitinib is selec-
tive or VEGF and other receptor tyrosine kinases expressed
in these cancers, its adverse e ects include serious in ections
o the perineum, respiratory tract, urinary tract, and skin as
well as sepsis and septic shock. These in ections may occur
with or without neutropenia, and necrotizing asciitis o the
perineum may lead to death. Increased risk o in ections
has also been observed with the tyrosine kinase inhibitors
a atinib, bosutinib, ibrutinib, and ponatinib.
Drug-Induced Hepatotoxicity
Many drugs are metabolized in and/or excreted by the liver,
and some o these metabolites can cause liver damage. A
clinically signif cant example is acetaminophen, a widely
used analgesic and antipyretic. In its therapeutic dose range,
acetaminophen is metabolized predominantly by glucuroni-
dation and sul ation, resulting in readily excreted metabo-
lites; a small raction o the dose is also excreted unchanged.
As shown in Figure 6-4, however, acetaminophen can also
be oxidized to a reactive and potentially toxic species,
N-acetyl-p-benzoquinoneimine (NAPQI). Glutathione can
conjugate with and thereby detoxi y NAPQI, but overdos-
ing with acetaminophen depletes glutathione reserves (as
can other conditions), leaving NAPQI ree to attack cellu-
lar and mitochondrial proteins, resulting ultimately in the
necrosis o hepatocytes. Timely (within about 10 hours o
acetaminophen overdosing) administration o the antidote
N-acetylcysteine (NAC) replenishes glutathione stores and
can avert liver ailure and death. This example underscores
the importance o dose : although acetaminophen is used
sa ely by millions o individuals every day, the same drug,
when taken in excess, is responsible or some 50% o the
cases o acute liver ailure in the United States.
The liver metabolizes and excretes many endogenous
compounds as well as drugs. O particular interest with
regard to drug-induced hepatotoxicity are the hepatocyte
transporters and enzymes responsible or bile acid absorp-
tion rom the blood, bile acid processing within the hepa-
tocyte, and bile acid secretion into the bile canaliculi (see
Chapter 5). Some drugs share these pathways with the en-
dogenous bile acids. Inhibition o bile acid transporters by a
drug or its metabolites can lead to decreased bile acid secre-
tion, with subsequent increases in intracellular and plasma
concentrations o bile acids and accompanying hepatocel-
lular injury. Inhibition o the bile salt export pump (BSEP)
was a contributing actor in the hepatotoxicity that caused
80 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

O inability to reproduce the injury in laboratory animals.

O A urther challenge is that hepatotoxicity may not be an-
NH
O
ticipated based on preclinical studies, because compounds
NH
exhibiting signif cant hepatotoxicity in animal studies at
NH doses near the anticipated therapeutic exposures in humans
-
O O Glucuronyl are generally withdrawn rom development. Further con-
transferase Sulfotransferase
O
O ounding the prevention o hepatotoxicity is that clinical tri-
OH -
O O als o a drug typically include a ew thousand patients, even
S
OH though a risk o drug-induced hepatotoxicity in the range o
OH OH O O
1 in 10,000 to 1 in 100,000 patients would be o su f cient
Ace ta minophe n Acetaminophen Ace ta minophe n concern to result in withdrawal rom the market. In other
glucuronide s ulfa te words, many clinical trials are too small, or have been de-
signed with exclusion criteria that are not maintained once
P450 enzyme the drug is marketed, to detect unacceptable risks o hepato-
or toxicity. Withdrawal o troglitazone, or example, occurred
only a ter it was noted that approximately 1 in 10,000 pa-
PHS
O
tients taking the drug died rom acute liver ailure.
O The serum levels o certain enzymes (alanine amino-
NH trans erase [ALT], aspartate aminotrans erase [AST], and
N
alkaline phosphatase [ALP]) and bilirubin are o ten used to
Gly
monitor or potential hepatotoxicity in patients. The com-
S O
bination o hepatocellular injury (indicated by increased
Gluta thione serum levels o ALT, AST, and ALP) and decreased hepatic
OH NH
O Glu unction (indicated by elevated bilirubin) is the best predic-
N-a ce tyl-p-be nzoquinone imine Gluta thione conjuga te tor o outcome or drug-induced hepatotoxicity. Elevation o
(NAP QI) serum ALT to 3 times the upper limit o normal, combined
with elevation o serum bilirubin to 2 times the upper limit
o normal, is associated with a mortality rate o at least 10%.
This predictor has become known as Hys rule, named or
Hepatotoxicity Excretion the hepatologist Hyman Zimmerman.
O
H
N
OH
Drug-Induced Renal Toxicity
O
The kidney is the major route o excretion o many drugs
HS and their metabolites. Nephrotoxicity may mani est as al-
N-acetylcysteine terations in renal hemodynamics, tubular damage and ob-
(NAC) struction, glomerular nephropathy, and interstitial nephritis.
Progressive renal ailure, characterized by progressive in-
FIGURE 6-4. Mechanism of acetaminophen poisoning and treatment. creases in serum creatinine, may result rom loss o unc-
Therapeutic doses of acetaminophen are nontoxic, but one metabolite tion o a su f cient number o nephrons. Examples o drug
formed at supratherapeutic doses can cause potentially lethal hepatotoxic- classes that can cause renal ailure include certain antibiot-
ity. Under ordinary circumstances, acetaminophen is metabolized primarily ics, NSAIDs, antineoplastic agents, immunomodulators, and
by glucuronidation ( 5560%) and sulfation ( 3035%); another 5% or less angiotensin converting enzyme (ACE) inhibitors. Here, we
is excreted unchanged. The remaining 510% is oxidized to a reactive inter-
describe the mechanisms o nephrotoxicity caused by the
mediate, N-acetyl-p-benzoquinoneimine (NAPQI). This oxidation is catalyzed
by cytochrome P450 enzymes (CYP), primarily CYP2E1, as well as CYP3A4
aminoglycoside antibiotic gentamicin and the anti ungal
and CYP1A2, and by prostaglandin H synthase (PHS). At therapeutic doses, agent amphotericin B. Renal injury is a common adverse e -
NAPQI reacts rapidly with glutathione to form a nontoxic metabolite that is ect o treatment with both o these agents.
readily excreted. Under conditions of overdosing, however, NAPQI formation Gentamicin causes renal injury in part through its
exceeds glutathione production, allowing free NAPQI to attack mitochon- inhibition o lysosomal hydrolases (sphingomyelinase,
drial and cellular proteins. If this process is unchecked, hepatocyte necrosis phospholipases) in proximal tubules o the kidney, leading to
and acute liver failure can result. Timely administration of the antidote the lysosomal accumulation o electron-dense lamellar struc-
N-acetylcysteine (NAC) can be lifesaving (within 10 hours of acetamino- tures containing undegraded phospholipids. This process
phen overdosing), in that NAC both reacts directly with NAPQI (not shown) is called renal phospholipidosis. Lysosomal rupture leads
and serves as a precursor to glutathione.
to cell death in the orm o acute tubular necrosis. Renal
tubular injury by gentamicin and other aminoglycoside
troglitazone , an insulin-sensitizing agent developed to treat antibiotics is reversible upon cessation o treatment, pro-
diabetes, to be withdrawn rom the market. vided that the initial injury is not too severe.
Unexpected hepatotoxicity is the most requent reason The polyene amphotericin B damages ungal cell mem-
or drug withdrawals in the United States. Many cases o branes by interacting with ergosterol and orming membrane
ulminant hepatitis a ter drug therapy are idiosyncratic pores through which potassium leaks, leading to cell death.
that is, the mechanism by which the patient develops he- Amphotericin-induced renal injury appears to occur via a sim-
patic injury is not knownmaking it di f cult to identi y ilar mechanism, with initial binding o drug to sterols in the
at-risk patients. In some cases, ailure to determine the membranes o renal tubular epithelial cells. Because the mech-
mechanism(s) responsible or hepatic injury is due to the anism responsible or e f cacy is shared by the mechanism

responsible or toxicity, the margin between the exposures
required or anti ungal activity and those required or renal
injury is small, leading to a high requency o renal injury in
patients receiving amphotericin B. Liposomal ormulations o
amphotericin B have been developed in an attempt to reduce
this toxicity and to increase the plasma hal -li e o the drug. I
the initial injury is not too severe, cessation o treatment with
amphotericin o ten results in recovery o renal unction.
Contrast media is administered intra-arterially or intrave-
nously to provide radiographic delineation o the vascula-
ture in organs such as the heart and the brain. These agents
appear to cause renal injury both by direct toxicity to renal
tubular epithelial cells and by constriction o the vasa recta,
leading to reduced renal medullary blood ow. The nephro-
toxicity o contrast media is dose-related, and patients with
preexisting reductions in medullary blood owdue, or
example, to renal insu f ciency, intravascular volume deple-
tion, heart ailure, diabetes, or diuretic or NSAID useare
at higher risk.
Drug-Induced Neurotoxicity
Drug-induced neurotoxicity is most o ten associated with
the use o cytotoxic cancer chemotherapeutic agents. In most
cases, neurotoxicity mani ests in the peripheral nerves, but
the central nervous system may be a ected as well. Periph-
eral neuropathy has been associated with vinca alkaloids (e.g.,
vincristine , vinblastine ), taxanes (e.g., paclitaxel), and plati-
num compounds (e.g., cisplatin). The neuropathy caused by
vinca alkaloids and taxanes is directly related to their primary
mechanism o action, microtubule disruption (see Chapter
39, Pharmacology o Cancer: Genome Synthesis, Stability,
and Maintenance). In peripheral nerves, microtubule disrup-
tion is thought to result in altered axonal tra f cking and both
sensory and motor neuropathy. Platinum-containing com-
pounds may have direct toxic e ects on peripheral nerves.
Methotrexate use has been associated with serious toxicity in
the CNS (e.g., leukoencephalopathy, seizures).
Drug-Induced Skeletal Muscle Toxicity
Drugs and drug classes associated with skeletal muscle in-
jury include HMG-CoA reductase inhibitors (statins ), cor-
ticosteroids (dexamethasone , betamethasone , prednisolone ,
hydrocortisone ), zidovudine , and daptomycin. Statin-induced
myopathy appears to relate to the inhibition o geranyl-gera-
nylation o several muscle proteins. Corticosteroid-induced
muscle injury is complex, involving altered carbohydrate
metabolism, decreased protein synthesis, and alterations in
mitochondrial unction that reduce oxidative capacity. Pa-
tients treated with corticosteroids can mani est weakness,
atrophy, myalgia, and microscopic decreases in muscle f ber
size. Corticosteroid-associated muscle injury is reversible,
albeit slowly. Understanding the pathogenesis o zidovu-
dine-induced myopathy is complicated by the ability o HIV,
the retroviral in ection or which zidovudine is adminis-
tered, to induce myopathy in the absence o drug therapy.
Nonetheless, the improvement in muscle unction upon
withdrawal o zidovudine and the independent demonstra-
tion o zidovudine-induced myopathy in rodents suggest that
the drug itsel causes myopathy, at least in some patients.
The mechanism o zidovudine-associated myopathy is not
well understood, but accumulation o the drug in skeletal
muscle, disruption o mitochondrial cristae, and decreased
oxidative phosphorylation are thought to play a role.
C h a p t e r 6 Drug Toxicity 81
Daptomycin is a cyclic lipopeptide antibiotic active
against Gram-positive bacteria. Its mechanism o action is a
subject o active investigation. Daptomycin binds to the cell
membrane o bacteria. It appears to induce the ormation
o curved patches o membrane, leading to aberrant recruit-
ment o proteins involved in cell division, membrane ion
leaks, membrane depolarization, and bacterial cell death.
Its spectrum o action is thought to result rom the higher
content o negatively charged anionic phospholipids in the
membranes o Gram-positive bacteria compared to Gram-
negative bacteria. In preclinical studies o daptomycin, skel-
etal muscle was the main target organ o toxicity. The degree
o skeletal myopathy was related to both the requency o
dosing (i.e., the incidence and severity o toxicity increased
i the once-daily dose was divided into several smaller
doses) and the total exposure to drug (expressed as the area
under the curve [AUC]). The mechanism o skeletal muscle
injury by daptomycin is not ully understood. It is hypoth-
esized that daptomycin disrupts muscle cell membranes,
consistent with its lipophilic nature and its mechanism o
action in bacteria. The membrane injury causes leakage o
creatine kinase (CK), and increased CK activity in the serum
is a clinical indicator o myotoxicity. Myopathy associated
with an increase in CK has been observed in patients as well
as in animals and is reversible upon discontinuation o dap-
tomycin. Myopathy seldom occurs in patients administered
once-daily doses.
Drug-Induced Cardiovascular Toxicity
Three major mechanisms o drug-induced cardiovascular
toxicity have been recognized. First, as discussed earlier,
many drugs interact with cardiac potassium channels to
cause QTc prolongation, delayed repolarization, and car-
diac arrhythmias. Second, some drugs are directly toxic to
cardiac myocytes. The anthracycline antineoplastic agent
doxorubicin avidly binds to iron; in the presence o oxy-
gen, the iron can cycle between the iron(II) and iron(III)
states, leading to the production o reactive oxygen spe-
cies (ROS). These ROS promote cytotoxicity and death o
cardiac myocytes; the mechanism o cell death may relate
to the low activity o antioxidant enzyme systems in these
cells. Cardiotoxicity, leading to heart ailure and arrhyth-
mia, is o ten the dose-limiting toxicity in patients receiv-
ing this drug. Third, as noted earlier, some drugs are toxic
to heart valves. The amphetamine analog fenfluramine ex-
erts its desired anorectic e ect by increasing the release
and decreasing the uptake o serotonin. Fen uramine and
its metabolite nor en uramine also bind with high a f n-
ity to 5-HT2B receptors. Drug binding to 5-HT2B receptors
in heart valves activates mitogenic pathways, resulting in
proli eration o valvular myof broblasts that orm myxoid
plaques on the atrioventricular valves, leading to valvular
insu f ciency and death in some patients. The increased
serotonergic activity o en uramine can also increase
vascular resistance and remodel the pulmonary arterial
system, leading to pulmonary hypertension. As noted
earlier, the severe adverse e ects o en uramine have
caused the drug to be withdrawn rom the market. Be-
cause o the potential severity o all these cardiovascular
toxicities, there is a concerted e ort to avoid selection o
compounds or drug development that exhibit signif cant
prolongation o the QTc interval or binding a f nity or
5-HT2B receptors.
82 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Drug-Induced Pulmonary Toxicity
Adverse e ects in the lungs range rom acute, reversible
exacerbations o asthmatic symptoms to chronic injury char-
acterized by remodeling and/or f brosis. Reversible airway
obstruction can be associated with -adrenoceptor antago-
nist therapy, whereas chronic injury is observed in some
patients receiving the chemotherapeutic agent bleomycin or
the antiarrhythmic drug amiodarone . The response to injury
a ter cellular damage is largely determined by the regenera-
tive capacity o the target organ. Repeated insults to the lung,
particularly to the epithelial cells lining conducting airways
and alveoli, may be ollowed by regeneration. However,
repeated cycles o epithelial injury can also lead to exces-
sive deposition o collagen and extracellular matrix proteins
in alveolar septa and the alveolar spaces, causing f brosis .
Pulmonary f brosis is mani ested as loss o lung unction.
Bleomycin and amiodarone are contraindicated in patients
with existing disease o the lung parenchyma because both
o these agents can cause pulmonary f brosis.
Carcinogenesis Due to Drug Therapy
Drugs (and other agents) that can cause cancer are termed
carcinogens. More broadly, a carcinogen is a chemical, phys-
ical, or biological insult that acts by causing specif c types o
DNA damage (these agents are termed initiators) or by a-
cilitating proli eration o cells carrying precancerous muta-
tions (these agents are promoters ). Initiators act by damaging
DNA, inter ering with DNA replication, or inter ering with
DNA repair mechanisms. Most initiators are reactive species
that covalently modi y the structure o DNA, preventing ac-
curate replication and, i unrepaired or misrepaired, leading
to one or more mutations. I the mutation a ects a gene that
controls cell cycle regulation, neoplastic trans ormation may
be initiated. Carcinogenesis is a complex process, involving
multiple genetic and epigenetic changes, that usually takes
place over years or decades.
For most therapeutic areas, compounds that cause di-
rect DNA damage are avoided. Yet DNA damage and/or
inter erence with DNA repair is the desired therapeutic
e ect o many agents used to treat neoplasia. Damage to
normal blood cell progenitors is an important on-target
adverse e ect o cytotoxic alkylating agents used in can-
cer chemotherapy (chlorambucil, cyclophosphamide , mel-
phalan, nitrogen mustards , and nitrosoureas ). These agents
can cause myelodysplasia and/or acute myeloid leukemia
(AML). Indeed, 10% to 20% o cases o AML in the United
States arise secondary to treatment o other cancers with
such anticancer drugs.
Tamoxi en, a nongenotoxic estrogen receptor modulator,
is an e ective treatment in patients with estrogen-sensitive
breast cancer. However, this agent also increases the risk o
some tumors. Although tamoxi en is an antagonist o estro-
gen receptors in the breast, it is a partial agonist in other
tissues that express the estrogen receptor, most notably the
uterus. There ore, an adverse e ect o breast cancer treat-
ment with tamoxi en can be the development o endome-
trial cancer. Newer estrogen receptor modulators, such as
raloxi ene , do not stimulate uterine estrogen receptors and
may be used to treat or prevent breast cancer with a lower
risk o endometrial cancer (see Chapter 30, Pharmacology
o Reproduction).
Product labels describe the preclinical assessment o each
drug in the section o the label entitled Carcinogenesis,
Mutagenesis, Impairment o Fertility. In this section, it is
not unusual to f nd descriptions o rodent studies that sug-
gest carcinogenic potential or drugs. Since mutagens are
not typically developed as drugs (with the exceptions noted
above), the treatment-related tumors observed in these li e-
time studies in rodents administered high doses o drug are
generally attributed to nongenotoxic (epigenetic) mecha-
nisms. To assess whether the rodent f ndings represent a risk
to the intended patient population, it is important to under-
stand the mechanism by which these tumors occur. The pro-
ton pump inhibitor omeprazole , or example, causes tumors
o the gastric enterochroma f n-like (ECL) cells in rodents.
The development o these tumors results rom a dose-related
and sustained increase in gastrin, which is secondary to the
desired e ect o the compound (decreased acid secretion).
However, the exposures required or sustained gastrin eleva-
tion and tumor ormation in rodents ar exceed the exposures
required or e f cacy in patients. Further, the gastrin eleva-
tions noted in patients are o low magnitude and are not sus-
tained. Thus, the carcinogenic f nding in the rodent studies
is not considered to signal a risk or tumor development in
patients treated with omeprazole.
Teratogenesis Due to Drug Therapy
Drugs given to pregnant patients may adversely a ect the
etus. Teratogenesis is the induction o structural de ects
in the etus, and a teratogen is a substance that can induce
such de ects. The etuss exposure to a drug is determined
by maternal absorption, distribution, metabolism, and ex-
cretion o the drug and by the ability o the active teratogen
to cross the placenta. These issues are urther discussed in
Box 6-1.
Drugs that might have ew adverse e ects on the mother
may cause substantial damage to the etus. Because develop-
ment o the etus is precisely timed, the teratogenic e ect
o any substance is dependent on the developmental timing
o the exposure. In humans, organogenesis generally occurs
between the third and eighth weeks o gestation, and it is
during this period that teratogens have the most pro ound
e ects. Be ore the third week, most toxic compounds result
in death to the embryo and spontaneous abortion, whereas
a ter organogenesis, teratogenic compounds may a ect
growth and unctional maturation o organs but do not a -
ect the basic developmental plan. For example, retinoic acid
(vitamin A) possesses signif cant on-target teratogenic toxic-
ity. Retinoic acid activates nuclear retinoid receptors (RARs)
and retinoid X receptors (RXRs) that regulate a number o
key transcriptional events during development. Given the se-
verity o birth de ects that can occur, women who take RAR/
RXR agonists such as isotretinoin or acne must sign FDA-
mandated in ormed consent orms to demonstrate that they
are aware o the risk o serious drug-related birth de ects.
Another example o an on-target teratogenic e ect is
in utero exposure o the etus to ACE inhibitors . Although
ACE inhibitors were previously not contraindicated in the
f rst trimester o pregnancy, recent data indicate that etal
exposure during this period signif cantly increases the
risks o cardiovascular and central nervous system mal or-
mations. ACE inhibitors can cause a group o conditions
including oligohydramnios, intrauterine growth retarda-
tion, renal dysplasia, anuria, and renal ailure, re ecting
the importance o the angiotensin pathway on renal devel-
opment and unction.

B O X 6 - 1 Ap p lica tio n to Th e ra p e u tic De cis io n Ma kin g : Dru g s in Pre g n a n cy
Prescribing drugs to women who are, or might become, pregnant
requires a riskbenef t evaluation or both the mother and the
etus. However, many drugs have not been systematically studied
in pregnant populations, so such riskbenef t evaluations may be
uncertain. The FDA places drugs into f ve pregnancy catego-
ries based on data rom studies in laboratory animals, observa-
tions rom well-controlled epidemiologic studies (or lack thereo ),
and/or case reports. These categories appear on drug labels and
are listed below. Note that the categories are not strictly scaled
according to risk; although Category A drugs are typically the sa -
est or use in pregnancy, and Category X drugs are, as the name
suggests, contraindicated, drugs in Category B or which, by
def nition, human data are limited or inadequateare not neces-
sarily almost as sa e as those in Category A.
Category A
Adequate and well-controlled studies have ailed to demonstrate
a risk to the etus in the f rst trimester o pregnancy (and there is
no evidence o risk in later trimesters).
Category B
Animal reproduction studies have ailed to demonstrate a risk to
the etus, and there are no adequate and well-controlled studies
in pregnant women.
Category C
Animal reproduction studies have shown an adverse e ect on
the etus, and there are no adequate and well-controlled studies
in humans, but potential benef ts may warrant use o the drug in
pregnant women despite potential risks.
Category D
There is positive evidence o human etal risk based on adverse
reaction data rom investigational or marketing experience or
studies in humans, but potential benef ts may warrant use o the
drug in pregnant women despite potential risks.
PRINCIPLES FOR TREATING PATIENTS
WITH DRUG-INDUCED TOXICITY
Treatment o drug-induced toxicity may include (1) reduc-
ing or eliminating exposure to the drug, (2) administering
specif c treatments based on antagonizing the mechanism o
action o the drug or altering its metabolism, and/or (3) pro-
viding supportive measures.
Reduction o exposure to a therapeutic agent in a patient
who experiences adverse e ects may seem intuitive, but it
is not always the correct choice. The appearance o an ad-
verse e ect during therapy does not necessarily indicate that
the e ect is due to the drug, despite the temporal relation-
ship between the initiation o therapy and the appearance
o the adverse e ect. Even i the adverse e ect most likely
occurred because o the drug, the risks o cessation must be
weighed against the benef ts o continuing the drug. Ces-
sation o therapy is more obviously a correct choice when
the adverse e ects have been previously associated with the
C h a p t e r 6 Drug Toxicity 83
Category X
Studies in animals or humans have demonstrated etal abnormali-
ties and/or there is positive evidence o human etal risk based on
adverse reaction data rom investigational or marketing experi-
ence, and the risks involved in use o the drug in pregnant women
clearly outweigh potential benef ts.
Category Xdrugs include not only teratogens but also drugs that
have no proper use in pregnant patients. Statins are in this category,
or example, because the normal physiologic increase in serum cho-
lesterol that occurs during pregnancy should not be suppressed.
Despite their long history o use, the label categories remain a
source o con usion, even occasionally within the FDA itsel . For
example, the antibiotic tigecycline is classif ed in Category D, but
the absence o controlled data rom humans indicates that it should
instead be placed in Category C. More generally, the FDA preg-
nancy categorization o drugs, like any such scheme, is not per ect
and may ail to capture the nuances o some drug-specif c and pa-
tient-specif c circumstances. Thus, the physician should also rely
on his or her own judgment, keeping in mind the ollowing issues:
What are the risks to both etus and mother o nott treating
the illness or which the drug is being considered?
Is the drug known to cross the placenta? Based on its
molecular weight, charge, hydrophobicity, and/or potential or
carrier-mediated transport, is it likely to cross the placenta?
Is there a pharmacologic rationale or how the drug could
a ect the etus (e.g., through e ects on organogenesis,
organ development, organ unction, or a delivery compli-
cation) should the etus be exposed?
When appropriate, drugs that have proven e ective or treat-
ing a patients condition should be continued. To minimize etal
risk, drugs should be prescribed at the lowest therapeutic dose,
taking into account the metabolic and physiologic changes that
occur during pregnancy.
drug and are li e-threatening, such as anaphylaxis due to a
beta-lactam antibiotic. Needless to say, or such patients,
uture therapy with this class o antibiotics would also be
contraindicated. Adverse e ects that are irreversible and/or
likely to increase in severity with continued treatment may
also lead to the appropriate decision to terminate therapy.
Many adverse e ects, however, are considered tolerable and
reversible. Depending on the severity o the disease condi-
tion being treated, it may be that the overall benef t to the pa-
tient is greater with drug treatment than without. An example
o such circumstances is the leukopenia that o ten occurs in
patients receiving chemotherapy with cytotoxic drugs. Thus,
the decision to withdraw or reduce therapy can be complex
and o ten requires evaluation o many actors a ecting the
patients immediate and long-term health.
Therapies designed to counteract the adverse e ects pro-
duced by a drug are o ten based on antagonizing the phar-
macologic (on-target) activity o the drug or inter ering with
e ects related to metabolism o the drug. Antagonizing the
84 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
pharmacologic activity o a drug is a use ul approach in
overdoses o opioids, benzodiazepines, and acetylcholines-
terase (AChE) inhibitors. Inter erence with the toxic e ects
o drug metabolites is a use ul approach in the treatment
o acetaminophen toxicity. These examples are brie y dis-
cussed below.
Conceptually, the simplest treatment or drug overdose
is the administration o an antagonist that blocks the action
o the drug (see Fig. 2-4). For example, an opioid overdose
can be treated with naloxone , a competitive antagonist at the
-opioid receptor. By competitively binding to opioid recep-
tors, naloxone prevents or reverses the toxic e ects o natu-
ral or synthetic opioids, including respiratory depression,
sedation, and hypotension. Naloxone has a rapid onset o ac-
tion and is highly potent; indeed, i no clinical improvement
is observed within 10 minutes a ter naloxone doses o up to
10 mg, a di erent diagnosis or multiple toxic entities should
be considered. Naloxone has a relatively short hal -li e, so it
must be given every 1 to 4 hours to provide adequate recep-
tor antagonism while the opioid is being cleared.
Flumazenil, a competitive antagonist at the GABAA
(benzodiazepine) receptor, is used to treat benzodiazepine
overdose. Flumazenil acts by competitive antagonism at
benzodiazepine receptors in the central nervous system to
completely or partially reverse the sedative e ects o ben-
zodiazepines. Like naloxone, it has a rapid onset o action
and is highly potent; its e ects should be seen within 5 min-
utes at a dose o not more than 3 mg. Flumazenil also has
a short hal -li e (approximately 1 hour) and must be given
requently to provide adequate receptor antagonism while
the benzodiazepine is being cleared.
Pharmacologic antagonism can also be used when the
toxic agent is not a direct agonist but instead indirectly in-
creases the concentration o the natural ligand or a receptor.
AChE inhibitors produce a supraphysiologic concentration
o acetylcholine at cholinergic synapses and a characteris-
tic toxidrome o cholinergic excessbradycardia, miosis,
hypersalivation, sweating, diarrhea, vomiting, bronchocon-
striction, weakness, respiratory paralysis, and convulsions.
Although it is sometimes possible to restore AChE activ-
ity, the treatment o AChE inhibition generally depends on
administering an anticholinergic agent such as atropine . By
antagonizing the muscarinic acetylcholine receptor, atropine
restores cholinergic balance and prevents bronchoconstric-
tion, the most common cause o death in patients exposed to
AChE inhibitors.
As noted earlier, a consequence o acetaminophen overdose
is depletion o intracellular glutathione by the drugs metabo-
lite N-acetyl-p-benzoquinoneimine (NAPQI). Glutathione
stores can be replenished by administering N-acetylcysteine
(NAC), a metabolic precursor o glutathione (see Fig. 6-4
or details). In addition to supportive therapy (gastric lavage
and/or charcoal), NAC is given orally or intravenously within
about 10 hours a ter ingestion o a potentially hepatotoxic
dose o acetaminophen to prevent or lessen hepatic injury.
Finally, supportive therapy can be provided in the ace
o drug-induced toxicity. One example is the administration
o intravenous uids to patients with renal injury in order
to maintain adequate renal blood ow. In cases o severe
renal injury, dialysis may be required until renal unction is
regained. Another example is the treatment o bone marrow
suppression resulting rom the administration o cytotoxic
agents in cancer chemotherapy. Filgrastim, a recombinant
human granulocyte colony-stimulating actor (G-CSF), can
be used to stimulate leukocyte production and provide sup-
portive therapy until endogenous production o leukocytes
resumes in the bone marrow.
TOWARD EARLY DETECTION AND
PREDICTION OF DRUG TOXICITY
A key element o the US FDAs strategic plan o August
2011 states: Modernizing toxicology and continually im-
proving the ability o nonclinical tests, models, and mea-
surements to predict product sa ety issues will increase the
likelihood that toxicity risks will be identif ed earlier in
product development, assuring patient sa ety, and mitigating
the need to withdraw previously approved products. One
e ective approach toward early detection and prediction o
drug toxicity is the use o sensitive, specif c, and qualif ed
translational biomarkers.
Many current approaches to detect and predict drug toxicity
in animal studies use a combination o microscopic tissue ex-
amination and measurement o traditional biomarkers to as-
sess organ injury. As described above, examples o traditional
biomarkers include serum concentrations o urea nitrogen and
creatinine to evaluate potential adverse renal e ects and serum
activities o alanine aminotrans erase (ALT), aspartate ami-
notrans erase (AST), and gamma-glutamyltrans erase (GGT)
and serum concentrations o bilirubin and bile acids to evalu-
ate potential adverse hepatic e ects. However, these traditional
markers are now viewed as relatively insensitive, particularly
those or monitoring renal injury. Because o renal reserve,
or instance, creatinine may not increase until there has been
considerable (greater than 70%) loss o renal unction. O ad-
ditional concern is drug-induced renal injury in patients with
preexisting renal dys unction, since these patients have dimin-
ished reserve capacity. It is also important to note that the de-
gree o loss o renal unction in drug studies cannot be equated
with the potential or reversibility o the morphologic changes
that may accompany the loss o unction. As noted above, non-
clinical studies and clinical experience have demonstrated that
drug-induced renal injury is o ten reversible, depending on the
extent o injury.
With these considerations in mind, the goal o recent e -
orts is to identi y sa ety biomarkers that may improve the
detection and prediction o drug toxicity by (1) identi ying
toxicity early in drug development, thereby reducing the rate
o attrition o drug candidates during later stage clinical tri-
als, and (2) providing markers to monitor toxicity in patients,
with the goal o reducing the entry o drugs into the market
that have unacceptable toxicity and acilitating the manage-
ment o patients who su er organ damage or injury.
Over the last decade, consortia such as the European In-
novative Medicines Initiative (IMI), Predictive Sa ety Test-
ing Consortium (PSTC), and Health and Environmental
Sciences Institute (HESI) have dedicated resources to identi-
ying translational biomarkers or early detection o toxicity.
In 2008, the US FDA, European Medicines Agency (EMA),
and Japanese Pharmaceuticals and Medical Devices Agency
(PMDA) jointly announced the qualif cation o seven urinary
biomarkers to monitor kidney toxicity in preclinical studies.
This international e ort showed that, in many instances,
kidney injury molecule-1 (KIM-1), clusterin (CLU), albu-
min, total protein, 2-microglobulin, cystatin C, and tre oil
 C h a p t e r 6 Drug Toxicity 85

TABLE 6-2 Online Resources for Information on Drug Toxicity

TYPE OF INFORMATION SOURCE WEBSITE
Product labels Physicians Desk Reference http://csi.micromedex.com/Login.asp
Drug manufacturer Various websites by manufacturer

Regulatory agencies US Food and Drug Administration http://www.fda.gov/

European Medicines Agency (EMA) http://www.ema.europa.eu/

Government databases National Library of Medicine http://www.ncbi.nlm.nih.gov/pubmed/

National Toxicology Program http://ntp.niehs.nih.gov/
TOXNET http://toxnet.nlm.nih.gov/
International Conference on Harmonization http://www.ich.org/products/guidelines.html
of Technical Requirements for
Registration of Pharmaceuticals for
Human Use (ICH)

Commercial databases Pharmapendium https://www.pharmapendium.com/

Medscape http://www.medscape.com/
DiscoveryGate https://www.discoverygate.com
INCHEM http://www.inchem.org

actor 3 (TFF3) provide an earlier signal than traditional
biomarkers and also add signif cant in ormation with regard
to potential localization o the adverse renal e ects. Notably,
these newer biomarkers correlated with the gold standard
o kidney toxicity, quantitative histopathology. Thus, al-
though the newer biomarkers generally do not o er higher
sensitivity in nonclinical models, they do provide important
perspective on which biomarkers would be use ul to monitor
in both clinical studies (be ore drug approval) and in patients
(a ter drug approval) in order to better understand potential
risks to humans.
As with traditional biomarkers, decisions on whether
to withdraw therapy or individual patients or to continue
clinical development o a drug in which increases in these
biomarkers have been observed still require a riskbenef t
analysis (see Principles or Treating Patients with Drug-
Induced Toxicity earlier in this chapter). The kidney bio-
marker qualif cation process has led some pharmaceutical
companies to include an assessment o newer biomarkers
in nonclinical and clinical data submitted or review to reg-
ulatory agencies in the United States, Europe, and Japan.
Similar e orts are underway to identi y sa ety biomark-
ers or liver, heart, skeletal muscle, testicular, and vascu-
lar toxicity, including an evaluation o the per ormance o
these biomarkers in diagnosis and prognosis o toxicity in
clinical studies.
CONCLUSION AND FUTURE
DIRECTIONS
This chapter has presented a mechanism-based approach to
understanding drug toxicity and provided examples to illus-
trate these principles in major organ systems. Drug devel-
opment aims to discover compounds that are both e ective
and highly selective and thus less likely to cause serious
or otherwise undesirable o -target e ects. The challenges
o the uture lie particularly with understanding the basis
or variability o therapeutic and toxic responses to drugs.
In an attempt to predict which patient populations will be
most susceptible to an adverse drug reaction, one approach
under evaluation is to f nd correlations between individual
single nucleotide polymorphisms (SNPs) and possible ad-
verse reactions by comparing the SNPs o patients who have
adverse reactions with those who do not. The identif cation
o patients with genetic variants o the molecular target
(and closely related targets) o a drug could provide use ul
in ormation about patients who might be more likely to ex-
perience adverse e ects.
Predicting e f cacy and sa ety in individual patients re-
mains a challenge to the treating physician. The decision to
use drug therapy requires knowledge o the potential ben-
ef ts and risks o the therapy. Moreover, physicians have the
responsibility to communicate these risks and benef ts to
the patient so that the ull range o therapeutic options can
be considered. One challenge to the physician is where to
f nd this in ormation. Sources include the scientif c litera-
ture, the product label, direct communications to prescrib-
ing physicians, and reviews o the preclinical and clinical
data prepared by the FDA during its review o a New Drug
Application (NDA; see Chapter 52).
The key toxicity in ormation, both preclinical and clini-
cal, is contained in the product label. Revisions o the label
may occur as serious adverse events are attributed to drugs
during postmarketing surveillance, and it is incumbent
on the physician to consult the most recent version o the
product label. Alerts o serious consequences may also be
transmitted in the orm o direct communications to pre-
scribing physicians, and the FDA website can be consulted
or current regulatory actions related to a drugs sa ety.
The European Medicines Agency (EMA) website contains
in ormation regarding regulatory actions or medicines
marketed in Europe. Table 6-2 lists some o the online
sources that can be consulted or in-depth in ormation
about drug toxicity. Good sources o detailed in ormation
on preclinical toxicity and clinical adverse events are the
documents prepared by the FDA pharmacologist (preclini-
cal) and medical reviewer (clinical) as part o their review
o the NDA.
86 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Acknowledgment
We thank Cullen Taniguchi, Sarah R. Armstrong, Vivian
Gonzalez Le ebre, and Robert H. Rubin or their valuable
contributions to this chapter in the First, Second, and Third
Editions o Principles o Pharmacology: The Pathophysio-
logic Basis o Drug Therapy.
Suggested Reading
Agranat I, Caner H, Caldwell J. Putting chirality to work: the strategy o
chiral switches. Nat Rev Drug Discov 2002;1:753768. (An overview o
enantiomeric-specif c properties o drugs and the strategies o switching
drugs rom achiral to chiral preparations.)
Bonventre JV, Vaidya VS, Schmouder R, Feig P, Dieterle F. Next-generation
biomarkers or detecting kidney toxicity. Nat Biotechnol 2010;28:436440.
(Reviews potential new biomarkers or assessing renal unction in both
nonclinical and clinical studies.)
Bugelski PJ. Genetic aspects o immune-mediated adverse drug e ects. Nat
Rev Drug Discov 2005;4:5969. (Overview o immune-mediated adverse
e ects, including detailed mechanistic in ormation.)
Campion S, Aubrecht J, Boekelheide K, et al. The current status o biomarkers
or predicting toxicity. Expert Opin Drug Metab Toxicol 2013;9:13911408.
(Reviews sensitivity and utility o currently used biomarkers or assessment
o toxicity during drug development.)
Elangbam CS. Current strategies in the development o anti-obesity
drugs and their sa ety concerns. Vet Pathol 2009;46:1024. (Provides
examples o drug development guided by knowledge o mechanisms o
toxicity.)
Fujimoto K, Kumagai K, Ito K, et al. Sensitivity o liver injury in hetero-
zygous Sod2 knockout mice treated with troglitazone or acetaminophen.
Toxicol Pathol 2009;37:193200. (Demonstrates use o genetically
engineered animals to study mechanisms o toxicity.)
Hondeghem LM. QTc prolongation as a surrogate or drug-induced
arrhythmias: act or allacy? Acta Cardiol 2011;66:685689. (Commentary
on relative utility o drug-induced changes in QTc as a predictor o arrhyth-
mogenic potential o drugs.)
International Con erence on Harmonisation o Technical Requirements or
Registration o Pharmaceuticals or Human Use. ICH harmonised tripartite
guideline: immunotoxicity studies or human pharmaceuticals S8, 2005.
http://www.ich.org/f leadmin/Public_Web_Site/ICH_Products/Guidelines/
Sa ety/S8/Step4/S8_Guideline.pd . (Summary o principles and guidelines
or evaluating potential immunotoxicity o drug candidates.)
Liebler DC, Guengerich FP. Elucidating mechanisms o drug-induced tox-
icity. Nat Rev Drug Discov 2005;4:410420. (Introduces the concept o a
mechanism-based approach to drug toxicity.)
Morgan RE, Trauner M, van Staden CJ, et al. Inter erence with bile salt export
pump unction is a susceptibility actor or human liver injury in drug devel-
opment. Toxicol Sci 2010;118:485500. (Correlation between drug-induced
inhibition o bile salt export protein (BSEP) and hepatotoxicity in patients.)
Morgan RE, van Staden CJ, Chen Y, et al. A multi actorial approach to
hepatobiliary transporter assessment enables improved therapeutic com-
pound development. Toxicol Sci 2013;136:216241. (Describes in vitro ap-
proaches or reducing risk o hepatotoxicity during selection o candidates
or drug development.)
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med
2006;354:731739. (Overview o pharmacogenomic approaches to under-
standing and predicting drug hepatotoxicity.)
Owczarek J, Jasiska M, Orszulak-Michalak D. Drug-induced myopathies:
an overview o the possible mechanisms. Pharmacol Rep 2005;57:2334.
(Overview o mechanisms leading to skeletal muscle toxicity.)
Sager PT, Gintant G, Turner JR, Petit S, Stockbridge N. Rechanneling the
cardiac proarrhythmia sa ety paradigm: a meeting report rom the Cardiac
Sa ety Research Consortium. Am Heart J 2014;167:292300. (A summary
o new initiatives to better evaluate risk o arrhythmogenic potential o
drugs and reduce the need or thorough QTc studies.)
U.S. Food and Drug Administration. Pregnancy, lactation, and reproduc-
tive potential: labeling or human prescription drug and biological prod-
uctscontent and ormat. June 2015. Washington, DC: U.S. Department
o Health. (Reviews proposals to revise product labels to better describe
reproductive and developmental risks.)
 OH
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CYP 2D6 Am b e r DaS

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ULT a n1dAKe
T 1 la n Ta n t is ira

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INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . 87
8 88 88 Pathway Basedd PhPhar
arma
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g netics-
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PHYSIOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
Endo o x
xife
xif
ife
fe n
Pharmacogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Genomic Variationn an a d Pharmacogenomics . . . . . . . . . . . . . . . 87 Role of Epigenetics in Pharmacogenetics-
PHARMACOLOGY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Pharm
ha r acogenomics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
9
Vari
a riat
atio
ion in Enzymes of Drug ug Metabolism: Modern Pharmrmac
acog
ogenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Pha
h rmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Pharmacogenomics and nd Regul
egu atory Science . . . . . . . . . . . . . . 94
Variation in Drug Ta
Targrget
ets:s: CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . 95
Pharmacodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95

B
INTRODUCTION PHYSIOLOGY
Modern pharmacologic100
agents are used to treat or control Genomic Variation and Pharmacogenomics
diseases that range rom hypertension to human immuno-
)
The human genome contains approximately 3 billion nucle-
%
def ciency virus (HIV) in ection. In many cases, the same
otides. According to current estimates, the genome contains
drug regimens are used or populations o people. Large
approximately 19,00020,000 protein-coding genes that,
variations among individuals are o ten ound in response
through alternative splicing and post-translational modif ca-
to drug therapy, however. These variations range rom po-
tion, may encode 100,000 or more proteins. On average, any
tentially li e-threatening adverse drug reactions to equally
two people di er at about one nucleotide in every 1,000 in
serious lack o therapeutic e f cacy. Many actors in uence
their genome, totaling an average interindividual di erence
the drug response phenotype, including age, gender, and un-
o 3 million base pairs throughout the genome. The majority
derlying disease, and genetic variation plays an important
o these di erences are so-called single nucleotide polymor-
role. Interindividual di erences in the genes that encode
phisms or SNPs (pronounced snips), in which one nucleo-
drug targets, drug transporters, and enzymes that catalyze
tide is exchanged or another at a given position. SNPs and
drug metabolism can pro oundly a ect the success or ailure
other di erences in DNA sequence can occur anywhere in
o pharmacotherapy.
the genome, in both coding regions and noncoding regions.
Pharmacogenetics is the study o the role o inheritance
I a SNP changes the encoded amino acid, it is called a non-
in variation in drug response. The convergence o recent
synonymous coding SNP (cSNP). The remaining di erences
advances in genomic science and equally striking advances
in DNA sequence involve insertions, deletions, duplications,
in molecular pharmacology has resulted in the evolution o
and reshu ings, sometimes o just one or a ew nucleotides
pharmacogenetics into pharmacogenomics. The promise o
but occasionally o whole genes or larger DNA segments
pharmacogenetics-pharmacogenomics is the possibility that
that include many genes. Functionally signif cant DNA se-
knowledge o a patients DNA sequence could be used to en-
quence di erences that we currently understand tend to all
hance pharmacotherapy, maximize drug e f cacy, and reduce
within genes, either within their coding sequences or in the
the incidence o adverse drug reactions. There ore, pharma-
promoters, enhancers, splice sites, or other sequences that
cogenetics and pharmacogenomics represent an important
control gene transcription or mRNA stability. Heritable ge-
aspect o the aspiration to personalize or individualize
netic regulation that does not occur through DNA sequence
medicinein this case, drug therapy. This chapter describes
changes, termed epigenetics, also contributes to unctionally
the principles o pharmacogenetics and pharmacogenomics
signif cant variation in genes and gene expression. Taken
as well as recent developments in this discipline. Several
together, these di erences constitute each persons genetic
key examples are cited in which knowledge o pharmaco-
individuality. Some o that individuality a ects the way in
genetics-pharmacogenomics may help to individualize drug
which each person will respond to drug treatment.
therapy.

