Pharmacology Pharmacology

DEFINITIONS:
Pharmacology is the study of how drugs exert their Divisions of Pharmacology
effects on living systems.  Pharmacokinetics
 Pharmacodynamics
 Pharmacogenomics

PHARMACOLOGY FOR NURSES

Pharmacokinetics Pharmacodynamics Pharmacogenetics

Is what the drug does to the body. Area of pharmacology concerned with unusual
Is what the body does to the drug. responses to drugs caused by genetic differences
The magnitude of the pharmacological effect Interaction of drugs with cellular proteins, such as between individuals.
of a drug depends on its concentration at the receptors or enzymes, to control changes in
Responses that are not found in the general
site of action. physiological function of particular organs. population, such as general toxic effects, allergies,
 Absorption  Drug-Receptor Interactions or side effects, but due to an inherited trait that
 Binding produces a diminished or enhanced response to a
 Distribution drug.
 Metabolism  Dose-Response
 Differences in Enzyme Activity
 Effect
 Elimination  Acetylation polymorphism
 Signal Transduction  Butylcholinesterase alterations
 Mechanism of action, Pathways  Cytochrome P450 aberration

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 Drugs
Drugs can be defined as chemical agents that uniquely
interact with specific target molecules in the body,
thereby producing a biological effect.
Drugs can be stimulatory or
inhibitory
Drugs
 Drugs, as well as hormones, neurotransmitter, autocoids
and toxins can make possible the transfer of information to
cells by interaction with specific receptive molecules called
“receptors”.
DRUG
Drugs
 Drugs interact with biological systems in ways that mimic,
resemble or otherwise affect the natural chemicals of the
body.
 Drugs can produce effects by virtue of their acidic or basic
properties (e.g. antacids, protamine), surfactant properties
(amphotericin), ability to denature proteins (astringents),
osmotic properties (laxatives, diuretics), or physicochemical
interactions with membrane lipids (general and local
anesthetics).

Receptor

Receptors Endogenous compounds act on their Receptor

Most drugs combine (bind) with specific receptors Receptors
to produce a particular response. This association or Classification of Receptors
binding takes place by precise physicochemical and
steric interactions between specific groups of the drug 1) Pharmacological
and the receptor. Mediator (i.e. Insulin, Norepinephrine, estrogen)

1. Proteins
2) Biophysical and Biochemical
a. Carriers Second messenger system (i,.e. cAMP, PLC, PLA)
b. Receptors Neurotransmitter 3) Molecular or Structural
i. G protein-linked Subunit composition (i.e. 5HT1A )
Neuropeptides
ii. Ligand gated channels
iii. Intracellular Hormones 4) Anatomical
c. Enzymes Tissue (i.e muscle vs ganglionic nAChRs)
Ions
2. DNA Cellular (i.e. Membrane bound vs Intracellular)

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 Types of Receptors Enzyme-like Receptors
MEMBRANE BOUND RECEPTORS G Protein–linked Receptors
 G-Protein-linked receptors
Serotonin, Muscarinic, Dopaminergic, Noradrenergic
 Enzyme receptors
Tyrosine kinase
 Ligand-gated ion channel receptors
Nicotinic, GABA, glutamate

INTRACELLULAR AND NUCLEAR RECEPTORS

 Hormone receptors
 Autocoid receptors
 Growth factors receptors
 Insulin receptors

Ligand-gated Ion-Channel Nuclear Receptors Drug-Receptor Interactions

Receptors
Physicochemical and steric interactions
1) Lipophilic
2) Hydrophilic
3) Ionic
4) Hydrogen bonds
5) Steric (stereospecificity) effects
6) Electronic effect
7) pK effects

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Drug-Receptor Interactions Receptor Signaling Pathways Receptor Signaling Pathways
Chemical Bonds SECOND
Van der Waals Interactions Second Messengers: EFFECTORS MESSENGER
1. Ions(Ca2+, Na+, K+, Cl-) Adenylate Cyclase (AC) cAMP
2. cAMP, cGMP, IP3, Diacylglycerol Guadenylyl Cyclase (GC) cGMP
3. DNA binding – Transcriptional regulation.
Phospholipase C (PLC) DAG and IP3
4. Phosphorylated proteins and enzymes via
tyrosine kinase receptors. Phospholipase A (PLA2) Arachidonic acid
Nitric oxide Synthase NO and CO
Third Messengers: Ions Na+, Ca2+, K+, Cl-
1. Enzymes (PKC, PKA)
2. Ions (Ca2+, K+)
Hydrophobic Interactions

Drug-Receptor Interactions Law of Mass Action

Theory and assumptions of drug-receptor
interactions. When a drug (D) combines with a receptor (R), it
 Drug Receptor interaction follows simple mass-action does so at a rate which is dependent on the
relationships, i.e. only one drug molecule occupies each concentration of the drug and the concentration of
receptor and binding is reversible (We know now there are
some exceptions). the receptor.
PHARMACOLOGIC PRINCIPLES
 For a given drug the magnitude of the response is
proportional to the fraction of total receptor sites occupied
by drug molecules.

 Combination or binding to receptor causes some event

which leads to a response.

 Response to a drug is graded or dose-dependent.

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Pharmacologic Principles Pharmacologic Principles Pharmacologic Principles: Drug
Names
Chemical name
Drug Pharmacology  The drug’s chemical composition and molecular
 Any chemical that affects the processes of  The study or science of drugs structure
a living organism
Generic name (nonproprietary name)
 Name given by the United States Adopted
Name Council

Trade name (proprietary name)

 The drug has a registered trademark; use
of the name restricted by the drug’s owner
(usually the manufacturer)

Pharmacologic Principles: Drug Pharmacologic Principles Pharmacologic Principles

Names
Chemical name  Pharmaceutics Pharmaceutics
 (+/-)-2-(p-isobutylphenyl) propionic acid  Pharmacokinetics  The study of how various drug forms influence
pharmacokinetic and pharmacodynamic activities
 Pharmacodynamics
Generic name  Pharmacotherapeutics
 ibuprofen  Pharmacognosy

Trade name
 Motrin

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Pharmacologic Principles Pharmacologic Principles Pharmacologic Principles

Pharmacokinetics Pharmacodynamics Pharmacotherapeutics

 The study of what the body does to the drug:  The study of what the drug does to the body:  The use of drugs and the clinical indications for
 Absorption drugs to prevent and treat diseases
 The mechanism of drug actions in living tissues
 Distribution
 Metabolism
 Excretion

Pharmacologic Principles Drug Absorption of Various Pharmacokinetics:

Oral Preparations Absorption
Pharmacognosy Liquids, elixirs, syrups Fastest
 The rate at which a drug leaves its site of
 The study of natural (plant and animal) drug sources Suspension solutions 
administration, and the extent to which
Powders 
absorption occurs.
Capsules 
 Bioavailability
Tablets 
 Bioequivalent
Coated tablets 
Enteric-coated tablets Slowest

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Pharmacokinetics: Pharmacokinetics: Pharmacokinetics:
Absorption Absorption Absorption
Factors That Affect Absorption Enteral Route
Routes
 Administration route of the drug  A drug’s route of administration affects the rate  Drug is absorbed into the systemic circulation
 Food or fluids administered with the drug and extent of absorption of that drug. through the oral or gastric mucosa, the small intestine,
or rectum.
 Dosage formulation  Enteral
 Oral
 Status of the absorptive surface  Parenteral
 Sublingual
 Rate of blood flow to the small intestine  Topical
 Acidity of the stomach  Buccal
 Status of GI motility  Rectal

First-Pass Effect First-Pass Effect Pharmacokinetics:

Absorption
 Routes that bypass the liver: Parenteral Route
The metabolism of a drug and its passage
from the liver into the circulation.  Sublingual Transdermal
 Intravenous*
 Buccal Vaginal
 A drug given via the oral route may be extensively  Intramuscular
 Rectal* Intramuscular
metabolized by the liver before reaching the systemic  Subcutaneous
circulation (high first-pass effect).  Intravenous Subcutaneous
 Intranasal Inhalation  Intradermal
 The same drug—given IV—bypasses the liver,
preventing the first-pass effect from taking place, and *Rectal route undergoes a higher degree of first-  Intrathecal
more drug reaches the circulation. pass effects than the other routes listed.  Intraarticular
*Fastest delivery into the blood circulation

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Pharmacokinetics: Pharmacokinetics: Pharmacokinetics:
Absorption Distribution Metabolism
Topical Route The transport of a drug in the body by the The biologic
(also known astransformation of a drug into
Biotransformation)
 Skin (including transdermal patches)
bloodstream to its site of action. an inactive metabolite, a more soluble
 Eyes  Protein-binding compound, or a more potent metabolite.
 Ears  Water soluble vs. fat soluble  Liver (main organ)
 Nose  Blood-brain barrier  Kidneys
 Lungs (inhalation)  Areas of rapid distribution: heart, liver,  Lungs
 Vagina kidneys, brain  Plasma
 Areas of slow distribution: muscle, skin, fat  Intestinal mucosa

Pharmacokinetics: Pharmacokinetics: Pharmacokinetics:

Metabolism Metabolism Metabolism
Factors that increase metabolism: Delayed drug metabolism results in:
Factors that decrease metabolism:
 Fast acetylator  Accumulation of drugs
 Cardiovascular dysfunction
 Barbiturates  Prolonged action of the effects of the drugs
 Renal insufficiency
 Rifampin therapy
 Starvation
 Obstructive jaundice Stimulating drug metabolism causes:
 Slow acetylator
 Diminished pharmacologic effects
 Erythromycin or ketoconazole drug therapy

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Pharmacokinetics: Excretion Pharmacokinetics Pharmacodynamics