87
88 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
Ro b e rt H, a 66-ye a r-o ld m a n , is s h o ve l-
in g s n o w o n e w in try m o rn in g in Min -
n e s o ta w h e n h e s lip s a n d fa lls o n a
p a tch o f ice . He im m e d ia te ly fe e ls p a in
in h is le ft h ip a n d is u n a b le to s ta n d . He
is b ro u g h t to th e h o s p ita l, w h e re x-ra ys
re ve a l th a t h e h a s fra ctu re d h is h ip . He u n d e rg o e s
s u rg e ry th e n e xt d a y a n d is d is ch a rg e d to a re h a b ili-
ta tio n h o s p ita l 3 d a ys la te r. Afte r le s s th a n 24 h o u rs
a t th e re h a b ilita tio n h o s p ita l, Mr. H d e ve lo p s th e
s u d d e n o n s e t o f p le u ritic ch e s t p a in . He is b ro u g h t
to th e e m e rg e n cy d e p a rtm e n t, w h e re a co m p u te d
to m o g ra p hy (CT) s ca n w ith in tra ve n o u s co n tra s t re -
ve a ls a p u lm on a ry e m b o lu s . He is tre a te d w ith h e p a -
rin a n d is a n tico a g u la te d w ith wa rfa rin a t a s ta rtin g
d o s e o f 5 m g e a ch d a y, w ith a ta rg e t in te rn a tio n a l
n o rm a lize d ra tio (INR) o f 2.03.0. Mr. H is d is ch a rg e d
b a ck to h is re h a b ilita tio n h o s p ita l a n d re fe rre d to h is
PHARMACOLOGY
The concept that inheritance might be an important determi-
nant o individual variation in drug response emerged hal a
century ago. It originally grew out o clinical observations
o striking di erences among patients in their response to
standard doses o a drug. Those observations, coupled
with twin and amily studies that showed inherited varia-
tions in plasma drug concentrations and other pharmaco-
kinetic parameters, led to the birth o pharmacogenetics.
Many o those original examples o pharmacogenetic varia-
tion, and many o the most striking examples even today,
involve pharmacokinetics actors that in uence the con-
centration o drug reaching its target(s). However, examples
o pharmacogenetic variation in the drug target, so-called
pharmacodynamic actors, are also being reported with
increasing requency. Pharmacogenetic variation related
to unpredicted (idiosyncratic) adverse e ects rom drugs
has also been described. While not detailed urther in this
chapter, an example o an idiosyncratic pharmacogenetic
e ect is provided by the serious hypersensitivity reaction
associated with the HLA-B*5701 allele in patients taking
abacavir, a reverse transcriptase inhibitor and anti-HIV agent
(see Chapter 38, Pharmacology o Viral In ections). Predrug
testing or HLA-B*5701 has been shown to nearly eliminate
such hypersensitivity reactions.
Variation in Enzymes of Drug Metabolism:
Pharmacokinetics
Inherited variation in enzymes that catalyze drug metabolism
is the most common actor responsible or pharmacogenetic
variation in response to medications. The enzymes involved
in drug metabolism are discussed in Chapter 4, Drug Metab-
olism. There are two broad categories o drug-metabolizing
enzymes: those that catalyze phase I reactions ( unctional-
ization reactions that typically involve oxidation or reduc-
tion) and those that catalyze phase II reactions (typically,
conjugation reactions that add groups, such as glucuronic
acid, that enhance drug solubility and thus drug excretion).
lo ca l p hys icia n . Wh e n th e INR is s u b s e q u e n tly m e a -
s u re d , it is 6.2, a va lu e a s s o cia te d w ith a n in cre a s e d
ris k o f h e m o rrh a g e . He is ta kin g n o o th e r m e d ica tio n
th a t m ig h t in te rfe re w ith p la s m a le ve ls o f wa rfa rin .
Th e p hys icia n a d vis e s Mr. H to s to p ta kin g wa rfa rin
fo r 2 d a ys . Afte r m u ltip le a tte m p ts a t a d ju s tin g h is
d o s e o f wa rfa rin , Mr. H e ve n tu a lly re a ch e s a s ta b le
INR o f 2.5 w h e n ta kin g 1 m g o f wa rfa rin e a ch d a y.
Questions
1 . What molecular mechanisms could be responsible for
the apparent sensitivity of Mr. H to warfarin?
2 . What additional laboratory information could assist in
anticoagulating this patient?
3 . Would that information have helped in the selection of
Mr. Hs initial warfarin dose?
Phase I and phase II reactions do not necessarily occur in
that order, and metabolic intermediates resulting rom both
types o reactions may be pharmacologically active. In act,
some medications are administered as inactive prodrugs that
must undergo phase I and/or phase II metabolism be ore
they can exert their pharmacologic e ect.
Genetic polymorphisms are common in enzymes that cat-
alyze drug metabolism, and clinically signif cant polymor-
phisms have been ound in nearly all o the major enzymes
involved in both phase I and phase II reactions (Table 7-1).
Two classic examples are provided by the inherited varia-
tions in the enzymatic hydrolysis o the short-acting muscle
relaxant succinylcholine by the enzyme butyrylcholinester-
ase (BChE; also known as serum cholinesterase) and the
enzymatic acetylation o drugs such as the antituberculosis
drug isoniazid (see Chapter 35, Pharmacology o Bacterial
and Mycobacterial In ections: Cell Wall Synthesis). Patients
with variations in BChE have a decreased rate o metabolism
o succinylcholine, resulting in prolonged paralysis a ter
drug exposure. A genetically polymorphic phase II enzyme,
N-acetyltrans erase 2 (NAT2), catalyzes the acetylation o
isoniazid. Patients treated with isoniazid can be classif ed as
either slow acetylators, who metabolize isoniazid slowly
and have high blood drug levels, or ast acetylators, who
metabolize isoniazid rapidly and have low blood drug lev-
els. Family studies have shown that the rate o isoniazid bio-
trans ormation is inherited.
The slow-acetylator phenotype is associated with drug
toxicities that result rom excessive drug accumulation;
examples include hydralazine- and procainamide-induced
lupus and isoniazid-induced neurotoxicity and liver injury.
Although the antihypertensive agent hydralazine is rarely
used today in the treatment o hypertension, this drug has
recently reemerged as one o the two active components in
BiDil, a combination drug approved or the treatment o pa-
tients with symptomatic heart ailure. It is o interest that
the US Food and Drug Administration (FDA) has approved
BiDil or use only in patients o A rican ancestry, presum-
ably because o an ethnically dependent genetic di erence
in response to this drug.
 C h a p t e r 7 Pharmacogenomics 89

TABLE 7-1 Examples of Genetic Polymorphisms and Drug Metabolism

ENZYME AFFECTED DRUG, CLASS, OR COMPOUND

Phase I (Oxidation/Reduction) Enzyme

CYP1A2 Acetaminophen, ca eine, propranolol

CYP1B1 Estrogens

CYP2A6 Halothane, nicotine

CYP2B6 Cyclophosphamide

CYP2C8 Paclitaxel, retinoic acid

CYP2C9 Nonsteroidal anti-inf ammatory drugs, phenytoin, war arin

CYP2C19 Omeprazole, phenytoin, propranolol

CYP2D6 Antidepressants, -adrenergic antagonists, codeine, debrisoquine, dextromethorphan

CYP2E1 Acetaminophen, ethanol

CYP3A5 Calcium channel blockers, cyclosporine, dapsone, etoposide, lidocaine, lovastatin, macrolides,
midazolam, quinidine, steroids, tacrolimus, tamoxi en

Phase II (Conjugation) Enzyme

N-Acetyltrans erase 1 Sul amethoxazole

N-Acetyltrans erase 2 Dapsone, hydralazine, isoniazid, procainamide, sul onamides

Sul otrans erases (SULTs) Acetaminophen, dopamine, epinephrine, estrogens

Catechol-O-methyltrans erase Catecholamines, levodopa, methyldopa

Histamine N-methyltrans erase Histamine

Thiopurine S-methyltrans erase Azathioprine, mercaptopurine, thioguanine

UDP-glucuronosyltrans erases Androgens, ibupro en, irinotecan, morphine, naproxen

Early examples o the importance o pharmacogenetic
variation, such as those represented by BChE and NAT2,
served as a stimulus to search or additional examples. Most
o the second-generation examples continued to be asso-
ciated with pharmacokinetics and continued to be recog-
nized rom clinical observationso ten rom adverse drug
responses. They were most o ten studied either by adminis-
tering a probe drug to a group o subjects and measuring
plasma or urinary drug and/or metabolite concentrations or
by directly assaying a drug-metabolizing enzyme in an easily
accessible tissue such as the red blood cell (e.g., a series o
methyltrans erase enzymes). Two prototypic examples that
have become pharmacogenetic icons are the cytochrome
P450 2D6 (CYP2D6) and thiopurine S-methyltransferase (TPMT)
genetic polymorphisms. Because o the clinical implications
o these polymorphisms, the FDA in its 2003 Guidance on
Pharmacogenomic Data cited CYP2D6 and TPMT as ex-
amples o valid pharmacogenomic biomarkers.
CYP2D6 is a member o the cytochrome P450 (CYP)
amily o microsomal, phase I drug-metabolizing enzymes.
CYP2D6 contributes to the metabolism o a large number
o medications, including antidepressants, antipsychotics,
antiarrhythmics, and analgesics. The CYP2D6 polymor-
phism was originally described by two di erent laborato-
ries studying two di erent probe drugs: the antihypertensive
debrisoquine and the oxytocic agent sparteine . The requency
distribution o the debrisoquine urinary metabolic ratio, the
ratio o the parent drug to its oxidized metabolite, is shown
in Figure 7-1A or a Northern European population. Shown
at the ar right o the f gure is a group o poor metabolizers
o debrisoquine, subjects homozygous or recessive alleles
(genes) coding or enzymes with decreased activity or or
deletion o the CYP2D6 gene; shown in the middle is the
large group o extensive metabolizers, subjects heterozy-
gous or homozygous or the wild-type allele; and shown
at the ar le t is a small subset o ultrarapid metabolizers,
some o whom have multiple copies o the CYP2D6 gene.
Several molecular genetic mechanisms are responsible
or variation in CYP2D6 enzyme activity, including non-
synonymous cSNPs, gene deletion, and gene duplication;
some ultrarapid metabolizers can have up to 13 copies o the
gene. It has been estimated that 6% to 10% o Caucasians
are CYP2D6 poor metabolizers. Among East Asians, in
contrast, the poor-metabolizer phenotype is present at a re-
quency o just 1% to 2%. The ultrarapid-metabolizer pheno-
type, rare in most Caucasian populations, has a requency o
3% in Spaniards and up to 13% in Ethiopians. These ethnic
di erences have potentially important medical implications
because CYP2D6 metabolizes many commonly prescribed
medications, including the -adrenergic blocker metoprolol,
90 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY

A CYP2D6 pharmacogenetics and poor metabolizers, alternative analgesics are now rec-
ommended as substitutes or codeine.
CYP2D6 genetic polymorphisms are also important or the
Ultra ra pid Exte ns ive P oor
me ta bolize rs me ta bolize rs me ta bolize rs e f cacy o the breast cancer drug tamoxi en. Tamoxi en is used
120 to block the estrogen receptor (ER) in approximately 60% o
breast cancer patients with ER-positive tumors. However,
tamoxi en is a prodrug that requires metabolic activation to orm
s
t
4-hydroxytamoxi en and 4-hydroxy-N-desmethyltamoxi en
c
e
j
80
b
(endoxi en) (Fig. 7-2A). These metabolites are approximately
u
s
100 times more potent as antagonists o the ER than the parent
f
o
drug. As a result, patients who are CYP2D6 poor metabolizers
r
e
b
(Fig. 7-1) are relatively unable to orm the active 4-hydroxy
m
40
u
metabolites o tamoxi en. Poor-metabolizer patients have
N
worse outcomes with respect to breast cancer recurrence than
do CYP2D6 extensive metabolizers (EMs) (Fig. 7-2B). Fur-
0 thermore, i EM patients are co-administered other drugs such
0.01 0.10 1 10 100 as antidepressants that are good CYP2D6 substrates, they may
De bris oquine : 4-Hydroxyde bris oquine me ta bolic ra tio receive less benef t rom tamoxi en therapy than do CYP2D6
EMs who are not co-administered drugs that compete with
tamoxi en or CYP2D6-catalyzed metabolism.
In the past, an individuals genotype or CYP2D6 and
B AmpliChip CYP450 array
many other genes encoding drug-metabolizing enzymes was
in erred rom phenotype (e.g., the urinary metabolic ratio
that can be measured by assaying the urinary excretion o a
specif c metabolite a ter the administration o a probe drug)
(Fig. 7-1A). As discussed below, genotype assignment is
now increasingly dependent on DNA-based tests per ormed
with commercially available, direct-to-consumer testing de-
vices such as the genotyping chip shown in Figure 7-1B.
TPMT represents another example o an important and
clinically relevant genetic polymorphism or drug metabo-
lism. TPMT catalyzes the S-methylation o thiopurine drugs
such as 6-mercaptopurine and azathioprine (see Chapter 39,
Pharmacology o Cancer: Genome Synthesis, Stability, and
Maintenance). Among other indications, these cytotoxic and
immunosuppressive agents are used to treat acute lympho-
blastic leukemia and in ammatory bowel disease. Although
FIGURE 7-1. CYP2D6 pharmacogenetics. A. Frequency distribution o the thiopurines are use ul drugs, they have a narrow therapeutic
metabolic ratio or the cytochrome P450 2D6 (CYP2D6)-catalyzed metabo- index (i.e., the ratio between the toxic dose and the thera-
lism o debrisoquine to orm its 4-hydroxy metabolite. Data or 1,011 Swedish peutic dose is small), with occasional patients su ering rom
subjects are plotted as the ratio o metabolites in the urine. Most subjects li e-threatening thiopurine-induced myelosuppression.
metabolize debrisoquine extensively, while some subjects metabolize the
In Caucasians, the most common variant allele or TPMT
compound ultrarapidly and others metabolize the compound poorly. B. The
AmpliChip CYP450 array can be used to determine variant genotypes or cy-
is TPMT*3A; the requency o this allele is approximately 5%,
tochrome P450 genes that inf uence drug metabolism. so 1 in 300 subjects carries two copies o the TPMT*3A allele.
TPMT*3A is predominantly responsible or the trimodal re-
quency distribution o the level o red blood cell TPMT activ-
the neuroleptic haloperidol, the opioids codeine and dextro- ity shown in Figure 7-3. TPMT*3A has two nonsynonymous
methorphan, and the antidepressants f uoxetine , imipramine , cSNPs, one in exon 7 and another in exon 10 (Fig. 7-3). The
and desipramine , among many others (Table 7-1). There ore, presence o TPMT*3A results in a striking decrease in tis-
poor metabolizers or CYP2D6 can potentially experience sue levels o TPMT protein. Mechanisms responsible or the
an adverse drug e ect when treated with standard doses o observed decrease in TPMT*3A protein level include both ac-
agents such as metoprolol that are inactivated by CYP2D6, celerated TPMT*3A degradation and intracellular TPMT*3A
whereas codeine is relatively ine ective in poor metabolizers aggregation, probably as a result o protein mis olding. As a
because it requires CYP2D6-catalyzed metabolism to orm result, drugs such as 6-mercaptopurine are poorly metabo-
the more potent opioid morphine. Conversely, ultrarapid me- lized and may reach toxic levels. Subjects homozygous for
tabolizers may require unusually high doses o drugs that TPMT*3A are at greatly increased risk for life-threatening my-
are inactivated by CYP2D6, but those same subjects can be elosuppression when treated with standard doses of thiopurine
overdosed with codeine, su ering respiratory depression drugs. These patients should be treated with approximately
or even respiratory arrest in response to standard doses. one-tenth to one-f teenth the standard dose.
In one tragic case, a nursing in ant whose mother was an There are striking ethnic di erences in the requency o
ultrarapid CYP2D6 metabolizer died when the mother was variant alleles or TPMT. For example, TPMT*3A is rarely
prescribed a standard dose o codeine and the baby was over- observed in East Asian populations, whereas TPMT*3C,
dosed on morphine present in the breast milk. For ultrarapid which has only the exon 10 SNP, is the most common variant
 C h a p t e r 7 Pharmacogenomics 91

A
N N

y
O O

t
vi
TPMTH/TPMTH

i
t
c
a
CYP2D6 SULT1A1 10

f
o
(CYP2B6, CYP2C9,

s
t
CYP2C19, CYP3A)

i
n
OH

u
Tamoxifen (TAM) 4-hydroxyTAM

5
TPMTL/TPMTH

.
0
r
5

e
p
CYP3A4/5 TPMTL/TPMTL

s
t
c
(CYP2C9 + other CYP3A4/5

e
CYP isoforms)

j
b
u
S
%
N
N
0
O
H O H
0 5 10 15 20
TP MT a ctivity (units /ml RBC)
CYP2D6 SULT1A1

OH
1 2 3 4 5 6 7 8 9 10
TPMT*1
N-de s me thylTAM Endoxife n (wild type )
VNTR

TPMT*3A

B VNTR
G460A A719G
Ala154Thr Tyr240Cys
100
)
FIGURE 7-3. TPMT pharmacogenetics. Frequency distribution o red blood
%
80
(
cell (RBC) thiopurine S-methyltrans erase (TPMT) activity or 298 unrelated
l
va
Caucasian subjects. TPMTL indicates an allele or alleles or the trait o low
vi
EM
60 activity, while TPMTH re ers to the wild type (TMPT*1) allele or the trait
r
u
s
IM o high activity. The observed trimodal requency distribution or RBC TPMT
e
activity is due mainly to the e ect o TPMT*3A, the most common variant
e
40
r
f
allele or low activity in a Caucasian population. TMPT*1 and TPMT*3A di -
-
PM
e
s
er by two nonsynonymous single nucleotide polymorphisms (SNPs), one in
p
20
a
exon 7 and one in exon 10. VNTR, variable number tandem repeat.
l
P =0.013
e
R
0
0 2 4 6 8 10 12 allele in those populations. For these populations, alternative
agents or dose reductions are recommended or thiopurine
Ye a rs a fte r ra ndomiza tion drugs. Because o its clinical signif cance, TPMT was the
f rst example selected by the FDA or public hearings on the
100
inclusion o pharmacogenetic in ormation in drug labeling.
)
For the same reason, clinical testing or TPMT genetic poly-
%
80
(
morphisms is widely available. The phenomenon o marked
l
va
EM
changes in the level o a protein as a result o the alteration o
vi
60
r
only one or two amino acids in the protein has been observed
u
IM
s
repeatedly or multiple other genes o pharmacogenetic sig-
e
e
40 nif cance and is a common explanation or the unctional e -
r
f
-
PM ects o nonsynonymous cSNPs within these genes.
e
s
a
20 The BChE, NAT2, CYP2D6, and TPMT genetic polymor-
e
P =0.009
s
phisms all behave as monogenic (single-gene) Mendelian
i
D
0 traits, as do many other early examples rom pharmacoge-
0 2 4 6 8 10 12 netics. However, pharmacogenetics-pharmacogenomics has
Ye a rs a fte r ra ndomiza tion now moved beyond monogenic traits with pharmacokinetic
phenotypes, and the ocus increasingly involves unctionally
FIGURE 7-2. Tamoxifen pharmacogenetics. A. Tamoxi en is metabolized and clinically signif cant variation in drug targets as well as
by two cytochrome P450 pathways to orm the active metabolites 4-hydroxy- drug-metabolizing enzymes. Variation can also involve mul-
tamoxi en (4-hydroxyTAM) and endoxi en, which are urther metabolized by tiple genes and pathways that in uence both pharmacokinet-
sul otrans erase (SULT) 1A1 (not shown). Genetic variations in CYP2D6 can ics and pharmacodynamics.
inf uence the extent o tamoxi en metabolism. B. Kaplan-Meier curves show-
ing the inf uence o CYP2D6 metabolizer status on the survival o women
with estrogen receptor-positive (ER[ ]) breast cancer who were treated
Variation in Drug Targets: Pharmacodynamics
with tamoxi en. Patients who were extensive metabolizers (EM) o tamoxi- Drugs generally exert their e ects by interacting with spe-
en had improved relapse- ree survival and disease- ree survival relative to cif c target proteins. There ore, genetic variations in these
intermediate metabolizers (IM) and poor metabolizers (PM). target proteins, or in signaling pathways downstream rom
92 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
TABLE 7-2 Examples of Genetic Polymorphisms and
Drug Targets
AFFECTED DRUG CLASS
PROTEIN (EXAMPLE)
5-Lipoxygenase Zileuton
Angiotensin converting enzyme ACE inhibitors (lisinopril)
(ACE)
Apolipoprotein E Statins (pravastatin)
2-Adrenergic receptor -Adrenergic agonists (albuterol)
Epidermal growth actor receptor Gef tinib
Sul onylurea receptor Tolbutamide
Vitamin K epoxide reductase War arin
complex 1
the target proteins, can in uence the outcome o pharmaco-
therapy (Table 7-2). One example o genetic variation or a
drug target in germline DNA involves a class o drugs used
to treat asthma. As noted in Chapter 48, Integrative In am-
mation Pharmacology: Asthma, the anti-asthma medication
zileuton decreases airway in ammation by inhibiting the
enzyme 5-lipoxygenase , an enzyme encoded by the gene
ALOX5. Variations in 5-lipoxygenase illustrate the point that
variation in many areas o a gene can a ect protein unc-
tion. Polymorphisms in gene regulatory regions, such as
the gene promoter, can in uence transcription and thereby
alter protein expression. The promoter o the ALOX5 gene
displays variation in the number o tandem repeats o the
sequence GGGCGG. These repeat sequences bind the tran-
scription actor complex Sp1, which up-regulates ALOX5
transcription.
The most common ALOX5 allele contains f ve repeats
and is present in about 77% o ALOX5 transcripts. As a re-
sult, approximately 94% o the population has at least one
copy o the f ve-repeat allele. The most common variant al-
leles contain our and three repeats and are present at re-
quencies o about 17% and 4%, respectively. Because o
increased Sp1 binding, people who carry the f ve-repeat
allele are thought to express more 5-lipoxygenase than
those who lack it. Interestingly, there seems to be no rela-
tionship between the presence or absence o the f ve-repeat
allele and the severity o asthma in the population; that is,
this ALOX5 promoter polymorphism does not seem to a ect
the disease process itsel . However, in trials o zileuton and
closely related 5-lipoxygenase inhibitors, only subjects who
had at least one copy o the f ve-repeat allele responded to
the drug. This result suggests that zileuton-like compounds
are unlikely to help the 6% o the population who lack the
f ve-repeat allele and that identi ying this subgroup would
allow the use o alternative, more e ective medications. The
ALOX5 example demonstrates that pharmacodynamic-phar-
macogenetic variation (i.e., variation in genes encoding drug
targets) can be just as important, i not more important, than
the pharmacokinetic-pharmacogenetic variation represented
by CYP2D6 and TPMT. Table 7-2 lists several drug target
proteins with genetic polymorphisms that have been asso-
ciated with variation in drug response. This example also
illustrates an important principle, that a polymorphism in a
drug target need not cause a disease in order to inf uence the
treatment o that disease.
Pathway-Based Pharmacogenetics-
Pharmacogenomics
Each o the preceding examples o CYP2D6, TPMT, and
ALOX5 involves clinically signif cant pharmacogenetic vari-
ation as a result o sequence variation in a single gene (i.e.,
monogenic inheritance). However, it is also possible or mul-
tiple genes encoding proteins that in uence both pharmaco-
kinetics and pharmacodynamics to alter the drug response
phenotype. One o the best examples o this type is provided
by the anticoagulant warfarin. War arin (see Chapter 23, Phar-
macology o Hemostasis and Thrombosis) is one o the most
widely prescribed oral anticoagulants in both North America
and Europe. However, despite the existence o a laboratory
test that is used universally to ollow war arins e ect on co-
agulation (INR), serious adverse reactionsinvolving both
hemorrhage and undesired thrombosiscontinue to compli-
cate war arin therapy. These complications are illustrated by
the case o Mr. H at the beginning o this chapter: a ter a
standard dose o war arin, his INR was elevated to 6.2, a
level associated with increased risk o hemorrhage.
Why might that have occurred? First, we need to remem-
ber that war arin is a racemic mixture. S-war arin is three
to f ve times more potent than R-war arin, and S-war arin
is metabolized predominantly by the cytochrome P450 iso-
orm CYP2C9. CYP2C9 is a highly polymorphic gene, and
the variant alleles CYP2C9*2 (Arg144Cys) and CYP2C9*3
(Ile358Leu) are associated with only 12% and 5%, respec-
tively, o the level o enzyme activity observed with the
wild-type allele (CYP2C9*1). Patients who carry these vari-
ant alleles require decreased doses o war arin to achieve an
anticoagulant e ect, and these same subjects have increased
risk o hemorrhage during war arin therapy. However, this
pharmacokinetic-pharmacogenetic variation ails to explain
most o the variance in the therapeutic war arin dose in pa-
tients who are anticoagulated with this power ul, but poten-
tially dangerous, drug.
The molecular target o war arin was not identif ed until
2004. The gene encoding that target, vitamin K epoxide reduc-
tase complex 1 (VKORC1), was also cloned that year. When
the VKORC1 gene was sequenced in a number o patients,
although no nonsynonymous cSNPs were ound, a series o
haplotypes (combinations o SNPs on a single chromosome)
was observed that were associated with the war arin dose re-
quirement. In one study, patients with VKORC1 haplotypes
that were associated with a low dose requirement had an av-
erage war arin maintenance dose approximately hal o that
required by subjects with haplotypes associated with a high
dose requirement. Several subsequent studies conf rmed that
the VKORC1 haplotype is associated with approximately 25%
to 30% o the variance in the war arin maintenance dose, while
5% to 15% can be explained by the CYP2C9 genotype. The
roles o CYP2C9 and VKORC1 in war arin pharmacokinetics
and pharmacodynamics are shown schematically in Figure 7-4.
Because the genes encoding both o these proteins contribute
to variation in drug response, genotyping or CYP2C9 and
haplotyping or VKORC1 represent potentially use ul strate-
gies or the determination o an initial war arin dose or Mr. H.
An initial analysis o combined data or over 5,000 pa-
tients worldwide who were anticoagulated with war arin
 C h a p t e r 7 Pharmacogenomics 93

P re curs ors of Active as clinical variables are important or anticoagulant therapy,

clotting fa ctors
O2
clotting fa ctors in 2010, the FDA guidelines or war arin recommended that
CO 2 patient genotypes (i known) should be considered in war-
arin dose selection and monitoring. However, the question
o whether genotype-guided dosing regimens are superior to
dosing regimens that utilize clinical variables alone is not yet
Vitamin K-dependent
-glutamyl carboxylase
answered. In particular, two o three recent multicenter ran-
domized controlled clinical studies to evaluate the e f cacy
o including patient genotype in ormation in clinical dosing
regimens demonstrated little improvement over clinical dos-
Vita min K re duce d Vita min K e poxide ing protocols or algorithms in terms o time spent within the
therapeutic range. It remains uncertain whether genotype-
guided war arin dosing improves clinical outcomes and
Vitamin K epoxide prevents the bleeding complications associated with supra-
reductase therapeutic war arin dosing. To date, such e f cacy measures
have been associated with genotype guidance, but only in a
6-Hydroxywa rfa rin
study comparing a large cohort o subjects with historical
7-Hydroxywa rfa rin
CYP2C9
controls.
War arin provides an important example o a situation in
which pharmacokinetic-pharmacogenetic data may prove
S-Warfarin inadequate or clinical translation because those data explain
too little o the variation in therapeutic drug dose. Thus, war-
FIGURE 7-4. Warfarin pharmacokinetics and pharmacodynamics.
Vitamin K is a required co actor or the post-translational -carboxylation
arin may represent, probably in a simplif ed orm, the type
o glutamate residues in certain clotting actor precursors (see Chapter 23). o polygenic, pathway-based pharmacogenetic-pharmacoge-
Vitamin Kis oxidized to the inactive epoxide as a consequence o the carbox- nomic model (i.e., one that combines pharmacokinetic and
ylation reaction. The enzyme vitamin Kepoxide reductase (VKORC1) converts pharmacodynamic variants) that may become increasingly
the inactive epoxide into the active, reduced orm o vitamin K. War arin acts common in the uture.
as an anticoagulant by inhibiting VKORC1 and thereby preventing the regen-
eration o reduced vitamin K. S-war arin is metabolized to 6-hydroxywar arin
and 7-hydroxywar arin by cytochrome P450 2C9 (CYP2C9). Role of Epigenetics in Pharmacogenetics-
Pharmacogenomics
and were genotyped or both CYP2C9 and VKORC1 showed Epigenetics is an emerging area o pharmacogenomics
that adding genotype data to clinical variables provided a (Fig. 7-5). Epigenetics re ers to heritable changes in gene
superior prediction o the war arin dose requirement than an unction and expression that are not a result o DNA sequence
algorithm that used only clinical data such as age, diet, and changes. Several recent studies show that, in addition to
weight. Due to the increasing evidence that genetic as well DNA sequence changes, epigenetic changes including DNA

Compone nts of the e pige ne tic ma chine ry

DNA methylation proteins Histone modifying proteins miRNAs

DNMT1 TET1-3 P CAF EZH1/2 miR-24
DNMT3A MBD1-4 p300/CBP DOT1L miR-27b
DNMT3B MECP 2 S IRT1-7 S ET7/9 miR-125b
HDAC1-11 MLL2 miR-126*
G9a miR-378 P TGS
LS D1 mRNA
miR-631 miRNA
J ARID1A-C
miRNA

miRNA
Ribos ome
Me t
CG
TGS ADME ge ne
GC Ge nomic DNA
Me t Nucle os ome
Drug tra ns porte r or
me ta bolizing e nzyme

FIGURE 7-5. Epigenetic control of absorption, distribution, metabolism, and excretion (ADME) genes. The molecules that regulate epigenetic e ects include
a host o proteins or DNA methylation (DNMT1, DNMT3A, DNMT3B, TET1-3, MBD1-4, MECP2), histone modif cation (HDAC1-11, p300/CBP, PCAF, SIRT1-7,
EZH1/2, DOT1L, MLL2, and others), and miRNAs (miR-24, miR-27b, miR-125b, miR-126*, miR-378, and miR-631). Collectively, these proteins and miRNAs contrib-
ute to transcriptional gene silencing (TGS) and post-transcriptional gene silencing (PTGS) o drug transporters and metabolizing enzymes. Down-regulation o
expression o ADME genes can lead to variations in the pharmacokinetic and pharmacodynamic prof les o the drugs that interact with their gene products.
94 FUNDAMENTAL PRINCIPLES OF PHARMACOLOGY
methylation, histone modif cation, and post-transcriptional
regulation via noncoding RNAs (including micro RNAs
[miRNAs]) can regulate the expression o genes involved in
pharmacokinetic and pharmacodynamic responses. Further-
more, since DNA variation alone cannot entirely explain in-
terindividual di erences in drug response and adverse drug
event phenotypes, investigation o epigenetic mechanisms is
likely to have clinical benef t.
The most common orm o epigenetic change is DNA
methylation. DNA methyltrans erases (DNMTs) add a methyl
group rom S-adenosylmethionine to cytosine in specif c pro-
moter sites called CpG sites. In the human genome, up to 80%
o the CpG sites are methylated. Large regions o unmethyl-
ated CpG sites, called CpG islands, are present near promot-
ers and are associated with increased transcription, whereas
methylation o CpG sites within promoters is associated with
gene silencing. Examples o pharmacoepigenetic mecha-
nisms related to variation in drug responses may include al-
tered methylation o specif c CpG sites in promoters o genes
involved in drug absorption, distribution, metabolism, and ex-
cretion (ADME). For instance, di erential methylation o the
CYP3A4 promoter correlates with its hepatic gene expression.
Drug- and toxin-related changes in CYP1A1 and CYP1B1 ex-
pression are also directly related to altered methylation pat-
terns o these genes. In one investigation, treatment o HepG2
liver cells with the anticancer agent decitabine (a DNA meth-
yltrans erase inhibitor) led to partial demethylation o the
CYP1B1 promoter and restored CYP1B1 inducibility.
Evidence also exists or the role o tissue-specif c
miRNAs in regulating the expression o multiple pharma-
cokinetic enzymes and transporters, including CYP3A4,
CYP1B1, ABCB1, ABCG2, and ABCC1. Clari ying the
role o miRNAs in the control o ADME gene expression
will improve mechanistic understanding o variation in drug
levels and pharmacodynamic e ects and help in identi ying
new potential therapeutic targets.
Modern Pharmacogenomics
Completion o the Human Genome Project and the ongo-
ing 1,000 Genomes Project points the way to uture deve-
lopments in pharmacogenetics and pharmacogenomics in
the postgenomic era. Application o modern genomic
assay techniques such as genome-wide association studies
(GWAS), combined with an increasing ocus on pathways
pathways that encompass genes encoding all o the drug-
metabolizing enzymes and transporters that could in uence
the f nal concentration o drug reaching the target (i.e., phar-
macokinetics), together with genes encoding the drug target
and signaling pathways downstream rom that target (i.e.,
pharmacodynamics)represent the uture or this aspect o
individualized medicine.
Attaining the goal o truly personalized drug therapy and
translating genomic knowledge into clinical practice rap-
idly will require the application o high-throughput geno-
typing technologies. Simvastatin was one o the f rst drugs
to be identif ed through GWAS as a genomic biomarker.
Cholesterol-lowering HMG-CoA reductase inhibitors, such
as simvastatin and atorvastatin (see Chapter 20, Pharmacol-
ogy o Cholesterol and Lipoprotein Metabolism), are among
the most widely prescribed drugs worldwide. Although these
drugs are generally very sa e, statins can rarely cause se-
rious myopathy with rhabdomyolysis and renal ailure. In
an attempt to predict and prevent this serious adverse drug
reaction, the SEARCH collaborative group per ormed a
GWAS in which approximately 300,000 SNPs across the
genome were genotyped using DNA rom 85 patients who
had developed severe statin-induced myopathy and 90 con-
trol subjects who had not developed this adverse drug reac-
tion. A single SNP located within the SLCO1B1 gene, which
encodes an organic anion transporter that mediates statin
uptake by the liver, had a strong association with myopathy.
The odds ratio or myopathy risk in subjects homozygous
or the variant nucleotide at the SNP was 16.9, and it was
estimated that more than 60% o the cases o myopathy in
this 12,064-patient trial were associated with this one SNP.
Patients homozygous or the variant SNP may have higher
plasma levels o statins and there ore be more likely to de-
velop rhabdomyolysis at any given dose o drug.
Over the last decade, a growing number o GWASs have
identif ed additional genes and SNPs that can predict treatment
response to an increasing list o medications. For example, a
pharmacogenomic GWAS was conducted to evaluate the symp-
tomatic response to inhaled corticosteroids in more than 900
patients with asthma. That study identif ed a unctional SNP in
the promoter region o GLCCI1, a suspected mediator o gluco-
corticoid-induced apoptosis. Patients who carried the SNP had
worse therapeutic responses to inhaled glucocorticoids a ter
48 weeks o therapy and were there ore at higher risk o de-
veloping treatment-resistant asthma and asthma exacerbations.
While GWAS has success ully identif ed multiple genes
that may explain a portion o the variability observed in
therapeutic responses to various drugs, these genes alone ail
to account or the majority o the heritability in therapeutic
response. The variability observed in drug responses is likely
due to the coordinated e ects o unctional SNP genotypes,
gene pathways, epigenetic e ects, and environmental actors.
In recent years, integrative pharmacogenomics and systems
biology approaches have been utilized to integrate diverse
data types and to per orm predictive modeling o the most
important interactions that contribute to clinical response
phenotypes. These models not only provide insight into the
pharmacogenetic mechanisms but can also be evaluated and
tested in cell lines, animal models, and clinical trials. In ad-
dition, these models may help to identi y new potential drug
targets or therapeutic intervention. As an example, investiga-
tors interested in pharmacogenetic variation in response to
statin medications per ormed an expression quantitative trait
loci (QTL) study in which global gene expression was mea-
sured in immortalized patient-derived B cells treated with
and without simvastatin. Six genes related to statin levels
were identif ed in these cellular models; glycine amidino-
trans erase (GATM) was the most signif cant gene. (GATM
is essential or the synthesis o creatine.) Subsequent asso-
ciation analyses demonstrated that variation in this gene was
strongly associated with the presence o statin-induced my-
opathy in multiple independent cohorts. Thus, in this evolving
f eld, downstream approaches involving integration o GWAS
in ormation with gene expression and computational model-
ing o gene interactions can in er mechanistic in ormation to
clari y the roles o pharmacogenomic candidates.
Pharmacogenomics and Regulatory Science
To achieve individualized drug therapy, we need not only to un-
derstand the science underlying pharmacogenetics and phar-
macogenomics and to develop state-o -the-art technologies to
detect and assay DNA sequence data but also to translate that

knowledge into the clinic. That translation process will require
the active involvement o the FDA and the pharmaceutical in-
dustry, which develops virtually all new drugs. Early e orts
by the FDA began with thiopurine drugs and TPMT and were
ollowed by hearings on a genetic polymorphism in UGT1A1,
a gene encoding a phase II enzyme involved in biotrans or-
mation o the antineoplastic agent irinotecan. Public hearings
have also been held on CYP2C9, VKORC1, and war arin
resulting in relabelingand on tamoxi en and CYP2D6.
Incorporating in ormation rom pharmacogenetics could
also contribute to postmarketing surveillance, not only to
help avoid adverse reactions but also to rescue drugs that
might be o benef t to groups o patients selected on the
basis o genetic variation in drug response. The latter situ-
ation was highlighted by reports that a polymorphism in the
1-adrenoceptor in uences response to the 1-adrenergic
antagonist bucindololboth in vitro and in patients with
heart ailure. This -antagonist had initially ailed in a clini-
cal trial that did not include genotyping, perhaps because
only patients with the wild-type 1-adrenoceptor genotype
displayed the desired clinical response.
CONCLUSION AND FUTURE
DIRECTIONS
Pharmacogenetics and pharmacogenomics involve the study
o ways in which DNA sequence variation a ects the re-
sponse o individual patients to medications. The goal o
pharmacogenetics and pharmacogenomics is to maximize
e f cacy and minimize toxicity based on knowledge o an
individuals genetic composition. Although many actors
other than inheritance in uence di erences among patients
in their response to drugs, the past hal -century has demon-
strated that genetics is an important actor responsible or
variation in the occurrence o adverse drug reactions or the
ailure o individual patients to achieve the desired thera-
peutic response. Pharmacogenetics has evolved during that
hal -century rom classical examples, such as CYP2D6 and
TPMT, to include more complex situations such as that rep-
resented by the pharmacogenetics o war arin, a drug that
displays both pharmacokinetic and pharmacodynamic phar-
macogenetic variation, and that represented by new loci and
SNPs related to pharmacogenomic phenotypes identif ed
through GWAS. The areas o genomic medical science, epi-
genetics, and systems biology also present unique challenges
C h a p t e r 7 Pharmacogenomics 95
in translation into the clinic. However, there can no longer
be any doubt that pharmacogenetics and pharmacogenomics
will be applied to clinical medicine with increasing breadth
and depth and that, ultimately, they will enhance our ability
to individualize drug therapy.
Acknowledgment
The authors would like to acknowledge Liewei Wang and
Richard M. Weinshilboum, the authors o this chapter in the
Second and Third Editions o Principles o Pharmacology:
The Pathophysiologic Basis o Drug Therapy, who provided
the template or and insight into the construction o this
chapter.
Suggested Reading
Caudle KE, Klein TE, Ho man JM, et al. Incorporation o pharmagenom-
ics into routine clinical practice: the Clinical Pharmacogenetics Imple-
mentation Consortium (CPIC) guideline development process. Curr Drug
Metab 2014;15:209217. (Overview o metrics used to determine which
pharmacogenetic variants are suitable or clinical implementation.)
Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association be-
tween ALOX5 promoter genotype and the response to anti-asthma treat-
ment. Nat Med 1999;22:168171. (Original study that showed di erent
pharmacologic responses in people with di erent polymorphisms o the
ALOX5 gene.)
Ingelman-Sundberg M, Zhong XB, Hankinson O, et al. Potential role o
epigenetic mechanisms in the regulation o drug metabolism and transport.
Drug Metab Dispos 2013;41:17251731. (Review o emerging evidence or
the role o epigenetics in drug transport and metabolism.)
Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening or hyper-
sensitivity to abacavir. N Engl J Med 2008;358:568579. (A double-blind
randomized study o a genetic biomarker or an idiosyncratic adverse drug
response.)
Mangravite LM, Engelhardt BE, Medina MW, et al. A statin-dependent
QTL or GATM expression is associated with statin-induced myopathy.
Nature 2013;502:377380. (Investigation o pharmacogenetic variation in
response to statin medications.)
SEARCH Collaborative Group. SLCO1B1 variants and statin-induced
myopathya genomewide study. N Engl J Med 2008;359:789799. (The
f rst genome-wide association study o a drug response.)
Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association be-
tween GLCCI1 and response to glucocorticoid therapy in asthma. N Engl
J Med 2011;365:11731183. (The f rst genome-wide association study to
evaluate lung unction changes in response to corticosteroid treatment in
asthma.)
Zineh I, Pacanowski M, Woodcock J. Pharmacogenetics and coumarin
dosingrecalibrating expectations. N Engl J Med 2013;369:22732275.
(Perspective on caveats or adopting genotype-guided dosing regimens or
anticoagulants.)
 C e n tra l p e rc e ptionn Corr tex

II Thh a la mus

R e lay a n d d e s c e n d in g
m o d u la tion

Principles of
Neuropharmacology
Braa ins te m

Tra ns m is s ion
S pinn a l cord

C onduu c tion
P e rip h e ra l s timuluss

S igna l tra nss d u c tio n

 IIA
Fundamental Principles of
Neuropharmacology
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Acc ti
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2 Ne urotra ns mitte r

8
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Principles of Cellular Excitability C a 2+

and Electrochemical 3
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INTRO
INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 98
9899
889
9
99 PHARMA
ARMA
ARM AGDP
CO
COL LO
LOGY
LOG OF ION GTPCHANN
ON C
CHANNELS
HAA . . . . . . . . . . . . . . . . . . . . . 105
CELLULAR EXCITABILITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 9 ELECTROCHEMICAL TRANSMISSION
ANSMISSIO ON . . . . . . . . . . . . . . . . . . . . . 105
Ohms Law . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 999
Oh Synaptic Vesicle Regulation
ATP
AT P . . .c.AMP
A. MP
. . P. . . . . . . . . . . . . . . . . . . . . 107
Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 Postsynaptic Recepttors . . . . . . . . . . . . .7. . . . . . . . . . . . . . . . . . 10 1077
Channel Selectivity, the Nernst Equation,
Ch Po o s ts ynaptic p c e ll Transmitter Metabolism and Reuptake upP hos phodie
p s te ra s e. . . . . . . 108
and the Resting Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 CONCLUSION AND FUTURE DIRECTIONS DIRE EC
E C . . . . . . . . . . . . . . . . . . 109
The Goldman Equation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 Su AMP
Sugggges
este
tedd Re
Read
adin
ingg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10 1099
The Action Potential.
Potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102

INTRODUCTION Many drugs modi y chemical or electrical signaling to in-

Cellular communication is essential or the e ective unc-
tioning o any complex multicellular organism. The major
mode o intercellular communication is the transmission o
chemical signals, such as neurotransmitters, neuropeptides,
and hormones. In excitable tissues, such as nerves and mus-
cles, rapid intracellular communication relies on the propa-
gation o electrical signalsaction potentialsalong the
plasma membrane o the cell. Both chemical and electrical
transmission commonly involve the movement o ions across
the plasma membrane or across the membranes o internal
organelles such as the endoplasmic reticulum. Ionic move-
ments can directly change the cytoplasmic concentration o
ions, such as Ca2 , that are key regulators o biochemical
and physiologic processes like phosphorylation, secretion,
and contraction. Ionic movements also change the electrical
potential across the membrane through which the ions f ow,
thus regulating various voltage-dependent unctions includ-
ing the opening o other ion channels. Some o these events
are brie , with durations and actions o several milliseconds
(0.001 sec). Others can take many seconds, with biochemical
consequences or example, phosphorylation o proteins
that can persist or minutes or hours. Even gene expression
can be regulated by changes in ion concentrations, resulting
in long-term changes in cellular physiology, growth, di er-
entiation, and death.
crease or decrease cellular excitability and electrochemical
transmission. To appreciate how such drugs act, the present
chapter explains the electrochemical oundations that un-
derlie signaling within and between electrically active cells.
These general principles are applicable to many areas o
pharmacology, including those discussed in Chapters 10 to
12 (Section IIB, Principles o Autonomic and Peripheral Ner-
vous System Pharmacology), Chapters 13 to 19 (Section IIC,
Principles o Central Nervous System Pharmacology), and
Chapter 24, Pharmacology o Cardiac Rhythm.
CELLULAR EXCITABILITY
Excitability re ers to the ability o a cell to generate and
propagate electrical action potentials . Neuronal, cardiac,
smooth muscle, skeletal muscle, and many endocrine cells
have an excitable character. Action potentials may propagate
over large distances, as in peripheral nerve axons that con-
duct over several meters, or they may stimulate activity in
cells o much smaller size such as the 30- to 50- m-diameter
interneurons that are contained within a single autonomic
ganglion. The unction o action potentials di ers depending
on the cell in which they occur. Propagating waves o action
potentials rapidly conduct encoded in ormation with delity
over long distances along axons. Within a small cell, action
potentials excite the whole cell at once, causing an increase