The elimination of drugs from the body Half-Life Drug actions:

 Kidneys (main organ)  The time it takes for one half of the original amount  The cellular processes involved in the drug and
 Liver of a drug in the body to be removed. cell interaction
 Bowel  A measure of the rate at which drugs are removed from
the body.
 Biliary excretion Drug effect:
 Enterohepatic circulation  The physiologic reaction of the body to the drug

Pharmacodynamics Pharmacodynamics: Pharmacodynamics:

Mechanisms of Action Mechanisms of Action
Onset The ways by which drugs can produce  Receptor interaction
 The time it takes for the drug to elicit a
therapeutic response therapeutic effects:  Enzyme interaction
 Once the drug is at the site of action, it can modify the
 Nonspecific interactions
Peak rate (increase or decrease) at which the cells or tissues
 The time it takes for a drug to reach its maximum function.
therapeutic response  A drug cannot make a cell or tissue perform a function it
was not designed to perform.
Duration
 The time a drug concentration is sufficient to elicit
a therapeutic response

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Pharmacotherapeutics:
Types of Therapies
 Acute therapy
 Maintenance therapy
 Supplemental therapy
 Palliative therapy
 Supportive therapy
 Prophylactic therapy
General Considerations
 Rs of Drug administration
 Drug orders
 Prescription checking
 Dosage computation
Pharmacotherapeutics: Pharmacotherapeutics:
Monitoring Monitoring
 The effectiveness of the drug therapy must  Therapeutic index
be evaluated.  Drug concentration
 One must be familiar with the drug’s  Patient’s condition
 intended therapeutic action (beneficial)  Tolerance and dependence
 and the drug’s unintended but potential side  Interactions
effects (predictable, adverse drug reactions).  Side effects/adverse drug effects
Pharmacotherapeutics: Pharmacotherapeutics:
Monitoring Monitoring
Therapeutic Index Tolerance
 The ratio between a drug’s therapeutic benefits  A decreasing response to repetitive drug doses
and its toxic effects
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Pharmacotherapeutics: Pharmacotherapeutics: Pharmacotherapeutics:
Monitoring Monitoring Monitoring
Dependence Interactions may occur with other drugs or food Interactions
 A physiologic or psychological need for a drug  Drug interactions: the alteration of action of  Additive effect
a drug by:  Synergistic effect
 Other prescribed drugs  Antagonistic effect
 Over-the-counter medications  Incompatibility
 Herbal therapies

Pharmacotherapeutics: Pharmacotherapeutics: Pharmacotherapeutics:

Monitoring Monitoring Monitoring
Medication Misadventures Adverse Drug Reaction
Some adverse drug reactions are classified as
Adverse drug events side effects.
 ALL are preventable  Expected, well-known reactions that result in little An undesirable response to drug therapy
 Medication errors that result in patient harm or no change in patient management  Idiosyncratic
 Predictable frequency  Hypersensitivity reactions
Adverse drug reactions  The effect’s intensity and occurrence is related to  Drug interactions
 Inherent, not preventable event occurring in the normal
the size of the dose
therapeutic use of a drug
 Any reaction that is unexpected, undesirable, and occurs at
doses normally used

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Pharmacotherapeutics: Pharmacotherapeutics:
Monitoring Monitoring
Iatrogenic Responses Other Drug-Related Effects
 Teratogenic
Unintentional adverse effects that are  Mutagenic
treatment-induced  Carcinogenic
 Dermatologic
 Renal damage
PHARMACODYNAMICS
 Blood dyscrasias
 Hepatic toxicity

LOCUS OF ACTION TISSUE

“RECEPTORS” RESERVOIRS
Bound Free Free Bound

AIDS MEMORIZATION OF:

• FDA Approved and Unapproved Uses

ABSORPTION Free Drug EXCRETION
• Interactions with Other Drugs
SYSTEMIC
Bound Drug CIRCULATION • Adverse Effects and Contraindications

BIOTRANSFORMATION

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 WHY BE CONCERNED ABOUT
HOW DRUGS WORK?
AIDS EVALUATION OF MEDICAL LITERATURE:
• Better assessment of new modalities for using drugs
• Better assessment of new indications for drugs
• Better assessment of new concerns regarding risk-benefit
HOW DO DRUGS WORK?
• Some antagonize, block or inhibit endogenous proteins
• Some activate endogenous proteins
• A few have unconventional mechanisms of action
WHY BE CONCERNED ABOUT WHY BE CONCERNED ABOUT
HOW DRUGS WORK? HOW DRUGS WORK?
AIDS PATIENT-DOCTOR RELATIONSHIP:
The patient has more respect for and trust in a therapist who PEACE OF MIND!
can convey to the patient how the drug is affecting the
patient’s body.
Knowledge of how a drug works increases the therapist’s
A patient who understands his/her therapy is more inclined confidence that the drug is being used appropriately.
to become an active participant in the management
of the patient’s disease.
HOW DO DRUGS ANTAGONIZE, BLOCK OR
INHIBIT ENDOGENOUS PROTEINS? Definition of RECEPTOR:
• Antagonists of Cell Surface Receptors
• Antagonists of Nuclear Receptors
A macromolecular component of the organism that
• Enzyme Inhibitors binds the drug and initiates its effect.
• Ion Channel Blockers Most receptors are proteins that have undergone various
post-translational modifications such as covalent
• Transport Inhibitors attachments of carbohydrate, lipid and phosphate.
•Inhibitors of Signal Transduction Proteins
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 HOW DO DRUGS WORK BY HOW DO DRUGS WORK BY ANTAGONIZING
ANTAGONIZING CELL SURFACE RECEPTORS? CELL SURFACE RECEPTORS?
Definition of CELL SURFACE RECEPTOR:
KEY CONCEPTS:
• Cell surface receptors exist to transmit chemical signals from Extracellular Unbound Endogenous Activator (Agonist) of Receptor
the outside to the inside of the cell.
A receptor that is embedded in the cell membrane and functions Compartment
to receive chemical information from the extracellular
• Some compounds bind to cell surface receptors, yet do not
compartment and to transmit that information to
activate the receptors to trigger a response. Cell Membrane
the intracellular compartment.
Inactive Cell Surface Receptor
• When cell surface receptors bind the molecule,
the endogenous chemical cannot bind to the
Intracellular
receptor and cannot trigger a response.
Compartment
• The compound is said to “antagonize” or “block” the receptor
and is referred to as a receptor antagonist.

HOW DO DRUGS WORK BY ANTAGONIZING HOW DO DRUGS WORK BY ANTAGONIZING HOW DO DRUGS WORK BY ANTAGONIZING
CELL SURFACE RECEPTORS? CELL SURFACE RECEPTORS? CELL SURFACE RECEPTORS?
Displaced Endogenous Activator (Agonist) of Receptor
Footnote:
Extracellular Bound Endogenous Activator (Agonist) of Receptor Extracellular
Compartment Compartment Bound Antagonist of Receptor (Drug) Most antagonists attach to binding site on receptor for
endogenous agonist and sterically prevent
endogenous agonist from binding.
Cell Membrane Cell Membrane If binding is reversible - Competitive antagonists
Active Cell Surface Receptor If binding is irreversible - Noncompetitive antagonists
Inactive Cell Surface Receptor Upon being Bound
Intracellular
Intracellular However, antagonists may bind to remote site on receptor and
Compartment
Compartment cause allosteric effects that displace endogenous agonist
or prevent endogenous agonist from
Cellular Response activating receptor. (Noncompetitive antagonists)

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HOW DO DRUGS WORK BY ANTAGONIZING ARE DRUGS THAT ANTAGONIZE CELL ARE DRUGS THAT ANTAGONIZE NUCLEAR
CELL SURFACE RECEPTORS? SURFACE RECEPTORS CLINICALLY RECEPTORS CLINICALLY USEFUL?
Displaced Endogenous Activator (Agonist) of Receptor USEFUL?
Extracellular Bound Antagonist of Receptor Some important examples: Some important examples:
Compartment
• Angiotensin Receptor Blockers (ARBs) for high blood pressure,
heart failure, chronic renal insufficiency • Mineralocorticoid Receptor Antagonists for edema due to
Cell Membrane (losartan [Cozaar®]; valsartan [Diovan®]) liver cirrhosis and for heart failure
(spironolactone [Aldactone®])
Active Receptor Inactive Receptor
Intracellular • Beta-Adrenoceptor Blockers for angina, myocardial infarction,
Compartment heart failure, high blood pressure, performance anxiety • Estrogen Receptor Antagonists for the prevention and
(propranolol [Inderal®]; atenolol [Tenormin®]) treatment of breast cancer (tamoxifen [Nolvadex®])
Allosteric Inhibitor

HOW DO DRUGS ANTAGONIZE, BLOCK OR HOW DO DRUGS WORK BY

ARE DRUGS THAT INHIBIT ENZYMES
INHIBIT ENDOGENOUS PROTEINS? INHIBITING ENZYMES?
CLINICALLY USEFUL?
KEY CONCEPTS:
• Antagonists of Cell Surface Receptors
Some important examples:
• Enzymes catalyze the biosynthesis of products from substrates.
• Antagonists of Nuclear Receptors • Cyclooxygenase Inhibitors for pain relief,
• Some drugs bind to enzymes and inhibit enzymatic activity. particularly due to arthritis (aspirin; ibuprofen [Motrin®])
• Enzyme Inhibitors
• Loss of product due to enzyme inhibition mediates the • HMG-CoA Reductase Inhibitors for hypercholesterolemia
• Ion Channel Blockers effects of enzyme inhibitors. (atorvastatin [Lipitor®]; pravastatin [Pravachol®])

• Angiotensin Converting Enzyme (ACE) Inhibitors for

• Transport Inhibitors high blood pressure, heart failure, and
chronic renal insufficiency
•Inhibitors of Signal Transduction Proteins (captopril [Capoten®]; ramipril [Altace®])

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HOW DO DRUGS ANTAGONIZE, BLOCK OR ARE DRUGS THAT BLOCK ION ARE DRUGS THAT INHIBIT TRANSPORTERS
INHIBIT ENDOGENOUS PROTEINS? CHANNELS CLINICALLY USEFUL? CLINICALLY USEFUL?