98
 C h a p t e r 8 Principles o Cellular Excitability and Electrochemical Transmission
Du rin g a b u s in e s s trip to J a p a n , Ka rl G
a tte n d s a d in n e r in h is h o n o r a t a re s -
ta u ra n t th a t s p e cia lize s in u g u f s h . Ka rl
is im p re s s e d b e ca u s e h e h a s h e a rd th a t
th is s p e cia l d is h is n o t a va ila b le in th e
Un ite d S ta te s a n d is a n e xp e n s ive d e lica cy in J a p a n .
Be o re th e m e a l is ove r, Ka rl n o te s a n u n u s u a l a n d
d e lig h t u l s e n s a tio n o tin g lin g a n d n u m b n e s s in h is
m o u th a n d a ro u n d h is lip s . His h o s ts a re p le a s e d
th a t h e is e xp e rie n cin g th e d e s ire d e e ct o u g u f s h
in g e s tio n .
Ka rl is a s cin a te d a n d s o m e w h a t e a r u l o th e
p o te n tia l toxic e e cts o th e u g u n e u ro toxin (te tro -
d o to xin ) a s th e y a re d e s crib e d to h im b y h is kn o w l-
e d g e a b le h o s ts . Ho w e ve r, h is h o s ts a s s u re h im th a t
in intracellular ions (e.g., Ca2 ) ollowed by a rapid release
o chemical transmitter molecules or hormones. These
chemicals then travel to speci c receptors, near or ar rom
the releasing cell, to e ect chemical transmission, which is
discussed in the second part o this chapter.
Cellular excitability is fundamentally an electrical event.
There ore, an understanding o basic electricity is necessary
to explain the biological processes o excitability and synaptic
transmission. The ollowing sections present basic principles o
electricity as applied to two important cellular components
the plasma membrane and ion-selective channels.
Ohms Law
The magnitude o a current (I , measured in amperes) f owing
between two points is determined by the potential di erence
(V, measured in volts) between those two points and the re-
sistance to current f ow (R, measured in Ohms):
I V/R Equation 8-1a
For example, current may f ow rom the extracellular to the
intracellular compartment in response to an electrical poten-
tial di erence (also known as a voltage difference) across the
plasma membrane. Voltage can be thought o as a potential
energy or as the propensity or charged particles to f ow rom
one area to another. Resistance is the obstacle to this f ow.
Decreased resistance allows greater ion f ow and there ore
increased current (current has units o charge/time). When
this relationship, known as Ohms law, is applied to biologi-
cal membranes such as the plasma membrane, the electrical
resistance is o ten replaced by its reciprocal, the conductance
(g, measured in reciprocal ohms, or siemens [S]):
I gV Equation 8-1b
For simplicity, assume that all resistive elements in the cell
membrane behave in an ohmic way; that is, their current
voltage (I-V) relationship is described by Equations 8-1a, b.
In this case, the I-V relationship is linear, with a slope given
by the conductance, g. Figure 8-1 represents the transmem-
brane current (I ) measured at di erent transmembrane po-
tentials (V ) in a hypothetical cell. The slope o the I-V curve
equals the conductance. From a conceptual perspective, cur-
rent increases as voltage increases because a higher voltage
results in a greater potential energy di erence between the
99
th e s u s h i ch e a t th e re s ta u ra n t is u lly lice n s e d to
p re p a re u g u f s h a n d is ce rtif e d b y th e g ove rn m e n t.
Ka rl is re lie ve d w h e n h e a wa ke n s th e n e xt m o rn -
in g w ith o u t a n y s ig n s o w e a kn e s s o r p a ra lys is .
Ho w e ve r, h e d e cid e s th a t h e w ill p o lite ly o rg o s e a -
o o d o r th e re s t o th e trip a n d a s k o r Ko b e b e e
in s te a d .
Questions
1 . What is the molecular mechanism o action o
tetrodotoxin?
2 . What is the e ect o tetrodotoxin on the action
potential?
inside and outside o the cell, which in turn avors an in-
creased rate o charge movement across the membrane.
The convention used in most texts and in this chapter is that
the voltage across a membrane, the membrane potential,
is expressed as the di erence between the intracellular and
extracellular potentials (Vm Vin Vout). For most normal
cells, Vm is negative when the cell is at rest (Vin Vout). The
membrane is termed hyperpolarized when Vm is more negative
than at rest, and it is described as depolarized when Vm is more
positive than at rest. Current is conventionally de ned with re-
spect to the direction in which positive charge f ows. Positive
charge moving rom inside to outside is called outward cur-
rent and is represented graphically by positive values. Positive
charge moving rom outside to inside is called inward current
and is represented graphically by negative values. Movement
o negative charge is de ned in the exact opposite way. Note
that an e f ux o K cations is electrically equivalent to an
inf ux o Cl anions; both are outward currents.
Outwa rd curre nt
I
I=gV
Ne ga tive P os itive
pote ntia l pote ntia l
V
Inwa rd curre nt
FIGURE 8-1. Ohms law. Ohms law states that there is a linear relationship
between current (I) and voltage (V) and that the slope o the I versus V plot
yields the conductance (g). By convention, outward current is the f ow o
positive charge rom inside the cell to outside the cell. Transmembrane
potential is de ned by the di erence in electric potential (voltage) between
the inside and outside o the cell. For most cells, the resting potential inside
the cell is negative relative to that outside the cell. Conductance, g, is the
reciprocal o resistance.
100 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY
Ion Channels
How does current actually f ow across a cell membrane? Bi-
ological membranes are composed o a lipid bilayer within
which some proteins are embedded and to which other pro-
teins are attached (schematically represented in Fig. 8-2).
Pure lipid membranes are virtually impermeable to most
polar or charged substances, thus having a very high intrinsic
resistance. From an electrical perspective, the lipid bilayer
also acts as a capacitor by separating the extracellular and
intracellular ions. To enable the passage o ions that carry
electrical current, ion channels span the membrane. Most ion
channels are gatedthat is, they remain closed until speci c
signals dictate their opening. Once open, they exhibit ion se-
lectivity, allowing only certain ions or types o ions to pass.
From an electrical perspective, a set o gated ion channels is
a variable conductor: it provides many individual conduc-
tances or di erent ions to f ow between the extracellular
and intracellular environments. The magnitude o the overall
conductance depends on the raction o channels in the open
state and the conductance o the individual open channels.
Channel Selectivity, the Nernst Equation, and
the Resting Potential
By itsel , the hypothetical I-V relation in Figure 8-1 does
not explain the electrical behavior o most real cells. I a cell
behaved according to Equation 8-1, then the potential di er-
ence across the membrane would be zero in the absence o
an externally applied current. Instead, most cells maintain a
negative potential di erence across their plasma membrane.
Ca pa citor
Re s is tor (pla s ma me mbra ne )
(ion cha nne l)
Ii Ic
IT = Ii + Ic
FIGURE 8-2. Electric circuit model of the cell membrane. The cell mem-
brane can be modeled as a simple electric circuit containing a resistor
and a capacitor. Ion-selective channels unction as resistors (identical
to conductors), through which ions can f ow down their electrochemical
gradient. The lipid bilayer acts as a capacitor by maintaining a separation
o charges between the extracellular and intracellular spaces. This circuit
(re erred to as an RC, or resistor-capacitor, circuit) changes the timing be-
tween the f ow o charges across the membrane (current) and changes in
transmembrane potential (voltage), because the lipid bilayer, acting as a
capacitor, stores some o the charge that passes across the membrane.
Time is required to store this charge; there ore, the initial change in voltage
associated with a step o current is slow. As the capacitor (lipid bilayer) lls
with charges and the voltage change grows, more o the charge passes
through the resistor, until a new steady state is reached and the current
voltage relationship becomes more linear. (Ic , capacitor current; Ii, ionic
current; IT, total current.)
This voltage di erence is most pronounced in neuronal and
cardiac ventricular cells, where a resting potential (the volt-
age di erence across the membrane in the absence o exter-
nal stimuli) o 60 to 90 mV can be recorded. The resting
potential results rom three actors: (1) an unequal distri-
bution o positive and negative charges on each side o the
plasma membrane, (2) a di erence in selective permeabili-
ties o the membrane to the various cations and anions, and
(3) the current-generating action o active (energy-requiring)
and passive pumps that help to maintain the ion gradients.
The e ects o these interrelated actors can be explained best
with an example.
Consider the case when there are only potassium ions
(K ) and protein-bound anions (A ) inside the cell and no
other ions outside the cell (Fig. 8-3). I this cells membrane
is permeable to potassium alone, due to the presence o chan-
nels that are open at rest and pass only K ions, then K will
f ow outward, while A will remain inside. The K ions f ow
outward because o a chemical gradient; that is, K e f ux is
energetically avorable because the K concentration inside
the cell is greater than that outside the cell. A potential e f ux
o the anion, A , is also avored by its chemical gradient, but
the absence o transmembrane channels permeable to A pre-
vents this anion rom f owing across the membrane. Because
o this selective permeability or K , every K ion that exits
the cell leaves one net negative charge (an A ion) on the
inside o the cell and adds one net positive charge (a K ion)
on the outside o the cell. This separation o charges across
the membrane creates a negative membrane potential.
I a negative membrane potential were not established as
K leaves the cell, then K ions would continue to exit until
the extracellular concentration o K was equal to the intra-
cellular concentration o K . However, the establishment o
a voltage di erence creates an electrostatic force that even-
tually prevents net K e f ux (Fig. 8-3B). Thus, the electri-
cal gradient (Vm) and the chemical gradient pull the K
ions in opposite directions: the electrical gradient avors an
inward f ow o K ions, while the chemical gradient avors
an outward f ow o K ions. These orces combine to create
an electrochemical gradient, which is equal to the sum o the
electrical gradient and the chemical gradient. The transmem-
brane electrochemical gradient is the net driving force for
passive ion movement across biological membranes.
As a result o the electrochemical gradient, the extracel-
lular concentration o K does not equalize with the intra-
cellular concentration. Instead, an equilibrium is established
in which the electrostatic orce pulling K back into the
cell is balanced exactly by the chemical gradient driving K
e f ux. The electrical potential at which this equilibrium oc-
curs, or any permeant ion X, is a unction o the charge
o the ion (z), the temperature (T), and the intracellular and
extracellular concentrations o the ion. This relationship is
expressed as the Nernst equation:
RT [X]out
Vx Vin Vout ln Equation 8-2
zF [X]in
where Vx is the transmembrane potential that a membrane
selectively permeable to ion X would reach at equilib-
rium (i.e., the Nernst potential or that ion), Vin Vout is
the transmembrane voltage di erence, RT/zF is a constant
or a given temperature and charge (this number simpli es
to 26.7 mV or a charge o 1 at a temperature o 37C),
and [X]out and [X]in are the extracellular and intracellular
 C h a p t e r 8 Principles o Cellular Excitability and Electrochemical Transmission 101

A K+ s e le ctive cha nne l B + C +

+
K
K + K
K
+
K
+ + +
K K K
+
K - -
+ - - - A - - A -
K A - A A A A A
A + +
+ K + + K +
- + K K K K
A K - - -
- A - - A - - A
A A A A A
+
K A
- + A
- + A
- +
K K K

Che mica l force

Ele ctrica l force ZERO

Ele ctroche mica l gra die nt =
che mica l force + e le ctrica l force ZERO

FIGURE 8-3. Electrochemical basis of the resting membrane potential. A. Consider a prototypical cell that initially contains equal concentrations o intra-
cellular potassium ions (K ) and impermeant anions (A ). Assume urther that ions can exit the cell only via a single K -selective channel. In this case, there
is a strong chemical gradient or K to exit the cell, but there is no electrical orce avoring ion f ow because the electrical sum o the intracellular charges
is zero. B. K begins to exit the cell through the K -selective channel, but A remains inside the cell because it has no exit route. There ore, the K chemical
gradient across the membrane becomes smaller. As K exits the cell, the net negative charge rom the A remaining inside the cell produces a negative
membrane potential that exerts an electrical orce opposing K e f ux. This orce is opposite in direction to that o the chemical gradient; as a result, the total
electrochemical gradient (the sum o the chemical orce and the electrical orce) is less than the chemical gradient alone. C. When the electrical gradient
is equal and opposite to the chemical gradient, the system is in equilibrium and no net ion f ow occurs. The voltage resulting rom the separation o charges
at equilibrium is re erred to as the Nernst potential.

concentrations, respectively, of ion X. The electrochemical the Nernst potentials for these cations and anions at physio-
driving force on ion X is equal to the difference between the logic temperature and, hence, the value of the transmembrane
actual membrane potential and the Nernst potential for that potential at which the net driving force for each ion is equal
ion, Vm Vx. to zero (Table 8-1).
The third determinant of the resting membrane potential Variations in the magnitude and direction of transport for
is the active and passive ion pumps that move ions across each ion (mediated by pumps and exchangers in the plasma
the membrane. These pumps govern the concentration of membrane) and differences in the membrane permeability
ions inside and outside the cell and act as generators of net for each ion (mediated by channels selective for each ionic
current by moving net charge across the membrane, termed species) generate the distinct intracellular and extracellular
electrogenic transport. Numerous pumps play an important concentrations for each of the four key ions. The relative
physiologic role in maintaining ion gradients; these include ionic permeabilities of the neuronal membrane at rest are K
the ATP-dependent Na /K pump (which uses the energy of Cl Na Ca2 . Because the plasma membrane
ATP hydrolysis to extrude three Na ions for every two K contains K -selective channels that are open under resting
ions that enter the cell) and the Na /Ca2 exchanger (which conditions while most other channels are closed, the resting
extrudes one Ca2 for every three Na ions that enter the membrane potential most closely approximates the Nernst
cell). The coordinated action of these pumps closely regu- potential for K (about 90 mV). In reality, the additional,
lates the intracellular and extracellular concentrations of all weak permeabilities of other ionic species raise the resting
biologically important cations and anions. By knowing the membrane potential above that for K . Thus, although K is
values of these ion concentrations, it is possible to calculate the most permeant ion, the permeability of the other ions and

TABLE 8-1 Nernst Equilibrium Potentials for Major Ions

EXTRACELLULAR INTRACELLULAR NERNST EQUATION NERNST POTENTIAL
ION CONCENTRATION CONCENTRATION FOR ION FOR ION

Na 145 mM 15 mM 26.7 ln (145/15) VNa 61 mV

K 4 mM 140 mM 26.7 ln (4/140) VK 95 mV

Cl 122 mM 4.2 mM 26.7 ln (122/4.2) VCl 90 mV

Ca 2 1.5 mM 1 10 5 mM 26.7/2 ln (1.5/1 10 5) VCa 2 159 mV

The calculated values o the Nernst potential are typical o mammalian skeletal muscle. Many human cells have similar transmembrane ion gradients.
102 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY
I(nA)
IK
INe t = IK + INa
VK VNa
VR
V(mV)
INa g K : g Na = 5:1
-92 -70 +40
IK K+ curre nt
VK K+ Ne rns t pote ntia l
gK K+ conducta nce
INa Na + curre nt
VNa Na + Ne rns t pote ntia l
g Na Na + conducta nce
VR Re s ting me mbra ne pote ntia l
INe t Ne t curre nt
FIGURE 8-4. Relative contribution of K and Na to the resting membrane
potential. The relative membrane permeabilities o K , Na , and other
ions, and the Nernst (electrochemical equilibrium) potentials o these ions,
together determine the resting membrane potential. In the example shown,
the conductance o K is f ve times greater than the conductance o Na
(shown by the slopes o the I versus V lines or IK and INa , respectively). That
is, the membrane is f ve times more permeable to K than to Na . The K
current is described by IK [IK gK(V VK)], while the Na current is de-
scribed by INa [INa gNa (V VNa )]. (In this example, gK and gNa are constant
conductances over all voltages.) INet, the net membrane current, is the sum
o these two currents (INet IK INa ). The resting membrane potential
(VR) is the value o V at which INet equals zero. In this example, note that VR
is close to, but greater than, VK. This is because, although K is the primary
determinant o the resting potential, the minor Na current depolarizes VR to
a value more positive than VK.
the action o the electrogenic pumps also contribute to the
overall resting potential. At the steady state that describes
the true resting membrane potential (Fig. 8-4), Vm does not
equal the Nernst potential or any o the individual ions, and
each ionic species experiences a net electrochemical orce.
In other words, (Vm Vion ) is nonzero, and small ion f uxes
occur. The algebraic sum o these inward and outward cur-
rents is small and is balanced by currents rom active, elec-
trogenic pumps, so there is no net current across the resting
membrane. It has been estimated that up to 25% o all cel-
lular energy in excitable tissues is expended in maintaining
ion gradients across cellular membranes.
The Goldman Equation
The example shown in Figure 8-3 addresses a situation where
only one ionic species f ows across the plasma membrane. In
reality, many cells possess a number o di erent channels
that are selective or di erent ions, all o which contribute
to the overall resting membrane potential. When the resting
potential is determined by two or more species o ions, the
inf uence o each species is governed by its concentrations
inside and outside the cell and by the relative permeability o
the membrane to that ion. Quantitatively, this relationship is
expressed as the Goldman-Hodgkin-Katz equation:
RT P [K ]o PNa [Na ]o PCl[Cl ]i
Vm ln K Equation 8-3
F PK[K ]i PNa [Na ]i PCl [Cl ]o
where P x is the membrane permeability o ion x. (P x is
expressed as a raction, with a value o 1 indicating maxi-
mum permeability.) Essentially, this expression states that
the larger the concentration gradient o a particular ion and
the higher its membrane permeability, the greater its role is
in determining the membrane potential. In the extreme case,
when the permeability o one ion is exclusively dominant,
the Goldman equation reverts to the Nernst equation or that
ion. For example, i P K P Cl, P Na , the equation becomes
RT [K ]o
Vm ln
F [K ]i
Alternatively, i P Na greatly exceeds P K, P Cl, then Vm VNa ,
and the membrane is strongly depolarized. This important
concept links changes in ion channel permeability to changes
in membrane potential. Whenever an ion-selective channel
opens, the membrane potential shifts toward the Nernst po-
tential for that ion. The relative contribution o a given chan-
nel to the overall membrane potential depends on the extent
o ion f ow through that channel. Time-dependent changes in
the membrane permeabilities o Na and K (and, in cardiac
cells, Ca2 ) account or the major distinguishing eature o
electrically excitable tissuesthe action potential.
The Action Potential
According to Ohms law, passage o current across a cell
membrane causes the voltage across the membrane to change,
reaching a new steady-state value that is determined by the
membranes resistance (see above). The time course o this
voltage change is exponential, determined by the product o
the resistance r m and the capacitance cm o the membrane,
with a rate constant equal to [r m cm] 1. (The membranes
capacitance results rom having an insulator, the hydrocarbon
core o the phospholipids in the membrane, between two con-
ductors, the ionic solutions on either side o the membrane
[see Fig. 8-2]. Capacitors store charge at both sur aces and
require time to change the magnitude o this charge.) I the
stimulated potential change is less than the threshold value or
triggering an action potential (see below), then the membrane
voltage changes smoothly and returns to its resting value
when the stimulating current is turned o (Fig. 8-5A). On the
other hand, i the membrane voltage changes positively by
more than the threshold value, then a dramatic event occurs:
the membrane voltage rises much more rapidly, to a value o
approximately 50 mV, and then drops to its resting value
o approximately 80 mV (Fig. 8-5B). This suprathreshold
event is known as the action potential (AP). Importantly, hyper-
polarizing stimuli cannot trigger an AP (Fig. 8-5C).
In most neurons, the balance between voltage-gated Na
and K channels regulates the AP. (In cardiac cells and
many secretory cells, voltage-gated Ca2 channels are also
involved in AP regulation; see Chapter 24.) Voltage-gated
Na channels conduct an inward current that depolarizes the
cell at the beginning o the AP. Voltage-gated K channels
conduct an outward current that repolarizes the cell at the
end o the AP, in preparation or the next excitatory event.
 C h a p t e r 8 Principles o Cellular Excitability and Electrochemical Transmission 103

are open; as the membrane is rapidly depolarized through

A 0 mV, most or all Na channels open; and ast depolariza-
0 tions to 25 mV open about hal o the Na channels. These
)
V
m
are the relations that occur when a constant depolarization
Thre s hold volta ge is imposed on the membrane (in a process called voltage-
(
-50
e
clamping); when the brie depolarization o an AP stimulates
g
a
the membrane, ewer Na channels have time to reach the
t
l
o
-90 open state, and a large reserve o unopened channels pro-
V
S ma ll de pola rizing s timulus vides a margin o sa ety or impulse transmission.
Recall that ionic current is the product o the ionic con-
ductance (g) and a potential di erence. For ions, the potential
B di erence is the same as the electrochemical driving orce,
Vm Vx, where Vx is the Nernst potential or the speci ed
ion. For example, or Na current:
)
V
0 I Na gNa (Vm VNa )
m
(
e
or Equation 8-4
g
Thre s hold volta ge
a
-50
t
l
I Na gNa Po (Vm VNa )
o
V
-90 Here, gNa is the Na conductance o the membrane when
La rge de pola rizing s timulus
all Na channels are open, and P o is, as above, the prob-
C
ability that any individual Na channel is open. The graphic
0 illustration o this equation is shown in Figure 8-6B, where
La rge hype rpola rizing s timulus
the Na current or a ully activated membrane is de-
)
V
scribed by the straight line that passes with positive slope
m
Thre s hold volta ge
(
-50 through VNa. I there were no voltage dependence to the
e
g
Na conductance (i.e., i gNa were always equal to gNa ), this
a
t
l
o
-90 line would extend throughout the negative voltage range, as
V
shown by its dashed-line extrapolation. However, the volt-
age dependence o P o (Fig. 8-6A) causes the actual Na con-
ductance gNa to be voltage-dependent, resulting in deviation
Time o the actual INa rom this theoretical ully activated condi-
tion. Thus, increasing depolarizations rom rest (caused, or
example, by an applied stimulus) result in inward Na cur-
FIGURE 8-5. The action potential. A. In the example shown, a resting cell rents that rst become larger as more channels open and then
has a membrane potential o approximately 80 mV. I a small depolarizing become smaller as Vm approaches VNa , reducing the driving
stimulus is applied to the cell (e.g., a stimulus that opens a ew voltage- orce through open channels (Fig. 8-6B).
gated Ca 2 channels), the membrane slowly depolarizes in response to the
Potassium channels conduct outward currents that oppose
inf ux o Ca 2 ions. Once the stimulus ends and the Ca 2 channels close, the
membrane returns to its resting potential. The time course o the voltage
the depolarizing actions o inward Na currents. Although
change is determined by the membrane capacitance (see Fig. 8-2). B. I a there are many types o K channels with diverse gating
larger depolarizing stimulus is applied to the cell, such that the membrane properties, only two types need to be considered in order to
potential exceeds its threshold voltage, the membrane rapidly depolarizes appreciate the role o K channels in excitability. These two
to about 50 mVand then returns to its resting potential. This event is known K channel types include the voltage-independent leak
as an action potential; its magnitude, time course, and shape are determined channels and the voltage-gated delayed recti er channels.
by voltage-gated Na and K channels that open in response to membrane Leak channels are the K channels that contribute to the rest-
depolarization. C. In comparison, application o a hyperpolarizing stimulus ing membrane potential by remaining open throughout the
to a cell does not generate an action potential, regardless o the magnitude negative range o membrane potentials. The K current that
o hyperpolarization.
f ows through these channels is shown by the dashed line
labeled IK in Figure 8-6B; or these channels, K current will
Figure 8-6 shows the currentvoltage (I-V) relationships or f ow or all Vm not equal to VK.
the voltage-gated Na channel and the resting K channel. The summation o INa and IK(leak) is represented by the
The total Na conductance o the membrane is the product dashed blue line in Figure 8-6C. Three important points on
o the constant conductance o a single open Na channel, this line de ne three critical aspects o the AP. The net ionic
the total number o Na channels, and the probability that an current (INet) is zero at all three o these points. First, at rest,
individual Na channel is open, P o. Po depends on the mem- Vm VK. Under this condition, small, transient membrane
brane potential and increases with depolarization (shown in depolarizations caused by external stimuli increase the
Fig. 8-6A), and it is this voltage dependence that enables a driving orce or K ions, resulting in net outward currents
cell to overcome the resting K conductance to generate and rom ion conductances through leak channels that repolar-
propagate action potentials in response to depolarizing in- ize the membrane back to rest when the external stimulus
puts. The open channel probability represents the raction o ends. Second, at Vm VT, the outward potassium currents
all Na channels that open (albeit transiently, see below) in are matched by inward sodium currents, and the net current
response to a single voltage step. For example, at very nega- is also zero. Under this condition, however, even a small
tive potentials (e.g., 85 mV), essentially no Na channels further depolarization results in a net inward current that
104 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY
A FIGURE 8-6. Voltage dependence o channel activity. A. Po, the probability that
1
P0
0 lation o voltage-gated Na channels, so that virtually 100% o voltage-gated
-50 0 50
B reversal potential or Na ). At voltages more negative than 50 mV, the Na
INa , IK
Outwa rd
Curre nt
Na + cha nne ls be gin to ope n IK
-90 -50 50
Inwa rd
Curre nt
All Na + cha nne ls ope n
C currents (IK ) demonstrates three key transition points in the I-V graph (denoted
INa , IK, INe t
Outwa rd
Curre nt VK VT VP
-90 -50 50
Inwa rd
Curre nt
INe t
urther depolarizes the membrane, which leads to a larger
inward current and urther membrane depolarization. This
positive feedback loop constitutes the rising phase of the AP.
Thus, the AP occurs in response to any rapid depolarization
beyond VT, which is de ned as the threshold potential. Third,
Vp is the potential at the peak o the AP. As the membrane
approaches Vp, it moves urther rom VK and closer to VNa,
so the driving orce or sodium inf ux decreases while that
or potassium e f ux grows. Once Vm reaches this maximum
depolarization, the net current switches sign rom inward
to outward, and consequently, the membrane begins to
be repolarized.
Voltage-gated (delayed rectif er) K channels contrib-
ute to the rapid repolarization phase o the AP. Although
membrane depolarization opens these channels, they open
and close more slowly than do Na channels in response
to depolarization. There ore, inward Na current dominates
the early (depolarization) phase o the AP, and outward K
current dominates the later (repolarization) phase (Fig. 8-7).
This is why the AP is characterized by an initial rapid de-
polarization (caused by ast inward Na current) ollowed
by a prolonged repolarization (caused by slower and more
sustained outward K current).
The nal eature determining membrane excitability is
the limited duration o Na channel opening in response
to membrane depolarization. A ter opening in response to
rapid membrane depolarization, most Na channels enter
a closed state in which they are inactivated (i.e., prevented
rom subsequent opening). Recovery rom inactivation
an individual voltage-gated Na channel will open, is a unction o the membrane
voltage (V). At voltages more negative than 50 mV, there is a very low prob-
ability that a voltage-gated sodium channel will open. At voltages more positive
than 50 mV, this probability begins to increase and approaches 1.0 (i.e., a 100%
chance o opening) at 0 mV. These probabilities are also generalizable to a popu-
Na channels in the membrane will open at 0 mV. B. The Na current across
V (mV)
a membrane (INa) is a unction o the voltage dependence o the Na channels
that carry the current and the driving orce (that is, how ar Vm is rom VNa , the
current is zero. As the voltage increases above 50 mV, Na channels begin to
INa open, and there is an increasing inward (negative) Na current. The maximum
inward Na f ux is reached at 0 mV, when all the channels are open. As the
voltage continues to increase above 0 mV, the Na current is still inward, but
decreasing, because inward f ow o the positively charged Na ions is opposed
V (mV) by the increasingly positive intracellular potential. The Na current is zero at VNa
VNa (the Nernst potential or Na ) because, at this voltage, the electrical and chemi-
cal gradients or Na ion f ow are balanced. At voltages more positive than VNa,
the Na current is outward (positive). The dashed line indicates the relationship
that would exist between Na current and voltage i the open probability o the
Na channels were not voltage-dependent. The potassium current that f ows
through voltage-independent K leak channels is shown by the dashed line
labeled IK. C. The summation o plasma membrane Na currents (INa ) and K
by blue circles) at which the net current is zero. The rst o these points oc-
IK INa curs at a membrane potential o 90 mV, where V VK. At this voltage, a small
increase in potential (i.e., a small depolarization) results in an outward (positive)
K current that brings the membrane potential back toward VK. The second point
occurs at VThreshold, the threshold voltage (VT ). At this voltage, INa IK; urther
V (mV) depolarization results in the opening o more voltage-dependent Na channels
and a net negative (inward) current, which initiates the action potential. The third
point occurs at VPeak, the peak voltage (VP). At this voltage, the transition occurs
rom a net negative current to a net positive (outward) current. As the Na chan-
nels inactivate, the net positive current is dominated by IK, and the membrane
potential returns toward VK (i.e., the membrane is repolarized).
occurs only when the membrane is repolarized, whereupon
the Na channels return relatively slowly to the closed, rest-
ing state rom which they can then open in response to a
stimulus. This inactivation o Na conductance, combined
with the slowly decaying voltage-gated K conductance,
produces dynamic changes in membrane excitability. Fol-
lowing just one AP, ewer Na channels are available to
open (i.e., gNa is temporarily smaller), more K channels
are open (i.e., gK is larger), the corresponding ionic cur-
rents are changed, and VT is therefore more positive than
it was before the AP. An excitable membrane is in its so-
called re ractory state during this period, which lasts rom
just a ter the AP until the conditions o ast gNa inactivation
and slow gK activation have returned to their resting values.
Very slow depolarizing stimuli will ail to induce an AP,
even when the membrane reaches the threshold potential
de ned by a rapid depolarizing stimulus, because o the
accumulation o inactivated Na channels during the slow
depolarizing stimulus.
The inactivation property o Na channels is impor-
tant in the concept o use-dependent block, as discussed in
Chapter 12, Local Anesthetic Pharmacology, and Chapter 24.
Also, under pathologic conditions, cells may express Na
channels that inactivate incompletely and there ore continue
to carry an inward current a ter termination o the AP. Such
currents may be adequate to raise the membrane potential
above VT and thus induce repetitive ring. Diseases such as
myotonia and certain types o neuropathic pain appear to
arise rom expression o this type o altered Na channel.
 C h a p t e r 8 Principles o Cellular Excitability and Electrochemical Transmission 105

lowering systemic vascular resistance. Some cardiovascular

VNa diseases are also treated by selective blockers o cardiac Ca2
channels (see Chapter 22, Pharmacology o Vascular Tone).
Highly potent and selective blockers o a certain class o neu-
Vm
ronal Ca2 channel have been puri ed rom the venom o
a marine snail (Conus sp.) and administered into the spinal
e
f uid to treat severe cases o neuropathic pain. Tetrodotoxin,
g
a
the ugu neurotoxin rom the introductory case, blocks most
t
l
o
V
neuronal voltage-gated Na channels with high a nity. As
a result, tetrodotoxin can inhibit AP propagation in the ner-
VT vous system, leading to atal paralysis i ingested in su cient
Vr amounts. Ion channel unction can also be modi ed through
VK pharmacologic modulation o the receptors that regulate the
channels, as described below.
0 1 2 3 4
ELECTROCHEMICAL TRANSMISSION
g Na
Neurons communicate with one another and with other cell
gK
e
types through the regulated release o small molecules or
c
n
peptides known as neurotransmitters . Neurotransmitters may
a
t
c
be released into the circulation, rom which they can act
u
d
on distant organs, or they may di use only a short distance
n
o
to act on juxtaposed target cells at specialized connections
C
0
called synapses . Synaptic transmission thus integrates elec-
trical signals (voltage changes in the plasma membrane o
0 1 2 3 4
the presynaptic cell) with chemical signals (release o neu-
rotransmitter by the presynaptic cell and subsequent binding
Time (ms ) o the transmitter to receptors in the membrane o the post-
De pola riza ting
s timulus synaptic cell). For this reason, synaptic transmission is o ten
re erred to as electrochemical transmission.
The general sequence o processes essential or electro-
FIGURE 8-7. Time course of voltage-dependent Na and K conduc- chemical transmission is as ollows (Fig. 8-8):
tances. During the course o an action potential, the transmembrane volt-
age (Vm) f rst increases rapidly rom VT toward VNa , then decreases below 1. Neurotransmitters are synthesized by cytoplasmic
VT, and more slowly approaches VK. The shape and duration o the action enzymes and stored in the neuron. Common neu-
potential can be explained by the di erential time courses o the voltage- rotransmitters include acetylcholine, norepinephrine, -
dependent Na and K currents. In response to a depolarizing stimulus, the aminobutyric acid (GABA), glutamate, dopamine, and
Na conductance (gNa ) increases rapidly because o the rapid opening o serotonin. Most neurons are specialized to release only
voltage-gated Na channels, then decreases because o Na channel inac- one type o neurotransmitter, and this specialization is
tivation. The K conductance (gK) increases concurrently with gNa but takes
determined largely by the synthetic enzymes expressed
a longer time to reach its maximum conductance because there is a slower
rate constant or opening o voltage-dependent K channels. Eventually, gK in that neuron. A ter synthesis, neurotransmitters are ac-
is greater than gNa , and the membrane repolarizes. (VNa , VK, Nernst potentials tively transported rom the cytoplasm into intracellular
or Na and K , respectively; Vr, resting membrane potential; VT, threshold vesicles (o ten called synaptic vesicles ) in which they
potential or action potential f ring.) reach high concentrations. Loading o these vesicles
is accomplished by the coordinated activity o a num-
ber o vesicular membrane proteins. In most cases, an
ATP-dependent transporter pumps protons rom the cy-
PHARMACOLOGY OF ION CHANNELS toplasm into the vesicle, thereby creating a proton gra-
Many drugs act directly on ion channels to produce changes in dient across the vesicle membrane. The electrochemical
membrane excitability. For example, local anesthetics are in- energy in this proton gradient is used to provide spe-
jected locally at high concentrations to block Na channels in cialized neurotransmitter transporters with the uel or
peripheral and spinal neurons; this Na channel block inhibits active transport o neurotransmitter molecules rom
AP propagation and prevents sensory transmission (e.g., pain) the cytoplasm into the vesicle. Neurotransmitter- lled
and motor nerve impulses by these nerves (see Chapter 12). vesicles undergo a docking process and are primed at
At much lower concentrations, these and structurally similar the active zone inside the plasma membrane o the
antiarrhythmic drugs act systemically to suppress abnormal presynaptic terminal, a cellular structure that is special-
APs in the heart and to treat neuropathic pain and some orms ized or neurotransmitter release.
o myotonia (see Chapter 24). Drugs that block K channels 2. When the threshold condition is reached in the neu-
are used to treat certain types o cardiac arrhythmias and may ron, an AP is initiated and propagated along the axonal
be used in the uture to overcome nerve conduction de cits membrane to the presynaptic nerve terminal.
secondary to demyelinating conditions such as multiple scle- 3. Depolarization o the nerve terminal membrane causes
rosis and spinal cord injury. Calcium channels are blocked opening o voltage-dependent Ca2 channels and inf ux
directly by some drugs used in the treatment o hyperten- o Ca2 through these open channels into the presyn-
sion; such drugs act by relaxing vascular smooth muscle and aptic nerve terminal. In many neurons, this Ca2 inf ux
106 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

is mediated by P/Q-type (Cav 2.1) or N-type (Cav 2.2)

Ca2 channels.
4. In the presynaptic terminal, the rapid rise in cytosolic
ree Ca2 concentration is sensed by specialized pro-
tein machinery, causing neurotransmitter- lled vesicles
Presynaptic to use with the presynaptic plasma membrane (see the
neuron
next section, Synaptic Vesicle Regulation). A ter
Action pote ntia l vesicle usion, neurotransmitter is released into the syn-
aptic cle t. The rate o neurotransmitter release di ers
2 Ne urotra ns mitte r depending on the substance released.
tra ns porte r 5. Released neurotransmitter di uses across the synaptic
1 cle t, where it can bind to two broad classes o recep-
6b
P re curs or tors localized in the nearby postsynaptic membrane and
Na +
Na + present more sparsely at distant sites:
Ne urotra ns mitte r a. Binding o neurotransmitter to ligand-gated iono-
tropic receptors directly opens channels that mediate
Ca 2+ ion f ux across the postsynaptic membrane. Within
milliseconds, this ion f ux leads to excitatory or
inhibitory postsynaptic potentials .
3 b. Binding o neurotransmitter to metabotropic recep-
4 tors (e.g., G protein-coupled receptors) causes acti-
vation o intracellular second messenger signaling
cascades. These signaling events (e.g., phosphory-
Synaptic cleft lation by speci c kinases) can then modulate ion
channel unction, leading to changes in channel gat-
5a K+ 5b Ade nylyl cycla s e 6a ing and thus altering the postsynaptic potential. The
Ca 2+
Na + time course o changes mediated by metabotropic
E receptors is generally seconds to minutes, which is


slower than the time course o changes mediated by
GDP GTP
ionotropic receptors. Both ionotropic and metabo-
tropic receptors are commonly present on the same
ATP cAMP cell, accounting or ast and slow changes, respec-
7
tively, in the postsynaptic membrane potential.
Postsynaptic cell Phosphodiesterase Some neurotransmitters may also bind to a third class
AMP o receptors on the presynaptic membrane. These recep-
tors are called autoreceptors because they regulate neu-
rotransmitter release.
6. Excitatory postsynaptic potentials (EPSPs) and inhibi-
tory postsynaptic potentials (IPSPs) propagate passively
(i.e., without generating an AP) along the membrane
o the postsynaptic cell. A large number o EPSPs can
summate to raise the postsynaptic membrane potential
FIGURE 8-8. Steps in synaptic transmission. Synaptic transmission can
be divided into a series of steps that couple electrical depolarization of the beyond threshold voltage (VT). I this occurs, a single or
presynaptic neuron to chemical signaling between the presynaptic and post- multiple APs can be generated in the postsynaptic cell.
synaptic cells. 1. Neuron synthesizes neurotransmitter from precursors and (This process is not shown in Fig. 8-8.)
stores the transmitter in vesicles. 2. An action potential traveling down the 7. Stimulation o the postsynaptic cell is terminated by
neuron depolarizes the presynaptic nerve terminal. 3. Membrane depolar- removal o the neurotransmitter rom the synaptic cle t,
ization activates voltage-dependent Ca 2 channels, allowing Ca 2 entry into desensitization o the postsynaptic receptor, or a com-
the presynaptic nerve terminal. 4. The increased cytosolic Ca 2 stimulates bination o both. Neurotransmitter removal occurs by
vesicle fusion with the plasma membrane of the presynaptic neuron, with two mechanisms:
subsequent release of neurotransmitter into the synaptic cleft. 5. Neurotrans- a. Degradation o the neurotransmitter by enzymes in
mitter diffuses across the synaptic cleft and binds to one of two types of
the synaptic cle t; and
postsynaptic receptors. 5a. Neurotransmitter binding to ionotropic receptors
causes channel opening and changes the permeability of the postsynaptic b. Uptake o the neurotransmitter by speci c transporters
membrane to ions. This may also result in a change in the postsynaptic mem- into the presynaptic terminal (or the closely surround-
brane potential. 5b. Neurotransmitter binding to metabotropic receptors on ing glial cells), which terminates synaptic action and
the postsynaptic cell activates intracellular signaling cascades; the example allows the neurotransmitter to be recycled into synap-
shows G protein activation leading to the formation of cAMP by adenylyl tic vesicles in preparation or a new release event.
cyclase. In turn, such a signaling cascade can activate other ion-selective 8. For G protein-coupled metabotropic receptors in the post-
channels (not shown). 6. Signal termination is accomplished by removal of synaptic cell, termination o the response to a transmitter
transmitter from the synaptic cleft. 6a. Transmitter can be degraded by en- stimulus is also dependent on intracellular enzymes that
zymes (E) in the synaptic cleft. 6b. Alternatively, transmitter can be recycled inactivate second messengers (e.g., phosphodiesterases
into the presynaptic cell by reuptake transporters. 7. Signal termination can
that convert cAMP to its inactive metabolite AMP) or
also be accomplished by enzymes (such as phosphodiesterase) that degrade
postsynaptic intracellular signaling molecules (such as cAMP). that reverse phosphorylation o target proteins.
 C h a p t e r 8 Principles of Cellular Excitability and Electrochemical Transmission 107

The prototypic chemical synapse is that o the neuromus- Synaptic Vesicle Regulation
cular junction (see Fig. 10-4 or more detail). At this junc-
Nerve terminals contain two types o secretory vesicles:
tion, terminal branches o the motor axon lie in synaptic
small, clear-core synaptic vesicles and large, dense-core syn-
troughs on the sur ace o the muscle cells. When the neuron
aptic vesicles . The clear-core vesicles store and secrete small
res, acetylcholine (ACh) is released rom the motor neu-
organic neurotransmitters such as acetylcholine, GABA,
ron terminals. The released ACh di uses across the synaptic
glycine, and glutamate. Dense-core vesicles are more likely
cleft to bind to ligand-gated ionotropic receptors located on
to contain neuropeptide or amine neurotransmitters. As de-
the postsynaptic muscle membrane. This binding o ACh to
scribed above, the larger dense-core vesicles are similar to the
its receptors causes a transient increase in the probability o
secretory granules o endocrine cells because their release is
opening o receptor-associated ion channels. The channel
not limited to active zones on the presynaptic cell. Dense-
pore is equally permeable to Na and K , so these channels
core vesicle release is also more likely to ollow a train o im-
have a reversal potential (i.e., a potential at which there is no
pulses (continuous or rhythmic stimulation) than a single AP.
net current f owing through the channel) o approximately
Hence, the smaller clear-core vesicles are involved in rapid
10 mV (the average o the individual Na and K Nernst
chemical transmission, while the larger dense-core vesicles
potentials; see Eq. 8-3). The net inward current passing
are implicated in slow, modulatory, or distant signaling.
through these open channels depolarizes the muscle cell
Recently, many o the proteins that control synaptic vesi-
membrane. Although this particular end-plate potential, re-
cle tra cking have been identi ed. Synaptic vesicles interact
sulting rom one presynaptic AP, is su ciently large to stim-
with a amily o proteins called synapsins that bind to the
ulate an AP in the muscle, such a magnitude is exceptional.
actin cytoskeleton in a phosphorylation-dependent manner.
Because most neuronal excitatory postsynaptic potentials
Activity at the synapse drives phosphorylation and dephos-
are too small to stimulate an AP, several neuronal excitatory
phorylation o synapsins via a variety o protein kinases and
postsynaptic potentials must occur together, within a short
phosphatases, and synapsins are thus thought to regulate the
time ( 10 ms) and at closely spaced synapses (allowing
availability o vesicles or Ca2 -dependent exocytosis. Vesi-
temporal and spatial integration), in order or the postsyn-
cle docking and priming at the active zone are mediated by
aptic depolarization to reach the threshold value or ring
interactions between proteins in the synaptic vesicle mem-
o an AP.
brane and the plasma membrane. Once docked and primed,
Many neurons synthesize and release neuropeptides in
Ca2 -sensing proteins called synaptotagmins play a key role
addition to neurotransmitters. Neuropeptides, which are
in exocytosis. For both Ca2 -regulated and Ca2 -independent
short chains o amino acids, exert e ects on other neu-
vesicle exocytosis, usion between the synaptic vesicle and
rons and play key roles in processes as diverse as energy
plasma membranes is mediated by the SNARE/SM protein
homeostasis and cellular excitability. In contrast to the ast
complex present in both the vesicle membrane (synaptobrevin/
neurotransmission mediated by synaptic vesicle usion and
VAMP) and the plasma membrane (syntaxin-1, SNAP-25)
neurotransmitter release, neuropeptides signal more slowly
(Fig. 8-9). Certain neurotoxins, such as tetanus toxin and bot-
and are typically released via the regulated secretory path-
ulinum toxin (see Chapter 10, Cholinergic Pharmacology),
way. Indeed, the synthesis, storage, and release o neuropep-
appear to act by selectively cleaving SNAREs and thereby
tides are similar to hormone production and secretion, and
inhibiting synaptic vesicle exocytosis. Conversely, a toxin in
many neuropeptides were initially identi ed as hormones
the venom o the black widow spider binds to speci c recep-
acting outside the central nervous system. Like hormones,
tors in presynaptic nerve terminals and oligomerizes to orm
neuropeptides are synthesized as precursor polypeptides
pores in the presynaptic plasma membrane, thereby bypass-
(preproneuropeptides) on ribosomes at the endoplasmic
ing the physiologic regulation o synaptic vesicle usion to
reticulum and subsequently processed enzymatically into
stimulate spontaneous release o neurotransmitters. SNAREs
the propeptide, sorted, and packaged along with specialized
and associated proteins may provide uture targets or phar-
proteases into dense-core secretory vesicles in the Golgi ap-
macologic control o synaptic transmission.
paratus (see below).
As with hormones, the proneuropeptide may include
multiple distinct neuropeptides, and a neuron can there ore Postsynaptic Receptors
release more than one neuropeptide. Proteases within the A large number o neuropharmacologic drugs act on neu-
vesicle cleave the proneuropeptide into the individual neu- rotransmitter or neuropeptide receptors. These integral
ropeptides during ast axonal transport o the vesicle toward membrane proteins all into two classes: ionotropic and
the synapse. Unlike classical neurotransmitter vesicles, neu- metabotropic .
ropeptide vesicles do not undergo docking at the synapse, Ionotropic receptors, such as nicotinic acetylcholine recep-
and release may occur at sites other than the synaptic termi- tors, AMPA and NMDA glutamatergic receptors, and A type
nal. Exocytosis o neuropeptide vesicles thus tends to occur GABA receptors, are almost always composed o our to ve
only in response to sustained Ca2 elevation, which typically subunits that oligomerize in the membrane to orm a ligand-
requires repeated or prolonged stimuli. Once released, neu- gated channel. Relatively rapid binding o one or sometimes
ropeptides act almost exclusively at metabotropic receptors. two ligand molecules to the receptor leads to a slower alloste-
Because they are o ten released extrasynaptically, neuropep- ric con ormational change that opens the channel pore. The
tides typically di use over longer distances than neurotrans- subunits composing the same unctional receptor o ten di er
mitters to bind to receptors on numerous cells surrounding among di erent tissues and, as a consequence, the detailed
the release site, a process known as volume transmission. molecular pharmacology o the receptors is tissue-dependent.
The ollowing discussion highlights steps in the basic For example, although acetylcholine is the endogenous trans-
processes o neurotransmission that can be modi ed by mitter or all nicotinic cholinergic receptors, di erent syn-
pharmacologic agents. thetic agonists (or antagonists) selectively activate (or inhibit)
108 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

these receptors in skeletal muscle, autonomic ganglia, or the The transporters that acilitate neurotransmitter reuptake
central nervous system (see Chapter 10). Ionotropic receptors rom the synaptic cle t into the presynaptic cell are o even
are also ound presynaptically, where they modulate neu- greater importance. Because these reuptake transporters are
rotransmitter release rom the presynaptic terminal. crucial or the termination o synaptic transmission, their in-
Metabotropic receptors, which exert their e ects through hibition has pro ound e ects. For example, the psychotropic
activation o intracellular signaling cascades, are similarly e ects o cocaine derive rom this drugs ability to inhibit
diverse in ligands, location, and e ect. They are ound both dopamine and norepinephrine reuptake in the brain, and
pre- and postsynaptically and commonly coexist with iono- the therapeutic benef t o antidepressants such as f uoxetine
tropic receptors. Most metabotropic receptors are G protein- likely results rom inhibition o serotonin-selective reuptake
coupled receptors (GPCRs). Classical ast neurotransmitters
(glutamate, ACh, and GABA), monoamines (dopamine,
serotonin, and norepinephrine), and neuropeptides can all Ne urotra ns mitte r
act via metabotropic receptors. A neurotransmitter or pep- A
tide may have multiple distinct metabotropic receptors, each S yna ptic ve s icle
with di erent or even opposing intracellular signaling path- me mbra ne
ways. For example, dopamine increases cAMP levels via the
D1 amily o dopamine receptors but decreases cAMP levels Cytopla s m
via the D2 amily o dopamine receptors (see Chapter 14,
Pharmacology o Dopaminergic Neurotransmission). The S NARE comple x
intracellular e ects o metabotropic receptor activation are
numerous and diverse. Postsynaptically, metabotropic recep- P re s yna ptic pla s ma
tor signaling can open ion channels to create slow excitatory me mbra ne
or inhibitory postsynaptic currents or modulate channel Volta ge -ga te d
properties to change cellular excitability. Second messen- ca lcium cha nne l Action pote ntia l
ger cascades regulate the activity o a host o intracellular (clos e d)
targets and processes (see Chapter 1, DrugReceptor Inter-
B
actions, as well as chapters in Sections IIB and IIC). Acti-
vation o presynaptic receptors can regulate the probability
o neurotransmitter release at the synapse. The diversity
o structure and unction o metabotropic receptors makes S yna ptota gmin-1
(Ca 2+ s e ns or)
them prime candidates or development o selective agonists
or antagonists that activate or inhibit specif c subtypes o
metabotropic receptors.
Ca 2+

Transmitter Metabolism and Reuptake

Altering the metabolism o the neurotransmitter provides an Ca 2+
important mechanism or pharmacologic intervention at the
synapse. The two major types o intervention involve inhi-
bition o neurotransmitter degradation and antagonism o
C
neurotransmitter reuptake. Acetylcholinesterase, the enzyme
responsible or degrading acetylcholine, is an example o the
f rst type o drug target. Acetylcholinesterase inhibitors are the
mainstays o treatment or myasthenia gravis (see Chapter 10).