• Antagonists of Cell Surface Receptors

Some important examples: Some important examples:
• Antagonists of Nuclear Receptors
• Selective Serotonin Reuptake Inhibitors (SSRIs) for the
• Enzyme Inhibitors • Calcium Channel Blockers (CCBs) for angina and high blood treatment of depression
pressure (fluoxetine [Prozac®]; fluvoxamine [Luvox®])
• Ion Channel Blockers (amlodipine [Norvasc®]; diltiazem [Cardizem®])
• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in
• Transport Inhibitors • Sodium Channel Blockers to suppress cardiac renal epithelial cells to increase urine and sodium
arrhythmias output for the treatment of edema
•Inhibitors of Signal Transduction Proteins (lidocaine [Xylocaine®]; amiodarone [Cordarone®]) (furosemide [Lasix®]; bumetanide [Bumex®])

ARE DRUGS THAT INHIBIT SIGNAL HOW DO DRUGS WORK BY ACTIVATING HOW DO CHEMICALS WORK BY ACTIVATING
TRANSDUCTION PROTEINS ENDOGENOUS PROTEINS? CELL SURFACE RECEPTORS?
CLINICALLY USEFUL? KEY CONCEPTS:
• Agonists of Cell Surface Receptors
Some important examples: (e.g. alpha-agonists, morphine agonists)
•Cell surface receptors exist to transmit chemical signals from
the outside to the inside of the cell.
• Agonists of Nuclear Receptors
• Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (e.g. HRT for menopause, steroids for inflammation)
(imatinib [Gleevec®]) • Some chemicals bind to cell surface receptors and
trigger a response.
• Enzyme Activators
• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (e.g. nitroglycerine (guanylyl cyclase), pralidoxime)
(sildenafil [Viagra®]) • Chemicals in this group are called receptor agonists.
• Ion Channel Openers • Some agonists are actually the endogenous chemical signal,
• This is a major focus of drug development (e.g. minoxidil (K) and alprazolam (Cl))
whereas other agonists mimic endogenous chemical signals.

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HOW DO CHEMICALS WORK BY HOW DO DRUGS WORK BY UNCONVENTIONAL
MECHANISMS OF ACTION (Continued)? Characteristics of Drug-Receptor
UNCONVENTIONAL MECHANISMS OF ACTION?
Interactions
•Disrupting of Structural Proteins •Being Nutrients
e.g. vinca alkaloids for cancer, colchicine for gout e.g. vitamins, minerals  Chemical Bond: ionic, hydrogen,
• Exerting Actions Due to Physical Properties hydrophobic, Van der Waals, and covalent.
• Being Enzymes
e.g. streptokinase for thrombolysis e.g. mannitol (osmotic diuretic), laxatives  Saturable
• Working Via an Antisense Action  Competitive
• Covalently Linking to Macromolecules
e.g. cyclophosphamide for cancer
e.g. fomivirsen for CMV retininitis in AIDS  Specific and Selective
• Being Antigens  Structure-activity relationships
• Reacting Chemically with Small Molecules e.g. vaccines
e.g. antacids for increased acidity  Transduction mechanisms

• Binding Free Molecules or Atoms •Having Unknown Mechanisms of Action

e.g. general anesthetics
e.g. drugs for heavy metal poisoning, infliximab (anti-TNF)

Receptor Transduction Receptor Regulation Causes of Variability in Drug

Mechanisms Response
 Ion channel linked receptors e.g. Ach nicotinic  Sensitization or Up-regulation
(Na+) and GABA (Cl-) 1. Prolonged/continuous use of receptor blocker
 Second messenger generation, 2. Inhibition of synthesis or release of Those related to the biological system
adenylate cyclase stimulation or inhibition - cAMP, hormone/neurotransmitter - Denervation 1. Body weight and size
guanylate cyclase - cGMP,  Desensitization or Down-regulation 2. Age and Sex
phospholipase C - IP3, DAG 1. Prolonged/continuous use of agonist
3. Genetics - pharmacogenetics
 Some receptors are themselves protein kinases 2. Inhibition of degradation or uptake of agonist
4. Condition of health
 Intracellular receptors (e.g. corticosteroids,
thyroid hormone) Homologous vs. Heterologous 5. Placebo effect
Uncoupling vs. Decreased Numbers

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Causes of Variability in Drug Drug Effectiveness
Response  Dose-response (DR) curve:
Depicts the relation between
drug dose and magnitude of
 Those related to the conditions of administration drug effect
1. Dose, formulation, route of administration.  Drugs can have more than one
2. Resulting from repeated administration of drug:
PHARMACOKINETICS effect
drug resistance; drug tolerance-tachyphylaxis; drug allergy  Drugs vary in effectiveness
 Different sites of action
3. Drug interactions:  Different affinities for receptors
chemical or physical;  The effectiveness of a drug is
GI absorption; considered relative to its safety
protein binding/distribution; (therapeutic index)
metabolism (stimulation/inhibition);
excretion (pH/transport processes);
receptor (potentiation/antagonism);
changes in pH or electrolytes.

Drug Safety and Pharmacokinetics

Effectiveness
 Not all people respond to a similar dose of a drug
in the exact same manner, this variability is
based upon individual differences and is
associated with toxicity. This variability is
thought to be caused by:
 Pharmacokinetic factors contribute to differing
concentrations of the drug at the target area.
 Pharmacodynamic factors contribute to differing
physiological responses to the same drug
concentration.
 Unusual, idiosyncratic, genetically determined or
allergic, immunologically sensitized responses.
Routes of Administration
 Drug molecules interact with target sites to effect
the nervous system
 The drug must be absorbed into the bloodstream and then  Routes of Administration:Orally:
carried to the target site(s)  Rectally:
 Pharmacokinetics is the study of drug absorption,  Inhalation: Absorption through mucous
distribution within body, and drug elimination over membranes:
time.  Topical:
 Absorption depends on the route of administration
 Parenterally:
 Drug distribution depends on how soluble the drug
 Intravenous:
molecule is in fat (to pass through membranes) and on the
extent to which the drug binds to blood proteins (albumin)  Intramuscular:
 Drug elimination is accomplished by excretion into urine  Subcutaneous:
and/or by inactivation by enzymes in the liver

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 Routes of Administration Membranes
Drug Delivery Systems  Types of Membranes:
 Cell Membranes: This barrier is permeable to many drug
molecules but not to others, depending on their lipid
• Tablets • Candy solubility. Small pores, 8 angstroms, permit small
molecules such as alcohol and water to pass through.
• Injections (Syringe) • Gum  Walls of Capillaries: Pores between the cells are larger
• Cigarettes • Implants than most drug molecules, allowing them to pass freely,
without lipid solubility being a factor.
• Beverages • Gas  Blood/Brain Barrier: This barrier provides a protective
environment for the brain. Speed of transport across this
• Patches • Creams barrier is limited by the lipid solubility of the
• Suppositories • Others? psychoactive molecule.
 Placental Barrier: This barrier separates two distinct
– Stamps human beings but is very permeable to lipid soluble
drugs.
– Bandana

Drug Distribution
Pharmacokinetics vs Pharmacokinetics vs
 Dependent upon its route of administration and target area, every drug
has to be absorbed, by diffusion, through a variety of bodily tissue.
Pharmacodynamics…concept Pharmacodynamics…concept
 Tissue is composed of cells which are encompassed within membranes,  Fluoxetine increases plasma  If fluoxetine is given with tramadol serotonin
consisting of 3 layers, 2 layers of water-soluble complex lipid molecules
(phospholipid) and a layer of liquid lipid, sandwiched within these layers. concentrations of amitriptyline. This is a syndrom can result. This is a
Suspended within the layers are large proteins, with some, such as pharmacodynamic drug interaction.
receptors, transversing all 3 layers. pharmacokinetic drug interaction.
 The permeability of a cell membrane, for a specific drug, depends on a
ratio of its water to lipid solubility. Within the body, drugs may exist as a
mixture of two interchangeable forms, either water (ionized-charged) or  Fluoxetine inhibits the metabolism of  Fluoxetine and tramadol both increase
lipid (non-ionized) soluble. The concentration of two forms depends on availability of serotonin leading to the
characteristics of the drug molecule (pKa, pH at which 50% of the drug is amitriptyline and increases the plasma
ionized) and the pH of fluid in which it is dissolved. possibility of “serotonin overload” This
concentration of amitriptytline.
 In water soluble form, drugs cannot pass through lipid membranes, but to happens without a change in the
reach their target area, they must permeate a variety of types of
membranes. concentration of either drug.

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Clearance (CL) Clearance Half-Life and k

 Ability of organs of elimination (e.g. kidney,
liver) to “clear” drug from the bloodstream.
 Volume of fluid which is completely cleared
of drug per unit time.
 Units are in L/hr or L/hr/kg
 Pharmacokinetic term used in determination
of maintenance doses.
 Volume of blood in a defined region of the
body that is cleared of a drug in a unit time.
 Clearance is a more useful concept in reality
than t 1/2 or kel since it takes into account
blood flow rate.
 Clearance varies with body weight.
 Also varies with degree of protein binding.
 Half-life is the time taken for the drug
concentration to fall to half its original
value
 The elimination rate constant (k) is the
fraction of drug in the body which is
removed per unit time.