FIGURE 8-9. Current model o neurotransmitter release. A. Synaptic

vesicles are tethered close to the plasma membrane of the presynaptic
neuron by several proteinprotein interactions. The most important of these
interactions involve SNAREs (soluble N-ethylmaleimide-sensitive factor
attachment protein receptors) and SM (Sec1/Munc18-like) proteins present
in both the vesicle membrane and the plasma membrane. The SNARE pro-
teins include synaptobrevin (red), syntaxin-1 (yellow), and SNAP-25 (green). D
The SM proteins include Munc18-1 and others (not shown). Voltage-gated
Ca 2 channels are located in the plasma membrane in close proximity to
these SNARE/SM complexes; this facilitates the sensing of Ca 2 entry by
Ca 2 -binding proteins (synaptotagmin-1, in blue) localized to the presynaptic
plasma membrane and/or the synaptic vesicle membrane. BD. Voltage-
gated calcium channels open in response to an action potential, allowing
entry of extracellular Ca 2 into the cell. The increase in intracellular Ca 2
triggers binding of synaptotagmin-1 to the SNARE/SM complex and fusion of
the vesicle membrane with the plasma membrane, releasing neurotransmit-
ter molecules into the synaptic cleft. Several additional proteins (Munc13-1,
complexin-1, and others) are also involved in the regulation of synaptic
vesicle fusion (not shown).
 C h a p t e r 8 Principles of Cellular Excitability and Electrochemical Transmission
(see Chapter 15, Pharmacology o Serotonergic and Central
Adrenergic Neurotransmission). Because reuptake trans-
porters tend to be substrate-specif c, it is anticipated that
new drugs can be designed to selectively target other specif c
transporter subtypes as well.
CONCLUSION AND FUTURE
DIRECTIONS
Cellular excitability is a crucial component o intercellular
communication. The undamental basis or cellular excit-
ability lies in the electrochemical gradients that are estab-
lished by ion pumps across the lipid bilayer o the plasma
membrane and in the ion-selective channels that regulate the
permeability o the membrane selectively or di erent ionic
species, allowing a change in membrane voltage to be cou-
pled to a chemical stimulus or response. The action poten-
tial, a special type o stereotyped response ound in excitable
cells, is made possible by the voltage-dependent properties
o Na and K channels.
The basic processes o electrochemical transmission pro-
vide the substrate or pharmacologic modulation o cellular
excitation and communication, topics that are addressed in
more detail throughout this book.
109
Acknowledgment
We thank Michael Ty or his valuable contributions to
this chapter in the First and Second Editions o Principles
of Pharmacology: The Pathophysiologic Basis of Drug
Therapy.
Suggested Reading
Catterall WA, Raman IM, Robinson HP, Sejnowski TJ, Paulsen O.
The Hodgkin-Huxley heritage: rom channels to circuits. J Neurosci
2012;32:1406414073. (Historical overview of our understanding of the
action potential.)
Choquet D, Triller A. The dynamic synapse. Neuron 2013;80:691703.
(Conceptual overview of synaptic physiology, with an emphasis on recent
research advances.)
Kullmann DM, Waxman SG. Neurological channelopathies: new insights
into disease mechanisms and ion channel unction. J Physiol (London)
2010;588:18231827. (Review of neurologic diseases resulting from altera-
tions in ion channel physiology.)
Nestler EJ, Hyman SE, Holtzman DM, Malenka RC. Molecular neuro-
pharmacology: a foundation for clinical neuroscience. 3rd ed. New York:
McGraw-Hill Pro essional; 2015. (An overview of neuropharmacology.)
Sdho TC. Neurotransmitter release: the last millisecond in the li e o a
synaptic vesicle. Neuron 2013;80:675690. (Review of events and mecha-
nisms of synaptic vesicle fusion.)
van den Pol AN. Neuropeptide transmission in brain circuits. Neuron
2012;76:98115. (Review of neuropeptide functions.)
 B rai
Br a in c a pillary
9 Pe ric
Principles of Nervous System
Physiology and Pharmacology
J o s h u a M . Ga la n t e r, S u s a n n a h B. Co rn e s , a n d Da n ie l H. Low e n s t e in
Mito
Mitoch
c on
n dria
INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110111
INT
NEUROANATOMY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Anatomy of the Peripphee ra
An rall Ne
Nervous System . . . . . . . . . . . . . . 110
Auto
Au tono
nomi
micc Nerv
mi Ne rvouo s System m . . . . . . . . . . . . . . . . . . . . . . . . . 111
Peripheral Motor and Sensoory Sys ystetems
mss . . . . . . . . . . . . . . . 11 1122
Anat
An atom
omyy of the Cen
entr tral
al Nervous System. . . . . . . . . . . . . . . . . 11 1144
Cerebrum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
Dien
Di ence
ceph
phal
alon
onn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Cerebellum m . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
Brainstemm . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Spinal Cordd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Cellular Organization of the Nervous System . . . . . . . . . . . . . 116
Long-Tract Neuronal Organizationn . . . . . . . . . . . . . . . . . . . . 117
INTRODUCTION
The nervous system contains more than 10 billion neurons.
Most neurons orm thousands o synaptic connections, giv-
ing the nervous system complexity unlike that seen in any
other organ system. Interactions among neuronal circuits
mediate unctions ranging rom primitive ref exes to lan-
guage, mood, and memory. To per orm these unctions, the
individual neurons that comprise the nervous system must
be organized into unctional networks, which, in turn, are
organized into larger anatomical units.
The previous chapter reviewed the physiology o individual
neurons by describing electrical transmission within a neuron
and chemical transmission rom one neuron to another. This
chapter discusses neuronal systems by examining two levels
o organization. First, the gross anatomical organization o the
nervous system is presented to place in context the sites o ac-
tion o pharmacologic agents that act on this system. Second,
the major patterns o neuronal connectivity (so-called neuronal
tracts) are presented, because knowledge o the ways in which
neuronal cells are organized to transmit, process, and modu-
late signals acilitates a deeper understanding o the actions
o drugs on these tracts. This chapter also discusses the major
types o neurotransmitters and the bloodbrain barrier; these
unctional and metabolic concepts have important pharmaco-
logic consequences or drugs that act on the nervous system.
110
icyt
yte
te
As trro g li
liaa l p ro
r ce
c ss
Baa s e me nt me mb ra ne
Local Circuit Neuronal Org rganizattioonT.ight .g. . . . junction
j. . . . . . . . . . . . 117
Single-Source Divergent Neur uroonal Organization. . . . . . . . 11 1188
NEUROPHYSIOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Neurotransmittter
erss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
Amino
Amiino Acid Neurotransmitterss . . . . . . . . . . . . . . . . . . . . . . . 120
Biog
Biogen
e ic Aminess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Other Small Moleculle Neurottran ansmsmit itte
tersrs . . . . . . . . . . . . . . 123
Neuropeptidess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
The BloodBrain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
CONCLUSION AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . 124
Suggested Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125
NEUROANATOMY
The nervous system can be divided structurally and unc-
tionally into peripheral and central components. The periph-
eral nervous system includes all nerves traveling between
the central nervous system and somatic and visceral sites.
It is divided unctionally into the autonomic (involuntary)
nervous system and the sensory and somatic (voluntary)
nervous system.
The central nervous system (CNS) includes the cerebrum, di-
encephalon, cerebellum, brainstem, and spinal cord. The CNS
relays and processes signals received rom the peripheral ner-
vous system; the processing results in responses that are ormu-
lated and relayed back to the periphery. The CNS is responsible
or important unctions such as perceptionincluding sen-
sory, auditory, and visual processingwake ulness, language,
and consciousness.
Anatomy of the Peripheral Nervous System
The autonomic nervous system regulates involuntary re-
sponses o smooth muscle and glandular tissue. For example,
it controls vascular tone, heart rate and contractility, pupil-
lary constriction, sweating, salivation, piloerection (goose
bumps), uterine contraction, gastrointestinal (GI) motility,
and bladder unction. The autonomic nervous system is
 C h a p t e r 9 Principles o Nervous System Physiology and Pharmacology 111
Ma rth a P is a 66-ye a r-o ld w o m a n
w ith a 4-ye a r h is to ry o w o r s e n in g
Pa rkin s o n s d is e a s e , a n e u ro lo g ica l
d is o rd e r re s u ltin g ro m th e p ro g re s -
s ive d e g e n e ra tio n o n ig ro s tria ta l n e u -
ro n s th a t u s e d o p a m in e a s a n e u ro tra n s m itte r. Th e
d is e a s e ca u s e s a re s tin g tre m o r, rig id ity, d i f cu lty
in itia tin g m o ve m e n t, a n d p o s tu ra l in s ta b ility. Wh ile
vis itin g h e r p h ys icia n , Ms . P re g is te rs a n u n u s u a l
co m p la in t: It s e e m s th a t m y S in e m e t d o e s nt w o rk
a s w e ll w h e n I ta ke it w ith m e a ls . Ms . P e xp la in s
th a t s h e h a s re ce n tly s ta rte d o n a n e w lo w-ca rb
d ie t th a t h a s in cre a s e d h e r p ro te in in ta ke a t th e
e xp e n s e o h ig h -ca rb o h yd ra te o o d s . Co n ce rn e d ,
Ms . P a s ks , Co u ld m y d ie t h a ve a nyth in g to d o w ith
th is ? He r p hys icia n e xp la in s th a t le vo d o p a , a co m -
p o n e n t o h e r S in e m e t, h e lp s re p la ce a ch e m ica l in
h e r b ra in th a t is p ro d u ce d in in s u f cie n t q u a n titie s
b e ca u s e o th e lo s s o ce rta in n e u ro n s in h e r b ra in .
Alth o u g h m a ny a cto rs co u ld le a d to th e d e cre a s e d
e e ctive n e s s o h e r m e d ica tio n , Ms . Ps d o cto r co n -
f rm s h e r s u s p icio n th a t h e r h ig h -p ro te in d ie t co u ld
divided into the sympathetic nervous system, responsible or
ght or f ight responses, and the parasympathetic nervous
system, responsible or rest and digest responses. The sen-
sory and somatic peripheral nervous system carries sensory
signals rom the periphery to the CNS and motor signals
rom the CNS to striated muscle; these signals regulate vol-
untary movement (Fig. 9-1).
Autonomic Nervous System
Autonomic nerve f bers interact with their target organs by a
two-neuron pathway. The rst neuron originates in the brain-
stem or spinal cord and is termed a preganglionic neuron.
The preganglionic neuron synapses outside the spinal cord
with a postganglionic neuron that innervates the target organ.
As discussed below, the anatomical location o these con-
nections di ers or neurons o the sympathetic and parasym-
pathetic divisions o the autonomic nervous system.
Anatomy of the Sympathetic Nervous System
The sympathetic nervous system is also known as the tho-
racolumbar system, because its preganglionic bers arise
rom the rst thoracic segment to the second or third lumbar
segment o the spinal cord (Fig. 9-2). Speci cally, the pre-
ganglionic nerve cell bodies arise rom the intermediolateral
columns in the spinal cord. Preganglionic nerves exit the spi-
nal cord at the ventral roots o each vertebral level and make
synaptic connections with postganglionic neurons in sympa-
thetic ganglia. Most sympathetic ganglia are located in the
sympathetic chain, which consists o 25 pairs o intercon-
nected ganglia that lie on either side o the vertebral column.
The rst three ganglia, termed the superior cervical ganglion,
middle cervical ganglion, and inferior cervical ganglion, send
their postganglionic bers via the cranial and cervical spinal
nerves. The superior cervical ganglion innervates the pupil,
salivary glands, and lacrimal glands, as well as blood vessels
in d e e d b e in te r e rin g w ith th e m e d ica tio n s a b ility
to re a ch h e r b ra in . He re co m m e n d s th a t s h e m o d -
e ra te h e r p ro te in in ta ke , a n d , i n e ce s s a ry, ta ke a
h ig h e r d o s e o S in e m e t a te r a h ig h -p ro te in m e a l.
At h e r o llo w-u p vis it, Ms . P is h a p p y to re p o rt th a t
h e r m e d ica tio n is m o re e e ctive n o w th a t s h e is
e a tin g le s s p ro te in .
Questions
1 . Where is the nigrostriatal tract located? How does the
degeneration o a specif c group o neurons result in
specif c symptoms such as those seen in Parkinsons
disease?
2 . Why is levodopa used in the treatment o Parkinsons
disease, and what is the relationship o this compound
to dopamine?
3 . Why does protein consumption inter ere with the
action o levodopa?
4 . Why does Sinemet contain both levodopa and
carbidopa?
and sweat glands in the head and ace (Fig. 9-2). Postgangli-
onic neurons arising in the middle and in erior cervical gan-
glia, as well as the thoracic ganglia, innervate the heart and
lungs. Fibers arising rom the remaining paravertebral gan-
glia innervate sweat glands, pilomotor muscles, and blood
vessels o skeletal muscle and skin throughout the body.
Postganglionic neurons that innervate the GI tract down
to the sigmoid colon, including the liver and pancreas, arise
rom ganglia that are located anterior to the aorta, at the
origins o the celiac, superior mesenteric, and in erior mes-
enteric blood vessels (Fig. 9-2). Hence, these ganglia, col-
lectively known as prevertebral ganglia , are named the celiac
ganglion, superior mesenteric ganglion, and inferior mesen-
teric ganglion, respectively. In contrast to the paravertebral
ganglia, the prevertebral ganglia have long preganglionic
bers and short postganglionic bers.
The adrenal medulla is contained within the adrenal
glands that lie on the superior sur ace o the kidneys.
The adrenal medulla contains postsynaptic neuroendo-
crine cells (Fig. 9-2). Unlike sympathetic postganglionic
neurons, which synthesize and release norepinephrine,
neuroendocrine cells o the adrenal medulla synthe-
size primarily epinephrine (85%) and release this neu-
rotransmitter into the bloodstream rather than at synapses
on a speci c target organ (see Chapter 11, Adrenergic
Pharmacology).
Many pharmacologic agents modulate sympathetic ner-
vous system activity. As discussed in Chapter 11, the sym-
pathetic nervous system has an organ-speci c distribution
o adrenergic receptor types. This organ-speci c receptor
expression allows drugs to modulate sympathetic activity
selectively. For example, certain sympathetic agonists, such
as albuterol, can dilate bronchioles selectively, while certain
sympathetic antagonists, such as metoprolol, can selectively
decrease heart rate and contractility.
112 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

Dors a l root ga nglion

Dors a l root
Gra y ma tte r
White ma tte r

S ympa the tic ne rve trunk

S pina l cord

S kin

Ve ntra l root
P re ve rte bra l ga nglion
S mooth mus cle
S e ns ory ne uron S ke le ta l mus cle
P a ra ve rte bra l
S oma tic motor ne uron cha in ga nglion
P re ga nglionic ne uron
P os tga nglionic ne uron Adre na l me dulla

FIGURE 9-1. Organization of the peripheral nervous system. The peripheral nervous system contains sensory, somatic motor, and autonomic components.
Sensory neurons (solid blue line) arise principally in the skin or joints, have cell bodies and nuclei in the dorsal root ganglia, and project onto neurons located
in the dorsal horn o the spinal cord. Somatic motor neurons (solid black line) arise in the ventral horn o the spinal cord, exit through the ventral roots, and
join f bers o sensory neurons to orm spinal nerves, which then innervate skeletal muscle. The autonomic component o the peripheral nervous system con-
sists o a two-nerve system; the two nerves are called preganglionic and postganglionic neurons, respectively. Sympathetic preganglionic neurons (dashed
gray line) arise in the ventral horn o the thoracic and lumbar segments o the spinal cord and project onto postganglionic neurons in the paravertebral
and prevertebral ganglia. Sympathetic postganglionic neurons (dashed blue line) innervate many organs, including smooth muscle. The adrenal medulla
is also innervated by preganglionic neurons o the sympathetic nervous system (see Fig. 9-2). Parasympathetic preganglionic neurons (not shown) arise in
nuclei in the brainstem and the sacral segments o the spinal cord and project onto postganglionic neurons in ganglia located near the innervated organs.

Anatomy of the Parasympathetic Nervous System
Nearly all o the parasympathetic ganglia lie in or near the
organs they innervate. The preganglionic bers o the para-
sympathetic nervous system arise in the brainstem or in
sacral segments o the spinal cord; thus, the parasympathetic
system is also called the craniosacral system (Fig. 9-2). In
some cases, parasympathetic preganglionic neurons can
travel almost 1 meter be ore synapsing with their postgan-
glionic targets. Preganglionic nerve bers o cranial nerve
(CN) III, the oculomotor nerve , arise rom a region o the
midbrain termed the Edinger-Westphal nucleus and inner-
vate the pupil, stimulating it to constrict. The medulla o
the brain contains nuclei or parasympathetic nerve bers
in CNs VII, IX, and X. Parasympathetic bers in the acial
nerve (CN VII) stimulate salivary secretion by the submax-
illary and sublingual glands as well as tear production by
the lacrimal gland. Parasympathetic bers in the ninth cra-
nial nerve, the glossopharyngeal nerve , stimulate the parotid
gland. The 10th cranial nerve, termed the vagus nerve , pro-
vides parasympathetic innervation to the major organs in the
chest and abdomen, including the heart, tracheobronchial
tree, kidneys, and GI system down to the proximal colon.
Parasympathetic nerves originating in the sacral region o
the spinal cord innervate the remainder o the colon, urinary
bladder, and genitalia.
Many pharmacologic agents modulate parasympathetic
nervous system activity. For example, bethanechol is a
parasympathomimetic that promotes GI and urinary tract
motility.
Antagonists o parasympathetic activity include atro-
pine , a drug used locally to dilate the pupils or systemati-
cally to increase heart rate, and ipratropium, a drug used to
dilate bronchioles. These agents and others are discussed in
Chapter 10, Cholinergic Pharmacology.
Peripheral Motor and Sensory Systems
Fibers o the somatic nervous system innervate their target
striated muscles directly (Fig. 9-1). The rst-order neurons
rom the motor cortex send projections that cross in the
lower medulla and descend through the spinal cord in the
lateral corticospinal tract be ore synapsing on the second-
order neurons in the ventral horns o the spinal cord. Projec-
tions rom the second-order neurons exit through the ventral
roots and join the dorsal roots , carrying sensory nerve bers,
to orm the spinal nerves . Spinal nerves exit the vertebral
column through the intervertebral oramina, a ter which they
separate into peripheral nerves. Somatic components o the
peripheral nerves innervate muscles directly. Muscles are in-
nervated in a myotomal distribution. That is, neurons origi-
nating rom a particular ventral root level o the spinal cord
(e.g., C6) innervate speci c muscles (e.g., f exor muscles o
the orearm).
Sensory neurons have cell bodies in the dorsal root
ganglia . The endings o sensory nerves lie in the skin and
joints and enter the spinal cord through the dorsal roots .
Neurons or vibration and position sense (proprioception)
ascend through the ipsilateral dorsal columns in the spinal
cord and synapse with secondary neurons in the contralateral
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 113

Sympathetic Parasympathetic
nervous system nervous system

Eye s
Oculomotor ne rve (CN III)

S a liva ry gla nds

Fa cia l ne rve (CN VII)

Re s pira tory tra ct
Glos s opha rynge a l ne rve (CN IX)
Cra nia l

Va gus
ne rve
C1 (CN X)
C2
C3 He a rt
C4 Ce rvica l
C5 S kin
C6 Live r
C7
T1
T2
S toma ch
T3
T4
T5
T6 Thora cic
T7
T8 Ce lia c
ga nglion
T9
T10
Adre na l
T11 gla nd P a ncre a s
T12
L1 Inte s tine s
Kidne y
L2
L3 Lumba r
L4 Bla dde r
S upe rior
L5 me s e nte ric
S1 ga nglion
S2 P e riphe ra l
S3 blood ve s s e l S a cra l
S4
S5 S ympa the tic
trunk

Infe rior
me s e nte ric Exte rna l ge nita lia
ga nglion

S ympa the tic pre ga nglionic fibe rs

P a ra ve rte bra l P reve rte bra l
ga nglia ga nglia S ympa the tic pos tga nglionic fibe rs
P a ra s ympa the tic pre ga nglionic fibe rs
P a ra s ympa the tic pos tga nglionic fibe rs

FIGURE 9-2. Patterns of sympathetic and parasympathetic innervation. Sympathetic preganglionic neurons arise in the thoracic and lumbar segments
of the spinal cord. Sympathetic preganglionic neurons project onto postganglionic neurons in ganglia that lie close to the spinal cord, most notably the
paravertebral ganglia, and in the prevertebral ganglia located near the aorta. Parasympathetic ganglia generally lie close to the organs they innervate. Thus,
parasympathetic preganglionic neurons, which arise in nuclei in the brainstem and the sacral segments of the spinal cord, are generally long and project
onto short postganglionic neurons.

lower medulla. Sensory neurons that carry sensations of pain
and temperature synapse with secondary neurons in the pos-
terior horn of the spinal cord and then cross within the spi-
nal cord to ascend in the contralateral spinothalamic tract.
Both the spinothalamic tract and the dorsal column tracts
connect with third-order neurons in the thalamus, part of the
diencephalon (see below), before ultimately reaching the
somatosensory cortex. Sensory information is encoded in a
dermatomal distribution. That is, neurons originating from a
particular dorsal root level of the spinal cord (e.g., C6) carry
sensory information corresponding to a particular area of the
skin (e.g., the lateral aspects of the forearm and hand).
114 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

A number o pharmacologic agents modulate the activ- Ce re bra l he mis phe re :

ity o the somatic nervous system. For example, antagonists Ce re bra l corte x Die nce pha lon
o neuromuscular junction activity, such as pancuronium, Ba s a l ga nglia
are used to induce paralysis during surgery. In contrast,
drugs that increase neuromuscular junction activity, such
as edrophonium and neostigmine , are used in the diagnosis
and treatment o myasthenia gravis, an autoimmune disease
characterized by decreased skeletal muscle stimulation at Midbra in
the neuromuscular junction. These agents and others are dis- Bra ins te m P ons Ce re be llum
cussed in Chapter 10. Me dulla

Anatomy of the Central Nervous System Ce rvica l

The CNS is divided anatomically into seven major divisions,
namely, the cerebral hemispheres , diencephalon, cerebellum,
midbrain, pons , medulla , and spinal cord (Fig. 9-3). The mid-
brain, pons, and medulla are collectively known as the brain-
stem and together connect the spinal cord with the cerebrum,
diencephalon, and cerebellum.

Cerebrum S pina l cord

The cerebral hemispheres constitute the largest division o Thora cic
the human brain. These structures contain several subdivi-
sions, including the cerebral cortex, its underlying white
matter, and the basal ganglia (Fig. 9-4). The cerebral hemi-
spheres are divided into le t and right sides that are connected
by the corpus callosum. The cerebral cortex is responsible
or high-level unctions, including sensory perception, plan-
ning and ordering motor unctions, cognitive unctions, such
as abstract reasoning, and language. The cortex is divided
anatomically and unctionally into the frontal, temporal,
parietal, and occipital lobes (Fig. 9-4A). Subregions o the Lumba r
cortex have speci c unctions. For example, stimulation o
part o the precentral gyrus, which lies in the rontal cortex,
induces peripheral motor unction (movement), and abla-
tion o this structure inhibits movement. From a pharmaco-
logic perspective, the cerebral cortex is a site o action o
many drugs, sometimes as part o their intended mechanism
o action and sometimes as an adverse e ect. Barbiturates S a cra l
and benzodiazepines (see Chapter 13, Pharmacology o
GABAergic and Glutamatergic Neurotransmission) are com-
monly prescribed hypnotics and sedatives that potentiate the
action o inhibitory neurotransmitters in the cortex. General
anesthetics (see Chapter 17, General Anesthetic Pharmacol- FIGURE 9-3. Anatomic organization of the central nervous system. The
central nervous system is divided into seven major regions: the cerebral
ogy) are also thought to have e ects on the cerebral cortex.
hemispheres, diencephalon (thalamus), cerebellum, midbrain, pons, me-
The cerebral white matter, which includes the corpus cal- dulla, and spinal cord. The cerebral hemispheres include the cerebral cor-
losum (Fig. 9-4B), transmits signals between the cortex and tex, underlying white matter (not shown), and basal ganglia. The midbrain,
other areas o the central nervous system and rom one area pons, and medulla together make up the brainstem. The spinal cord is further
o the cortex to another. The white matter consists primarily divided into cervical, thoracic, lumbar, and sacral segments.
o myelinated axons that, as in other areas o the brain, have
an associated vascular network o small arteries, veins, and
capillaries. It is around these small vessels that inf ammatory
cells collect in diseases such as multiple sclerosis, and it is case o Ms. P, Parkinsons disease is caused by degenera-
the small arterioles that are especially a ected by systemic tion o a dopaminergic pathway that arises in the substan-
hypertension. tia nigra in the midbrain (see below) and terminates in the
The basal ganglia consist o three deep nuclei o gray striatum (hence its name, the nigrostriatal tract or pathway).
matter (Fig. 9-4C), including the caudate and putamen This degeneration prevents the basal ganglia rom properly
together known as the striatumand the globus pallidus . initiating motor activityresulting in decreased intended
In a general sense, these nuclei help initiate and control movement and an unintended tremorand causes the de-
cortical actions. These actions include not only intended creased (f at) a ect characteristic o Parkinsons disease.
movement but also behavior and certain rudimentary as- Levodopa , a component o Ms. Ps Sinemet medication, acts
pects o cognition. Regions o the basal ganglia responsi- on the striatum to ameliorate these clinical mani estations o
ble or movement ensure that intended actions are carried the disease (see Chapter 14, Pharmacology o Dopaminergic
out and irrelevant movements are inhibited. As seen in the Neurotransmission).
 C h a p t e r 9 Principles o Nervous System Physiology and Pharmacology 115
A available, although many agents a ecting this region o the
Fronta l lobe P a rie ta l lobe
Te mpora l lobe
Occipita l lobe
B
Cingula te gyrus Corpus ca llos um
C
e r n a l c a p s u le
In t
Ca uda te
Tha la mus
P uta me n
FIGURE 9-4. Anatomy o the cerebral hemispheres. A. In this lateral view,
the cerebral hemispheres are divided into our lobes rontal, parietal, oc-
cipital, and temporalwhich are structurally and unctionally distinct rom
each other. B. A sagittal view o the cerebral hemispheres shows the corpus
callosum and cingulate gyrus. The corpus callosum connects the le t and
right hemispheres and coordinates their actions. The cingulate gyrus is part
o the limbic system; it lies immediately superior to the corpus callosum.
C. The basal ganglia include the caudate and putamen, which are together
known as the striatum, and the globus pallidus (medial to the putamen, not
shown). The thalamus lies medial to the basal ganglia. Arrows indicate the
trajectory o neurons in the internal capsule, a bundle o white matter that
carries motor commands rom the cortex to the spinal cord.
A rim or limbus around the cortex has older, more
basic unctions and is loosely termed the limbic system.
This system consists o the cingulate gyrus (Fig. 9-4B), the
hippocampal ormation (including the hippocampus and sur-
rounding structures), and the amygdala . These structures are
responsible or emotion, social behavior, autonomic con-
trol, the perception o pain, and memory. For example, the
memory loss associated with Alzheimers disease is caused
by degeneration o the hippocampal ormation. Only a ew
drugs that specif cally a ect the limbic system are currently
brain are in development. It should be noted that many drugs
o abuse (see Chapter 19, Pharmacology o Drugs o Abuse)
stimulate the brain reward pathway, which includes the
nucleus accumbens and its projections to the limbic system.
Diencephalon
The diencephalon is divided into the thalamus and hypo-
thalamus . The thalamus, which has several distinct nuclei, is
located medially in the brain and in erior to the cerebral cor-
tex. Some thalamic nuclei link sensory pathways rom the
periphery to the cerebral cortex. Other nuclei act as connec-
tions between the basal ganglia and the cortex. The thalamus
is not a simple signal relay; rather, it f lters and modulates
sensory in ormation, in part dictating which signals reach
conscious awareness.
The hypothalamus lies ventral to the thalamus. It con-
trols the autonomic nervous system, the pituitary gland, and
essential behaviors such as hunger and thermoregulation.
Descending pathways rom the medial hypothalamus regulate
autonomic preganglionic neurons in the medulla and spinal
cord. It is generally believed that the antihypertensive e ect
o clonidine is mediated by its action at receptors on brainstem
neurons controlled by the hypothalamus (see Chapter 11).
Other neurons originating in the medial hypothalamus se-
crete hormones either directly into the systemic circulation
(e.g., vasopressin rom axon terminals in the posterior pitu-
itary gland) or into a portal system that, in turn, controls hor-
mone secretion by the anterior pituitary gland (see Chapter 27,
Pharmacology o the Hypothalamus and Pituitary Gland). The
hypothalamus also initiates complex behaviors in response to
hunger, extremes in temperature, thirst, and time o day.
Cerebellum
The cerebellum lies in erior to the posterior end o the ce-
rebrum and dorsal to the brainstem. It has three unction-
ally distinct regions: the central cerebellar vermis , the lateral
cerebellar hemispheres , and the small f occulonodular lobe
(Fig. 9-5). The cerebellum has a relatively well-def ned pat-
tern o neural connections, receiving inputs rom a wide
Flocculonodula r lobe
Ce re be lla r ve rmis
Ce re be lla r he mis phe re s
FIGURE 9-5. Anatomy o the cerebellum. The cerebellum is divided into
the cerebellar hemispheres (laterally), the vermis (medially), and the small
f occulonodular node. The area immediately above the f occulonodular lobe
in this drawing is a cross section o the cerebellar peduncles.
116 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY
variety o sources and sending output primarily to the motor
areas o the cerebral cortex via the thalamus. The cerebellum
coordinates voluntary movement in space and time, main-
tains balance, controls eye movement, and has roles in motor
learning ( or example, handeye coordination) and certain
cognitive unctions such as the timing o repetitive events
and language. Few drugs are designed primarily to a ect the
cerebellum. However, several agents, notably alcohol and
certain antiepileptic drugs, are toxic to the cerebellum. These
agents especially a ect the vermis, which controls balance.
Brainstem
The midbrain, pons, and medulla are collectively known as
the brainstem. The brainstem connects the spinal cord to the
thalamus and cerebral cortex. It is arranged with the mid-
brain superior, the medulla in erior, and the pons bridging
the midbrain and medulla (Fig. 9-3). White matter pathways
interconnecting the spinal cord, cerebellum, thalamus, basal
ganglia, and cerebral cortex course through this small region
o the brain. In addition, the brainstem gives rise to most o
the cranial nerves . Some o these nerves are conduits or sen-
sation rom the head and ace, including hearing, balance,
and taste. The cranial nerves also control the motor output to
the skeletal muscles o mastication, acial expression, swal-
lowing, and eye movement. The brainstem also regulates
parasympathetic output to the salivary glands and the iris.
The medulla contains several control centers that are es-
sential or li e, including centers that direct the output o the
autonomic nuclei, pacemakers that regulate heart rate and
breathing, and centers that control ref ex actions such as
coughing and vomiting. Several relay structures in the pons
also play a role (in conjunction with the midbrain) in regulat-
ing vital unctions such as respiration. The base o the pons
contains white matter tracts connecting the cerebral cortex
and the cerebellum. Neurons in the periaqueductal gray, es-
pecially in the midbrain, send descending projections to the
spinal cord that modulate pain perception (see Chapter 18,
Pharmacology o Analgesia).
Clusters o di usely projecting neurons lie throughout the
brainstem, hypothalamus, and the surrounding base o the
brain. These nuclei, which include the locus ceruleus , raphe
nucleus , and several others, comprise the reticular activating
system, which is responsible or consciousness and sleep
regulation. The nuclei each use a di erent neurotransmitter
system (see below), and thus a variety o classes o medica-
tions can have e ects on this system. For example, it is via
these nuclei that rst-generation antihistamines cause seda-
tion (see Chapter 44, Histamine Pharmacology) and stimu-
lants such as cocaine cause heightened alertness.
Spinal Cord
The spinal cord is the most caudal division o the central
nervous system. It runs rom the base o the brainstem (me-
dulla) at the level o the rst cervical vertebra down to the
rst lumbar vertebra. Like the cerebrum, the spinal cord is
organized into white matter tracts and regions o gray mat-
ter. The white matter tracts connect the periphery and spinal
cord to more rostral divisions o the CNS, while the gray
matter orms the nuclear columns that lie in an H-shaped
pattern in the center o the spinal cord (Fig. 9-6).
Neurons in the spinal cord can be de ned by their spatial
location relative to the gray matter H. These neurons in-
clude sensory neurons located in the dorsal horns o the H,
Gra y ma tte r Ve ntra l horn
White ma tte r
Dors a l horn
Dors a l root
Dors a l root
ga nglion
Dura
FIGURE 9-6. Anatomy of the spinal cord. The spinal cord has an H-shaped
wedge of gray matter that includes the dorsal and ventral horns. The dorsal
horn is responsible for sensory relays to the brain, and the ventral horn is
responsible for motor relays to skeletal muscle. The white matter carries
signals to and from more rostral divisions of the CNS.
motor neurons located in the ventral horns o the H, and
spinal interneurons. The sensory neurons relay in ormation
rom the periphery to more rostral divisions o the CNS via
the dorsal columns or spinothalamic tracts (see above). The
motor neurons relay commands arising in the central motor
areas and descend in the corticospinal tract to peripheral
muscles. Interneurons connect sensory and motor neurons
and are responsible or mediating ref exes, such as the deep
tendon ref exes, by coordinating the action o opposing mus-
cle groups. Because the spinal cord carries sensory signals
including sensations o painto the central nervous system,
it is an important target or analgesic drugs such as opioids
(see Chapter 18).
Cellular Organization of the Nervous System
Cellular organization in the autonomic and peripheral ner-
vous system involves a limited number o neurons that make
ew connections. For example, somatic and sensory in or-
mation is carried directly between the spinal cord and the
periphery. Autonomic nerves are slightly more complex, in
that the signal must undergo synaptic transmission between
a preganglionic and a postganglionic neuron. In both cases,
however, ew ancillary neuronal connections are made, and
little or no modi cation o in ormation occurs.
In contrast, cellular organization in the central nervous
system is ar more complex. In ormation is not simply re-
layed rom one area to another; instead, central neurons
receive signals rom numerous sources and distribute their
own axons widely. Some neurons synapse with hundreds
o thousands o other neurons. Moreover, not every syn-
aptic connection is excitatory (i.e., designed to depolarize
the postsynaptic neuron). Some connections are inhibitory
(i.e., designed to hyperpolarize the postsynaptic neuron).
Other neurons projecting onto a target neuron can modulate
the relative excitability o the cell, a ecting the response o
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 117

A Long-tra ct B Loca l circuit C S ingle -s ource dive rge nt

Conve rge nt
s igna ling

Dive rge nt
s igna ling

FIGURE 9-7. Cellular organization of the central nervous system. The CNS has three main organizational motifs. A. Long-tract neurons act as relays
between the periphery and higher sites in the CNS. Long-tract neurons receive signals from many different neurons (convergent signaling) and synapse
with many downstream neurons (divergent signaling). B. Local circuit neurons show a complicated structural motif, arranged in layers, which includes both
excitatory and inhibitory neurons. These circuits are used to process information. C. Single-source divergent neurons typically originate in a nucleus in the
brainstem and have axonal terminals that innervate thousands of neurons, usually in the cerebral cortex.

the postsynaptic neuron to other signals. The complexity
generated by this variability is needed to carry out the many
intricate processes per ormed by the brain.
Although the CNS possesses immense complexity at the
level o neuronal connectivity, three major moti s are used to
organize neurons into unctional units in the nervous system:
the long-tract neuronal systems , local circuits , and single-
source divergent systems (Fig. 9-7). The peripheral nervous
system is organized exclusively as a long-tract system, while
the central nervous system uses all three moti s.
Long-Tract Neuronal Organization
Long-tract neuronal organization involves neural pathways
that connect distant areas of the nervous system to one an-
other (Fig. 9-7A). It is the organization used by the periph-
eral nervous system, and it is important or the transmission
o signals rom one region to another within the central
nervous system.
In the peripheral nervous system, signals are transmitted
with little modi cation. Sensory neurons respond to stimuli
such as touch, temperature, pressure, vibration, and nox-
ious chemicals and, i the initial membrane depolarization
is strong enough, transmit an action potential directly to the
spinal cord. There, sensory neurons synapse directly with so-
matic motor neurons, orming ref ex arcs, and with ascend-
ing spinal neurons that transmit the in ormation to higher
levels. Motor neurons carry in ormation directly rom the
spinal cord out through the ventral roots and project directly
on the motor end plates o the muscles they innervate. The
long axon tracts o the peripheral sensory and motor neurons
are bundled together and travel as peripheral nerves.
As described above, preganglionic neurons o the auto-
nomic nervous system orm synaptic connections with post-
ganglionic neurons at ganglia that are located prevertebrally,
paravertebrally, or near the innervated visceral organs. One
preganglionic neuron typically makes synaptic connec-
tions with up to several thousand postganglionic neurons,
an organization that is termed divergent signaling. Although
divergent signaling does result in some processing and mod-
i cation o in ormation, the autonomic nervous system does
not generally modi y neural signals appreciably.
In contrast to neurons in the peripheral pathways, neurons
in long-tract systems o the central nervous system not only
relay but also integrate and modi y signals. CNS long-tract
neurons display divergent signaling like autonomic neurons
but also receive synaptic connections rom many upstream
neurons (convergent signaling). The CNS uses both excitatory
and inhibitory neurotransmitters to localize a signal, a strategy
that is known as center-surround signaling. For example, sen-
sory perception in the CNS can precisely localize a signal by
activating cortical neurons that map to one area o the body and
inhibiting neurons that map to surrounding areas o the body.
Local Circuit Neuronal Organization
Local circuit neurons maintain connectivity primarily within
the immediate area. These neurons are generally responsible
or modulating signal transmission (Fig. 9-7B). For example,
neurons in the cerebral cortex are organized in layers, usu-
ally six in number. While in ormation f ows into one layer
and out o a di erent layer through long-tract connections,
links between the layers process the signals and interpret the
inputs. Local synaptic connections can be both excitatory
and inhibitory, ensuring that only certain patterns o inputs
are passed along. For example, in ormation originating in
the lateral geniculate neurons enters the primary visual cor-
tex through a long-tract connection called the optic tract. In
an area o the cortex designed to perceive lines, the outgoing
neurons will be excited only i the incoming neurons re in
a particular pattern, in this case designating a line in a par-
ticular orientation. The outgoing signal might then serve as
the input to another area o the brain that recognizes shapes.
I this area receives an appropriate pattern o lines rom the
appropriate sources, it might recognize a particular object,
such as the grid on a tic-tac-toe board.
118 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

Single-Source Divergent Neuronal Organization and maintain vigilance and responsiveness to unexpected
Nuclei in the brainstem, hypothalamus, and basal ore- stimuli. Thus, drugs such as cocaine , which inhibits the
brain ollow single-source divergent circuit organization reuptake o catecholamines such as norepinephrine, can ac-
(Fig. 9-7C), in which neurons originating in one nucleus in- tivate this system and cause hypervigilance (see Chapter 19).
nervate many target cells. Because single-source divergent Neurons that originate in the raphe nuclei in the caudal
neuronal organization involves the action o signals on a brainstem use the neurotransmitter serotonin and are respon-
wide variety o neurons, it is also commonly re erred to as sible or modulating pain signals in the spinal cord and locus
a diffuse system of organization. Instead o stimulating their ceruleus (Fig. 9-8B). Other neurons originating in the raphe
targets directly, divergent neurons typically exert a modula-
tory inf uence by using neurotransmittersgenerally, bio-
genic amines (see below)that act on G protein-coupled A Dopa mine rgic a nd choline rgic pa thwa ys
receptors. These receptors alter the resting potential and ion
channel conductance o the neuronal membranes in which Me dia l s e pta l S tria tum
they are located, thereby altering the ease o depolarization nucle i
o these neurons. Neurons constituting single-source diver-
gent circuits do not generally have myelin sheaths, because
their modulatory inf uences vary over the course o minutes
or hours rather than ractions o a second. In addition, their
axons are highly branched, enabling synaptic connections
with a large number o target neurons.
The principal single-source divergent neuronal systems
are summarized in Table 9-1. They include pigmented do-
paminergic neurons that originate in the substantia nigra ,
widely innervate the striatum, and are responsible or regu- Nucle us ba s a lis
lating the activity o neurons that control intended actions Ve ntra l te gme nta l a re a
(Fig. 9-8A). Speci cally, neurons in the nigrostriatal tract P e dunculopontine
excite downstream pathways that initiate movement and in- S ubs ta ntia nigra nucle us
hibit pathways that suppress movement. The nigrostriatal
tract degenerates in Parkinsons disease, which is why Ms. P Dopa mine rgic ne urons Choline rgic ne urons
displayed a paucity o movement. Other dopaminergic neu-
rons medial to the substantia nigra project to the pre rontal
cortex and inf uence thought processes. B Nora dre ne rgic a nd s e rotone rgic pa thwa ys
Another example o a single-source divergent circuit
involves the noradrenergic nucleus in the pons termed the
locus ceruleus (Fig. 9-8B). Neurons originating in this nu-
cleus widely innervate the cerebral cortex and cerebellum

TABLE 9-1 Single-Source Divergent Neuronal Systems

ORIGIN NEUROTRANSMITTER FUNCTIONS
Substantia nigra Dopamine Enable intended
(midbrain) movement;
executive function;
emotional Locus ce rule us
regulation; memory Ra phe nucle i
Locus ceruleus Norepinephrine Vigilance; S pina l cord
(pons) responsiveness to
unexpected stimuli Nora dre ne rgic ne urons S e rotone rgic ne urons

Raphe nuclei Serotonin Perception of pain; FIGURE 9-8. Diffuse neuronal systems. A. Dopaminergic neurons (blue)
(medulla, pons, responsiveness arise in the substantia nigra and the ventral tegmental area and project to
and midbrain) of cortical the striatum and the cerebral cortex, respectively. These neurons are as-
neurons; mood (?) sociated with the initiation of movement and the brain reward pathways.
Cholinergic neurons (red) arise in the nucleus basalis, pedunculopontine
Basal nucleus of Acetylcholine Alertness nucleus, and medial septal nuclei. These neurons, which project widely
Meynert throughout the brain, are responsible for maintaining sleepwake cycles
and regulating sensory transmission. B. Noradrenergic neurons (blue) arise
Pedunculopontine Acetylcholine Sleepwake cycles
in the locus ceruleus and innervate the entire brain. These neurons are re-
nucleus
sponsible for maintaining alertness. Serotonergic neurons (red) arise in the
Tuberomamillary Histamine Forebrain arousal raphe nuclei and project to the diencephalon, to the basal ganglia, and, via
nucleus the basal forebrain, to the cerebral hemispheres as well as the cerebellum
(hypothalamus) and spinal cord. Serotonergic neurons are believed to have a role in modu-
lating affect and pain.
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 119

nuclei widely innervate the orebrain, modulating the re-
sponsiveness o neurons in the cortex. Serotonergic neurons
regulate wake ulness and sleep, and dys unction o the sero-
tonergic system is hypothesized to be a cause o depression.
Because antidepressants block the reuptake o serotonin, this
class o drugs may activate the serotonergic raphe pathway
(see Chapter 15, Pharmacology o Serotonergic and Central
Adrenergic Neurotransmission).
Three other important nuclei that widely innervate the
cortex are the basal nucleus of Meynert, the pedunculopon-
tine nucleus , and the tuberomamillary nucleus . The basal nu-
cleus and the pedunculopontine nucleus use acetylcholine as
a neurotransmitter (Fig. 9-8A). The ormer nucleus projects
to the cortex and regulates alertness, while the latter nucleus
controls sleepwake cycles and arousal. Cells in the basal
orebrain that receive inputs rom the pedunculopontine nu-
cleus degenerate in several diseases, including Alzheimers
disease. The tuberomamillary nucleus uses the neurotrans-
mitter histamine (see below) and may help maintain arousal
through its actions on the orebrain. The somnolence induced
by f rst-generation antihistamineshistamine H1 receptor
antagonists used to treat allergies (see Chapter 44)may be
caused by inhibition o transmission involving tuberomamil-
lary nucleus neurons.
NEUROPHYSIOLOGY
Neurotransmitters
The peripheral nervous system uses only two neurotransmit-
ters: acetylcholine and norepinephrine (Fig. 9-9). In con-
trast, the CNS uses not only a wide variety o small molecule
neurotransmitters, including acetylcholine and norepineph-
rine (Table 9-2), but also many neuroactive peptides . These
peptides may be transmitted concurrently with the small
molecule neurotransmitters, and they generally have a neu-
romodulatory role.
The small molecule neurotransmitters can be organized
into several broad categories based on both their structure
and unction (Fig. 9-10). The f rst category, the amino acid
neurotransmitters, includes glutamate , aspartate , GABA, and
glycine . The biogenic amine neurotransmitters, which are

A Sympathetic B Parasympathetic C Somatic

P re ga nglionic Ace tylcholine

ne uron

Nicotinic
re ce ptors

Ace tylcholine

Nicotinic
re ce ptors
P os tga nglionic
ne uron

Nore pine phrine Ace tylcholine Ace tylcholine

or Ace tylcholine

Adre ne rgic Mus ca rinic Nicotinic

Tis s ue re ce ptor
Mus ca rinic (s we a t gla nds )

FIGURE 9-9. Neurotransmitters in the peripheral nervous system (A-C). Only two neurotransmitters are required to mediate neurotransmission in the pe-
ripheral nervous system. Acetylcholine is released by sympathetic and parasympathetic preganglionic neurons, parasympathetic postganglionic neurons,
somatic motor neurons, and sympathetic postganglionic neurons that innervate sweat glands. All other sympathetic postganglionic neurons release nor-
epinephrine. Acetylcholine stimulates nicotinic acetylcholine receptors on sympathetic and parasympathetic postganglionic neurons and at the neuromus-
cular junction. Acetylcholine stimulates muscarinic acetylcholine receptors on sweat glands and on tissues innervated by parasympathetic postganglionic
neurons. Norepinephrine stimulates - and -adrenergic receptors on tissues (except for sweat glands) innervated by sympathetic postganglionic neurons.
120 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

TABLE 9-2 Small Molecule Neurotransmitters in the Central Nervous System

NEUROTRANSMITTER RECEPTOR SUBTYPE RECEPTOR MOTIF MECHANISM
GABA GABAA Ionotropic cAMP
GABAB Metabotropic Cl conductance
K , Cl conductance

Glycine , Subunits Ionotropic Cl conductance

Glutamate, Aspartate AMPA Ionotropic Na , K conductance

Kainate Ionotropic Na , K conductance
NMDA Ionotropic Na , K , Ca 2 conductance
mGlu (17) Metabotropic cAMP
IP3/DAG/Ca 2

Dopamine D1, D5 Metabotropic cAMP

D2, D3, D4 Metabotropic cAMP; K , Ca 2 conductance

Norepinephrine 1 Metabotropic IP3/DAG/Ca 2

2 Metabotropic cAMP; K , Ca 2 conductance
1, 2, 3 Metabotropic cAMP

Serotonin 5-HT1 Metabotropic cAMP; K conductance

5-HT2 Metabotropic IP3/DAG/Ca 2
5-HT3 Ionotropic Na , K conductance
5-HT47 Metabotropic cAMP

Histamine H1 Metabotropic IP3/DAG/Ca 2

H2 Metabotropic cAMP
H3 Metabotropic cAMP

Acetylcholine Nicotinic Ionotropic Na , K , Ca 2 conductance

Muscarinic Metabotropic IP3/DAG/Ca 2
cAMP; K conductance

Adenosine P1 Metabotropic cAMP; Ca 2 , K conductance

P2X Ionotropic Ca 2 , K , Na conductance
P2Y Metabotropic IP3/DAG/Ca 2

Neurotransmitters can be organized into several categories, including the amino acids, biogenic amines, acetylcholine, adenosine, and nitric oxide (NO). Each
neurotransmitter can bind to one or more receptors. Except or the NO receptor, which is intracellular (not shown), the other small molecule receptors are all at the
cell sur ace. These cell sur ace receptors may be ionotropic or metabotropic. The mechanism o action o each receptor is indicated. In addition to the small molecule
neurotransmitters, more than 50 neuroactive peptides have been identif ed. AMPA, kainate, and NMDA receptors are named a ter agonists that selectively activate them.
AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; cAMP, cyclic adenosine-3,5-monophosphate; DAG, diacylglycerol; IP3,
inositol-1,4,5-trisphosphate.

derived from decarboxylated amino acids, include dopa-
mine , norepinephrine , epinephrine , serotonin, and histamine .
Acetylcholine , which is neither an amino acid nor a biogenic
amine, is used as a neurotransmitter in both the CNS and
the peripheral nervous system. The purines adenosine and
adenosine triphosphate (ATP) are also used in central neu-
rotransmission, although their roles have not been studied
in as much detail as those of other neurotransmitters. The
lipid-soluble gas nitric oxide (NO), which has many effects
in peripheral tissues, has recently been shown to act as a dif-
fusible neurotransmitter in the CNS.
Amino Acid Neurotransmitters
The amino acid neurotransmitters are the primary excitatory
and inhibitory neurotransmitters in the CNS. Two types of
amino acid neurotransmitters are used: the acidic amino
acids glutamate and aspartate, which are primarily excit-
atory, and the neutral amino acids GABA and glycine, which
are primarily inhibitory. Glutamate, aspartate, and glycine
are all alpha-amino acids that are also building blocks for
protein synthesis. Glutamate is the primary excitatory neu-
rotransmitter; it acts on both ionotropic (ligand-gated ion
channels) and metabotropic (G protein-coupled) receptors
(see Chapter 13). Excessive excitation of certain glutamate
receptors is one of the mechanisms by which ischemic injury
causes neuronal death. For this reason, glutamate receptors
are a major target for pharmaceutical research. To date, how-
ever, there are few therapeutic agents in clinical use that bind
selectively to glutamate receptors. Felbamate , used in the
treatment of refractory epilepsy, inhibits the NMDA gluta-
mate receptor, thereby reducing the excessive neuronal activ-
ity associated with seizures. Unfortunately, its use is limited
by adverse effects such as bone marrow suppression and liver
failure (see Chapter 16, Pharmacology of Abnormal Elec-
trical Neurotransmission in the Central Nervous System).
GABA, which is also discussed in Chapter 13, is the primary
inhibitory neurotransmitter in the CNS. Several classes of
therapeutic agents, most notably the barbiturates and benzo-
diazepines, bind to GABA receptors and, by allosteric mech-
anisms, potentiate the effect of endogenous GABA.
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 121

FIGURE 9-10. Structures of the small molecule neurotransmitters. The

Amino Acid Neurotransmitters principal small molecule neurotransmitters can be divided into two broad
O categories. Amino acids are the primary excitatory (glutamate and aspar-
O
H2 N tate) and inhibitory (glycine and -aminobutyric acid) neurotransmitters in
H2 N OH the CNS. Their amino and carboxylic acid groups are shown in blue. Biogenic
OH amines are the primary modulatory neurotransmitters in the CNS. The amine
moiety is shown in blue. Dopamine, norepinephrine, and epinephrine share
HO a common catechol group; histamine has an imidazole group; and serotonin
has an indole group. Acetylcholine (a neurotransmitter in diffuse modulatory
O HO O systems in the CNS), adenosine, and nitric oxide (NO) do not fall into either
structural category. The bond order is 2.5 for the nitrogenoxygen bond in
As pa rtic a cid Gluta mic a cid NO, intermediate in strength between a double bond and a triple bond.

O O
H2 N H2 N Biogenic Amines
OH OH
The biogenic amines (along with acetylcholine) are used by
Glycine -Aminobutyric a cid (GABA) the di use neuronal systems to modulate complex central
nervous system unctions such as alertness and conscious-
ness. In the peripheral nervous system, norepinephrine is
Biogenic Amine Neurotransmitters released by sympathetic postganglionic neurons to e ect the
OH sympathetic response. The adrenal medulla is a neuroendo-
HO NH2 H crine tissue that releases the biogenic amine epinephrine into
HO N the circulation in response to stress.
The biogenic amines are all synthesized rom amino acid
precursors. Based on these precursors, the biogenic amines
HO HO can be divided into three categories. The catecholamines
Dopa mine Epine phrine (dopamine, norepinephrine, and epinephrine) are derivatives
OH o tyrosine. The indoleamine serotonin is synthesized rom
tryptophan. Histamine is ormed rom histidine. These three
HO NH2 categories are described brief y below.
The catecholamines are all derived rom tyrosine in a se-
ries o biochemical reactions (Fig. 9-11). First, tyrosine is ox-
HO idized to L-dihydroxyphenylalanine (L-DOPA). L-DOPA is then
Nore pine phrine decarboxylated to dopamine. In the case o Ms. P, L-DOPA
NH2 (levodopa) is one o the components o the medication used
HN to compensate or the loss o dopaminergic neurons in the
substantia nigra. (Dopamine is not an e ective therapeutic or
Parkinsons disease because it does not cross the bloodbrain
N NH2 barrier; see below.) Central dopaminergic receptors have been
the target o a wide variety o therapeutics. For example, both
dopamine precursors and direct dopamine receptor agonists
HN OH
are used in the treatment o Parkinsons disease, as discussed
His ta mine S e rotonin in Chapter 14. Dopamine receptor antagonists have been used
with success in treating the psychotic symptoms o schizo-
Other Neurotransmitters phrenia; this topic is also discussed in Chapter 14. Certain
drugs o abuse, such as cocaine and the amphetamines, can
O activate brain reward pathways that depend on dopaminergic
N
N+ neurotransmission, as discussed in Chapter 19.
H2 N N O Dopamine is synthesized rom tyrosine and L-DOPA in
Ace tylcholine
the cytoplasm but is then transported into synaptic vesicles.
N N
O In dopaminergic neurons, the dopamine contained in synaptic
OH
vesicles is released as the neurotransmitter. In adrenergic and
noradrenergic neurons, dopamine is converted to norepineph-
rine within the synaptic vesicles by the enzyme dopamine- -
HO OH NO hydroxylase . In a small number o neurons and in the adrenal
Ade nos ine Nitric oxide medulla, norepinephrine is then transported back into the
cytoplasm, where it is methylated to orm epinephrine.
Chapter 11 discusses the pharmacology o drugs that target
peripheral adrenergic receptors, including both agonists, such
as bronchodilators and vasopressors, and antagonists, such as
antihypertensives. Several classes o therapeutic agents act
on central adrenergic receptors. Clonidine is a partial agonist
that acts on presynaptic 2-receptors. Some antidepressants
increase the synaptic concentration o norepinephrine by
122 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

O blocking its reuptake (tricyclic antidepressants [TCAs] and

serotonin-norepinephrine reuptake inhibitors [SNRIs]), while
OH others increase the intracellular pool of norepinephrine avail-
able for synaptic release by inhibiting its chemical degrada-
NH2 tion (monoamine oxidase inhibitors [MAOIs]).
HO
5-Hydroxytryptamine (5-HT, also known as serotonin) is
Tyros ine formed from the amino acid tryptophan by enzymatic oxi-
dation at the 5 position followed by enzymatic decarboxyl-
Te tra hydrobiopte rin ation. This sequence of reactions is similar to that used in
Tyrosine hydroxylase (TH)
O 2 , Fe 2+ the synthesis of dopamine, although the enzymes that carry
out the reactions are different (Fig. 9-12). Several classes
O of drugs target serotonergic neurotransmission. TCAs and
HO SNRIs, which block norepinephrine reuptake, also block
OH serotonin reuptake. Selective serotonin reuptake inhibitors
(SSRIs), which act more selectively on serotonin reuptake
NH2
HO
transporters, are also used to treat depression. The role of
serotonergic neurons in depression and the various therapies
L-DOPA for depression that target serotonergic neurotransmission are
discussed in more detail in Chapter 15.
Aromatic L-amino acid Histamine is formed by decarboxylation of the amino acid
P yridoxa l phos pha te decarboxylase
histidine. Histamine functions as a diffuse neurotransmitter in

HO NH2
O

HO HN OH
Dopa mine NH2

As corbic a cid
Dopamine -hydroxylase
O 2 , Cu 2+
Tryptopha n

OH
HO NH2 Tryptophan hydroxylase (TPH)

O
HO
Nore pine phrine HN OH
NH2
Phenylethanolamine
S -a de nos ylme thionine
N-methyltransferase

OH
OH
H 5-Hydroxytryptopha n
HO N

Aromatic L-amino acid decarboxylase

HO
Epine phrine
NH2
FIGURE 9-11. Synthesis of catecholamines. Catecholamines are all syn- HN
thesized rom tyrosine. Sequential enzymatic reactions result in hydrox-
ylation o tyrosine to orm L-DOPA, decarboxylation o L-DOPA to orm
dopamine, hydroxylation o dopamine to orm norepinephrine, and meth-
ylation o norepinephrine to orm epinephrine. Depending on the enzymes
(shown in blue lettering) expressed in a particular type o presynaptic neu-
ron, the reaction sequence may stop at any o the last three steps, so that OH
dopamine, norepinephrine, or epinephrine can be the f nal product that is 5-Hydroxytrypta mine
synthesized and used as a neurotransmitter. (S e rotonin)

FIGURE 9-12. Synthesis of 5-hydroxytryptamine (serotonin). Tryptophan is

f rst oxidized by tryptophan hydroxylase (TPH) and then decarboxylated by
aromatic L-amino acid decarboxylase to yield serotonin.
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 123
the CNS; it also has a particular role in the maintenance o
arousal via the tuberomamillary nucleus o the hypothalamus
and in the sensation o nausea via the area postrema in the f oor
o the ourth ventricle. Few therapeutics intentionally target
central histaminergic neurotransmission. Instead, most drugs
in this class act on peripheral histamine H1 receptors, at which
histamine mediates the inf ammatory response to allergic stim-
uli, or on H2 receptors in the treatment o peptic ulcer disease
(see Chapters 44 and 47, Integrative Inf ammation Pharmacol-
ogy: Peptic Ulcer Disease). Peripherally acting antihistamines
are sometimes used to e ect sedation or as antiemetics, acting
via the central neuroanatomic substrates noted above.
Other Small Molecule Neurotransmitters
Acetylcholine plays a major role in peripheral neurotrans-
mission. At the neuromuscular junction, this molecule is
used by somatic motor neurons to depolarize striated mus-
cle. In the autonomic nervous system, acetylcholine is the
neurotransmitter used by all preganglionic neurons and by
parasympathetic postganglionic neurons. The multiple unc-
tions o acetylcholine in the peripheral nervous system have
spurred the development o a wide range o drugs that tar-
get peripheral cholinergic neurotransmission. These include
muscle paralytics, which inter ere with neurotransmission at
the motor end plate, acetylcholinesterase inhibitors, which
increase local acetylcholine concentration by inter ering
with the metabolic breakdown o the neurotransmitter, and
receptor-speci c agonists and antagonists.
In the CNS, acetylcholine acts as a di use-system neu-
rotransmitter. Like the biogenic amines, it is thought to
regulate sleep and wake ulness. Donepezil, a reversible ace-
tylcholinesterase inhibitor that acts at central cholinergic
synapses, helps to brighten patients with dementia (see
Chapter 10). Peripheral anticholinergic agents may cause
central cholinergic blockade and thereby result in major
adverse e ects. For example, the antimuscarinic drug scopol-
amine can cause drowsiness, amnesia, atigue, and dreamless
sleep. In contrast, cholinergic agonists such as pilocarpine
can induce adverse e ects o cortical arousal and alertness.
The purinergic neurotransmitters adenosine and adenosine
triphosphate have a role in central neurotransmission. This role
is most evident in the e ects o caffeine , which is a competitive
antagonist at adenosine receptors and causes a mild stimulant
e ect. In this case, the adenosine receptors, which are located
on presynaptic noradrenergic neurons, act to inhibit the release
o norepinephrine. Antagonism o these adenosine receptors by
ca eine causes the release o norepinephrine to be disinhibited,
which results in the characteristic stimulatory e ects o the drug.
Nitric oxide (NO), which has generated signi cant interest
as a peripheral vasodilator, acts in the brain as a neurotrans-
mitter. Unlike the other small molecule neurotransmitters,
NO di uses through the neuronal membrane and binds to
its receptors within the target cell. Receptors or NO are
thought to reside in presynaptic neurons, allowing NO to act
as a retrograde messenger. While many therapeutics target
the peripheral vasodilatory e ects o NO, none as o yet tar-
get its actions as a central neurotransmitter.
Neuropeptides
The neuroactive peptides are the last major class o neu-
rotransmitters. Many neuropeptides also have endocrine,
autocrine, and paracrine actions. Major examples o neuro-
active peptide amilies are the opioids , tachykinins , secretins ,
insulins , and gastrins . Neuropeptides also include the pitu-
itary hormone release and inhibiting actors, including cor-
ticotropin-releasing hormone (CRH), gonadotropin-releasing
hormone (GnRH), thyrotropin-releasing hormone (TRH), growth
hormone-releasing hormone (GRH), and somatostatin. The
opioid peptide amily includes the enkephalins , dynorphins ,
and endorphins . Opioid receptors, which are distributed
widely in areas o the spinal cord and brain that are involved
in pain sensation, are the principal pharmacologic targets o
opioid analgesics such as morphine (see Chapter 18) and o
some drugs o abuse such as heroin (see Chapter 19).
The BloodBrain Barrier
In the case o Ms. P, L-DOPA, the immediate precursor o
dopamine, is administered rather than the neurotransmitter
itsel . Unlike L-DOPA, which is able to cross rom the blood
to the brain tissue where it acts to treat Ms. Ps Parkinsons
disease, dopamine is unable to cross that boundary. The rea-
son or this exclusion is the existence o a selective lter,
termed the bloodbrain barrier, which regulates the transport
o many molecules rom the blood into the brain (Fig. 9-13).
The bloodbrain barrier protects the brain tissue both rom
toxic substances that circulate in the blood and rom neu-
rotransmitters such as epinephrine, norepinephrine, glu-
tamate, and dopamine that have systemic e ects in body
tissues but that would bind receptors in the CNS and cause
undesirable e ects i access were permitted.
The structural basis or the bloodbrain barrier resides in
the unique design o the cerebral microcirculation. In most
tissues, there are small gaps, called fenestrae , between the
endothelial cells that line the microvasculature. These gaps
allow water and small molecules to di use across the lin-
ing without resistance but lter out large proteins and cells.
In the CNS, the endothelial cells orm tight junctions that
prevent di usion o small molecules across the vessel wall.
Also, unlike peripheral endothelial cells, CNS endothelial
cells do not generally have pinocytotic vesicles that transport
f uid rom the blood vessel lumen to the extracellular space.
In addition, blood vessels in the CNS are covered by cel-
lular processes derived rom astroglia . These processes play
an important role in selectively transporting certain nutrients
rom the blood to central neurons.
In the absence o a selective transport mechanism, the
bloodbrain barrier generally excludes water-soluble sub-
stances. In contrast, lipophilic substances, including impor-
tant lipid-soluble gases such as oxygen and carbon dioxide,
can usually di use across the endothelial membranes. The
oil/water partition coe cient is a good indicator o the ease
with which a small molecule can enter the CNS. Lipophilic
substances with high oil/water partition coe cients can gen-
erally di use across the bloodbrain barrier, whereas hydro-
philic substances with low oil/water partition coe cients are
typically excluded (Fig. 9-14).
Many important hydrophilic nutrients, such as glucose
and a number o amino acids, would not be able to cross
the bloodbrain barrier without the existence o speci c
transporters. Glucose, or example, is transported across the
barrier by a hexose transporter that allows this nutrient to
move down its concentration gradient in a process called
facilitated diffusion. Amino acids are transported by three
di erent transporters: one or large neutral amino acids
such as valine and phenylalanine; one or smaller neutral
amino acids and polar amino acids, such as glycine and
124 FUNDAMENTAL PRINCIPLES OF NEUROPHARMACOLOGY

1.00
Nicotine Dia ze pa m

n
i
Etha nol

a
r
Peripheral capillary He roin

b
o
t
n
i
Glucos e Chlora mphe nicol

n
o
i
L-DOPA

t
0.10

a
r
t
P he nytoin

e
P he noba rbita l

n
e
p
Fe ne s tra

e
Dopa mine

v
i
t
Me thotre xa te

a
l
Morphine

e
Ma nnitol

R
P e nicillin
0.01 S odium
P inocytotic ve s icle s Endothe lia l ce ll 0.001 0.01 0.1 1.0 10 100
Oil/wa te r pa rtition coe fficie nt

FIGURE 9-14. Relative ability of compounds to enter the brain from the
blood. In general, there is a correlation between the oil/water partition co-
Brain capillary e f cient o a compound and its ability to enter the brain rom the systemic
circulation. Specif c transporters acilitate the entry into the brain o certain
compounds (squares), such as glucose (glucose transporter) and L-DOPA
P e ricyte (large neutral L-amino acid transporter). Transporters also pump certain
compounds out o the CNS (diamonds), such as phenobarbital and phe-
nytoin. The metabolic bloodbrain barrier, consisting o a number o drug-
metabolizing enzymes, also limits the CNS concentration o certain drugs.

brain by a class o proteins known as multiple drug resistance

As troglia l proce s s
Ba s e me nt me mbra ne
Mitochondria
Tight junction
FIGURE 9-13. Features of capillaries in the central nervous system com-
pared to the peripheral vasculature. In the periphery, capillary endothelial
cells have gaps (termed fenestrae) between them and use intracellular
pinocytotic vesicles to acilitate the transcapillary transport o uid and
soluble molecules. In contrast, CNS vessels are sealed by tight junctions
between the endothelial cells. The cells have ewer pinocytotic vesicles and
are surrounded by pericytes and astroglial processes. In addition, capillary
endothelial cells in the CNS have more mitochondria than those in systemic
vessels; these mitochondria may re ect the energy requirements necessary
or CNS endothelial cells to transport certain molecules into the CNS and
transport other molecules out o the CNS.
glutamate, respectively; and one or alanine, serine, and cys-
teine. L-DOPA is transported by the large neutral amino acid
transporter, but dopamine itsel is excluded by the blood
brain barrier. For this reason, L-DOPA is administered in
lieu o dopamine to patients with Parkinsons disease. A ter
meals with a high protein content, however, the transporter
can become overwhelmed, and its transport o L-DOPA can
become ine ective. This explains Ms. Ps complaint that her
medication was less e ective a ter she began a diet high in
protein. The bloodbrain barrier also contains a number o
ion channels, which ensure that ion concentrations in the
brain are maintained at homeostatic levels.
Just as certain vital hydrophilic nutrients are allowed ac-
cess to the brain tissue via particular transporters, many po-
tentially toxic lipophilic compounds can be excluded rom the
(MDR) transporters . These transporters pump hydrophobic
compounds out o the brain and back into the blood vessel
lumen. (Note that MDR transporters are present in many
cell types, playing an important role in processes such as
the resistance o tumor cells to chemotherapeutic agents; see
Chapter 5, Drug Transporters.) A metabolic bloodbrain bar-
rier adds a layer o protection against toxic compounds; this
barrier is maintained by enzymes that metabolize compounds
transported into CNS endothelial cells. One such enzyme, ar-
omatic L-amino acid decarboxylase (sometimes called DOPA
decarboxylase ), metabolizes peripheral L-DOPA to dopa-
mine, which is unable to cross the bloodbrain barrier. For
this reason, Ms. Ps medication includes a second compo-
nent, carbidopa , which is an inhibitor o DOPA decarbox-
ylase. Carbidopa ensures that L-DOPA is not metabolized
to dopamine peripherally be ore crossing the bloodbrain
barrier. Importantly, carbidopa itsel is unable to cross the
bloodbrain barrier and, there ore, does not inter ere with the
conversion o L-DOPA to dopamine in the CNS.
CONCLUSION AND FUTURE
DIRECTIONS
This chapter discusses the anatomical organization o the
peripheral and central nervous systems, the transmission
and processing o electrical and chemical signals by neu-
rons, the principal neurotransmitters used by CNS neurons,
and the structure and unction o the bloodbrain barrier.
Although this chapter introduces some specif c drugs as ex-
amples, the ocus is on the general principles o anatomy and
neurotransmission that are important or understanding the
action o all pharmacologic agents a ecting the nervous sys-
tem. The remaining chapters in this section discuss specif c
 C h a p t e r 9 Principles of Nervous System Physiology and Pharmacology 125
neurotransmitter systems and specif c agents that act on the
peripheral and central nervous systems. Thus, Chapters 10 and
11 describe peripheral cholinergic and adrenergic systems,
and Chapter 12, Local Anesthetic Pharmacology, discusses
the production o local anesthesia by inhibition o electrical
transmission through peripheral and spinal neurons. Chapter
13 describes central excitatory and inhibitory neurotransmis-
sion. Although ew therapeutics currently take advantage o
glutamatergic neurotransmission, two major classes o drugs,
the benzodiazepines and the barbiturates, a ect GABAergic
neurotransmission by potentiating the e ect o GABA at the
GABAA receptor. Chapter 14 discusses dopaminergic sys-
tems, describing in more detail the concept, introduced in the
present chapter, that some o the symptoms o Parkinsons
disease can be alleviated by drugs that increase dopaminergic
transmission. Chapter 14 also explains how inhibiting dopa-
minergic transmission can alleviate some o the symptoms
o schizophrenia, implying that dopamine may play a role in
this disease. Chapter 15 discusses drugs that modi y a ect,
the outward mani estations o mood. These agents include
antidepressants, which block reuptake or inhibit metabolism
o the biogenic amines norepinephrine and serotonin, as well
as the mood stabilizer lithium, which is thought to a ect a
signal transduction pathway. Chapter 16 explores the phar-
macology o abnormal electrical neurotransmission, includ-
ing the action o channel blockers, such as phenytoin, which
block the propagation o action potentials and thereby inhibit
many types o seizures. Chapter 17 describes the pharma-
cology o general anesthetics, agents whose mechanism o
action remains an area o active investigation. Chapter 18
discusses the pharmacology o analgesia, including opioid
receptor agonists and nonopioid analgesics. To conclude,
Chapter 19 ocuses on the pharmacology o drugs o abuse.
Suggested Reading
Blumen eld H. Neuroanatomy through clinical cases. 2nd ed. Sunderland,
MA: Sinauer Associates, Inc.; 2010. (Thorough review of human neuro-
anatomy with an emphasis on clinical correlation; includes many exem-
plary clinical cases.)
Squire LR, Berg D, Bloom F, du Lac S, Ghosh A, Spitzer NC, eds. Fun-
damental neuroscience. 4th ed. Waltham, MA: Academic Press; 2013.
(Comprehensive textbook containing detailed information on human neu-
roanatomy and neurophysiology.)
IIB
Principles of Autonomic and Peripheral
Nervous System Pharmacology
 Naa +

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Cholinergic Pharmacology
A h H+
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INTRODUCTION r&
Mus ca rinicCASE
inic
inic ACh
ACh re ce p tor. . . . . . . . . . . . . . . . . . . . . 12
c e pto
pt
ptor 1277 121288 PH HARMA
H MANicotinic CACh
HARMACOLOGIC CLASSES
ACh S AN
re ce ptor ND AGENTS . . . . . . . . . . . . . . . . 137
BIOCHEMISTRY AND (MD 2, P MHYSIOLOGY
4) OF F ACh
AC h Inhibitors of Acetylcholine Syntthesi
In he sis,s,
CHOLINERGIC NEUROT TRA
RANSMISSION . . . . . . . . . . . . . . . . . . . . 127 o Choline
Storage, and+Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1377
a ce
c taa ttee
S ynaptic c
cle ft
Synthesis of Acetylcholiine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 12 Acet
cet
etyl
ylchc olinesterase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . 13 137
Stor
Storag
agee a ndd Release of Acee ty tylcholine
oline
oli liinnee . . . . . . . . . . . . . . . . . . . 1288 Structur
St
Stru
hE
AChE
truc urA allChE
AChE Class
hEssess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Cholinergic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Clinical
Cli i Applications
Inhibito rs rs s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Ac etylcholineste ras
A rase
Muscarinic Rec ecepepto tors
rs.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 Rec
R
Reeceptor
eecep
cep Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
139
Nicotinic Receptors. . . . . . . . . . . . . . . . . . . . . . . . . .N Musca
uscar
usca carinic Receptor Agonistss . . . . . . . . . . . . . . . . . . . . . . . 13
car 1399
Nicoti
Nic
Ni nic 130
icotinic
cot
otinic
Degradation of Acetylcholine
P
Poo s ts ynap pin
ynaptic
ptnticc . . .Mus. . . .ca. .rinic
. . . . . . . .A
rinic .Ch re ce ppt
ACh 1331
ptor
or Nico
Ni coti tini
niic Re
nic Rece
ceptptor
ptor Ago goni nist
stss . . . . . . . . . . . . . . . . . . . . . . . . . 140
Physiologic Effects c e llllof Cholinergic A
ACh
Ch re ce pt
Transmission p tor
ptor . . . . . . . . . . 13
1322 Rece
Re ceptptor
pt orr Anntntag
agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 1411
Neuromuscular J unction onn M . .1., .M. 3. ,. M. .5. . M . .4 . . . . . . . . . . . 132 + + Muscari
. .2., .M riinnic Receptor Anttago goninist
stss . . . . . . . . . . . . . . . . . . . . 141
Ope ns N Na /K chaaNicotini
nne l
nic
niicc Receptor Antagonistss . . . . . . . . . . . . . . . . . . . . . . 143
Autonomic Effectss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Gq Gi
CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Ex CONCLUSIO
Excita tor
toryy IO
ON AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . 144
ON
The Non-Neuronal Cholinerg erg
rgi
giic
ggicP LCSystem ((NNCS) N
AC,
AC , . . . . . . . . . 136 Su Sugg ggesestetted
te
e d ReRead adiningg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14 1444
K+ h l

INTRODUCTION Chapter 47, Integrative In ammation Pharmacology: Peptic

Ulcer Disease; and Chapter 48, Integrative In ammation
Cholinergic pharmacology is centered on the properties o Pharmacology: Asthma.
the f rst identif ed neurotransmitter, acetylcholine (ACh). The
unctions o cholinergic pathways are diverse; generally,
they involve the neuromuscular junction (NMJ), the auto- BIOCHEMISTRY AND PHYSIOLOGY OF
nomic nervous system, the central nervous system (CNS),
and the non-neuronal cholinergic system (NNCS). In the
CHOLINERGIC NEUROTRANSMISSION
neuronal cholinergic systems, ACh acts as a neurotransmit- Acetylcholine synthesis, storage, and release ollow a simi-
ter at the NMJ, at autonomic ganglia, at terminal synapses o lar set o steps in all cholinergic neurons. The specif c e ects
parasympathetic postganglionic f bers and a ew sympathetic o ACh at a particular cholinergic synapse are largely deter-
postganglionic f bers, and in the CNS. Many non-neuronal mined by the ACh receptor type at that synapse. Cholinergic
cells also express ACh receptors and can thereby serve as receptors are divided into two broad classes. Muscarinic ace-
e ector cells or both neuronally and non-neuronally re- tylcholine receptors (mAChR) are G protein-coupled receptors
leased ACh. that are expressed at the terminal synapses o all parasym-
Despite the many physiologic actions o ACh, the current pathetic postganglionic f bers and a ew sympathetic post-
therapeutic uses or cholinergic and anticholinergic drugs ganglionic f bers, at autonomic ganglia, and in the CNS.
are limited by the ubiquitous nature o cholinergic path- Nicotinic acetylcholine receptors (nAChR) are ligand-gated
ways, and thus, by the inherent di f culty o e ecting a spe- ion channels that are concentrated postsynaptically at many
cif c pharmacologic intervention without inducing adverse excitatory autonomic synapses and presynaptically in the
e ects. Nonetheless, medications with somewhat targeted CNS. Acetylcholinesterase (AChE), the enzyme responsible
cholinomimetic and anticholinergic actions are in wide- or acetylcholine degradation, is also an important pharma-
spread clinical use or their e ects on the brain (especially cologic target. In this section, the biochemistry o each o
cognition and behavior), neuromuscular junction, heart, these pharmacologic targets is described and the physiologic
eyes, lungs, and genitourinary and gastrointestinal tracts. e ects o acetylcholine at the neuromuscular junction, in
Other chapters that discuss applications o cholinergic the autonomic nervous system, in the CNS, and in the non-
pharmacology are Chapter 18, Pharmacology o Analgesia; neuronal cholinergic system are discussed.

127
128 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
Th e ye a r is 1744. Virg in ia n s e ttle rs ca p -
tu re Ch ie Op e ch a n ca n o u g h , w a rrio r
ch ie o th e Po w h a ta n s a n d u n cle to
Po ca h o n ta s . Op e ch a n ca n o u g h is co n -
s id e re d a m a s te r ta cticia n a n d h a s a
re p u ta tio n a s a b ru ta l wa rrio r. On e co lo n ia l co rre -
s p o n d e n t p o rtra ys a d i e re n t p ictu re o th e ca p tu re d
ch ie , h o w e ve r: Th e e xce s s ive a tig u e s h e e n co u n -
te re d w re cke d h is co n s titu tio n ; h is f e s h b e ca m e
m a ce ra te d ; h is s in e w s lo s t th e ir to n e a n d e la s ticity
a n d h is e ye lid s w e re s o h e a vy th a t h e co u ld n o t s e e
u n le s s th e y w e re li te d u p b y h is a tte n d a n ts . . . h e
wa s u n a b le to wa lk; b u t h is s p irit, ris in g a b ove th e
ru in s o h is b o d y, d ire cte d [h is o llo w e rs ] ro m th e
litte r o n w h ich h e wa s ca rrie d b y h is In d ia n s . Du rin g
th e co n n e m e n t o Op e ch a n ca n o u g h to a p ris o n in
J a m e s to w n , it is d is co ve re d th a t, a te r a p e rio d o
in a ctivity, h e is a b le to ra is e h im s e l ro m th e g ro u n d
to a s ta n d in g p o s itio n .
It is th o u g h t th a t th e s to ry o Op e ch a n ca n o u g h
p ro vid e s th e e a rlie s t re co rd e d d e s crip tio n o m y-
a s th e n ia g ra vis , a n e u ro m u s cu la r d is e a s e re s u lt-
in g ro m th e a u to im m u n e p ro d u ctio n o a n tib o d ie s
d ire cte d a g a in s t ch o lin e rg ic re ce p to rs a t th e n e u -
ro m u s cu la r ju n ctio n . In 1934, a lm o s t 2 ce n tu rie s
la te r, th e En g lis h p hys icia n Ma ry Bro a d o o t Wa lke r
e n co u n te rs s e ve ra l p a tie n ts w ith s im ila r s ym p -
to m s o m u s cle w e a kn e s s , w h ich re m in d h e r o th e
Synthesis of Acetylcholine
Acetylcholine is synthesized in a single step rom choline
and acetyl coenzyme A (acetyl CoA) by the enzyme choline
acetyltransferase (ChAT):
Acetyl Coenzyme A Choline ChAT
(Km
Acetylcholine Coenzyme A H2O Equation 10-1
In the CNS, choline used or the synthesis o acetylcho-
line arises rom one o three sources. Approximately 35%
to 50% o the choline generated by acetylcholinesterase in
the synaptic cle t (see Fig. 10-1 and below) is transported
back into the axon terminal, where it comprises about hal
o the choline used in ACh synthesis. Plasma-based stores
o choline may also be transported to the brain as part o
phosphatidylcholine (a phospholipid), which is then me-
tabolized to ree choline. (The incorporation o choline into
phosphatidylcholine is essential, because choline itsel can-
not cross the bloodbrain barrier.) Choline is also stored in
phospholipids as phosphorylcholine, where it can be used
when needed.
Acetyl CoA or the synthesis reaction is derived mainly
rom glycolysis and is ultimately produced by the enzyme
pyruvate dehydrogenase. Although the synthesis o acetyl
CoA occurs at the inner membrane o mitochondria, cho-
line acetyltrans erase is located in the cytoplasm. It is hy-
pothesized that citrate serves as the carrier or acetyl CoA
rom the mitochondrion to the cytoplasm, where the citrate
is reed by citrate lyase.
s ym p to m s o p a tie n ts w ith tu b o cu ra re p o is o n in g .
Give n h e r n d in g s , Dr. Wa lke r a d m in is te rs a n a n ti-
d o te , p hys o s tig m in e , to h e r im m o b ile p a tie n ts . Th e
re s u lts a re s ta rtlin g w ith in m in u te s , h e r p a tie n ts
a re a b le to ris e a n d wa lk a cro s s th e ro o m . Dr. Wa lke r
h a s d is cove re d th e rs t tru ly e e ctive m e d ica tio n o r
m ya s th e n ia g ra vis . De s p ite th e s ig n i ca n ce o h e r
a cco m p lis h m e n t, it is la rg e ly rid icu le d b y th e s ci-
e n ti c co m m u n ity b e ca u s e th e tre a tm e n t im p rove s
th e s ym p to m s o m ya s th e n ia g ra vis to o ra p id ly a n d
e e ctive ly to b e b e lie va b le . It is n o t u n til m a ny ye a rs
la te r th a t th e s cie n ti c co m m u n ity co m e s to a cce p t
h e r n d in g s .
Questions
1 . Why do tubocurare poisoning and myasthenia gravis
produce similar symptoms?
2 . How does physostigmine improve the symptoms of
myasthenia gravis? Why is it dangerous to administer
physostigmine to every patient presenting with muscle
weakness?
3 . What are the therapeutic uses of anticholinergic drugs
in other diseases such as Alzheimers dementia?
4 . What are the advantages and disadvantages of using
medications with anticholinergic effects in older indi-
viduals and individuals with cognitive impairments?
The choline acetyltransferase reaction is not the rate-
limiting step in ACh synthesis. Rather, ACh synthesis is
limited by the availability of the choline substrate, which
depends on uptake of choline into the neuron. Two processes
are responsible or choline transport. The f rst is low-a f nity
10100 M) acilitated di usion. This transport
system is not saturable and is ound in cells that synthesize
choline-containing phospholipids, such as the corneal epi-
thelium. Far more important is a sodium-dependent, high-
a f nity transport system (Km 15 M) ound specif cally
in cholinergic nerve terminals. Because the high-a f nity
transporter is saturated at concentrations o choline 10 M,
it sets an upper limit on the supply o choline or ACh syn-
thesis. As the rate-limiting component in ACh synthesis,
this transporter is a target or several anticholinergic drugs
(e.g., hemicholinium-3, see Fig. 10-1).
Storage and Release of Acetylcholine
A ter its synthesis in the cytoplasm, ACh is transported into
synaptic vesicles or storage. An ATPase that pumps protons
into the vesicle provides the energy necessary or this pro-
cess. Transport o protons out o the vesicle (i.e., down the
H concentration gradient) is coupled to uptake o ACh into
the vesicle (i.e., against the ACh concentration gradient) via
an ACh-H antiport channel. This antiporter is a target or
some anticholinergic drugs, such as vesamicol, and its in-
hibition results in a def cit o ACh storage and subsequent
release (Fig. 10-1). Cholinergic synaptic vesicles contain not
only ACh but also ATP and heparan sul ate proteoglycans,
 C h a p t e r 1 0 Cholinergic Pharmacology 129

Na +

Choline
Cholinergic neuron

AcCoA + Choline Hemicholinium

Choline
Vesamicol acetyltransferase

ACh

Ca lcium Ca lcium
cha nne l cha nne l

Ca 2+ Ca 2+

ACh H+
LEMS
(a utoa ntibody)
Botulinum
toxin
ACh

Mus ca rinic ACh re ce ptor Nicotinic ACh re ce ptor

(M2 , M4 ) ACh
Choline +
a ce ta te
Synaptic cleft
AChE AChE
Inhibitors
Acetylcholinesterase

Nicotinic
Postsynaptic Mus ca rinic ACh re ce ptor
cell ACh re ce ptor
M1 , M3 , M5 M2 , M4
Ope ns Na +/K+ cha nne l
Gq Gi
Excita tory
P LC AC,
K+ cha nne l

Excita tory Inhibitory

FIGURE 10-1. Acetylcholine synthesis, storage, release, and degradation pathways and pharmacologic agents that act on these pathways. Choline is
transported into the presynaptic cholinergic nerve terminal by a high-a f nity Na -choline co-transporter. This transporter is inhibited by hemicholinium. The
cytosolic enzyme choline acetyltrans erase catalyzes the ormation o acetylcholine (ACh) rom acetyl coenzyme A (AcCoA) and choline. Newly synthesized
ACh is packaged (together with ATP and proteoglycans) into vesicles or storage. Transport o ACh into the vesicle is mediated by a H -ACh antiporter, which
is inhibited by vesamicol. The ACh-containing vesicles use with the plasma membrane when intracellular calcium levels increase in response to a presynaptic
action potential, releasing the neurotransmitter into the synaptic cle t. Lambert-Eaton myasthenic syndrome (LEMS) results rom an autoantibody that blocks the
presynaptic Ca 2 channel. Botulinum toxin prevents the exocytosis o presynaptic vesicles, thereby blocking ACh release. Acetylcholine di uses in the synaptic
cle t and binds to postsynaptic and presynaptic receptors. Acetylcholine receptors are divided into nicotinic and muscarinic receptors. Nicotinic receptors are
ligand-gated ion channels that are permeable to cations, while muscarinic receptors are G protein-coupled receptors that alter cell signaling pathways, includ-
ing activation o phospholipase C (PLC), inhibition o adenylyl cyclase (AC), and opening o K channels. Postsynaptic nicotinic receptors and M1, M3, and M5
muscarinic receptors are excitatory; postsynaptic M2 and M4 muscarinic receptors are inhibitory. Presynaptic nicotinic receptors enhance Ca 2 entry into the
presynaptic neuron, thereby increasing vesicle usion and release o ACh; presynaptic M2 and M4 muscarinic receptors inhibit Ca 2 entry into the presynaptic
neuron, thereby decreasing vesicle usion and release o ACh. Acetylcholine in the synaptic cle t is degraded by membrane-bound acetylcholinesterase (AChE)
into choline and acetate. Numerous inhibitors o AChE exist; most clinically relevant anticholinesterases are competitive inhibitors o the enzyme.

both of which serve as counter-ions for ACh. By neutral-
izing the positive charge of ACh, these molecules disperse
electrostatic forces that would otherwise prevent dense
packing of ACh within the vesicle. (Released ATP also acts
as a neurotransmitter, through purinergic receptors, to in-
hibit the release of ACh and norepinephrine from autonomic
nerve endings.)
Release of ACh into the synaptic cleft occurs via fusion of
the synaptic vesicle with the plasma membrane. This process
depends on axon terminal depolarization and the opening of
voltage-dependent calcium channels. The increase in intra-
cellular Ca2 facilitates the binding of synaptotagmin to the
SNARE-complex proteins, which together mediate vesicle
membrane attachment and fusion. The result is that the con-
tents of the vesicle are released as discrete quanta into the
synaptic cleft. (See Chapter 8, Principles of Cellular Excit-
ability and Electrochemical Transmission, for additional
details on electrochemical transmission.)
130 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
Two stores o ACh have distinct roles during the process
o ACh release. One store, known as the depot pool, con-
sists o vesicles positioned near the plasma membrane o the
axon terminal. Axonal depolarization causes these vesicles
to release ACh rapidly. The reserve pool serves to ref ll the
depot pool as it is being used. An adequate rate o reserve
pool mobilization is required to sustain ACh release or an
extended period o time. O the two stores, the depot pool is
replenished f rst by vesicles loaded with newly synthesized
ACh; this process displaces some o the older depot pool
vesicles into the reserve pool.
Cholinergic Receptors
A ter ACh has been released into the synaptic cle t, it binds
to one o two classes o receptors, usually on the membrane
sur ace o the postsynaptic cell. Muscarinic acetylcholine re-
ceptors (mAChR) are seven-transmembrane-helix G protein-
coupled receptors (GPCRs), and nicotinic acetylcholine
receptors (nAChR) are ligand-gated ion channels. Although
muscarinic receptors and nicotinic receptors are sensitive to
the same neurotransmitter, these two classes of cholinergic
receptors share little structural similarity.
Muscarinic Receptors
Muscarinic cholinergic transmission occurs mainly at auto-
nomic ganglia, at end organs innervated by the parasympa-
thetic division o the autonomic nervous system, and in the
CNS. As G protein-coupled receptors, muscarinic receptors
transduce signals across the cell membrane and interact with
GTP-binding proteins. Because the e ects o muscarinic
receptor activation occur through the actions o these G pro-
teins, there is a latency o at least 100250 ms associated
with muscarinic responses to receptor activation. (In con-
trast, nicotinic receptor channels have latencies on the order
o 5 ms.)
Activation o G proteins by agonist binding to muscarinic
receptors may have several di erent e ects on cells. These
include inhibition o adenylyl cyclase (via Gi) and stimu-
lation o phospholipase C (via Gq/11), both mediated by an
subunit o the G protein. (See Chapter 1, DrugReceptor
Interactions, or a discussion o these signaling mecha-
nisms.) Muscarinic activation also modulates ion channels
via the subunit o a G protein. The predominant e ect
o such mAChR stimulation is to increase the opening o
specif c potassium channels (G protein-modulated inwardly
recti ying K channels, or GIRKs), thereby hyperpolarizing
the cell. The subunit o the Gi protein binds to the chan-
nel and enhances its probability o being open.
Five distinct cDNAs or muscarinic receptors, denoted
M1M5, have been isolated and detected in human cells.
These receptor types orm two unctionally distinct groups.
M1, M3, and M5 are coupled to G proteins responsible or
the stimulation o phospholipase C. M2 and M4, on the other
hand, are coupled to G proteins responsible or adenylyl cy-
clase inhibition and K channel activation. The receptors o
each unctional group can be distinguished based on their
responses to pharmacologic antagonists (Table 10-1). Gen-
erally, M1 is expressed in cortical neurons and autonomic
ganglia, M2 in cardiac muscle, and M3 in smooth muscle and
glandular tissue. Because stimulation o M1, M3, and M5 re-
ceptors acilitates excitation o the cell, while stimulation o
M2 and M4 receptors suppresses cellular excitability, there is
a predictable correlation between the receptor subtype and
the e ect o ACh on the cell. The various muscarinic recep-
tor subtypes account or much o the diversity in cellular
responses to mAChR agonists.
Nicotinic Receptors
Nicotinic acetylcholine receptors (nAChRs) mediate nico-
tinic cholinergic transmission via a process known as direct
ligand-gated conductance (Fig. 10-2). The binding o two
ACh molecules to one nAChR elicits a con ormational
change in the receptor that creates a monovalent cation-
selective pore through the cell membrane. Open channels o
the activated nAChR are equally permeable to K and Na
ions. (Since the resting membrane potential is close to the
Nernst potential or K and ar below the Nernst potential
or Na , the predominant ion passing through the open
nACR is Na .) A relatively small permeability to Ca2 ions
also results in important elevations o intracellular [Ca2 ].
There ore, when open, these channels produce a net inward
current that depolarizes the postsynaptic cell. Stimulation o
multiple nAChRs may depolarize the cell su f ciently to gen-
erate action potentials and to open voltage-dependent cal-
cium channels. The latter action, and the direct entry o Ca2
through the nAChR pore, can lead to activation o several
intracellular signaling pathways.
Because ACh dissociates rapidly rom active-state recep-
tor molecules and acetylcholinesterase rapidly degrades ree
(unbound) ACh in the synaptic cle t (see below), the depo-
larization mediated by nAChRs is brie ( 10 ms). Although
the simultaneous binding o two ACh molecules is required
or channel opening, it is not necessary or both molecules to
dissociate rom the receptor in order or the channel to open
again; the binding o a second ACh molecule to a receptor
that still has one ACh bound may, once again, result in chan-
nel opening. The kinetics o nAChR binding and channel
opening are detailed in Figure 10-3.
Structurally, the nicotinic acetylcholine receptor com-
prises f ve subunits, each o which has a mass o approxi-
mately 40 kilodaltons (Fig. 10-2A). Several types o nAChR
subunits have been identif ed; these are designated , , ,
, and . All o these subunits share 3550% homology with
one another. Each receptor at the NMJ is composed o two
subunits, one and one subunit, and either one or
one subunit. (The 2 orm dominates at the neuromus-
cular junction in mature skeletal muscle, while the 2
orm is expressed in embryonic muscle.) Agonist molecules
bind at a hydrophobic pocket that is ormed between each
subunit and the adjacent, complementary subunitthis is
the structural basis or the binding o two ACh molecules to
each receptor. The con ormational change in the subunits
induced by the binding o ACh initiates the overall changes
in the pore that permit ion ow through the receptor (i.e., that
open the channel).
Besides simply opening and closing in response to ACh
binding, nicotinic receptors also modulate their responses to
various concentration prof les o ACh. The receptors react
di erently to discrete, brie pulses o ACh than to neu-
rotransmitter that is present continuously. As noted above,
under normal conditions, a closed, resting-state channel
responds to dual ACh binding by opening transiently, and
the low a f nity o the receptor or ACh causes rapid disso-
ciation o ACh rom the receptor and return o the receptor
to its resting con ormation. In contrast, continuous exposure
 C h a p t e r 1 0 Cholinergic Pharmacology 131

TABLE 10-1 Characteristics of Cholinergic Receptor Subtypes

TYPICAL PROTOTYPE
RECEPTOR LOCATIONS RESPONSES MECHANISM PROTOTYPE AGONIST ANTAGONIST
Muscarinic M1 Autonomic ganglia Late excitatory Gq/11 PLC IP3 Oxotremorine Pirenzepine
postsynaptic DAG Ca 2
potential (EPSP) PKC
CNS Complex: at least arousal,
attention, analgesia

Muscarinic M2 Heart: SA node Slowed spontaneous subunit o Gi AF-DX 117

depolarization; inhibits AC;
hyperpolarization subunit o Gi
Heart: AV node Conduction velocity K channel (GIRK)
Heart: atrium Re ractory period; opening
contractile orce
Heart: ventricle Slight in contractility

Muscarinic M3 Smooth muscle Contraction As M1 Hexahydrosiladi enidol

Muscarinic M4 CNS As M2; presynaptic Himbacine

autoreceptors,
negative eedback
to suppress ACh
release

Muscarinic M5 CNS As M1

Nicotinic NM Skeletal muscle at End-plate depolarization; Opening o nAChR Phenyltrimethylammonium Tubocurare

neuromuscular skeletal muscle Na /K channels
junction (NMJ ) contraction

Nicotinic NN Autonomic ganglia Depolarization and f ring Opening o nAChR Dimethylphenylpiperazinium Trimethaphan
o postganglionic Na /K channels;
neuron postsynaptic
Adrenal medulla Secretion o depolarization
catecholamines and presynaptic
CNS Complex: at least interactions with
arousal, attention, other receptors,
analgesia calcium channels

Cholinergic receptors are divided into nicotinic and muscarinic receptors. All nicotinic receptors are ligand-gated cation-selective channels, while muscarinic receptors
are G protein-coupled receptors. Specif c pharmacologic agonists and antagonists exist or most subclasses, although the majority o these agents are currently used only
or experimental purposes.

o the receptor to ACh causes it to undergo a change to a
desensitized con ormation in which the channel is locked
closed. The desensitized state is also characterized by a
greatly increased a f nity o the receptor or ACh, so that
ACh remains bound to the receptor or a relatively long
period o time. This prolonged binding o ACh to the desen-
sitized con ormation delays the conversion o the receptor
to its resting state and hence prolongs the time during which
the receptor is incapable o being activated by agonist.
Nicotinic cholinergic receptors at autonomic ganglia and
in the central nervous system (termed N2 or NN) are similar
to receptors at the NMJ (N1 or NM), with the exception that
the subunits in NN receptors are composed solely o and
subunits. To complicate matters, however, nine di erent
subunit types ( 2 10) and three subunit types ( 2 4)
have been detected in neuronal tissues. ( 1 and 1 re er to the
distinct subunit types ound at the NMJ.) This diversity o
and subunit combinations is responsible or the variable
responses o CNS and autonomic nAChRs to pharmacologic
agents. Presynaptic nAChRs in the CNS modulate the release
both o ACh itsel and o other excitatory and inhibitory neu-
rotransmitters. This e ect may involve prolonged elevations
o [Ca2 ] in the presynaptic nerve terminals, which lead to
inactivation o neuronal calcium channels.
Degradation of Acetylcholine
In order or acetylcholine to be use ul or rapid, repeated
neurotransmission, there must be a mechanism to limit its
duration o action. Degradation o ACh is essential not only
to prevent unwanted activation o neighboring neurons or
muscle cells but also to ensure proper timing o signaling at
the postsynaptic cell. A single receptor molecule is typically
capable o distinguishing between two sequential presynap-
tic release events because degradation o ACh in the synaptic
cle t occurs aster than the time course o nAChR activation.
Enzymes collectively known as cholinesterases are re-
sponsible or degrading acetylcholine. The two types o
cholinesterase, AChE and butyrylcholinesterase (BuChE, also
known as pseudocholinesterase or nonspecif c cholinester-
ase), are distributed widely throughout the body. AChE is
indispensable or the degradation o ACh and is capable o
hydrolyzing about 4 105 molecules o ACh per enzyme
molecule per minute; its turnover time o 150 s makes it one
132 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

A Ove ra ll S tructure o the most e f cient hydrolytic enzymes known. AChE is con-
centrated on the postsynaptic membrane, and the choline that
it rees there is e f ciently transported back into the presyn-
N
M4 C
aptic terminal. BuChE has a secondary role in ACh degrada-
M1 tion; the enzyme can hydrolyze ACh but at rates much slower
than that o AChE. Evidence suggests that BuChE may be in-
volved in early neural development as a co-regulator o ACh
M3
and may also be involved in the pathogenesis o Alzheimers
M2
disease. Because o its central importance to cholinergic
transmission, a class o drugs known as acetylcholinesterase
inhibitors has been designed to target AChE.