Steady-State Therapeutic Index

 Steady-state occurs after a drug has been given

for approximately five elimination half-lives.
 At steady-state the rate of drug administration
equals the rate of elimination and plasma
concentration - time curves found after each
dose should be approximately superimposable.
 Therapeutic index = toxic dose/effective
THERAPEUTIC DRUG dose
MONITORING
 This is a measure of a drug’s safety
Some Principles
 A large number = a wide margin of safety
 A small number = a small margin of safety

20
 Drug Concentrations may be
Useful when there is:
 An established relationship between
concentration and response or toxicity
 A sensitive and specific assay
 An assay that is relatively easy to perform
 A narrow therapeutic range
 A need to enhance response/prevent
toxicity
Elimination by the Kidney
 Excretion - major
1) glomerular filtration
glomerular structure, size constraints,
protein binding
2) tubular reabsorption/secretion
- acidification/alkalinization,
- active transport, competitive/saturable,
organic acids/bases
- protein binding
 Metabolism - minor
Why Measure Drug
Concentrations?
 Lack of therapeutic response
 Toxic effects evident
 Potential for non-compliance
 Variability in relationship of dose and
concentration
 Therapeutic/toxic actions not easily
quantified by clinical endpoints
Elimination by the
Liver
 Metabolism - major
1) Phase I and II reactions
2) Function: change a lipid soluble to more
water soluble molecule to excrete in kidney
3) Possibility of active metabolites with
same or different properties as parent
molecule
 Biliary Secretion – active transport, 4 categories
Potential for Error when using TDM
 Assuming patient is at steady-state
 Assuming patient is actually taking the drug
as prescribed
 Assuming patient is receiving drug as prescribed
 Not knowing when the [drug] was measured in
relation to dose administration
 Assuming the patient is static and that changes
in
condition don’t affect clearance
 Not considering drug interactions
Liver P450 systems
 Liver enzymes inactivate some drug molecules
 First pass effect (induces enzyme activity)
 P450 activity is genetically determined:
 Some persons lack such activity  leads to higher
drug plasma levels (adverse actions)
 Some persons have high levels  leads to lower
plasma levels (and reduced drug action)
 Other drugs can interact with the P450 systems
 Either induce activity (apparent tolerance)
 Inactivate an enzyme system
21
How are [drug] measured?
 Invasive: blood, spinal fluid, biopsy
 Noninvasive: urine, feces, breath, saliva
 Most analytical methods designed for plasma
analysis
 C-14, H-3
 Partition Coefficients: ratio of solubility of a
drug in water or in an aqueous buffer to its
solubility in a lipophilic, non-polar solvent
 pH and ionization: Ion Trapping
Therapeutic Window
 Useful range of concentration over which a drug
is therapeutically beneficial. Therapeutic
window may vary from patient to patient
 Drugs with narrow therapeutic windows require
smaller and more frequent doses or a different
method of administration
 Drugs with slow elimination rates may rapidly
accumulate to toxic levels….can choose to give
one large initial dose, following only with small
doses
The Compartment Model
 We can generally think of the body as a series
of interconnected well-stirred compartments
within which the [drug] remains fairly
constant. BUT movement BETWEEN
compartments important in determining
when and for how long a drug will be present
in body.
Distribution
 Rate & Extent depend upon
 Chemical structure of drug
 Rate of blood flow
 Ease of transport through membrane
 Binding of drug to proteins in blood
 Elimination processes
Partitioning into body fat and
other tissues
 A large, nonpolar compartment. Fat has
low blood supply—less than 2% of cardiac output,
so drugs are delivered to fat relatively slowly
For practical purposes: partition into body fat
important following acute dosing only for a few
highly lipid-soluble drugs and environmental
contaminants which are poorly metabolized and
remain in body for long period of time
22
IMPORTANT EFFECTS OF pH
PARTITIONING:
  urinary acidification will accelerate the
excretion of weak bases and retard that of weak
acids; alkalination has the opposite effects
  increasing plasma pH (by addition of
NaHCO3) will cause weakly acidic drugs to be
extracted from the CNS into the plasma;
reducing plasma pH (by administering a carbonic
anhydrase inhibitor) will cause weakly acidic
drugs to be concentrated in the CNS, increasing
their toxicity
A bound drug has no effect!
 Amount bound depends on:
 1) free drug concentration
 2) the protein concentration
 3) affinity for binding sites
Renal Elimination Plasma Proteins that Bind
Drugs
 Glomerular filtration: molecules below 20 kDa  albumin: binds many acidic drugs and a few
pass into filtrate. Drug must be free, not protein basic drugs
bound.
 Tubular secretion/reabsorption: Active
transport. Followed by passive and active.  b-globulin and an a1acid glycoprotein have
DP=D + P. As D transported, shift in equilibrium
also been found to bind certain basic drugs
to release more free D. Drugs with high lipid
solubility are reabsorbed passively and therefore
slowly excreted. Idea of ion trapping can be used
to increase excretion rate---traps drug in filtrate.
% Bound Bioavailability
 Renal failure, inflammation, fasting,  The fraction of the dose of a drug (F) that
malnutrition can have effect on plasma enters the general circulatory system,
protein binding.
 Competition from other drugs can also affect
% bound.
23