Physiologic Effects of Cholinergic

Transmission
B Ace tylcholine Binding S ite Neuromuscular J unction
Acetylcholine is the principal neurotransmitter at the neuro-
Amino a cids muscular junction (Fig. 10-4). ACh is released by motor

neurons and it binds to nicotinic receptors in the muscle cell

membrane, resulting in motor end-plate depolarization. The

extent o depolarization depends on the quantity o ACh
Y W
released into the synaptic cle t. Release o ACh is quantal
W
ACh in nature; that is, ACh is released in discrete quantities by
binding s ite s Y
the presynaptic motor neuron. Each quantum o ACh cor-
N
Y responds to the contents o a single synaptic vesicle and
Y
C C
elicits a small depolarization in the motor end-plate termed
Ace tylcholine a miniature end-plate potential (MEPP). Under resting condi-
binding s ite tions, sporadic MEPPs are detected at the motor end-plate,
corresponding to a low baseline level o unstimulated ACh
C Ion Cha nne l release that arises rom spontaneous synaptic vesicle usion
M2 M2 with the motor axons presynaptic membrane. In contrast,
M2 M2 the arrival o an action potential at the motor axon terminal
causes many more vesicles (up to thousands) to use with the
neuronal membrane and release their ACh. At the motor end-
plate, the result is a relatively large depolarization termed the
M2 M2
M2 end-plate potential (EPP) (Fig. 10-5). The magnitude o an
Amino Le ucine EPP is more than su f cient to trigger an action potential that
a cids ring
propagates rom the end-plate throughout the muscle f ber
and, hence, produces a single contraction or twitch.
Acetylcholine not only triggers muscle contraction as its
primary effect at the NMJ, but also modulates its own action
at this site. Presynaptic cholinergic receptors, located on the
axon terminal o the motor neuron, respond to ACh binding
by facilitating the mobilization o synaptic vesicles rom the
reserve pool to the depot pool. This positive eedback loop,
FIGURE 10-2. Structural biology of the nicotinic acetylcholine receptor. in which the release o ACh stimulates additional ACh re-
A. Overall structure o the nicotinic acetylcholine receptor (NM type) and its lease, is necessary to ensure su f cient ACh release when the
f ve subunits ( 2 ). Each subunit is composed o a transmembrane pro- nerve is stimulated with high requency ( 100 Hz). Despite
tein that has our membrane-spanning (hydrophobic) alpha-helical regions this mechanism, the ACh output per nerve impulse wanes
(M1, M2, M3, M4). The large hydrophilic N-terminal domains o the two sub- rapidly during prolonged high- requency stimulation. Fortu-
units contain the binding sites or acetylcholine. B. Acetylcholine binding
nately, because an excess o ACh is released and an excess
site viewed rom above (inset: lower magnif cation). The labeled amino acids
o the subunit hydrophilic domain are particularly important in binding ace-
o ACh receptors is present, there is a large sa ety margin.
tylcholine. The con ormational change that results rom the binding o two Only when 50% or more o the postsynaptic receptors are
acetylcholine molecules opens the channel. C. The M2 domains o the f ve desensitized is a decline in muscle tension observed during
subunits all ace the interior o the protein and together orm the transmem- tetanic stimulation (a phenomenon known as tetanic fade ).
brane channel (inset). Three negatively charged rings o f ve amino acids Importantly, selective blockade o the modulatory presyn-
(one rom each M2 subunit) draw positively charged ions through the chan- aptic cholinergic receptors by antagonists such as hexame-
nel. At the center, an uncharged leucine ring (purple) participates in closing thonium prevents acilitation and causes rapid tetanic ade to
the ion channel when the receptor becomes desensitized to acetylcholine. occur under otherwise normal conditions (Fig. 10-6).

Autonomic Effects
Autonomic activity can be classif ed as either tonic activity,
which accounts or end organ stimulation at rest, or phasic
activity, which triggers an elevated response to changing
 C h a p t e r 1 0 Cholinergic Pharmacology 133

ACh

ACh ACh ACh

binding
s ite s
ACh ACh ACh ACh ACh

Re ce ptor ga te Re ce ptor ga te
(clos e d)
kon k'on (ope n)
2A + R A + AR A2 R A2 R *
koff k'off
FIGURE 10-3. Kinetics of nicotinic acetylcholine receptor binding and channel opening. Each transition between states o receptor binding and chan-
nel opening is completely reversible, and it is not necessary to go through all o the possible con ormations be ore returning to a given state. For example,
a receptor with two associated ligands may lose one and then gain another to return to its initial state, without the need or both ligands to dissociate.
A, agonist ligand (ACh); R, nicotinic ACh receptor (closed); R*, nicotinic ACh receptor (open); kon, rate constant or association (binding) o the f rst ACh
molecule to the receptor; kon, rate constant or association o the second ACh molecule to the receptor; ko , rate constant or dissociation o the f rst ACh
molecule rom the receptor; ko , rate constant or dissociation o the second ACh molecule rom the receptor; , rate constant o channel opening a ter
both ACh molecules have bound; , rate constant o channel closure. Note that channel opening and closing are much aster events than binding and dis-
sociation o ACh to the receptor, so that a receptor with two bound ACh molecules can open and close multiple times be ore one o the agonists dissociates.

conditions. Neurotransmission through autonomic ganglia
is complicated because several distinct receptor types con-
tribute to the complex changes observed in postganglionic
neurons. The generalized postsynaptic response to presynap-
tic impulses can be separated into our distinct components
(Fig. 10-7). The primary event in the postsynaptic gangli-
onic response is a rapid depolarization mediated by nico-
tinic ACh receptors in the cell membrane of postganglionic
neurons. The mechanism is similar to that in the NMJ, in
that an inward current elicits a near-immediate excitatory
postsynaptic potential (EPSP) o 1050 ms in duration.
Typically, the amplitude o such an EPSP is only a ew mil-
livolts, and many such events must sum or the postsynap-
tic cell membrane to reach the threshold or f ring an action
potential (Fig. 10-7A). The three remaining events o gan-
glionic transmission modulate this primary signal and are
known as the slow EPSP, the IPSP (inhibitory postsynaptic
potential), and the late, slow EPSP. The slow EPSP occurs
a ter a latency o 1 second and is mediated by M1 muscarinic
ACh receptors. The duration o this e ect is 1030 seconds
(Fig. 10-7C). The IPSP is largely a product o catecholamine
(i.e., dopamine and norepinephrine) stimulation o dopami-
nergic and -adrenergic receptors (see Chapter 11, Adrener-
gic Pharmacology), although some IPSPs in a ew ganglia
are mediated by M2 muscarinic receptors. The latency and
duration o the IPSPs generally vary between those o the
ast and slow EPSPs. The late, slow EPSP is mediated by
a decrease in potassium conductance induced by stimula-
tion o receptors or peptide transmitters (i.e., angiotensin,
substance P, and luteinizing hormone-releasing hormone).
Lasting or several minutes, the late, slow EPSP is thought
to have a role in the long-term regulation o postsynaptic
neuron sensitivity to repetitive depolarization.
One pharmacologic consequence o such a complex pat-
tern o depolarization in autonomic ganglia is that drugs
selective or the IPSP, slow EPSP, and late, slow EPSP are
generally not capable o eliminating ganglionic transmission.
Instead, such agents alter only the e f ciency o transmission.
For example, methacholine , a muscarinic receptor agonist,
has modulatory e ects on autonomic ganglia that resemble
the stimulation o slow EPSPs (see below). Blockade o
excitatory transmission through autonomic ganglia relies on
inhibition o the nAChRs that mediate ast EPSPs.
The overall effect of ganglionic blockade is complex and
depends on the relative predominance of sympathetic and
parasympathetic tone at the various end organs (Table 10-2).
For example, the heart is in uenced at rest primarily by the
parasympathetic system, whose tonic e ect is a slowing o
the heart rate. Thus, blockade o autonomic ganglia that in-
nervate the heart by moderate to high doses o the antimus-
carinic agent atropine results in blockade o vagal slowing
o the sinoatrial node and hence in relative tachycardia. (It
should be noted that in low doses, the central parasympa-
thetic stimulating e ects o atropine predominate, initially
resulting in bradycardia prior to its peripheral vagolytic ac-
tion.) Blood vessels, in contrast, are innervated only by the
sympathetic system. Because the normal e ect o sympa-
thetic stimulation is to cause vasoconstriction, ganglionic
blockade results in vasodilation. It is important to realize,
however, that the responses described above ignore the pres-
ence o muscarinic ACh receptors at many o the end organs.
When stimulated directly by cholinergic agents, such recep-
tors o ten mediate a response that overrides the response
produced by ganglionic blockade. In general, the expected
net cardiovascular e ects o muscarinic blockade produced
by clinical doses o atropine in a healthy adult with a nor-
mal hemodynamic state are mild tachycardia, with or with-
out ushing o the skin, and no pro ound e ect on blood
pressure.
The muscarinic receptor subtypes expressed in visceral
smooth muscle, cardiac muscle, secretory glands, and en-
dothelial cells mediate highly diverse responses to cholin-
ergic stimulation. These e ects are detailed in Table 10-3.
In general, these end-organ e ects tend to predominate over
134 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

ganglionic in uences. That is, or systemically administered

cholinergic agonists, the overall response is generally simi-
lar to that caused by direct stimulation o the postganglionic
e ector sites and o ten di erent rom that caused by gangli-
Ne uron onic stimulation alone.

CNS Effects
CNS unctions o ACh include modulation o sleep, wake ul-
Ne uromus cula r
ness, learning, and memory; suppression o pain at the spinal
junction cord level; and essential roles in neural plasticity, early neu-
ral development, immunosuppression, and epilepsy. Both
Mus cle fibe r nicotinic and muscarinic receptors are expressed in central
neurons. Nicotinic receptors are primarily involved as pre-
synaptic heteroreceptors that modulate the release o other
neurotransmitters, such as glutamate, whereas muscarinic
presynaptic receptors are primarily autoreceptors that mod-
ulate the release o ACh. While the past two decades have
improved understanding o the diversity o subunits and
Mye lin molecular properties o neuronal nicotinic receptors, impor-
tant questions remain about the anatomical distributions and
Axon End-pla te
S chwa nn ce ll re gion
unctional roles o di erent neuronal receptor subtypes in
s he a th the CNS and o their changes in disease states and during
nicotine abuse (as occurs with smoking).
As part o the ascending reticular activating system, cho-
linergic neurons play an important role in arousal and at-
tention (see Fig. 9-8). Levels o ACh throughout the brain
increase during wake ulness and REM sleep and decrease
P re s yna ptic during inattentive states and non-REM/slow-wave sleep
boutons S yna ptic
cle fts (SWS). During an awake or aroused state, cholinergic pro-
jections rom the pedunculopontine nucleus, the lateral teg-
mental nucleus, and the nucleus basalis o Meynert (NBM)
Mitochondria are all active. Because the NBM projects di usely through-
out the cortex and hippocampus (see Fig. 9-8), activation o
S yna ptic ve s icle (ACh) the NBM causes a global increase in ACh levels. Acetylcho-
line markedly potentiates the excitatory e ects o other in-
De ns e ba r (a ctive zone ) puts to its cortical target cells without a ecting the baseline
P re s yna ptic activity o these neurons, an e ect that likely derives rom
me mbra ne its modulation o excitatory neurotransmitter release. This
primed state is thought to improve the ability o such neu-
S yna ptic cle ft rons to process incoming inputs. For the brain as a whole,
the result is a heightened state o responsiveness.
P os ts yna ptic The cholinergic link to memory processes is supported
me mbra ne by evidence rom diverse experimental models. Whereas
elevated ACh levels during wake ulness appear to benef t
J unctiona l fold memory encoding processes, consolidation o hippocampus-
mediated, episodic, explicit memories benef t rom SWS,
when ACh levels are at their minimum. By artif cially keep-
ing ACh levels elevated during SWS (e.g., by administration
ACh Ace tylcholine s te ra s e s o an AChE inhibitor), consolidation o newly acquired ex-
re ce ptors plicit learning and episodic memories can be disrupted. Cur-
rent understanding o the interplay among ACh, sleep, and
FIGURE 10-4. The neuromuscular junction (NMJ ). At the neuromuscular memory is as ollows. During awake states, ACh prevents
junction, motor neurons innervate a group o muscle f bers. The area o inter erence with initial learning in the hippocampus by sup-
muscle f bers innervated by an individual motor neuron is re erred to as the pressing retrieval o previously stored memories (to prevent
end-plate region. Multiple presynaptic terminals extend rom the axon o the them rom inter ering with new encoding), but release o
motor neuron. When the motor neuron is depolarized, its synaptic vesicles this suppression is necessary to allow consolidation o new
use with the presynaptic membrane, releasing ACh into the synaptic cle t. memories. During sleep (in particular, during SWS), lower
ACh receptors o the neuromuscular junction are exclusively nicotinic, and ACh levels are required or proper consolidation o newly
stimulation o these receptors results in depolarization o the muscle cell
acquired memories because stronger excitatory eedback
membrane and generation o an end-plate potential.
transmission is needed to reactivate memories or consoli-
dation within neocortical brain areas. There ore, it may be
use ul to remember to sleep, as sleep is needed to remember,
or at least to remember better.
 Thre s hold pote ntia l Action pote ntia l Action pote ntia l

)
V
of pos ts yna ptic ce ll
m
(
l
a
i
t
0
Re s ting
n
e
pote ntia l
t
o
p
e
-55
n
a
r
b
-70
m
e
M
Q Q Q Q 2Q

A S ubthre s hold, B Te mpora l s umma tion C S pa tia l s umma tion

no s umma tion

FIGURE 10-5. Quantal release of acetylcholine and muscle contraction. Muscle contraction relies on the accumulation o a su f cient concentration o
acetylcholine at the motor end-plate to depolarize the muscle beyond the threshold potential (typically, about 55 mV). A ter local depolarization occurs,
a sel -propagating action potential is generated that can spread along the muscle f ber and result in muscle contraction. A. As a single cholinergic vesicle
releases its contents into the NMJ , a small depolarization (Q), otherwise known as a miniature end-plate potential (MEPP), occurs in the local region o the
muscle. This MEPP is insu f cient to generate an action potential. When a su f cient number o individual cholinergic vesicles empty their contents into the
NMJ , either in quick succession (B) or simultaneously (C), su f cient depolarization occurs (termed the end-plate potential, or EPP) that the motor end-plate
threshold or action potential generation is exceeded, and muscle contraction occurs. An isolated action potential produces a twitch, while a train o action
potentials may produce sustained contraction o the muscle. Note that although this example uses two MEPPs or simplicity, many more than two MEPPs
are actually required to achieve threshold-level depolarization. In this f gure, the x-axis is time.

A Fa s t EP S P

B IP S P
)
V
m
(
0.1 Hz 2 Hz 50 Hz 0.1 Hz
e
g
a
C S low EP S P
t
l
o
V
B

D La te , s low EP S P

S timulus 15 s e c 30 s e c 5 min
a pplie d
0.1 Hz 2 Hz 50 Hz 0.1 Hz Time

FIGURE 10-7. Four types of synaptic signals in an autonomic ganglion.

FIGURE 10-6. Tetanic fade and the effects of hexamethonium. A. Control
stimulation. Rapid stimulation o muscle contraction relies on presynaptic
acetylcholine autoreceptors that provide positive eedback and thereby
increase the amount o acetylcholine released with each depolarization.
The diagram shows control muscle responses to single-shock stimulation
(0.1 Hz), a train o our stimulations (2 Hz), or tetanic stimulation (50 Hz). Posi-
tive eedback increases the amount o ACh released with each depolariza-
tion during tetanic stimulation, providing enhanced muscle contraction that
gradually ades back to baseline during subsequent single-shock stimulation.
B. Stimulation a ter the administration o hexamethonium. Note that although
the response to isolated (0.1 Hz) stimuli is unchanged in the presence o
hexamethonium, the drug prevents the increased e ect that normally occurs
with higher requency (50 Hz) stimulation. This is a result o hexamethoniums
antagonism o the acetylcholine autoreceptor on the presynaptic terminal
that is normally responsible or positive eedback o ACh release.
The response o autonomic ganglia to neurotransmission is a complex
event mediated by a number o di erent neurotransmitters and receptor
types and occurring on several distinct time scales. A. The primary mode
o neurotransmission is the action potential, which is produced by a su -
f ciently strong (suprathreshold) excitatory postsynaptic potential (EPSP).
The ast EPSP is mediated by acetylcholine acting on postsynaptic nicotinic
ACh receptors. B. The inhibitory postsynaptic potential (IPSP) is a membrane
hyperpolarization response. This response is thought to be mediated by sev-
eral di erent postsynaptic receptor types, including modulatory dopamine
receptors and -adrenergic receptors as well as M2 muscarinic ACh re-
ceptors. C. The slow EPSP is mediated by M1 muscarinic receptors, has a
latency o about 1 second a ter an initial depolarization, and lasts or 1030
seconds. D. The late, slow EPSP occurs on the order o minutes a ter a de-
polarization event. This excitatory response may be mediated by peptides
that are co-released with acetylcholine.

135
136 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

gross cognitive de ects. These abnormal f ndings are also

TABLE 10-2 Effects of Autonomic Ganglionic Blockade observed in etal alcohol syndrome and Rett syndrome, both
on Tissues o which demonstrate dramatically reduced numbers o cho-
PREDOMINANT EFFECTS OF linergic neurons in the brain. There is also some evidence
SITE TONE GANGLIONIC BLOCKADE or an immunomodulatory role or ACh, as many cells o the
immune system both release ACh and express ACh recep-
Arterioles Sympathetic Vasodilation; peripheral tors. Finally, mutations have been identif ed in nicotinic ACh
(adrenergic) blood f ow; hypotension receptor genes that are responsible or autosomal dominant
Veins Sympathetic Vasodilation; pooling o
nocturnal rontal lobe epilepsy (ADNFLE); this milestone in
(adrenergic) blood; venous return; epilepsy research is the f rst demonstration that alterations in
cardiac output a ligand-gated ion channel can cause epilepsy.

Heart Parasympathetic Tachycardia The Non-Neuronal Cholinergic System (NNCS)

(cholinergic) Cells o various non-neuronal tissues and organs produce ACh
(non-neuronal ACh [NN-ACh]). NN-ACh acts in an auto-
Iris Parasympathetic Mydriasis (pupil dilation)
(cholinergic)
crine and paracrine ashion on nicotinic and muscarinic ACh
receptors that are expressed on neighboring ACh-producing
Ciliary muscle Parasympathetic Cycloplegia ( ocused to ar or e ector cells. The NNCS regulates physiologic processes
(cholinergic) vision) including cell growth, adhesion, migration, and di erentiation.
Dys unction o the NNCS may contribute to the pathogenesis
Gastrointestinal Parasympathetic Tone and motility;
o disease in several organ systems, including the skin (e.g.,
tract (cholinergic) constipation; secretions
atopic dermatitis, pemphigus, psoriasis, vitiligo) and the uri-
Urinary bladder Parasympathetic Urinary retention nary (e.g., overactive bladder syndrome), gastrointestinal (e.g.,
(cholinergic) gastroesophageal re ux disease, peptic ulcer disease, pancre-
atitis), immune (e.g., Sjogrens syndrome, rheumatoid arthritis,
Salivary glands Parasympathetic Xerostomia (dry mouth)
sepsis), pulmonary (e.g., asthma, chronic obstructive pulmo-
(cholinergic)
nary disease, cystic f brosis), musculoskeletal (e.g., osteopo-
Sweat glands Sympathetic Anhidrosis (absence o rosis, tendinosis), reproductive (e.g., sperm dysmotility), and
(cholinergic) sweating) cardiovascular systems (e.g., atherosclerosis). For some con-
ditions, anticholinergic drugs are already standard therapeu-
tic choices. However, or most organ systems, the role o the
NNCS remains to be urther delineated, and specif c therapeu-
The clinical importance o ACh or cognitive unction is tic interventions targeted at the NNCS remain to be developed.
illustrated by the pathophysiology and treatment o Alzheimers
disease (AD) and other neurodegenerative dementias, includ-
ing di use Lewy body dementia (DLB) and Parkinsons dis-
TABLE 10-3 Effects of Acetylcholine on Muscarinic
ease with dementia (PDD). Neurodegenerative dementias and
Receptors in Peripheral Tissues
brain injury produce central cholinergic dys unction. Patients
with these conditions mani est cognitive, unctional, and be- TISSUE EFFECTS OF ACETYLCHOLINE
havioral def cits that are at least partially related to cholinergic
def cits and amenable to symptomatic treatment with procho- Vasculature (endothelial cells) Release o nitric oxide and
linergic medications. An example is the symptomatic treat- vasodilation
ment o AD with acetylcholinesterase inhibitors. Eye iris (pupillae sphincter Contraction and miosis
Acetylcholine also plays a role in pain modulation through muscle)
inhibition o spinal nociceptive transmission. Cholinergic
neurons located in the rostral ventromedial medulla extend Ciliary muscle Contraction and accommodation o
processes to the superf cial lamina o the dorsal horn at all lens to near vision
levels o the spinal cord, where secondary neurons in a erent Salivary and lacrimal glands Thin and watery secretions
sensory pathways are located. ACh released by the choliner-
gic neurons is believed to bind to muscarinic ACh receptors Bronchi Constriction; secretions
located on secondary sensory neurons specif c or pain trans-
mission, resulting in suppression o action potential f ring in Heart Bradycardia, conduction velocity,
AV block at high doses, slight in
these cells and consequently in analgesia (see Chapter 18).
contractility
Clinically, the analgesic properties o ACh can be demon-
strated by injecting AChE inhibitors into the spinal uid. Gastrointestinal tract Tone, secretions; relaxation o
Acetylcholine has CNS e ects unrelated to its role as a sphincters
neurotransmitter. ACh has been observed to inhibit neurite
growth. During the early phases o neural development, when Urinary bladder Contraction o detrusor muscle;
relaxation o sphincter
such growth is essential, AChE levels are increased. The
presence o ACh in chick limb buds and myotomes suggests Sweat glands Diaphoresis
other, morphogenetic roles or this compound. Lesioning o
rat cholinergic neurons during development results in corti- Reproductive tract, male Erection
cal abnormalities, including aberrant growth and positioning Uterus Variable
o pyramidal cell dendrites, altered cortical connectivity, and

PHARMACOLOGIC CLASSES AND
AGENTS
Pharmacologic manipulation o cholinergic transmission has
met with only limited success because the complex actions
o ACh make it di f cult to obtain selective e ects. For ex-
ample, many cholinergic agents are capable o both stimulat-
ing and blocking cholinergic receptors through a mechanism
known as depolarizing blockade (see below). There ore,
only a relatively small raction o the many cholinergic and
anticholinergic agents discovered over the past century are
used in clinical practice. These drugs are used primarily or
(1) modulation o gastrointestinal motility, (2) xerostomia
(dry mouth), (3) glaucoma, (4) motion sickness and anti-
emesis, (5) neuromuscular diseases such as myasthenia gra-
vis and Eaton-Lambert syndrome, (6) acute neuromuscular
blockade and reversal during surgery, (7) ganglionic blockade
during aortic dissection, (8) dystonias (e.g., torticollis), head-
ache, and pain syndromes, (9) reversal o vagal-mediated
bradycardia, (10) mydriasis, (11) bronchodilation in chronic
obstructive pulmonary disease, (12) bladder spasms and uri-
nary incontinence, (13) cosmetic e ects on skin lines and
wrinkles, and (14) treatment o Alzheimers disease and other
neurodegenerative dementias.
Slight variations in the pharmacologic properties o
individual cholinergic and anticholinergic agents are re-
sponsible or their large di erences in therapeutic utility.
The relative selectivity o action o the most use ul agents
depends on both pharmacodynamic and pharmacokinetic
actors, including inherent di erences in receptor binding
a f nity, bioavailability, tissue localization, and resistance
to degradation. These variations, in turn, derive rom the
molecular structure and charge o the drug. The structure
o pirenzepine , or example, allows the drug to bind M1
muscarinic receptors (located in autonomic ganglia) with
higher a f nity than M2 and M3 receptors (located at para-
sympathetic end organs). As a result, the drugs predomi-
nant e ect at clinically used doses is ganglionic blockade
(see Table 10-1). Similarly, the addition o a methyl group
to acetylcholine yields methacholine , which is more resis-
tant to degradation by AChE and, hence, possesses a longer
duration o action. Charged agents such as muscarine gener-
ally do not cross membrane barriers. The absorption o such
drugs through both the gastrointestinal (GI) mucosa and the
bloodbrain barrier is signif cantly impaired, unless specif c
carriers are available to transport the drug; there ore, such
drugs typically have little or no e ect on the CNS. In con-
trast, lipophilic agents have excellent CNS penetration. As
one example, the high CNS penetration o physostigmine
makes this drug the agent o choice or treating the CNS
e ects o anticholinergic overdose.
The ollowing discussion is ordered mechanistically.
For each class o drugs, the selectivity o individual agents
within the class is used as a basis to explain the therapeutic
uses o each agent.
Inhibitors o Acetylcholine Synthesis,
Storage, and Release
Drugs that inhibit the synthesis, storage, or release o ACh
have only recently begun to have clinical use (Fig. 10-1).
Hemicholinium-3 blocks the high-a f nity transporter or
choline and thus prevents the uptake o choline required
or ACh synthesis. Vesamicol blocks the ACh-H antiporter
C h a p t e r 1 0 Cholinergic Pharmacology 137
that transports ACh into vesicles, thereby preventing the
storage o ACh. Both o these compounds are utilized only
in research settings, however. Botulinum toxin A, produced
by Clostridium botulinum, degrades SNAP-25 and thus
prevents synaptic vesicle usion with the axon terminal
(presynaptic) membrane. This paralysis-inducing property
is currently used in the treatment o several diseases associ-
ated with increased muscle tone, such as torticollis, achala-
sia, strabismus, blepharospasm, and other ocal dystonias.
Botulinum toxin is also approved or cosmetic treatment o
acial lines or wrinkles and is used to treat various headache
and pain syndromes (e.g., by intrathecal delivery into the
spinal uid). Because it degrades a protein common to the
synaptic vesicle usion machinery in multiple types o nerve
terminals, botulinum toxin has a general e ect on the release
o many di erent neurotransmitters, not just ACh.
Acetylcholinesterase Inhibitors
Agents in this class bind to and inhibit AChE, thereby in-
creasing the concentration o endogenously released ACh in
the synaptic cle t. The accumulated ACh subsequently acti-
vates nearby cholinergic receptors. Agents in this class are
also re erred to as indirectly acting ACh receptor agonists
because they generally do not activate receptors directly. It is
important to note that a ew AChE inhibitors have a direct
action as well. For example, neostigmine , a quaternary car-
bamate, not only blocks AChE but also binds to and activates
nAChRs at the neuromuscular junction.
Structural Classes
All indirectly acting cholinergic agonists inter ere with the
unction o AChE by binding to the active site o the enzyme.
There are three chemical classes o such agents, including
(1) simple alcohols with a quaternary ammonium group,
(2) carbamic acid esters o alcohols bearing either quaternary
or tertiary ammonium groups, and (3) organic derivatives o
phosphoric acid (Fig. 10-8). The most important unctional
di erence among these classes is pharmacokinetic.
Edrophonium is a simple alcohol that inhibits AChE by
reversibly associating with the active site o the enzyme.
Because o the noncovalent nature o the interaction between
the alcohol and AChE, the enzymeinhibitor complex lasts
or only 210 minutes, resulting in a relatively rapid but
completely reversible block.
The carbamic acid esters neostigmine and physostigmine
are hydrolyzed by AChE, so a labile covalent bond is ormed
between the drug and the enzyme. However, the rate at which
this reaction occurs is many orders of magnitude lower than
for ACh. The resulting enzymeinhibitor complex has a hal -
li e o approximately 1530 minutes, corresponding to an
e ective inhibition lasting 38 hours.
Organophosphates such as diisopropyl f uorophosphate
have a molecular structure that resembles the transition state
ormed in carboxyl ester hydrolysis. These compounds are
hydrolyzed by AChE, but the resulting phosphorylated en-
zyme complex is extremely stable and dissociates with a
hal -li e o hundreds o hours. Furthermore, the enzyme
organophosphate complex is subject to a process known
as aging, in which oxygenphosphorus bonds within the
inhibitor are broken spontaneously in avor o stronger bonds
between the enzyme and the inhibitor. Once aging occurs,
the duration o AChE inhibition is increased even urther.
Thus, organophosphate inhibition is essentially irreversible,
138 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

A Simple Alcohols B Carbamic Acid Esters C Organophosphates

N+ O
HO N O N+
P
O O
O F
Edrophonium Neostigmine Isoflurophate

H
N O
N
O
N

Physostigmine

FIGURE 10-8. Structural classes of acetylcholinesterase inhibitors. Acetylcholinesterase (AChE) inhibitors are divided into three structural classes.
A. Simple alcohols such as edrophonium have a short half-time of AChE inhibition. Edrophonium is used in the diagnosis of myasthenia gravis and other
diseases of the neuromuscular junction. B. Carbamic acid esters are hydrolyzed by AChE. This results in the formation of a covalent bond between the
carbamic acid ester (boxed) and AChE and a consequently long half-time of AChE inhibition. Neostigmine is used to treat myasthenia gravis and, during
or after surgery, to reverse paralysis induced by nicotinic acetylcholine receptor antagonists. Physostigmine, because it has good CNS penetration, is the
agent of choice for treating anticholinergic poisoning. C. Organophosphates form an extremely stable phosphoruscarbon bond with AChE. This results in
irreversible inactivation of AChE. As a result, many organophosphates are extremely toxic.

and the body must synthesize new AChE molecules to re-
store AChE activity. However, i strong nucleophiles (such
as pralidoxime ) are administered be ore aging has occurred,
it is possible to displace the organophosphate rom the inhib-
ited AChE and recover enzymatic unction.
Clinical Applications
Acetylcholinesterase inhibitors have a number o clinical ap-
plications, including (1) increasing transmission at the neu-
romuscular junction, (2) increasing parasympathetic tone,
and (3) increasing central cholinergic activity (e.g., to treat
symptoms o AD).
Because o their ability to increase the activity o en-
dogenous ACh, AChE inhibitors are especially use ul in
diseases o the neuromuscular junction, where the primary
de ect is an insu f cient quantity o either ACh or AChR. In
myasthenia gravis, autoantibodies are generated against NM
receptors. These antibodies both induce NM receptor inter-
nalization and block the ability o ACh to activate the re-
ceptors. As a result, patients with myasthenia gravis present
with signif cant weakness (recall the description o Chie
Opechancanough in the introductory case). Eaton-Lambert
syndrome is also characterized by muscle weakness, but this
disorder is caused by autoantibodies generated against Ca2
channels; both presynaptic Ca2 entry and the subsequent re-
lease o ACh in response to axon terminal depolarization are
attenuated. Certain anticholinergic drugs, such as tubocurare,
also cause weakness or paralysis by acting as competitive
antagonists at the nAChR, preventing ACh rom binding to
the receptor and causing nondepolarizing blockade o cho-
linergic transmission. Acetylcholinesterase inhibitors (such
as the physostigmine used in the introductory case) improve
all three o these conditions by increasing the concentration
o endogenously released ACh at the neuromuscular junction
and thereby increasing ACh signaling.
Because ACh binding to NM receptors results in mus-
cle cell depolarization, AChE inhibitors are ineffective at
reversing the action of agents that cause paralysis by in-
ducing sustained depolarization, such as succinylcholine
(see below). In act, AChE inhibitors in su f ciently high
doses can exacerbate existing weakness and paralysis caused
by depolarizing blockade. Thus, it is o undamental impor-
tance that the cause o the muscle weakness should be de-
termined be ore treatment is initiated. Short-acting AChE
inhibitors such as edrophonium are ideal or such diagnostic
purposes. Edrophonium mitigates weakness i the blockade is
attributable to competitive AChR antagonists or to diseases
such as myasthenia gravis or Eaton-Lambert syndrome. In
contrast, i muscle strength decreases urther with edropho-
nium administration, then depolarizing blockade may be
suspected. The short hal -li e o edrophonium ensures that
exacerbation o the latter condition will last or a minimal
amount o time. For chronic treatment o myasthenia gravis,
longer acting AChE inhibitors such as pyridostigmine , neo-
stigmine , and ambenonium are the pre erred agents.
AChE inhibitors exert other therapeutic e ects by po-
tentiating parasympathetic actions in target tissues. Topi-
cal application o AChE inhibitors to the cornea o the eye
decreases intraocular pressure by acilitating the out ow
o aqueous humor. The main e ect o AChE inhibitors
on the gastrointestinal system is an increase in smooth
muscle motility because o enhancement o ganglionic
transmission at Auerbachs plexus, although these agents
also cause increased secretion o gastric acid and saliva.
Neostigmine, the most popular drug or this application, is
typically used or relie o abdominal distention. The use
o anticholinesterases in reversing anticholinergic drug
poisoning is also well established. The agent o choice
or this indication is typically physostigmine ; its tertiary
amine structure allows it ready access to the brain and spi-
nal cord, where it can counteract the CNS e ects o anti-
cholinergic toxicity.
Acetylcholinesterase inhibitors are also used to treat the
symptoms o AD dementia and other conditions causing

TABLE 10-4 Pharmacokinetic and Mechanistic Characteristics of Donepezil, Rivastigmine, Rivastigmine Transdermal
Patch, Galantamine, and Galantamine ER
BIOAVAILABILITY
DRUG (%) TMAX (H)
Donepezil 100 35
Rivastigmine 40 0.81.8
Rivastigmine 5565 3.4
Patch
Galantamine 85100 0.51.5
Galantamine ER 85100 4.55
*Rivastigmine is a pseudo-irreversible inhibitor of AChE and BuChE.
Tmax, time to peak plasma concentration; AChE, acetylcholinesterase; BuChEI, butyrylcholinesterase inhibitor; nAChR agonist, allosteric (potentiating) ligand at some
nicotinic acetylcholine receptors in the CNS.
dementia (e.g., Parkinsons disease with dementia, di use
Lewy body dementia, vascular-ischemic dementia), brain in-
jury (e.g., traumatic brain injury), and cognitive impairment
(e.g., cognitive impairment associated with multiple sclerosis
and schizophrenia). Donepezil and rivastigmine are second-
generation AChE inhibitors indicated or the treatment
o AD dementia in the mild, moderate, and severe stages;
galantamine is a second-generation AChE inhibitor indicated
or the treatment o AD dementia in the mild and moderate
stages. Rivastigmine is also approved by the US Food and
Drug Administration (FDA) or the treatment o Parkinsons
disease with dementia. Tacrine is a f rst-generation AChE
inhibitor that is no longer in clinical useit had the disad-
vantage o our-times-daily dosing and it had the potential to
cause hepatic toxicity.
In both short-term (2452 weeks) e f cacy trials and
long-term clinical e ectiveness studies, these AChE inhibi-
tors have demonstrated benef cial e ects in producing im-
provement or stabilization o symptoms and in slowing the
progression o cognitive, unctional, and behavioral decline
in AD dementia. Although there are mechanistic and phar-
macokinetic di erences among these drugs (Table 10-4),
there are no signif cant di erences in their e f cacy in the
treatment o AD. For example, rivastigmine is a pseudo-
irreversible cholinesterase inhibitor because it orms a
labile carbamoylate complex with AChE (and BuChE), inac-
tivating the enzyme until the covalent bond is broken. While
rivastigmine is available as a twice-daily oral preparation, it
is now used mostly as a once-daily transdermal patch ormu-
lation. Galantamine is both a reversible AChE inhibitor and
an allosteric (potentiating) nicotinic receptor ligand. All o
these drugs exhibit linear pharmacokinetics, and their time
to peak plasma concentration (Tmax) values and elimination
hal -lives are prolonged in elderly patients.
With appropriately slow titration, these medications
are generally well tolerated and have a avorable adverse
e ect prof le (with the exception o tacrine, which is no
longer used clinically; see above). While these medica-
tions are relatively selective or AChE in the CNS, the most
common adverse e ectsincluding nausea, vomiting, an-
orexia, atulence, loose stools, diarrhea, and abdominal
crampingare related to peripheral cholinomimetic e ects
C h a p t e r 1 0 Cholinergic Pharmacology 139
OTHER
ELIMINATION HEPATIC REVERSIBLE CHOLINOMIMETIC
HALF-LIFE (H) METABOLISM INHIBITION OF AChE EFFECTS
6090 Yes Yes
2 No No* BuChEI
812 No No* BuChEI
58 Yes Yes nAChR agonist
2535 Yes Yes nAChR agonist
on the GI tract. The rivastigmine transdermal patch can also
cause skin irritation, redness, and rash at the site o applica-
tion. The adverse e ects o AChE inhibitors may occur in
520% o patients, are usually mild and transient, and are
related to the dose and rate o dose escalation. For the oral
preparations, the adverse GI e ects o AChE inhibitors can
be minimized by administering the drug a ter a meal or in
combination with memantine, an NMDA channel blocker
that is indicated or the treatment o moderate to severe AD.
For transdermal rivastigmine, adverse e ects can be mini-
mized by applying the patch to a di erent site each day.
These medications may also increase the risk o syncope,
particularly in susceptible individuals and with overdose.
Use o these agents is contraindicated in patients with un-
stable or severe cardiac disease (particularly cardiac ar-
rhythmias), uncontrolled epilepsy, unexplained or recurrent
syncope, or active peptic ulcer disease.
Receptor Agonists
All cholinergic receptor agonists bind to the ACh bind-
ing site o cholinergic receptors. Receptor agonists can be
divided into muscarinic and nicotinic receptor-selective
agents, although some cross-reactivity exists with virtually
all o these agents. Muscarinic receptor agonists are used
clinically in the diagnosis o asthma and as miotics (agents
that cause pupil constriction). Nicotinic receptor agonists are
used clinically or induction o muscle paralysis.
Muscarinic Receptor Agonists
Agents in this class are divided structurally into choline
esters and alkaloids (Fig. 10-9). The choline esters are
charged, highly hydrophilic molecules that are poorly
absorbed by the oral route and ine f ciently distributed to
the CNS. Choline esters include acetylcholine, methacho-
line, carbachol, and bethanechol (Table 10-5). Acetylcholine
is not administered in clinical settings because o its broad
actions and its extremely rapid hydrolysis by AChE and
pseudocholinesterase.
Methacholine is at least three times more resistant to
hydrolysis by AChE than is ACh. This agent is relatively
selective or cardiovascular muscarinic cholinergic re-
ceptors, and it has relatively little a f nity or nicotinic
140 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

[parasympathetic] stimulation, which typically includes

A Choline Esters B Alkaloids bradycardia, decreased contractility, and compensatory sym-
pathetic re exes). Currently, methacholine is used only in
the diagnosis o asthma; in this application, the bronchial
HO
O hyperreactivity that is characteristic o asthma causes an
N+ exaggerated bronchoconstriction response to parasympatho-
O N+ mimetics (see Chapter 48).
Ace tylcholine
O Both carbachol and bethanechol are resistant to cho-
Mus ca rine linesterases because, in these drugs, a carbamoyl group is
O substituted or the acetyl ester group o ACh (Fig. 10-9).
This resistance to AChE extends their duration o action
N+ and allows time or distribution o the intact drug to areas
O
N o lower blood ow. Carbachol has enhanced nicotinic ac-
O
Methacholine tivity relative to other choline esters. This agent cannot be
O N used systemically because its nicotinic action at autonomic
O ganglia leads to unpredictable responses. Instead, the agent
Pilocarpine is used principally as a topical miotic agent, typically in
N+
H2 N O the treatment o glaucoma. Local application o the drug to
the cornea o the eye results in both pupillary constriction
Carbachol (miosis) and decreased intraocular pressure.
Bethanechol is almost completely selective or musca-
O rinic receptors. It is an agent o choice or promoting GI and
urinary tract motility, particularly or postoperative, postpar-
N+ tum, and drug-related urinary retention and or hypotonic
H2 N O
neurogenic bladder.
Bethanechol In contrast to the choline esters, the alkaloids vary greatly
in structure. Some are amphipathic, while others are highly
charged. Most o these agents are tertiary amines, although
FIGURE 10-9. Structural classes of muscarinic receptor agonists. Mus- a ew are quaternary amines with protonated or permanently
carinic receptor agonists are divided into choline esters and alkaloids. charged nitrogens substituting or the choline-centered N o
A. Choline esters are charged molecules and therefore have little CNS
ACh. The amphipathic nature o the tertiary amine alkaloids
penetration. Methacholine is highly resistant to AChE and is used in the
diagnosis of asthma. Carbachol has both nicotinic and muscarinic recep-
permits absorption through the GI mucosa and penetration
tor activity; it is only used topically for treatment of glaucoma. Bethanechol into the CNS. Muscarine is an example o a quaternary
is highly selective for muscarinic receptors; it is used to promote GI and amine alkaloid that has low bioavailability because o its
bladder motility. Shown in blue are groups in the drug molecules that dif- permanently charged nature.
fer from acetylcholine. B. Alkaloids have highly variable structures; some Most alkaloids are primarily o value in pharmacologic
have excellent CNS penetration. Muscarine, the prototypical muscarinic research. The most clinically used alkaloid is pilocarpine , a
receptor agonist, is an alkaloid that is structurally similar to acetylcholine miotic agent and a sialagogue (saliva-inducing agent) used to
(boxed areas). Until recently, pilocarpine was the only alkaloid muscarinic treat xerostomia (dryness o the mouth secondary to reduced
receptor agonist used clinically. It is used to treat xerostomia (dry mouth) in salivary secretion). Cevimeline , an M1 and M3 agonist, is
patients with Sjgrens syndrome and postradiation syndromes. Cevimeline,
used to treat xerostomia in Sjgrens syndrome.
an M1 and M3 agonist, is also effective in xerostomia related to Sjgrens
syndrome (not shown).
Nicotinic Receptor Agonists
Succinylcholine is a choline ester that has high a f nity or
cholinergic receptors. Although methacholine can stimu- nicotinic receptors and is resistant to AChE. It is used to
late receptors expressed on cardiovascular tissues, the induce paralysis during surgery by means o depolarizing
magnitude o its response is unpredictable. This act has blockade . This e ect can be caused by any direct nAChR
limited its use as a vasodilator or cardiac vagomimetic (i.e., agonist because such drugs activate receptor-associated
a drug that mimics the cardiac response to vagus nerve channels and produce depolarization o the cell membrane.

TABLE 10-5 Relative Pharmacologic Properties of Choline Esters

SUSCEPTIBILITY CARDIAC URINARY EYE ACTIVITY ATROPINE NICOTINIC
ESTER TO AChE ACTIVITY GI ACTIVITY ACTIVITY (TOPICAL) ANTAGONISM ACTIVITY
Acetylcholine

Methacholine

Carbachol

Bethanechol

Note that all actions are mediated by muscarinic receptors, with the exception of nicotinic activity. indicates negligible activity. indicates unpredictable.
 C h a p t e r 1 0 Cholinergic Pharmacology 141

TABLE 10-6 Comparison of Nondepolarizing and Receptor Antagonists

Depolarizing NMJ -Blocking Agents Antagonists o AChRs act by binding directly to the agonist site
and competitively blocking stimulation o the receptor by en-
EFFECT NONDEPOLARIZING DEPOLARIZING dogenous ACh or exogenously administered receptor agonists.
Effect on motor Increased activation Partial; persisting
end-plate threshold to ACh; no depolarization
Muscarinic Receptor Antagonists
depolarization Anticholinergic compounds that act on muscarinic receptors
are used to produce a parasympatholytic e ect in target organs.
Initial excitatory None Transient By blocking normal cholinergic tone, these compounds allow
effect on muscle fasciculations sympathetic responses to predominate (Table 10-2). The most
commonly used anticholinergics are either naturally occurring
Muscle response to Poorly sustained Well-sustained
tetanic stimulation contraction contraction
alkaloids or synthetic quaternary ammonium compounds. The
during partial alkaloids are relatively selective or antagonist activity at mus-
block carinic receptors, whereas the synthetic compounds also dem-
onstrate substantial antagonism at nicotinic receptors.
Effect of previous Additive effect Antagonistic The prototypical muscarinic receptor antagonist is
administration of a effect atropine , a naturally occurring alkaloid ound in the plant At-
competitive NMJ - ropa belladonna, or deadly nightshade. Belladonna derived
blocking agent
its name rom Italian or beauti ul womanduring the Re-
Effect of previous No effect or No effect or naissance, women in Italy ingested or applied to their eyes
administration of a antagonistic effect additive effect extracts and juices o berries rom the plant to cause dilation
depolarizing NMJ - o the pupils, which was considered a mark o beauty. Atro-
blocking agent pine is used clinically to induce mydriasis (pupil dilation)
or ophthalmologic examinations, to reverse symptomatic
sinus bradycardia, to inhibit excessive salivation and mucus
In order to produce depolarizing blockade, the agent must secretion during surgery, to prevent vagal ref exes induced
persist at the neuromuscular junction and activate the nico- by surgical trauma o visceral organs, and to counteract the
tinic receptor channels continuously. Note that this e ect is e ects o muscarine poisoning rom certain mushrooms (see
unlike the depolarization pattern seen in the generation o Box 10-1). Because o its marginal activity at nicotinic re-
a standard action potential or end-plate potential, in which ceptors, extremely high doses o atropine are required or
ACh is present at the neuromuscular junction or only a brie any e ects to be seen at the NMJ. Similarly, because nico-
period o time. tinic receptors are primarily responsible or excitatory trans-
The overall pattern is a brie period o excitation, mani- mission at autonomic ganglia, atropine produces only partial
ested by widespread asciculations in muscle cells, ollowed block at these sites and only at relatively high doses.
by f accid paralysis. The paralysis occurs or two reasons. Scopolamine (hyoscine hydrobromide), a tertiary amine,
First, the open cholinergic channels maintain the cell mem- di ers rom atropine by virtue o its substantial CNS e ects.
brane in a depolarized state, e ecting inactivation o voltage- Scopolamine is requently used or the prevention and treat-
gated sodium channels so that they cannot open to support ment o motion sickness, as an antiemetic, and, in the hospice
urther action potentials. Second, the agonist-bound nAChRs setting, as an adjunct to end-o -li e com ort care medications
spontaneously desensitize, preventing their opening and re- to e ect mild sedation and management o oral secretions.
sponse to any subsequently delivered, additional agonist. Be- A transdermal patch system has been developed to e ect
cause o this mechanism, any nAChR agonist, including ACh, slow absorption and long duration o the anti-motion sick-
is capable o producing depolarizing blockade at su f ciently ness e ect while avoiding a rapid rise in plasma levels and
high concentrations. Generally, depolarizing blockade with adverse CNS e ects (e.g., anterograde disruption o novel
succinylcholine is used or only short durations because pro- learning and memory encoding, inattention, and slowing
longed depolarization can lead to li e-threatening electrolyte o psychomotor speed). Scopolamine can also be used to
imbalances (caused by prolonged Na inf ux and K e f ux). ameliorate nausea, particularly that associated with chemo-
Table 10-6 compares the e ects o depolarizing and nonde- therapy, and can be administered intravenously during pro-
polarizing NMJ-blocking agents. cedures in which minimizing oral secretions is desirable.
The concept o depolarizing blockade pertains to all Methscopolamine and glycopyrrolate are quaternary amine
cholinergic receptors and is not strictly limited to the NMJ. antimuscarinics with low CNS penetration that are used or
For example, this mechanism accounts or the paradoxical their peripheral e ects to decrease oral secretions, decrease
suppression o parasympathomimetic activity at autonomic GI spasms, and, in the case o glycopyrrolate, prevent brady-
ganglia by high levels o agonists, such as nicotine, that are cardia during surgical procedures. Both drugs have delayed
selective or nicotinic receptors. The potential or inducing but measurable CNS and cognitive anticholinergic e ects.
depolarizing blockade is partially responsible or the un- Pirenzepine , which is selective or M1 and M4 receptors, was
predictable e ects o nAChR agonists. Although musca- a potential alternative to H2 receptor antagonists in the treat-
rinic receptor agonists can also cause depolarizing blockade ment o peptic ulcer disease, but its use has been supplanted
at autonomic ganglia, this e ect is obscured by the over- by the advent o the proton pump inhibitors (see Chapter 47).
whelmingly parasympathomimetic responses seen at other Ipratropium, a synthetic quaternary ammonium com-
neuroe ector sites. pound, is more e ective than -adrenergic agonists in
The toxic e ects o cholinergic agents and poisons are the treatment o chronic obstructive pulmonary disease
described in Box 10-1. (COPD) but less e ective in treating asthma. Tiotropium has
142 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
B O X 1 0 - 1 Ch o lin e rg ic Toxicity
The toxic e ects o cholinergic agents are a unction o their
mechanism o action (e.g., muscarinic versus nicotinic stimula-
tion), dose and duration o exposure, route o absorption, CNS
penetration, and metabolism.
Muscarinic Cholinergic Toxicity
Acute toxicity with direct muscarinic agents is o ten due to inges-
tion o toxic mushrooms (e.g., mushrooms in the genus Inocybe)
and drugs such as pilocarpine. Adverse e ects o muscarinic
overstimulation typically mani est within 1530 minutes and in-
clude nausea, vomiting, diarrhea, sweating, hypersalivation,
cutaneous f ushing, ref ex tachycardia (sometimes bradycardia),
and bronchoconstriction. Intoxication with these agents can be
treated by competitive blockade using atropine.
Nicotinic Cholinergic Toxicity
Acute toxicity with nicotine, o ten due to ingestion o cigarettes
and insecticides, produces adverse e ects on the CNS, skeletal
muscle end-plate, and cardiovascular system. Acute nicotinic
toxicity can cause CNS hyperexcitation (seizures progressing
to coma and respiratory arrest), skeletal muscle depolarization
blockade (respiratory arrest), and cardiovascular abnormalities
(hypertension and arrhythmias). As little as 40 mg o nicotine
(equivalent to 1 mg o pure liquid nicotine, or the amount o nico-
tine ound in two regular cigarettes) can be atal, especially in
in ants. Treatment, including antiepileptic drugs and mechanical
ventilation, is dictated by symptoms. Atropine may be used to
counteract parasympathetic stimulation.
Cholinesterase Inhibitor Poisoning
Acute cholinesterase inhibitor toxicity is o ten due to exposure to
organophosphate pesticides. Such exposures remain an impor-
tant threat to children and those in the developing world. Initially,
similar, and possibly superior, e f cacy to ipratropium as a
bronchodilator in the treatment o COPD. The superior e f -
cacy o ipratropium and tiotropium in COPD is likely due to
the act that the major reversible bronchoconstrictive com-
ponent in COPD is mediated by cholinergic neural tone (see
Chapter 48). In poorly controlled asthma, the addition o
tiotropium to inhaled glucocorticoids and long-acting beta-
agonists may signif cantly increase the time to f rst severe
exacerbation and provide modest sustained bronchodilation.
Some antimuscarinic drugs are used in the treatment o
urinary incontinence and overactive bladder syndrome. Mus-
carinic stimulation promotes voiding by causing (1) detrusor
muscle contraction and (2) bladder trigone and sphincter
muscle relaxation. Antimuscarinics produce the opposite
e ects by promoting detrusor relaxation and tightening
the bladder sphincter. Antimuscarinics currently approved
or the treatment o overactive bladder include oxybu-
tynin, propantheline , terodiline , tolterodine , fesoterodine ,
trospium, darifenacin, and solifenacin. Among these agents,
oxybutynin, propantheline, tolterodine, esoterodine, and
trospium are nonspecif c muscarinic receptor antagonists,
whereas dari enacin and soli enacin are selective M3 receptor
signs o muscarinic toxicity predominate, including vomiting,
diarrhea, pro use sweating, hypersalivation, miosis, and bron-
choconstriction. Signs o nicotinic toxicity o ten ollow rapidly,
including con usion and seizures due to CNS hyperexcitation
and respiratory compromise due to depolarizing neuromuscular
blockade. Treatment includes emergency management o vital
signs (particularly maintaining respiratory integrity), decontami-
nation, symptomatic treatment with atropine, and pralidoxime
(PAM) administration to regenerate active enzyme rom the or-
ganophosphoruscholinesterase complex (mostly at skeletal
muscle neuromuscular junctions; PAM does not readily penetrate
the CNS). Time is o the essence to maximize the potential or re-
covery. Large doses o atropine may be necessary in some cases
(e.g., when toxicity is due to potent agents such as parathion and
chemical nerve agents); 12 mg o intravenous atropine is admin-
istered every 515 minutes until signs o e ect (such as reversal
o miosis and dry mouth) are noted and maintained. Repeated
administration o atropine may be required or hours or days, de-
pending on the elimination hal -li e o the organophosphate.
Examples o misuse o cholinergic chemical agents include
the use o Sarin nerve gas in the 1980s by Iraq against Kurdish
civilians and Iranian troops and in 1995 by a J apanese terrorist in
an attack on Tokyo subway passengers. Sarin, one o a class o
nerve agents known as G agents that also includes tabun and
soman, is a colorless and odorless gas with high toxic potency;
as little as 0.5 mg o Sarin is lethal or adults. Time is o the utmost
importance in recognizing an exposure, providing rapid decon-
tamination in accordance with hazmat protocols, and adminis-
tering atropine and pralidoxime. When exposure to nerve agents
can be expected, prophylaxis may be achieved with pyridostig-
mine or physostigmine (e.g., as prophylactically administered to
some US troops in the Gul War).
antagonists. These agents appear to have similar clinical e -
f cacy. Clinical trials suggest that tolterodine may cause less
dry mouth than oxybutynin and that the newer M3-selective
agents dari enacin and soli enacin may cause less dry mouth
and constipation than the nonselective agents.
Atropine, rom belladonna extract, was one o the drugs
f rst used to treat symptoms o Parkinsons disease (PD).
Antimuscarinics are still used at times to ameliorate tremor
and rigidity in patients with PD. These medications in-
clude amantadine , biperiden, benztropine , procyclidine , and
trihexyphenidyl. Although antimuscarinics may be help ul in
the treatment o PD-related tremor and rigidity, the use of
antimuscarinics in elderly and cognitively susceptible pa-
tients should be avoided because o the high risk o potential
adverse e ects (see Box 10-2). Benztropine and trihexyphe-
nidyl are commonly used to treat extrapyramidal symptoms,
dystonias, and akathisia associated with neuroleptics; these
adverse e ects are thought to be due to an imbalance be-
tween dopaminergic and cholinergic pathways secondary
to excessive neuroleptic-induced dopamine antagonism.
Trihexyphenidyl is also used to treat neuroleptic-induced
hypersalivation syndrome.
 C h a p t e r 1 0 Cholinergic Pharmacology 143

B O X 1 0 - 2 Po te n tia l Ad ve rs e Effe cts o f Dru g s w ith An tich o lin e rg ic Pro p e rtie s in Ge ria tric a n d
Co g n itive ly Im p a ire d Pa tie n ts

Drug-related anticholinergic adverse e ects are potentially

TABLE 10-7 Medications with Anticholinergic
hazardous to elderly patients, especially those with cognitive
Properties That Can Be Inappropriate for
impairment, and cause signif cant morbidity in this population.
Use by Cognitively Impaired Older Adults
Additive anticholinergic e ects rom medications can compro- (2012 AGS Beers Criteria)
mise the sa ety o geriatric patients because (1) many common
drugs possess at least a small measure o anticholinergic activity, Antihistamines Antiparkinson Antidepressants
Brompheniramine Agents Amitriptyline
(2) the elderly, and especially the cognitively impaired elderly,
Carbinoxamine Benztropine Amoxapine
are exquisitely sensitive to cholinergic blockade (due to central Chlorpheniramine Trihexyphenidyl Clomipramine
cholinergic hypo unction and dys unction in aging and dementia, Clemastine Desipramine
respectively), and (3) polypharmacy is a common practice in the Cyproheptadine Skeletal Muscle Doxepin
geriatric population. Adverse e ects rom anticholinergic drugs Dimenhydrinate Relaxants Imipramine
Diphenhydramine Carisoprodol Nortriptyline
in the elderly may include acute encephalopathy (delirium, con u-
Hydroxyzine Cyclobenzaprine Paroxetine
sional state), alls, urinary retention, constipation, and exacerba- Loratadine Orphenadrine Protriptyline
tion and decompensation o underlying cognitive, unctional, and Meclizine Tizanidine Trimipramine
behavioral def cits (particularly in patients with dementia) and
Antispasmodics Antipsychotics Antimuscarinics
may necessitate increased care and hospitalization. It should be
Atropine products Chlorpromazine (urinary
noted that many over-the-counter medications have anticholin- Belladonna Clozapine incontinence)
ergic e ects. For example, a common o ender in causing con- alkaloids Fluphenazine Dari enacin
usion and cognitive dys unction in the elderly and cognitively Dicyclomine Loxapine Fesoterodine
impaired individuals is diphenhydramine, an antihistamine with Homatropine Olanzapine Flavoxate
Hyoscyamine Perphenazine Oxybutynin
anticholinergic properties that is o ten used as a hypnotic either
products Pimozide Soli enacin
alone or in combination with acetaminophen. Clinicians and phar- Loperamide Prochlorperazine Tolterodine
macists should be vigilant to minimize polypharmacy in the geri- Propantheline Promethazine Trospium
atric population and to monitor and prevent medication-related Scopolamine Thioridazine
anticholinergic adverse events. The updated Beers Criteria o Thiothixene
Tri uoperazine
potentially inappropriate drugs or elderly patients identif es
medications (many with anticholinergic properties) and classes Adapted with permission rom The American Geriatrics Society. American
o medications, and specif c medications in patients with certain Geriatrics Society updated Beers Criteria or potentially inappropriate
medication use in older adults. J Am Geriatr Soc 2012;60:616631. doi:10.1111
conditions, that may pose greater potential risks than benef ts in /j.1532-5415.2012.03923.x.
persons older than 65 years o age. Particular caution must be
used with medications with strong anticholinergic e ects; these
include diphenhydramine, scopolamine, antimuscarinic agents
used or urinary incontinence, antispasmodics, skeletal muscle
relaxants, tricyclic antidepressants, and some antipsychotics
(Table 10-7).

Antimuscarinic toxicity causes substantial morbidity
and unctional impairment in the geriatric population (see
Box 10-2). Depending on the dose, antimuscarinic agents
such as atropine and scopolamine may cause bradycardia and
sedation at low to medium levels o muscarinic blockade, and
tachycardia and CNS hyperexcitation (with delirium, halluci-
nations, and seizures) at higher levels. Other adverse e ects
may include blurred vision (cycloplegia and mydriasis), dry
mouth, ileus, urinary retention, f ushing and ever, agitation,
and tachycardia. Antimuscarinic medications are contraindi-
cated in patients with glaucoma. Patients with angle-closure
glaucoma, which may be precipitated in individuals with
shallow anterior chambers, are especially at risk. Antimus-
carinics should also be used with caution in patients with
prostatic hypertrophy and in patients with dementia or cogni-
tive impairment. Antimuscarinic toxicity is considered dan-
gerous in in ants and children, who are exquisitely sensitive
to the hyperthermic adverse e ects caused by an overdose.
Symptomatic treatment may include controlled cooling and
antiepileptic drugs, but slow administration o low doses o
intravenous physostigmine may also be required.
High doses o quaternary antimuscarinics and short-
acting ganglionic blockers (such as trimethaphan) can cause
parasympathetic ganglionic toxicity, mani ested as auto-
nomic blockade and severe orthostatic hypotension. The an-
timuscarinic e ects may be treated with neostigmine, and
the hypotension may require treatment with sympathomi-
metics such as phenylephrine.
Nicotinic Receptor Antagonists
Selective nicotinic receptor antagonists are used primar-
ily to produce nondepolarizing (competitive) neuromuscu-
lar blockade during surgical procedures. Nondepolarizing
neuromuscular junction (NMJ) blockers, such as tubocurare ,
act by antagonizing nicotinic ACh receptors directly, thus
preventing binding o endogenously released ACh and
subsequent muscle cell depolarization. This leads to f ac-
cid paralysis that is similar in presentation to the paralysis
144 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
in myasthenia gravis. In selecting a specif c agent, the pri-
mary consideration is its duration o actionranging rom
very long-lasting agents (d-tubocurarine, pancuronium) to
intermediate-duration agents (vecuronium, rocuronium) to
rapidly degraded compounds (mivacurium). Because nico-
tinic receptors are expressed in autonomic ganglia as well as
the NMJ, nondepolarizing blocking agents o ten have vari-
able adverse e ects associated with ganglionic blockade.
Both the muscular paralysis and the autonomic blockade can
be reversed by administration o AChE inhibitors. A new
class o agents, epitomized by sugammadex, can also be
used to accelerate the recovery o blockade by vecuronium
and rocuronium. These agents act by chelating vecuronium
or rocuronium in an inactive complex, which is then slowly
cleared rom the circulation. Sugammadex is investigational
in the United States.
In special cases, compounds with relatively selective an-
tagonist activity at nAChRs can be used to induce autonomic
blockade. The e ects o autonomic ganglionic blockade are
discussed above and are listed in detail in Table 10-2. Most
commonly, mecamylamine and trimethaphan are administered
when ganglionic blockade is desired. The only current use or
these agents is to treat hypertension in patients with acute aortic
dissection, because the drugs lower blood pressure while si-
multaneously blunting the sympathetic re exes that would nor-
mally cause a deleterious rise in pressure at the site o the tear.
CONCLUSION AND FUTURE
DIRECTIONS
There are two major classes o cholinergic receptors: nico-
tinic and muscarinic. Nicotinic receptors are ligand-gated
channels that require the direct binding o two acetylcholine
molecules to open. These receptors comprise all o the cho-
linergic receptors at the neuromuscular junction (NM), and
they predominate at autonomic ganglia (NN). Thus, the pri-
mary cholinergic unctions mediated by nAChRs include
skeletal muscle contraction and autonomic activity. The pre-
dominant applications o pharmacologic agents directed at
nAChRs are (1) neuromuscular blockade, through competi-
tive antagonists and depolarizing blockers, and (2) ganglionic
blockade, which results in e ector organ responses that are
opposite to those produced by physiologic autonomic tone.
Muscarinic receptors are G protein-coupled receptors
that bind acetylcholine and initiate signaling through several
intracellular pathways. These receptors are expressed in the
autonomic ganglia and e ector organs, where they mediate
a parasympathetic response. The primary use o muscarinic
receptor agonists and antagonists is to modulate autonomic
responses o e ector organs. Both nicotinic and muscarinic
receptors are ubiquitous in the CNS, where the e ects o
acetylcholine include analgesia, arousal, and attention. The
relative roles o mAChRs and nAChRs in the brain and spi-
nal cord are not ully understood, and the most e ective cur-
rently available CNS drugs increase endogenous cholinergic
transmission by inhibiting the action o acetylcholinesterase,
the enzyme that hydrolyzes ACh.
Although cholinergic pharmacology is a relatively mature
f eld with several receptor-selective agents, the specif city
o action o the various agents continues to be ref ned. The
discovery o muscarinic receptor subtype diversity may lead
to the development o agents selective or subtypes that are
expressed in a tissue-specif c pattern. Similarly, elucidation
o the role o nicotinic receptor subunit diversity in the CNS
has spurred development o more selective agents that mod-
ulate the activity o these receptor subtypes. For example, a
selective partial agonist at the 7 nicotinic ACh receptor is
in late-stage clinical trial testing in AD dementia. Another
avenue or uture investigation involves positive allosteric
modulators o nicotinic receptors; these agents may aug-
ment endogenous cholinergic tone in a manner that is more
spatially and temporally specif c, thus potentially providing
di erential e f cacy and improved sa ety.
Acetylcholinesterase inhibitors are widely used in clinical
practice and are standard o care in the treatment o AD and
other dementias. They may provide short-term (612 month)
symptomatic benef ts in AD and, when used chronically,
slow clinical decline. Several nicotinic and muscarinic ago-
nists and receptor modulators are in clinical development
or the treatment o cognitive impairment, AD dementia,
neuropathic pain syndromes, and neuroprotection. Nicotinic
receptors may also provide targets or uture treatment ap-
proaches in epilepsy.
Finally, the physiologic and pathophysiologic roles o the
non-neuronal cholinergic system remain to be ully delin-
eated, and specif c therapies targeted at this system remain
to be developed.
Suggested Reading
Abirishami A, Ho J, Wong J, Yin L, Chung F. Sugammadex, a selective
reversal medication or preventing postoperative residual neuromuscular
blockade. Cochrane Database Syst Rev 2009;4:CD007362. (Reviews clini-
cal trials on the e ectiveness o sugammadex in postoperative recovery.)
Albuquerque EX, Pereira EFR, Alkondon M, Rogers SW. Mammalian
nicotinic acetylcholine receptors: rom structure to unction. Physiol Rev
2009;89:73120. (Excellent review o nAChR structure, gating, and physi-
ologic roles.)
Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and
e ectiveness o combination therapy in Alzheimer disease. Alzheimer Dis
Assoc Disord 2008;22:209221. (Assesses long-term clinical e ectiveness
o cholinergic and glutamatergic anti-AD medications in slowing the course
o AD dementia.)
Beckmann J, Lips KS. The non-neuronal cholinergic system in health and
disease. Pharmacology 2013;92:286302. (Reviews the non-neuronal cholin-
ergic system and its role in normal and pathologic processes and conditions.)
Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cho-
linergic mechanisms o the central nervous system. Ann Rev Pharmacol
Toxicol 2007;47:699729. (A thorough review o the nicotinic cholinergic
system, with many citations.)
Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly con-
trolled with standard combination therapy. N Engl J Med 2012;367:
11981207. (Replicate clinical trials demonstrating that the addition
o tiotropium to inhaled glucocorticoids and long-acting beta-agonists
signif cantly increases time to f rst severe exacerbation and provides
sustained bronchodilation in poorly controlled asthma.)
Marchi M, Grilli M. Presynaptic nicotinic receptors modulating neurotrans-
mitter release in the central nervous system: unctional interactions with
other coexisting receptors. Prog Neurobiol 2010;92:105111. (A brie and
readable review.)
Rountree SD, Atri A, Lopez OL, Doody RS. E ectiveness o antidemen-
tia drugs in delaying Alzheimers disease progression. Alzheimers Dement
2013;9:338345. (Reviews the evidence base or cholinergic and other
medications in AD dementia.)
Sher E, Chen Y, Sharples TJW, Broad LM. Physiological roles o neuronal
nicotinic receptor subtypes: new insights on the nicotinic modulation o neu-
rotransmitter release, synaptic transmission and plasticity. Curr Topics Med
Chem 2004;4:283297. (A thorough treatise on this important topic.)
Uteshev VV. The therapeutic promise o positive allosteric modulation
o nicotinic receptors. Eur J Pharmacol 2014;727:181185. (Reviews
theoretical and practical considerations or the role o positive allosteric
modulators o nicotinic ACh receptors.)
D R U G S U M M A R Y T A B L E : C H A P T E R 1 0 C hol i ne r gi c P ha r m a c ol ogy
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C h a p t e r 1 0 Cholinergic Pharmacology 145
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148 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
S
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C h a p t e r 1 0 Cholinergic Pharmacology 149
 Tyros ine
Na +
Tyross iinne
ne
Tyros
ro
o s in e h oxy
hydro xylyla
yl s e

Dihydr
D
Dih y oxyyphe
p nyly a laa nninn e
yl
Adre
A d ne rg iic (L-DOPA
P A)
ne uro n Aromaa ti
ttic

11
L-a minn o a cid
no
de ca rbo
booxxyla
la s e
Acttion
Act on pote ntia l
Dop mine
Dopa
VMAT
VMA
AT NE tra ns p o rte r

Na +

Adrenergic Pharmacology Ca 2+ H+ Dopa mine

NE
NE
Dopa mi
hyd
m inne
ydr
droxyla
dro x se
N
NE

N
NE
Nid h i Ge ra , Eh rin J . Arm s t ro n g , a n d David E. Go la n
2 (a uto
u re ce pt
p or) MAO
a ddr
dree ne rgic
i ree ce pt
pto
toorr NE
DOP GAL

INTRODUCTION & CASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150151 PHARMA

PHAR MACOLOGIC
OLO
OLOG
LOGIC
OG C CLASSES
CLAS SSES S AN
AND
A ND A AGEN
AGENTS
AGE E . . . . . . . . . . . . . . . . 156
BIOCHEMISTRY AND PHYS HYSIOLOGY Y OF In
nhihibbitors off CCatecholamine
chhol
olaa ine Synthesisynthe . . . . . . . . . . . . . . . . . . . 156
ADRENERG RG
GIC FUNCT
UNCTIO ION N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 150 Inhibiitors
S ynaptic
naptic rs of Ca
C techolamine min Storage torage . . . . . . . . . . . . . . . . . . . . 156
Cate
Ca te cholamine
h Synthesis, Storage, and Release . . . . . . . . . . 150 cle Inhibitors
f
ft of Catecholamin aminee Re Reup uupta
t kee . . . . . . . . . . . . . . . . . . . 158
Reuptake and Metabolism of Catecholami mine ness . . . . . . . . . . . . 153 Inhibitors of Catecholamine
ate chh
atech e Me
Meta
M
Met et
e ta bo
bolism m . . . . . . . . . . . . . . . . . 158
Catecholamine Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 Receptor Agonists iist
stss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
1- an
andd 2-A
Adr
dree noceptorss . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 -Adrenergi
renergic
ergic Ago Aggon
Agon onisists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
-Adrenoceptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 -A
-Adre
-Adr
Adren ner
ergi
gic Agon gonnis ts . . . ..1. . . . . . .
ists . . . . . . . . . . . . . . . . . . 159
1 2
Regulation of Recept p orr Res espopons nsee . . . . . . . . . . . . . . . . . . . . . . . 1555 Receptor
Re ec Antagonists . . . . . . . . . . . . . . . 159
P os ts
t yna ptic
p ti a ddre ne rgic i
Physiologic and Pharmacologic Effects of -Adrenergic Antagonists ptors . . . . . . . . . . . . . . . . . . . . . . 159
re ccee ptors
Endoggenenou
ouss Ca
Cate
tech
chol olam
amiines . . . . . . . . . . . . . . . . . . . . . . . . 155 -Adrenergic Antagoniists ts . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
1600
Poo s tss yynaptic
app tic c e lll
Epinephrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 CONCLUSION
C
CL AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . 161
Norepinephrinee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156 Suggested e
est
es Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .161
Dopaminee . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156

INTRODUCTION presents the biochemistry o catecholamine action, rom

Adrenergic pharmacology involves the study o agents that
act on pathways mediated by the endogenous catechol-
amines norepinephrine, epinephrine, and dopamine. The
sympathetic nervous system is the major source o endog-
enous catecholamine production and release. Signaling
through catecholamine receptors mediates diverse physi-
ologic e ects, including increasing the rate and orce o
cardiac contraction, modi ying the peripheral resistance o
the arterial system, inhibiting the release o insulin, stimu-
lating hepatic release o glucose, and increasing adipocyte
release o ree atty acids. Drugs that target the synthesis,
storage, reuptake, and metabolism o norepinephrine and
epinephrine or that directly target the postsynaptic receptors
or these transmitters are requent therapies or many major
diseases, including hypertension, shock, asthma, and angina.
This chapter examines the biochemical and physiologic
basis or adrenergic action and then discusses the action o
the di erent classes o adrenergic drugs.
BIOCHEMISTRY AND PHYSIOLOGY OF
ADRENERGIC FUNCTION
The autonomic nervous system contributes to homeostasis
through the concerted action o its sympathetic and para-
sympathetic branches. Catecholamines are the major e -
ectors o sympathetic signaling. The ollowing discussion
synthesis to metabolism to receptor activation. The physi-
ologic roles o the endogenous catecholamines epinephrine
(adrenaline), norepinephrine (noradrenaline), and dopamine
are then discussed, with emphasis on the specif city o recep-
tor expression in di erent organ systems.
Catecholamine Synthesis, Storage,
and Release
Catecholamines are synthesized by sequential chemical
modif cations o the amino acid tyrosine. This synthesis
occurs primarily at sympathetic nerve endings and in chro-
ma f n cells. Epinephrine is predominantly synthesized in
chroma f n cells o the adrenal medulla; sympathetic neurons
produce norepinephrine as their primary neurotransmitter
(Fig. 11-1). Tyrosine, the precursor or catecholamine syn-
thesis, is transported into neurons via an aromatic amino acid
transporter that uses the Na gradient across the neuronal
membrane to concentrate tyrosine (as well as phenylalanine,
tryptophan, and histidine). The f rst step in catecholamine
synthesis, the oxidation o tyrosine to dihydroxyphenylala-
nine (DOPA), is mediated by the enzyme tyrosine hydroxy-
lase (TH). TH is the rate-limiting enzyme in catecholamine
synthesis, and it is regulated by eedback (end-product)
inhibition and by kinase-mediated phosphorylation o the
enzyme. DOPA is converted to dopamine by a relatively
nonspecif c aromatic amino acid decarboxylase. Dopamine
is then hydroxylated by dopamine- -hydroxylase to yield

150

Th e ye a r is 1960. Ms . S h a s e lt d e -
p re s s e d o r a n u m b e r o ye a rs . S h e h a s
trie d s e ve ra l d i e re n t m e d ica tio n s to
a lle via te h e r e e lin g s o h o p e le s s n e s s
a n d la ck o m o tiva tio n , b u t n o th in g
s e e m s to h e lp . Re ce n tly, h o w e ve r, h e r d o cto r h a s
p re s crib e d ip ro n ia zid , a n e w m e d ica tio n re p o rte d to
b e o b e n e f t in m a ny ca s e s o d e p re s s io n . He te lls
h e r th a t s cie n tis ts b e lie ve th a t th e d ru g h a s b e n e f -
cia l e e cts in d e p re s s io n b y in h ib itin g a n e n zym e in
th e b ra in ca lle d m o n o a m in e o xid a s e (MAO). MAO
is o n e o th e e n zym e s re s p o n s ib le o r ca te ch o l-
a m in e d e g ra d a tio n , a n d its in h ib itio n s ig n if ca n tly
in cre a s e s th e a va ila b le co n ce n tra tio n s o ca te ch o l-
a m in e s . Be ca u s e ip ro n ia zid is a n e w d ru g , its p o -
te n tia l a d ve rs e e e cts a re n o t w e ll d e f n e d , s o h e r
d o cto r a d vis e s Ms . S to re p o rt a ny u n u s u a l e e cts
o th e m e d ica tio n .
Ho p e u l, b u t n o t e xp e ctin g s ig n if ca n t ch a n g e s ,
Ms . S ta ke s th e m e d ica tio n . With in a e w w e e ks ,
s h e b e g in s to e e l m o tiva te d a n d e n e rg e tic o r
th e f r s t tim e in 20 ye a r s . Exu b e ra n t a t h e r n e w
s e n s e o e n e rg y, Ms . S re cla im s h e r p a s t li e a s
a s o cia lite b y h o s tin g a g a la w in e a n d ch e e s e re -
ce p tio n . Th e b e s t a n d b rig h te s t o th e city tu rn u p ,
e xp e ctin g a f n e e ve n in g . As s h e s ta n d s u p to g ive
th a n ks to h e r a tte n d e e s , Ms . S ce le b ra te s w ith
norepinephrine. In tissues that produce epinephrine, norepi-
nephrine is then methylated on its amino group by phenyl-
ethanolamine N-methyltransferase (PNMT). Expression o
PNMT in the adrenal medulla is largely dependent on the
high concentrations o cortisol that ow into the medulla via
veins draining the adrenal cortex.
The conversions o tyrosine to DOPA and o DOPA to do-
pamine occur within the cytoplasm. Dopamine is transported
into synaptic vesicles by a 12-helix membrane-spanning
proton antiporter called the vesicular monoamine transporter
(VMAT). Unlike all the other enzymes in the catecholamine
biosynthesis pathways, dopamine- -hydroxylase is associ-
ated with the inner sur ace o secretory vesicles, and it cata-
lyzes the conversion o dopamine to norepinephrine inside
these vesicles.
There are three distinct vesicular transporters that di -
er in substrate specif city and localization. VMAT1 and
VMAT2 (also known as Uptake 2 [Fig. 11-2]) both transport
serotonin (5-HT), histamine, and all catecholamines. The
tissue-specif c expression o VMAT1 and VMAT2 is mutu-
ally exclusive: VMAT1 expression is restricted mainly to
nonneuronal cells (adrenal gland, gastric mucosa, intestine,
and sympathetic ganglia) and VMAT2 is expressed primar-
ily in the central nervous system (CNS). In addition to these
expression di erences, the a f nity o VMAT2 or histamine
(Km, 3 M) is signif cantly higher than that o VMAT1
or histamine (Km, 436 M). The vesicular acetylcholine
transporter (VAChT) is expressed in cholinergic neurons, in-
cluding motor nerves (see Chapter 10, Cholinergic Pharma-
cology). These antiporters use the proton gradient generated
C h a p t e r 1 1 Adrenergic Pharmacology 151
a la rg e s w ig o h e r a vo rite 1954 Ch ia n ti. By th e
e n d o th e p a rty, Ms . S h a s a s e ve re h e a d a ch e a n d
n a u s e a . Re ca llin g h e r d o cto r s w a rn in g , Ms . S h a s
a rie n d ru s h h e r to th e n e a re s t h o s p ita l. In th e
e m e rg e n cy d e p a rtm e n t, th e a tte n d in g p h ys icia n
re co rd s a b lo o d p re s s u re o 230/160 m m Hg . Re c-
o g n izin g th a t Ms . S is e xp e rie n cin g a h yp e rte n s ive
e m e rg e n cy, th e d o cto r a d m in is te rs p h e n to la m in e
(a n -a d re n o ce p to r a n ta g o n is t). Ms . S s b lo o d
p re s s u re q u ickly n o rm a lize s , a n d th e d o cto r s s u b -
s e q u e n t clin ica l in ve s tig a tio n id e n tif e s a n e w ,
a n d n o w a m o u s , d ru g o o d in te ra ctio n in vo lvin g
MAO in h ib ito rs . Th is p o te n tia l a d ve rs e in te ra ctio n
is s h a re d b y s o m e o th e r MAO in h ib ito r s ; m o re
re ce n t w o rk o n s u b typ e -s e le ctive a n d re ve r s ib le
MAO in h ib ito r s h a s m in im ize d th e in cid e n ce o
th is in te ra ctio n .
Questions
1 . Which enzymes metabolize catecholamines? What are
the specif cities o iso orms o these enzymes or the
various catecholamines?
2 . What is the mechanistic explanation or the interaction
o MAO inhibitors with red wine and aged cheese?
3 . How did phentolamine lower Ms. Ss blood pressure?
by a H -ATPase in the vesicular membrane to concentrate
dopamine (or, in the case o VAChT, acetylcholine) inside
the vesicle. Norepinephrine concentrations within the vesicle
can reach 100 mM. To stabilize the osmotic pressure result-
ing rom the high concentration gradient or norepinephrine
across the vesicle membrane, norepinephrine is thought to
condense with ATP. Consequently, ATP and norepinephrine
are co-released upon vesicle exocytosis.
In adrenal medullary cells, norepinephrine is transported
or di uses rom vesicles back into the cytoplasm, where
PNMT converts it to epinephrine. Epinephrine is then trans-
ported back into vesicles or storage until its eventual re-
lease by exocytosis. The nonselective nature o VMAT1 and
VMAT2 has important pharmacologic consequences, as dis-
cussed below.
Activation o the sympathetic nervous system and subse-
quent catecholamine release are initiated by signals originat-
ing in an array o processing areas in the CNS, especially
the limbic system. These CNS neurons project axons that
synapse on sympathetic preganglionic neurons in the inter-
mediolateral columns o the spinal cord. The preganglionic
axons project to the sympathetic ganglia. The preganglionic
neurons use acetylcholine as the neurotransmitter to activate
nicotinic acetylcholine (ACh) receptors, which are cation-
selective channels that depolarize the neuronal membrane
and thereby generate postsynaptic potentials in postgangli-
onic neurons. Ganglionic blockers such as hexamethonium
and mecamylamine block the ganglionic nicotinic ACh recep-
tor, without signif cant e ects on skeletal muscle ACh recep-
tors (see Chapter 10). The sympathetic postganglionic axons
152 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

Aroma tic L-a mino a cid A Norma l upta ke of nore pine phrine from s yna ptic cle ft a nd
tra ns porte r conce ntra tion of NE in s yna ptic ve s icle

Tyros ine Cytopla s m S yna ptic cle ft

+
Na
Tyrosine ATP H+ ADP
Tyros ine hydroxylase

Dihydroxyphe nyla la nine

VMAT
Adrenergic (L-DOPA) NE tra ns porte r
Aromatic H+
neuron NE (NET)
L-amino acid Na +
decarboxylase NE NE
Action pote ntia l NE

Dopa mine NE
NE
VMAT NE tra ns porte r NE NE

Na +
Ca 2+ H+ Dopa mine NE
Dopamine
hydroxylase B Coca ine inhibits NE tra ns porte r
NE

NE
ATP H+ ADP
2 (a utore ce ptor) MAO
a dre ne rgic re ce ptor NE Cocaine
DOP GAL
VMAT NET

NE
H+

NE NE NE

Synaptic NE NE
NE
cleft NE

1 1 2 C Re s e rpine inhibits VMAT

P os ts yna ptic a dre ne rgic
re ce ptors
Postsynaptic cell ATP H+ ADP

VMAT NET
Na +

FIGURE 11-1. Catecholamine synthesis, storage, release, and reuptake
pathways. The endogenous catecholamines dopamine, norepinephrine,
and epinephrine are all synthesized rom tyrosine. The rate-limiting step in
catecholamine synthesis, the oxidation o cytoplasmic tyrosine to dihydroxy-
phenylalanine (L-DOPA), is catalyzed by the enzyme tyrosine hydroxylase.
Aromatic L-amino acid decarboxylase then converts L-DOPA to dopamine.
Vesicular monoamine transporter (VMAT) translocates dopamine (and other
monoamines) into synaptic vesicles. In adrenergic neurons, intravesicular
dopamine- -hydroxylase converts dopamine to norepinephrine (NE). Nor-
epinephrine is then stored in the vesicle until release. In adrenal medul-
lary cells, norepinephrine returns to the cytosol, where phenylethanolamine
N-methyltrans erase (PNMT) converts norepinephrine to epinephrine.
The epinephrine is then transported back into the vesicle or storage (not
shown). -Methyltyrosine inhibits tyrosine hydroxylase, the rate-limiting en-
zyme in catecholamine synthesis (not shown). Released norepinephrine can
stimulate postsynaptic 1-, 1-, or 2-adrenergic receptors or presynaptic
2-adrenergic autoreceptors. Released norepinephrine can also be taken
up into presynaptic terminals by the selective NE transporter. NE in the cy-
toplasm o the presynaptic neuron can be urther taken up into synaptic
vesicles by VMAT (not shown) or degraded to 3,4-dihydroxyphenylglycoal-
dehyde (DOPGAL; see Fig. 11-3) by mitochondrion-associated monoamine
oxidase (MAO).
NE
NE
NE
NE
Reserpine
FIGURE 11-2. Mechanisms of action of cocaine and reserpine. A. Norepi-
nephrine (NE) that has been released into the synaptic cle t can be taken up
into the cytoplasm o the presynaptic neuron by the selective NE transporter
(NET), an Na -NE co-transporter. Cytoplasmic NE is concentrated in synap-
tic vesicles by the nonselective vesicular monoamine transporter (VMAT),
an H -monoamine antiporter. An H -ATPase uses the energy o ATP hy-
drolysis to concentrate protons in synaptic vesicles and thereby generates
a transmembrane H gradient. This H gradient is used by VMAT to drive
monoamine transport into the synaptic vesicle. B. Cocaine inhibits the NE
transporter, allowing released NE to remain in the synaptic cle t or a longer
period o time. By this mechanism, cocaine potentiates neurotransmission at
adrenergic synapses. C. Reserpine inhibits the vesicular monoamine trans-
porter, preventing the ref lling o synaptic vesicles with NE and eventually
depleting the adrenergic terminal o neurotransmitter. By this mechanism,
reserpine inhibits neurotransmission at adrenergic synapses.
 C h a p t e r 1 1 Adrenergic Pharmacology 153

orm varicosities or en passant connections with target or- Ne urotra ns mitte r

gans. The arrival o an action potential at these endings opens
voltage-gated neuronal Ca2 channels, and the ensuing Ca2 OH
HO NH2
in ux triggers exocytosis o the catecholamine-containing
Catechol-O-methyl Monoamine oxidase
synaptic vesicles. Various novel substancesincluding pep- transferase HO (MAO)
tides rom sea snailsblock these Ca2 channels; ziconotide (COMT) Nore pine phrine OH
is an example o a drug in this class that has e f cacy in the HO H
treatment o severe pain (see Chapter 18, Pharmacology o OH
O
Analgesia). Norepinephrine rapidly di uses away rom the O NH2 Aldehyde HO
DOP GAL
sympathetic nerve endings and locally regulates target tissue reductase
HO
responses (e.g., smooth muscle tone) by activating adrener- Norme ta ne phrine
Aldehyde
OH
gic receptors expressed on target tissues. (An exception is dehydrogenase
HO OH
that ACh is the transmitter used at sympathetic nerve end- OH
ings in sweat glands.) Importantly, adrenergic receptors are MAO
HO HO OH
also expressed at sympathetic nerve endings; these receptors OH DOP EG
O
may serve as an autoregulatory mechanism or modulating O H HO
the extent o neurotransmitter release. DOMA
O COMT
HO
MOP GAL Aldehyde
Reuptake and Metabolism of Catecholamines reductase OH
COMT

The action o a catecholamine molecule at its postsynaptic O OH

receptor is terminated by one o three mechanisms: (1) reup-
take o catecholamine into the presynaptic neuron, (2) me-
tabolism o catecholamine to an inactive metabolite, and
(3) di usion o the catecholamine away rom the synaptic
cle t. The f rst two o these mechanisms require specif c
transport proteins or enzymes and, there ore, are targets or
pharmacologic intervention.
Reuptake o catecholamine into the neuronal cytoplasm is
mediated by a selective catecholamine transporter (e.g., nor-
epinephrine transporter, or NET) that is also known as Uptake 1
(Fig. 11-2). Approximately 90% o the released norepineph-
rine is taken up by this process (recycled); the remainder is
either metabolized locally or di uses into the blood. Uptake 1
is a symporter that uses the inward Na gradient to concen-
trate catecholamines in the cytoplasm o sympathetic nerve
endings, thus limiting the postsynaptic response and allow-
ing neurons to recycle the transmitter or subsequent release.
Inside the nerve terminal, catecholamines can be urther con-
centrated in synaptic vesicles via VMAT, the same transporter
used to transport dopamine into the vesicle or catecholamine
synthesis. Thus, the pool of catecholamines available for re-
lease comes from two sources: molecules that are synthesized
de novo and molecules that are recycled via neuronal reuptake.
Catecholamine metabolism involves the two enzymes MAO
and catechol-O-methyltransferase (COMT) (Fig. 11-3). MAO is
a mitochondrial outer-membrane enzyme that is expressed in
most neurons. It exists in two iso orms: MAO-A and MAO-
B. The two iso orms have some degree o ligand specif city:
MAO-A pre erentially degrades serotonin, norepinephrine,
and dopamine, while MAO-B degrades dopamine more rap-
idly than serotonin and norepinephrine. As indicated in the
clinical case, MAO inhibitors are e f cacious in the treatment
o depression. The MAO-A iso orm is responsible or detoxi-
ying substances in cheese and wine be ore they reach the
general circulation. COMT is a cytosolic enzyme that is rela-
tively nonspecif c and is expressed primarily in the liver.
Catecholamine Receptors
Adrenergic receptors (also called adrenoceptors ) are selec-
tive or norepinephrine and epinephrine. Supraphysiologic
concentrations o dopamine can also activate some adreno-
ceptors. These receptors are divided into three main classes,
OH
O OH
HO
MOP EG
O
HO
Va nillylma nde lic
Aldehyde
a cid (VMA)
dehydrogenase
Ma jor me ta bolite
(e xcre te d in urine )
FIGURE 11-3. Norepinephrine metabolism. Norepinephrine is degraded to
metabolites by two main enzymes. Catechol-O-methyltransferase (COMT)
is a widely distributed cytosolic enzyme; COMT in the liver is particularly
important in the metabolism of circulating catecholamines. Monoamine
oxidase (MAO), which is localized to the outer surface of mitochondria,
is found in many monoaminergic (including adrenergic) neurons. COMT,
MAO, aldehyde reductase, and aldehyde dehydrogenase metabolize cat-
echolamines to multiple intermediates (abbreviated as DOPGAL, MOPGAL,
DOPEG, DOMA, and MOPEG) that are eventually excreted. Vanillylmandelic
acid (VMA) is the major metabolite excreted in urine.
termed 1, 2, and (Table 11-1). Each o these major
classes has three subtypes: 1A, 1B, and 1D; 2A, 2B, and
2C; and 1, 2, and 3. Each o the adrenergic receptor sub-
types is a member o the G protein-coupled receptor (GPCR)
super amily (also known as seven-transmembrane helix
receptors). GPCRs regulate complex intracellular signal-
ing networks through intermediate transducing molecules,
which are called G proteins because o their GTP binding
and hydrolysis activity. G proteins are heterotrimeric, with
, , and subunits. In the resting (inactive) state, G binds
guanosine 5 -diphosphate (GDP) and is associated with G .
Binding o agonist to the GPCR triggers the dissociation o
GDP and the binding o guanosine 5-triphosphate (GTP)
to the G subunit. GTP binding initiates a con ormational
change that leads to the dissociation o G and to the activa-
tion o G . Both G and G can activate downstream e ec-
tors. In mammals, at least 27 G , 5 G , and 13 G subtypes
are present, and downstream GPCR signaling depends on
the specif c G combination. On the basis o the primary
sequence o the G subunit, G proteins can be divided into
our major amiliesGs, Gi, Gq/11, and G12and each am-
ily o G subunit activates specif c downstream signaling
pathways (see Chapter 1, DrugReceptor Interactions).
154 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

TABLE 11-1 Adrenoceptor Actions

RECEPTOR SUBTYPE SIGNALING MEDIATORS TISSUE EFFECTS

1 Gq / Gi / Go Vascular smooth muscle Contraction

Genitourinary smooth muscle Contraction
Intestinal smooth muscle Relaxation
Heart Inotropy and excitability
Liver Glycogenolysis and gluconeogenesis

2 Gi / Go Pancreatic -cells Insulin secretion

Platelets Aggregation
Nerve Norepinephrine release
Vascular smooth muscle Contraction

1 Gs Heart Chronotropy and inotropy

Heart AV node conduction velocity
Renal juxtaglomerular cells Renin secretion

2 Gs Smooth muscle Relaxation

Liver Glycogenolysis and gluconeogenesis
Skeletal muscle Glycogenolysis and K uptake

3 Gs Adipose Lipolysis

1- and 2-Adrenoceptors
1-Receptors are expressed in vascular smooth muscle, gen-
itourinary tract smooth muscle, intestinal smooth muscle,
prostate, brain, heart, liver, and other cell types. The pro-
totypical signaling mechanism o 1-receptors involves
Gq/11, which is generally a stimulatory protein that activates
various e ectors including phospholipase C, phospholipase
D, phospholipase A2, Ca2 channels, K channels, Na /
H exchangers, several members o the mitogen-activated
protein (MAP) kinase pathways, and a variety o other
kinases including phosphatidylinositol 3-kinase. Phospho-
lipase C cleaves phosphatidylinositol-4,5-bisphosphate,
generating the two second messengers inositol trisphos-
phate (IP3) and diacylglycerol (DAG). IP3 acts to increase
intracellular [Ca2 ] via both release o endogenous Ca2
stores and in ux o Ca2 rom extracellular uid. Increased
intracellular [Ca2 ] activates various regulatory proteins that
mediate physiologic responses in various tissues. DAG ac-
tivates protein kinase C, which urther activates a variety o
protein substrates including ion channels such as Na /H
exchangers, Ca2 channels, and K channels. Phospholipase
D catalyses the hydrolysis o phosphatidylcholine to phos-
phatidic acid and choline. Phosphatidic acid may act directly
as a signaling molecule or be urther metabolized to DAG
by phosphatidic acid hydrolase. Gq/11-stimulated activation
o phospholipase A2 is mediated by increased intracellular
[Ca2 ] or by activation o protein kinase C and MAP kinase
pathways. The various 1-receptor subtypes likely di er in
their tissue-specif c localization and their capacity to acti-
vate downstream signaling pathways.
The downstream signaling pathways activated by 1-
receptors can be complex. Stimulation o 1-receptors in
vascular smooth muscle cells increases intracellular [Ca2 ],
leading to activation o calmodulin, phosphorylation o
myosin light chain, increased actinmyosin interaction, and
muscle contraction (see Chapter 22, Pharmacology o Vas-
cular Tone). There ore, 1-receptors are important in medi-
ating increases in peripheral vascular resistance, which can
increase blood pressure and redistribute blood ow. While
1-receptor antagonists would seem to be attractive in the
therapy o hypertension, their clinical e f cacy in preventing
the complications o hypertension is uncertain. 1-Receptor
activation also causes contraction o genitourinary smooth
muscle, and 1-receptor antagonists are clinically e f ca-
cious in the symptomatic treatment o benign prostatic hy-
perplasia (BPH) (see below).
2-Adrenoceptors activate Gi, an inhibitory G protein. Gi
has multiple signaling actions, including inhibition o ade-
nylyl cyclase (thus decreasing cAMP levels), activation o G
protein-coupled inward rectif er K channels (causing mem-
brane hyperpolarization), and inhibition o neuronal Ca2
channels. These e ects tend to decrease neurotransmitter
release rom the target neuron. 2-Receptors are ound on
both presynaptic neurons and postsynaptic cells. Presynap-
tic 2-receptors function as autoreceptors to mediate feed-
back inhibition of sympathetic transmission. 2-Receptors
are also expressed on platelets and pancreatic -cells, where
they mediate platelet aggregation and inhibit insulin release,
respectively. The latter observations have led to the develop-
ment o agents that are selective inhibitors o 2-receptors.
The main pharmacologic approach to 2-receptors, however,
has been in the treatment o hypertension. 2-Receptor ago-
nists act at CNS sites to decrease sympathetic out ow to the
periphery, resulting in decreased norepinephrine release at
sympathetic nerve terminals and, there ore, decreased vas-
cular smooth muscle contraction.
-Adrenoceptors
-Adrenoceptors are divided into three subclasses, termed 1,
2, and 3 (Table 11-1). All three subclasses activate a stim-
ulatory G protein, Gs. Gs activates adenylyl cyclase, which
catalyzes the ormation o intracellular cAMP rom adenosine
triphosphate (ATP). Increased intracellular cAMP activates
protein kinases, especially protein kinase A (PKA), by bind-
ing to the regulatory subunit o the enzyme. This results in the
release and activation o the catalytic subunit o PKA, which

phosphorylates and activates a variety o intracellular proteins
including ion channels and transcription actors. The nature o
the signaling di erences among the -adrenoceptor subtypes
is unclear since they all appear to couple e f ciently to Gs, and
stimulation o 1- and 2-adrenoceptors causes increased in-
tracellular cAMP. It has been suggested that specif city may be
con erred by di erences in the composition o the G protein
subunits associated with the two receptors. 1-Adrenoceptors
couple exclusively to Gs, but 2-adrenoceptors can also acti-
vate e ectors via coupling to Gi. Thus, 2-adrenoceptors can
limit and spatially restrict cAMP production by switching be-
tween Gs- and Gi-mediated signaling, which, in turn, a ects
PKA-dependent regulation o target proteins.
Pharmacologic selectivity among the -adrenoceptors
appears to reside in the tissue-selective distribution o each
-adrenoceptor subtype. 1-Adrenoceptors are localized pri-
marily in the kidney and heart. In the kidney, they are present
mainly on renal juxtaglomerular cells, where receptor acti-
vation causes renin release (see Chapter 21, Pharmacology
o Volume Regulation). Stimulation o cardiac 1-receptors
(which represent 7080% o all cardiac -adrenergic
receptors) causes an increase in both inotropy ( orce o con-
traction) and chronotropy (heart rate). The inotropic e ect is
mediated by increased phosphorylation o Ca2 channels by
protein kinase A, including calcium channels in the sarco-
lemma and phospholamban in the sarcoplasmic reticulum,
and by phosphorylation o troponin I and troponin C, which
reduces myof lament sensitivity to Ca2 (see Chapter 25,
Pharmacology o Cardiac Contractility). The increased chro-
notropy results rom a 1-mediated increase in the rate o
phase 4 depolarization o sinoatrial node pacemaker cells.
Both e ects contribute to increased cardiac output (recall
that cardiac output heart rate stroke volume). Activa-
tion o 1-receptors also increases conduction velocity in
the atrioventricular (AV) node because the 1-stimulated
increase in Ca2 entry increases the rate o depolarization
o AV node cells.
2-Adrenoceptors are expressed in smooth muscle
(including bronchial smooth muscle), liver, skeletal muscle,
and heart. In smooth muscle, receptor activation stimulates
Gs, adenylyl cyclase, cAMP, and protein kinase A. Pro-
tein kinase A phosphorylates several contractile proteins,
especially myosin light chain kinase. Phosphorylation o
myosin light chain kinase reduces its a f nity or calcium-
calmodulin, leading to relaxation o the contractile appa-
ratus. 2-Adrenoceptor activation may also relax bronchial
smooth muscle by Gs-independent activation o K channels.
Increased K e ux leads to bronchial smooth muscle cell
hyperpolarization and, there ore, opposes the depolarization
necessary to elicit contraction. In hepatocytes, activation o
the Gs signaling cascade initiates a series o intracellular
phosphorylation events that result in glycogen phosphory-
lase activation and glycogen catabolism. The result o 2-
adrenoceptor stimulation o hepatocytes is, there ore, an
increase in plasma glucose. In skeletal muscle, activation
o these same signaling pathways stimulates glycogenolysis
and promotes K uptake. Recent studies in cardiac myocytes
suggest that 2-adrenoceptor-mediated activation o the G
subunit o Gi leads to activation o phosphatidylinositide-3
kinase , which, in turn, activates the protein kinase B (also
known as Akt) pathway that con ers anti-apoptotic activity.
3-Adrenoceptors are expressed in adipose tissue and in
the gastrointestinal tract. Stimulation o 3-receptors leads to
C h a p t e r 1 1 Adrenergic Pharmacology 155
an increase in lipolysis and thermogenesis in adipocytes and
to a decrease in gastrointestinal tract motility. These physi-
ologic actions have led to speculation that 3-agonists may
be use ul in the treatment o obesity, noninsulin-dependent
diabetes mellitus, and other potential indications, but such
selective pharmacologic agents remain to be developed or
clinical use.
Regulation of Receptor Response
The ability o receptor agonists to initiate downstream sig-
naling is related to the number o receptors activated, and
changes in the density o receptors on the cell sur ace o ten
alter the apparent e f cacy o an agonist. Thus, both short-term
(desensitization) and long-term (down-regulation) changes in
the number o unctional adrenoceptors are important in regu-
lating tissue response (see Fig. 1-10).
When an agonist activates an adrenoceptor, the dissocia-
tion o its associated heterotrimeric G protein subunits leads
not only to downstream signaling, as discussed above, but
also to a negative eedback mechanism that limits tissue
responses. Activation o -adrenoceptors recruits GPCR-
specif c protein kinases (GRKs), which phosphorylate serine
and threonine residues in the carboxyl-terminal tail o the re-
ceptor. Protein kinase A and protein kinase C can also phos-
phorylate G protein-coupled receptors. The phosphorylated
state o the receptor promotes the translocation to the mem-
brane o a cytosolic protein called -arrestin, which binds
to the intracellular domain o the receptor and sterically in-
hibits interaction between the receptor and the G protein.
This e ectively silences receptor signaling. -Arrestins also
recruit clathrin and the clathrin adaptor protein AP2 to the
phosphorylated receptor, and this complex targets the adre-
noceptors to clathrin-coated pits. These pits are pinched o
rom the membrane with the help o the large GTPase dy-
namin, and the internalized receptors are then either rapidly
recycled, targeted to endosomes and recycled more slowly,
or degraded in lysosomes. Each o these processes is impor-
tant in regulating tissue responsiveness on a short- or long-
term basis. Over the last decade, evidence has suggested that
-arrestins can turn on (rather than o ) novel signaling path-
ways by serving as sca old proteins or signaling complexes
that promote G protein-independent pathways involving the
activation o Erk1/2, Src, and small GTP-binding proteins.
A newly discovered aspect o GPCR signaling is that some
antagonists that block G protein signaling pathways may also
unction as agonists in alternative signaling pathways such
as -arrestin signaling. In this way, both the desensitization/
down-regulation and the signaling roles or -arrestins may
be involved in physiologic and pathologic situations.
Physiologic and Pharmacologic Effects of
Endogenous Catecholamines
The endogenous catecholamines epinephrine and norepi-
nephrine act as agonists at both - and -adrenoceptors. At
supraphysiologic concentrations, dopamine can also act as
an agonist at - and -receptors. The overall e ect o each
catecholamine is complex and depends on the concentration
o the agent and on tissue-specif c receptor expression.
Epinephrine
Epinephrine is an agonist at both - and -adrenoceptors. At
low concentrations, epinephrine has predominantly 1 and 2
156 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
effects, while at higher concentrations, its 1 effects become
more pronounced. Acting at 1-receptors, epinephrine increases
cardiac contractile orce and cardiac output, with consequent
increases in cardiac oxygen consumption and systolic blood
pressure. Vasodilation mediated by 2-receptors causes a de-
crease in peripheral resistance and a decrease in diastolic blood
pressure. Stimulation o 2-receptors also increases blood ow
to skeletal muscle, relaxes bronchial smooth muscle, promotes
glycogenolysis, and increases the concentrations o glucose
and ree atty acids in the blood. Recent studies suggest that
1-receptors are responsible or vasodilation in large arteries
such as the emoral and pulmonary arteries, while 2-receptors
have a predominant role in vasodilation o the arterioles that
contribute to peripheral vascular resistance. These 1 and 2
e ects are all components o the f ght-or- ight response.
Epinephrine was used to treat acute asthmatic attacks
shortly a ter its discovery more than 100 years ago; other
drugs with higher selectivity or 2-receptors, and which are
delivered directly to pulmonary 2-receptors by inhalation,
are now more o ten used in the treatment o asthma, chronic
obstructive pulmonary disease, and other pulmonary condi-
tions. Epinephrine remains a drug o choice or the treat-
ment o anaphylaxis. Locally injected epinephrine causes
vasoconstriction and prolongs the action o local anesthetics;
or example, it is o ten used in combination with a local an-
esthetic in dentistry. It is ine ective orally due to extensive
f rst-pass metabolism. Epinephrine has a rapid onset and a
brie duration o action when injected intravenously. Ad-
verse consequences o rapid intravenous in usions include
increased cardiac excitability that may lead to cardiac ar-
rhythmias and excessive increases in blood pressure.
Norepinephrine
Norepinephrine is an agonist at 1- and 1-receptors but has
relatively little effect at 2-receptors. Because o the lack
o action at 2-receptors, systemic administration o norepi-
nephrine increases not only systolic blood pressure ( 1 e -
ect) but also diastolic blood pressure and total peripheral
resistance. Norepinephrine is used in the pharmacologic
treatment o hypotension in patients with distributive shock,
most requently due to sepsis.
Dopamine
Although dopamine is a prominent CNS neurotransmitter,
systemic administration has ew CNS e ects because it does
not readily cross the bloodbrain barrier. Dopamine activates
one or more subtypes o catecholamine receptor in peripheral
tissues, and the predominant e ect is dependent on the local
concentration o the compound. At low doses ( 2 g/kg per
min), a continuous intravenous in usion o dopamine acts
predominantly on D1 dopaminergic receptors in renal, mes-
enteric, and coronary vascular beds. D1 dopaminergic recep-
tors activate adenylyl cyclase in vascular smooth muscle cells,
leading to increased cAMP levels and vasodilation. At higher
rates o in usion (210 g/kg per min), dopamine is a positive
inotrope via its activation o 1-adrenergic receptors. At still
higher rates o in usion ( 10 g/kg per min), dopamine acts
on vascular 1-adrenergic receptors to cause vasoconstriction.
Dopamine is used in the treatment o shock, particularly
in states o shock caused by low cardiac output and accom-
panied by compromised renal unction leading to oliguria.
However, e f cacy in protecting the kidneys has not been
clearly demonstrated.
PHARMACOLOGIC CLASSES AND
AGENTS
Pharmacologic intervention is possible at each o the major
steps in catecholamine synthesis, storage, reuptake, metabo-
lism, and receptor activation. The ollowing discussion pre-
sents the various classes o agents in the order o their action
on adrenergic pathways, rom neurotransmitter synthesis to
receptor activation.
Inhibitors of Catecholamine Synthesis
Inhibitors o catecholamine synthesis have limited clinical
utility because such agents nonspecif cally inhibit the orma-
tion o all catecholamines (see Fig. 11-1). -Methyltyrosine
is a structural analogue o tyrosine that is transported into
nerve terminals, where it inhibits tyrosine hydroxylase, the
f rst enzyme in the catecholamine biosynthesis pathway.
This agent is used occasionally in the treatment o hyper-
tension associated with pheochromocytoma (a tumor o the
enterochroma f n cells o the adrenal medulla that produces
norepinephrine and epinephrine). Its clinical use is limited,
however, because it causes signif cant orthostatic hypoten-
sion and sedation, and many other antihypertensive drugs
with ewer adverse e ects are available or this indication.
Inhibitors of Catecholamine Storage
Catecholamines originate rom two poolsde novo syn-
thesis and recycled transmitter. An agent that inhibits cat-
echolamine storage in vesicles generally has two sequential
e ects. In the short term, the agent increases the net re-
lease o catecholamine rom the synaptic terminal, and thus
mimics sympathetic stimulation (sympathomimetic ). Over
a longer time period, however, the agent depletes the pool
o available catecholamine and thus acts as a sympatholytic
(inhibitor o sympathetic activity) (Fig. 11-4).
Reserpine binds tightly to the vesicular antiporter VMAT
at or very near the substrate-binding site on the cytoplasmic
sur ace o the transporter. Although the time course o bind-
ing is relatively slow, the tight binding results in irreversible
inhibition o the antiporter (see Figs. 11-1 and 11-2). VMAT
inhibition causes the secretory vesicles to lose their ability
to concentrate and store norepinephrine and dopamine. At
low doses, reserpine causes neurotransmitter to leak into the
cytoplasm, where the catecholamine is destroyed by MAO.
At high doses, the rate o transmitter leak can be su f ciently
high to overwhelm the MAO in the presynaptic neuron.
Under these conditions, there is a high concentration o
transmitter in the neuronal cytoplasm, and transmitter can
exit rom the cytoplasm to the synaptic space through NET
acting in reverse. The e ux o catecholamine has a transient
sympathomimetic e ect. Because reserpines inhibition o
VMAT is irreversible, new storage vesicles must be synthe-
sized and transported to the nerve terminal to restore proper
vesicular unction. The recovery phase may require days to
weeks a ter an individual stops taking reserpine. Reserpine
can also be used experimentally to assess whether drugs need
to be concentrated in presynaptic terminals to exert their ac-
tion. In the past, reserpine was used to treat hypertension.
However, the irreversible nature o its action and its asso-
ciation with severe depression make it an unattractive agent
now that more e f cacious and less toxic drugs are available
or the treatment o hypertension. Nonetheless, there has

A Acute e ffe ct of indire ct s ympa thomime tic
Cytopla s m S yna ptic cle ft
NE
NE
G VMAT NET
G NE NE
G NE NE
G NE
NE G NE NE
NE
MAO NE
Mitochondrion
DOP GAL
B Chronic e ffe ct of indire ct s ympa thomime tic
VMAT NET
G
G not elicit a postsynaptic response. In the past, guanethidine
G G NE
NE G NE
MAO
Mitochondrion DOP GAL
FIGURE 11-4. Acute and chronic effects of indirect sympathomimetics.
Indirect sympathomimetics have di erent e ects on sympathetic out-
f ow depending on whether they are administered acutely or chronically.
A. Administered acutely, an indirect sympathomimetic such as guanethidine
(G) displaces norepinephrine (NE) that is stored in the synaptic vesicles
o adrenergic neurons. This results in a massive e f ux o norepinephrine
through the NE transporter acting in reverse; the resultant f ooding o the
synapse with norepinephrine causes marked sympathetic stimulation.
B. Administered chronically, an indirect sympathomimetic such as guanethi-
dine (G) is concentrated in synaptic vesicles and replaces norepinephrine.
In addition, monoamine oxidase (MAO) degrades the small pool o norepi-
nephrine that remains in the cytoplasm. Both o these e ects contribute to
decreased sympathetic stimulation.
been some interest in the possibility that reserpine may be
a use ul drug or the treatment o hypertension when used
at doses lower than those associated with severe depression.
Tyramine is a dietary amine that is ordinarily metabo-
lized by MAO in the gastrointestinal tract and liver. In pa-
tients taking MAO inhibitors (MAOIs; see below), tyramine
is absorbed in the gut, transported through the blood, and
taken up by sympathetic neurons, where it is transported
into synaptic vesicles by VMAT. Uptake o tyramine by the
synaptic vesicles causes displacement o vesicular norepi-
nephrine and nonvesicular release o norepinephrine rom
the nerve terminal via reversal o NET. By this mechanism,
an acute challenge with large amounts o dietary tyramine,
or with modest dietary tyramine in patients taking MAOIs,
can cause acute and massive release o norepinephrine rom
nerve terminals. In turn, the massive norepinephrine release
C h a p t e r 1 1 Adrenergic Pharmacology 157
causes a pressor response with markedly elevated systolic
blood pressure. Fermented oods such as red wine and aged
cheese possess high concentrations o tyramine; this is why,
in the introductory case, Ms. S developed a hypertensive cri-
sis shortly a ter her wine and cheese party.
Although tyramine itsel is poorly retained in synap-
tic vesicles, its hydroxylated metabolite octopamine (the
synthesis o which is catalyzed by vesicular dopamine
-hydroxylase) can be stored at high concentrations in the
vesicles. Under conditions o chronic MAOI treatment and
modest dietary tyramine intake, norepinephrine may gradu-
ally be replaced by octopamine in storage vesicles. Because
octopamine has little agonist activity at most mammalian
adrenoceptors, postsynaptic responses to sympathetic stimu-
lation may gradually be diminished, leading ultimately to
postural hypotension. Migraine and cluster headaches have
been associated with elevated levels o circulating neu-
rotransmitters and neuromodulators, including tyramine and
octopamine.
Like tyramine, guanethidine is actively transported by
NET into neurons, where it concentrates in transmitter
vesicles and displaces norepinephrine, leading to gradual
depletion o norepinephrine (Fig. 11-4). Like octopamine,
guanethidine is not an agonist at postsynaptic adrenoceptors,
so its vesicular release upon sympathetic stimulation does
was used to treat uncontrolled hypertension. Guanethidine
inhibits cardiac sympathetic nerves, leading to reduced car-
diac output, and it blocks sympathetically mediated vaso-
constriction, leading to reduced cardiac preload. Inhibition
o these sympathetic responses by guanethidine can lead to
symptomatic hypotension ollowing exercise or standing up
(postural hypotension).
Guanadrel also acts as a alse neurotransmitter. As with
guanethidine, this agent can be used in the treatment o hy-
pertension, but it is no longer a f rst-line agent. The adverse
e ect prof le o guanadrel is similar to that o guanethidine.
Amphetamine has several adrenergic actions: (1) it dis-
places endogenous catecholamines rom storage vesicles
(similar to tyramine); (2) it is a weak inhibitor o MAO-A;
(3) it competitively inhibits catecholamine reuptake medi-
ated by NET and DAT; and (4) it is an agonist at the trace
amine-associated receptor 1 (TAAR1), a Gs/Gq coupled re-
ceptor on presynaptic neurons. Stimulation o TAAR1 by
amphetamine activates protein kinases A and C, causing
DAT phosphorylation and thereby noncompetitively inhib-
iting dopamine reuptake. Although amphetamine binds to
postsynaptic adrenergic receptors, the drug has little agonist
action at - or -adrenoceptors. Amphetamine has marked
behavioral e ects including increased alertness, decreased
atigue, depressed appetite, and insomnia. Thus, it has been
used to treat depression, attention-def cit hyperactivity dis-
order (ADHD), and narcolepsy (recurrent attacks o drowsi-
ness and sleep during the daytime) and to suppress appetite.
Its adverse e ects can be substantial, including atigue and
depression ollowing the period o central stimulation.
Ephedrine , pseudoephedrine , and phenylpropanolamine
are structurally related agents that have some capacity to
activate various adrenergic responses. Ephedrine has been
used medically or the treatment o persistent hypotension.
An herbal source o ephedrine (and various isomers) called
ma huang was used to treat asthma in China or at least
2,000 years. Pseudoephedrine is used as an over-the-counter
158 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY
decongestant and is ound in some cold remedies. Phenyl-
propanolamine was removed rom the over-the-counter mar-
ket in the United States due to concerns about an association
with cerebral hemorrhage.
Methylphenidate , a structural analogue o amphetamine,
is widely used in psychiatry to treat ADHD in children; its
major e ect is thought to be related to enhanced attention.
Amphetamine can cause psychological and physiologic
dependence as well as tolerance. Amphetamine may cause
paranoia and hallucinations. Methamphetamine (crank or
crystal meth) is a major drug o abuse. See Chapter 15,
Pharmacology o Serotonergic and Central Adrenergic Neu-
rotransmission, or more detailed discussion o the pharma-
cology o amphetamine and related drugs.
Inhibitors of Catecholamine Reuptake
Inhibitors o catecholamine reuptake can exert an acute and
power ul sympathomimetic e ect by prolonging the time
that released neurotransmitter remains in the synaptic cle t.
Cocaine is a potent inhibitor o NET; unlike other uptake
inhibitors (such as imipramine and uoxetine), cocaine es-
sentially eliminates catecholamine transport (see Fig. 11-2).
It is used occasionally as a local anesthetic because o its
independent activity as an inhibitor o neuronal action po-
tentials (see Chapter 12, Local Anesthetic Pharmacology); in
addition, in this setting, cocaine promotes vasoconstriction
due to its capacity to inhibit norepinephrine uptake. Cocaine
is a controlled substance with high abuse potential. It is a
major public health concern because o its role as an agent
o abuse (see Chapter 19, Pharmacology o Drugs o Abuse).
Tricyclic antidepressants (TCAs) and serotonin-norepi-
nephrine reuptake inhibitors (SNRIs) inhibit NET-mediated
reuptake o norepinephrine into presynaptic terminals and
thus promote accumulation o norepinephrine in the synap-
tic cle t. Because o their important role in the treatment o
depression, TCAs, SNRIs, and other inhibitors o norepi-
nephrine reuptake are discussed in more detail in Chapter 15.
Inhibitors of Catecholamine Metabolism
Monoamine oxidase inhibitors (MAOIs) prevent secondary
deamination o catecholamines that are transported into
presynaptic terminals or taken up into tissues such as the
liver. In the absence o metabolism, more catecholamine
accumulates in presynaptic vesicles or release during each
action potential. Most MAOIs are oxidized by MAO to reac-
tive intermediates, which then act as irreversible inhibitors
o MAO. Nonselective agents in this class (i.e., agents that
inhibit both MAO-A and MAO-B) include tranylcypromine ,
phenelzine , and iproniazid (the drug used in the introductory
case; this drug was later withdrawn rom the market in the
United States and some other countries). Selective inhibi-
tors include clorgyline , which is selective or MAO-A, and
selegiline and rasagiline , which are selective or MAO-B.
Moclobemide is a reversible inhibitor o MAO-A.
As with the tricyclic antidepressants, MAOIs are used to
treat depression. Selegiline and rasagiline are also approved
or the treatment o Parkinsons disease; their mechanism
o action may include both potentiation o dopamine in
the remaining nigrostriatal neurons and decreased orma-
tion o neurotoxic intermediates. As noted above, patients
taking MAOIs should avoid eating certain ermented or
aged oods containing large amounts o tyramine and other
monoamines, such as most cheeses and some f shes, poultry,
bee , and wines, because MAOIs block oxidative deamina-
tion o these monoamines in the gastrointestinal tract and
liver, allowing them to enter the circulation and precipitate
a hypertensive crisis. Concomitant use o MAOIs and selec-
tive serotonin reuptake inhibitors (SSRIs) or SNRIs is also
contraindicated, because this may precipitate the serotonin
syndrome . This syndrome is characterized by agitation, rest-
lessness, tremors, seizures, tachycardia, hypertension, and
possibly coma and death. Serotonin syndrome may also
occur with concomitant use o MAOIs and other drugs, such
as meperidine, tramadol, and amphetamine. The reversible
inhibitors o MAO-A may be less prone to adverse e ects
and drug interactions. MAOIs and SSRIs are also discussed
in Chapter 14, Pharmacology o Dopaminergic Neurotrans-
mission, and Chapter 15.
Receptor Agonists
Because adrenoceptors are important in mediating vascular
tone, smooth muscle tone, and cardiac contractility, selective
agonists and antagonists o these receptors are mainstays o
therapy or hypertension, asthma, ischemic heart disease,
heart ailure, and other conditions. In the ollowing discus-
sion, the agents are organized according to receptor subtype
specif city (see Table 11-1 or an overview o the relevant
receptor subtypes).
-Adrenergic Agonists
The 1-selective adrenergic agonists increase peripheral vas-
cular resistance and thereby maintain or elevate blood pres-
sure. These drugs may also cause sinus bradycardia through
activation o re ex vagal responses mediated by barorecep-
tors. Systemically administered 1-agonists, such as methox-
amine , have limited clinical use but are sometimes employed
to increase blood pressure in the treatment o shock. A num-
ber o topically administered 1-agonists, such as phenyl-
ephrine , oxymetazoline , and tetrahydrozoline , are used in the
nonprescription remedies A rin and Visine (and others) to
constrict vascular smooth muscle in the symptomatic relie
o nasal congestion and ophthalmic hyperemia. Oxymetazo-
line is also a partial agonist at 2-receptors. Damage to the
nasal mucosa and possible rebound hypersensitivity and re-
turn o symptoms o ten accompany extended use o these
medications. Phenylephrine is also used intravenously in the
treatment o distributive shock.
Clonidine is an 2-receptor agonist that lowers blood pres-
sure and decreases heart rate by acting in brainstem vasomo-
tor centers to suppress sympathetic out ow to the periphery.
Evidence supporting its capacity to decrease adverse cardio-
vascular outcomes in patients with hypertension is limited.
Clonidine has limited utility in ameliorating symptoms o
withdrawal rom ethanol and opioid drugs. Adverse e ects
include bradycardia caused by decreased sympathetic activ-
ity and increased vagal activity, as well as dry mouth and
sedation. Because sympathetic nervous system activation is
an important mechanism in maintaining blood pressure on
standing, postural hypotension may also complicate therapy
with this drug. Other centrally acting 2-agonists include the
seldom-used agents guanabenz and guanfacine . These agents
have adverse e ect prof les similar to that o clonidine.
Dexmedetomidine is an 2-receptor agonist whose capac-
ity to cause sedation has been exploited as a benef cial e ect

in surgical patients, because sedation is induced by this drug
without additional respiratory depression. Suppression o
sympathetic nervous system activity by dexmedetomidine
helps to avoid swings in blood pressure in surgical patients,
who are care ully monitored by anesthetists during surgical
procedures. Dexmedetomidine may also possess analgesic
properties. Note that the 2-mediated e ects o sedation and
decreased sympathetic activity are adverse e ects o cloni-
dine in the setting o outpatient treatment or hypertension
but benef cial e ects o dexmedetomidine in the controlled
setting o the surgical patient.
-Methyldopa is a precursor (prodrug) to the 2-agonist
-methylnorepinephrine. Dopamine -hydroxylase cata-
lyzes the metabolism o methyldopa to methylnorepineph-
rine, and the -methylnorepinephrine is then released by the
adrenergic nerve terminal, where it can act presynaptically
as an 2-agonist. This action results in decreased sympa-
thetic out ow rom the CNS and consequent lowering o
blood pressure in hypertensive patients. Methyldopa is also
a competitive inhibitor o DOPA decarboxylase, which con-
verts DOPA to dopamine, and thereby reduces adrenergic
neurotransmission in the peripheral nervous system. Be-
cause -methyldopa use can be associated with rare hepa-
totoxicity, autoimmune hemolytic anemia, and adverse CNS
e ects, this drug is very rarely used in the treatment o hy-
pertension in the United States, with one exceptionthere
is considerable experience with methyldopa as an antihyper-
tensive drug in pregnancy, and it is still used as a pre erred
drug in that context.
-Adrenergic Agonists
Stimulation o 1-adrenergic receptors causes increases in
the heart rate and the orce o cardiac muscle contraction,
resulting in increased cardiac output, while stimulation o
2-adrenergic receptors causes relaxation o vascular, bron-
chial, and gastrointestinal smooth muscle. Isoproterenol is
a nonselective -agonist. This drug lowers peripheral vas-
cular resistance and diastolic blood pressure (a 2 e ect),
while systolic blood pressure remains unchanged or slightly
increased (a 1 e ect). Because isoproterenol is a positive
inotrope (increases cardiac contractility) and chronotrope
(increases heart rate), cardiac output is increased. Isoproter-
enol can be used to relieve bronchoconstriction in asthma
( 2 e ect). However, because isoproterenol is a nonselective
activator o 1- and 2-adrenoceptors, its use or relie o
bronchoconstriction is o ten accompanied by adverse car-
diac e ects. Use o this drug in asthma has there ore been
supplanted by newer 2-selective agonists (see below). Iso-
proterenol may occasionally be used to increase the heart
rate in emergency situations o pro ound bradycardia, typi-
cally in anticipation o the placement o an electrical cardiac
pacemaker.
The overall e ect o dobutamine depends on the di -
erential e ects o the two stereoisomers contained in the
racemic mixture (see Chapter 1 or a discussion o stereo-
isomers). The ( ) isomer acts as both an 1-agonist and a
weak 1-agonist, whereas the ( ) isomer acts as both an
1-antagonist and a potent 1-agonist. The 1-agonist and
antagonist properties e ectively cancel each other out when
the racemic mixture is administered, and the observed clini-
cal result is that o a selective 1-agonist. This agent has more
prominent inotropic than chronotropic e ects, resulting in
increased contractility and cardiac output. Dobutamine can
C h a p t e r 1 1 Adrenergic Pharmacology 159
be used intravenously in the urgent treatment o severe heart
ailure. It is also used as a diagnostic agent, in conjunction
with imaging o the heart, in the investigation o ischemic
heart disease.
2-Selective agonists are valuable in the treatment o
asthma. These drugs represent pharmacologic improvements
over epinephrine (an agonist at all adrenergic receptors) and
isoproterenol (an agonist at 1- as well as 2-receptors) in
that their e ects are more limited at nontarget tissues. It is
particularly important that these selective drugs have lim-
ited capacity to stimulate 1-adrenoceptors in the heart and,
there ore, limited capacity to produce adverse cardiac e -
ects. Specif city or the lung rather than the heart or other
peripheral tissues has been urther enhanced by generally
delivering these drugs via aerosols inhaled into the lungs.
Administration o the drugs directly into the lungs lowers
the amount o drug that reaches the systemic circulation,
again limiting the activation o cardiac 1-receptors and
skeletal muscle 2-receptors. The most important e ects o
these agents are relaxation o bronchial smooth muscle and
decrease in airway resistance. 2-Selective agonists are not
completely specif c or airway 2-receptors, however, and
adverse e ects can include skeletal muscle tremor (through
2-stimulation) and tachycardia (through 1-stimulation).
Metaproterenol is the prototype 2-selective agonist.
This drug is used to treat obstructive airway disease and
acute bronchospasm. Terbutaline and albuterol are two other
agents in this class that have similar e f cacy and duration
o action. Salmeterol is a long-acting 2-agonist; its e ects
last or about 12 hours. The clinical utility o 2-selective
agonists is discussed more ully in Chapter 48, Integrative
In ammation Pharmacology: Asthma.
Receptor Antagonists
A broad spectrum o disease states respond to modula-
tion o adrenoceptor activity, and antagonists at - and -
adrenoceptors are among the most widely used drugs in
clinical practice.
-Adrenergic Antagonists
-Adrenergic antagonists block the binding o endogenous
catecholamines to 1- and 2-adrenoceptors. These agents
cause vasodilation, decreased blood pressure, and decreased
peripheral resistance. The baroreceptor re ex usually at-
tempts to compensate or the all in blood pressure, resulting
in re ex increases in heart rate and cardiac output.
An important laboratory tool since the 1950s, phenoxy-
benzamine is an alkylating agent that blocks both 1- and
2-receptors irreversibly. In addition, phenoxybenzamine
inhibits catecholamine uptake into both adrenergic nerve
terminals and extraneuronal tissues. Because o its many
direct and indirect e ects on the sympathetic nervous sys-
tem and target tissues, phenoxybenzamine, once used in the
treatment o hypertension and benign prostatic hyperplasia
(BPH), is now rarely used clinically. Some physicians use
preoperative phenoxybenzamine to prepare patients with
pheochromocytoma or surgery with the intent to decrease
operative complications. Phenoxybenzamine has been ound
to cause tumors in laboratory animals, although the implica-
tions o these f ndings or humans are unclear.
Phentolamine is a reversible, nonselective -adrenoceptor
antagonist. This drug can also be used in the preoperative
160 PRINCIPLES OF AUTONOMIC AND PERIPHERAL NERVOUS SYSTEM PHARMACOLOGY

management o pheochromocytoma. Phentolamine was the
pharmacologically ideal agent or use in the introductory
case, because it blocked the -adrenergicmediated vasocon-
striction that caused Ms. Ss hypertension. However, most
physicians have very little clinical experience with phentol-
amine, and other drugs are more requently used in the treat-
ment o severe hypertension.
Prazosin has a 1,000- old higher a f nity or 1-receptors
than or 2-receptors. Its selective blockade o 1-receptors in
arterioles and veins results in decreased peripheral vascular
resistance and dilation o the venous (capacitance) vessels.
The latter e ect decreases venous return to the heart; because
o this reduction in cardiac preload, prazosin has little ten-
dency to increase cardiac output and heart rate. Prazosin is
an antihypertensive drug. Because patients may experience
marked postural hypotension and syncope with the f rst dose,
the drug is generally prescribed initially at a very low dose and
is titrated to higher doses depending on the clinical response.
Used in this manner, postural hypotension is uncommon, pre-
sumably due to the development o tolerance (by an unclear
mechanism). Other agents in this class include terazosin and
doxazosin; these agents have a longer hal -li e than prazosin,
allowing less requent dosing. 1-Receptor antagonists are not
o ten used clinically in the treatment o hypertension, because
comparative studies have suggested that other antihyperten-
sive medications, such as diuretics, may be more e ective.
Because 1-adrenoceptors mediate contraction o genito-
urinary as well as vascular smooth muscle, some 1-antagonists
have ound clinical application in the symptomatic treatment
o benign prostatic hyperplasia (BPH). 1-Adrenoceptor
antagonists may be more e f cacious than f nasteride (a 5 -
reductase inhibitor; see Chapter 30, Pharmacology o Repro-
duction) in the medical treatment o BPH. Also, their onset o
action is relatively rapid, whereas that o 5 -reductase inhibi-
tors is generally delayed by months or more. As noted above,
there are three subtypes o the 1-receptor, namely 1A, 1B,
and 1D. Evidence points to pre erential expression o the
1A-receptor in genitourinary smooth muscle. Tamsulosin is
a relatively selective antagonist at 1A-receptors; however,
the selectivity is modest: the drug binds with approximately
six old higher a f nity to 1A- than to 1B-receptors. The in-
creased selectivity o tamsulosin or 1A-receptors may de-
crease the incidence o orthostatic hypotension relative to
that associated with prazosin and other nonsubtype-selective
1-adrenoceptor antagonists. However, this modest advantage
has been demonstrated only at low doses o tamsulosin.
the mechanism o this e ect remains unclear. The decreases
in peripheral vascular resistance and cardiac output both con-
tribute to the antihypertensive e ect o these drugs. Nonse-
lective -adrenoceptor antagonists also block 2-receptors in
bronchial smooth muscle, which can cause li e-threatening
bronchoconstriction in patients with asthma. In addition,
nonselective -receptor blockade may mask symptoms o
hypoglycemia in diabetic patients. For these reasons, selec-
tive inhibitors o 1-adrenoceptors have been developed.
Pharmacologic antagonists at -adrenergic receptors can
be divided into nonselective -antagonists, nonselective
-antagonists with concomitant action as 1-antagonists,
-adrenergic partial agonists, and 1-selective antagonists
(Table 11-2). Selective blockers o 2-adrenergic receptors
have not been developed clinically as there is no obvious
indication or selective 2-receptor antagonism.
Propranolol, nadolol, and timolol do not distinguish be-
tween 1- and 2-receptors in their binding a f nities. This is
the origin o the term nonselective -blockers. At clinical
doses, these drugs do not block -receptors. Nonselective -
blockers have been used or many years in the treatment o
hypertension and angina. Although nonselective -blockers
are relatively contraindicated in patients with asthma, these
drugs are o ten well tolerated in patients with chronic ob-
structive pulmonary disease (COPD) and may be initiated
cautiously in many such patients i they have a compelling
indication (e.g., coronary artery disease). Nadolol is also
e f cacious in the prevention o bleeding rom esophageal
varices in patients with cirrhosis. It is pharmacologically
attractive or this indication because it has a long hal -li e,
TABLE 11-2 Selectivity of Some -Adrenoceptor
Antagonists
DRUG NOTES
Nonselective -Adrenergic Antagonists
Propranolol Short half-life
Nadolol Long half-life
Timolol Lipophilic, high CNS penetration
Nonselective - and 1-Antagonists
Labetalol Also partial agonist at 2-receptors

Selective blockade o 2-autoreceptors by drugs such as

Carvedilol Intermediate half-life
yohimbine leads to increased release o norepinephrine, with
subsequent stimulation o cardiac 1-receptors and peripheral -Adrenergic Partial Agonists
vasculature 1-receptors. 2-Selective antagonists also cause
increased insulin release through blockade o 2-receptors in Pindolol -Nonselective
the pancreatic islets, which suppress insulin secretion. Yohim-
Acebutolol 1-Selective
bine has been used to treat erectile dys unction on the basis o
very limited data suggesting possible clinical e f cacy. 1-Selective Adrenergic Antagonists
-Adrenergic Antagonists Esmolol Short half-life (34 minutes)
-Adrenergic antagonists block the positive chronotropic
Metoprolol Intermediate half-life
and inotropic actions o endogenous catecholamines at 1-
receptors, resulting in decreased heart rate and myocardial Atenolol Intermediate half-life
contractility. These drugs decrease blood pressure in hyper-
tensive patients but generally do not lower blood pressure in Celiprolol Also agonist at 2-receptors

normotensive individuals. Long-term use o -adrenoceptor CNS, central nervous system.

blockers decreases peripheral vascular resistance, although

allowing once-daily administration, and, because the drug
is excreted primarily by renal elimination without hepatic
metabolism, no dosing adjustments are needed on account
o hepatic insu f ciency. Penbutolol is an additional drug in
this class. An ocular ormulation o timolol is used in the
treatment o glaucoma; even when administered to the eye,
systemic absorption o the drug may be su f ciently high to
cause adverse e ects in susceptible patients. Levobunolol
and carteolol are additional nonselective -blockers that are
indicated or administration via eye drops in the treatment
o glaucoma.
Labetalol and carvedilol block 1-, 1-, and 2-receptors.
Labetalol has two chiral centers; the clinically used drug is a
combination o our stereoisomers that have di ering phar-
macologic properties. Two o these isomers are inactive
(S,S) and (R,S). The (S,R) isomer is a power ul 1-blocker,
and the (R,R) isomer is a nonselective blocker at 1-, 1-,
and 2-receptors. Because the e ect and metabolism o
these isomers may vary among individual patients, the rela-
tive proportion o 1- versus -blockade is variable. The
1-receptor blockade tends to lower peripheral resistance;
-blockade also contributes to a decrease in blood pressure,
as indicated above. An intravenous ormulation o labetalol
is available or the lowering o blood pressure in patients
with hypertensive emergencies. Drug-induced hepatitis is an
unpredictable and idiosyncratic adverse e ect o labetalol.
In addition to its action as an 1-, 1-, and 2-receptor
blocker, carvedilol acts as a G protein-independent, -
arrestin biased ligand at both 1- and 2-adrenergic receptors.
Moreover, while carvedilol is e f cacious in the outpatient
management o hypertension, much interest in this drug has
been due to its e f cacy in the management o heart ailure
with decreased systolic unction. Carvedilols cardioprotec-
tive e ect may be related to its action as a -arrestin biased
ligand at 1-adrenoceptors, leading to transactivation o the
epidermal growth actor receptor.
Pindolol is a partial agonist at 1- and 2-receptors. The
drug blocks the action o endogenous norepinephrine at
1-receptors and is use ul in treating hypertension. As a
partial agonist, pindolol also causes partial stimulation o
1-receptors, leading to overall smaller decreases in resting
heart rate and blood pressure than those caused by pure -
antagonists. Acebutolol is a partial agonist at 1-adrenoceptors
but has no e ect at 2-receptors. This agent is also used to
treat hypertension and ischemic heart disease. While it has
been suggested that partial agonists may be less likely to
cause adverse e ects in patients with bradycardia, the clini-
cal advantages o drugs in this category remain unclear.
Esmolol, metoprolol, atenolol, and betaxolol are 1-
selective adrenergic antagonists. The elimination hal -li e is
the main eature that distinguishes among these agents. Es-
molol has an extremely short hal -li e (34 minutes); meto-
prolol and atenolol have intermediate hal -lives (49 hours).
Because o its short hal -li e, esmolol may be sa er in un-
stable patients requiring -blockade. Esmolol is rapidly
metabolized by esterases. Clinical trials have shown that
some -blockers, including metoprolol, prolong li e expec-
tancy in patients with mild to moderate heart ailure and
in patients who have survived a f rst myocardial in arction
(see Chapter 26, Integrative Cardiovascular Pharmacology:
Hypertension, Ischemic Heart Disease, and Heart Failure).
Nebivolol is a novel 1-selective adrenergic antagonist that
C h a p t e r 1 1 Adrenergic Pharmacology 161
has the ancillary property o promoting vasodilation via
nitric oxide release rom endothelial cells.
Many o the major adverse e ects o -adrenergic antag-
onists are a predictable extension o their pharmacologic e -
ects. Such e ects include worsening o bronchoconstriction
in patients with asthma, decreased cardiac output in patients
with decompensated heart ailure, and potentially impaired
recovery rom hypoglycemia in diabetic patients receiving
insulin. While 1-selective adrenergic antagonists may have
a lower propensity to block 2-receptors in bronchial smooth
muscle, the selectivity o these drugs is modest and may not
be a clinically reliable sa eguard against adverse e ects.
With chronic administration o -receptor antagonists, phar-
macologic adaptations may occur that render cells hypersen-
sitive to catecholamines when the drug is stopped suddenly.
CONCLUSION AND FUTURE
DIRECTIONS
Adrenergic pharmacology encompasses drugs that act at es-
sentially every step o adrenergic neurotransmission, rom
synthesis o catecholamines to stimulation o - and -
receptors. Other classes o drugs, such as L-channel Ca2
blockers, inter ere with e ector responses activated by these
receptors. Novel drugs are being developed that selectively
inhibit the downstream e ector pathways activated by ad-
renergic receptors. The drugs discussed in this chapter are
mainstays o therapy or hypertension, angina, heart ailure,
shock, asthma, pheochromocytoma, and other conditions.
The benef cial pharmacologic actions o these drugs, as well
as many o their important adverse e ects, can be anticipated
rom knowledge o their molecular and cellular mechanisms
o action and how these actions a ect the processes o ad-
renergic neurotransmission. While nine subtypes o adrener-
gic receptor have been identif ed, three in each o the major
classes, the clinical relevance o these subtypes has not yet
been ully determined and the pharmacologic implications
o these discoveries have not been ully exploited. The de-
velopment o novel, subtype-selective agonists and antag-
onists may lead to more e ective and less toxic therapies.
Biased ligands represent an opportunity or the discovery o
new drugs that may expand and diversi y the therapeutic op-
tions available to clinicians.
Acknowledgment
We thank Freddie M. Williams, Timothy J. Turner, and Brian
B. Ho man or their valuable contributions to this chapter in
the First, Second, and Third Editions o Principles of Phar-
macology: The Pathophysiologic Basis of Drug Therapy.
Suggested Reading
DeWire SM, Ahn S, Le kowitz RJ, Shenoy SK. Beta-arrestins and cell sig-
naling. Annu Rev Physiol 2007;69:483510. (Review of novel mechanisms
of signaling via seven transmembrane receptors.)
Reiter E, Ahn S, Shukla AK, Le kowitz RJ. Molecular mechanism o -
arrestin-biased agonism at seven transmembrane receptors. Annu Rev Phar-
macol Toxicol 2012;52:179197. (Review of biased ligands that have the
ability to alter the balance between G protein-dependent and -arrestin-
dependent signal transduction.)
Rosenbaum DM, Rasmussen SG, Kobilka BK. The structure and unction
o G-protein-coupled receptors. Nature 2009;459:356363. (Detailed re-
view of the structure of adrenergic receptors.)
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