Bioavailability
 A concept for oral administration
 Useful to compare two different drugs or
different dosage forms of same drug
 Rate of absorption depends, in part, on rate of
dissolution (which in turn is dependent on
chemical structure, pH, partition coefficient,
surface area of absorbing region, etc.) Also first-
pass metabolism is a determining factor
 Metabolism (biotransformation) of compounds is
essential for survival of the organism.
 Accomplished by a limited number of enzymes
with broad and overlapping substrate specificity.
 Many of the enzymes are constitutively
expressed, but some require the presence of a
DRUG METABOLISM drug or toxic compound to be induced = enzyme
induction.
 Primary aims of Metabolism:
- the parent molecule is transformed into a
more polar metabolite, often by the addition of
an ionizable group – usually more H2O-soluble
than the parent compound.
- MW often increases.
- Excretion, and therefore, elimination,
facilitated.

IMPLICATIONS FOR DRUG METABOLISM

Consequences of Metabolism

 The biological t1/2 decreases.

1. Termination of drug action
 Exposure duration decreases. 2. Activation of prodrug
 Compound does not accumulate in the body. IMPLICATIONS FOR DRUG METABOLISM 3. Bioactivation and toxication
 But biological activity may change.
4. Carcinogenesis
 Duration of biological activity may be affected.
5. Tetratogenesis
 Although H2O-solubility and elimination are
often increases, detoxification is not always the
result.

24
 Factors Affecting Drug Metabolism
Termination of Drug Action
 Age
 Diet

Conversion of drug to active metabolite to  Genetic Variation

active metabolite to inactive metabolite  State of Health
FACTORS AFFECTING DRUG METABOLISM  Gender
 Degree of Protein Binding
 Species Variation
 Substrate Competition
 Enzyme Induction
 Route of Drug Administration

Factors Affecting Drug Metabolism
 Route of drug administration
 Oral versus systemic administration
Many Drugs Undergo First Pass Metabolism Organ Sites of Drug Metabolism
Upon Oral Administration
 Liver
 Oral administration  Small intestine
 Drug travels from gut to portal vein to liver  Kidney
 Vigorous metabolism occurs in the liver. Little drug  Skin
gets to the systemic circulation
 The wall of the small intestine also contributes to first
 Lungs
pass metabolism  Plasma
 All organs of the body

25
Cellular Sites Of Drug Metabolism Factors Affecting Drug Metabolism
Factors Affecting Drug Metabolism

 Enzyme induction
 Enzyme Induction - increased enzyme protein
 Cytosol  Age levels in the cell
 Mitochondria  Diet  Phenobarbital type induction by many drugs
 Lysosomes  Polycyclic hydrocarbon type induction by
 Genetic variation
polycyclic hydrocarbons such as 3,4-benzopyrene
 Smooth endoplasmic reticulum  State of health and 3-methylcholanthrene
(microsomes)  Gender
 Degree of protein binding
 Species Variation
 Substrate competition

FACTORS AFFECTING DRUG METABOLISM Some Enzymes That Exhibit Genetic

FACTORS AFFECTING DRUG METABOLISM
Variation
 Diet
 Charcoal broiled foods (contain polycyclic
 Age  Pseudocholinesterase
hydrocarbons that increase certain enzyme protein in
 Neonates cells)  typical enzyme
 Children  Grapefruit juice (the active component is the  atypical enzyme
 Elderly furancoumarin 6,7-dihydroxybergamottin which  N-Acetyltransferase (isoniazid is a substrate)
inhibits a certain a group of microsomal enzymes)  fast acetylation
 slow acetylation
 Cytochrome P450 2D6
 Cytochrome P450 2C19
 TMPT -Thiomethylpurinetransferase
 Dihydropyrimidine Dehydrogenase

26
FACTORS AFFECTING DRUG METABOLISM FACTORS AFFECTING DRUG METABOLISM
FACTORS AFFECTING DRUG METABOLISM

 State of health  Gender

 Degree of protein binding
 Hepatitis  Most studies are performed in the rat. In general,
male rats metabolize drugs faster than female  Conditions that displace bound drug from protein
 Liver cancer allows more of the drug to be accessible to the
rats.
 Cardiac insufficiency enzyme for which it serves as a substrate e.g.
 Alcohol: men vs. women
 Uremia uremia, low plasma albumin
 degree of protein binding

FACTORS AFFECTING DRUG METABOLISM Factors Affecting Drug Metabolism

Factors Affecting Drug Metabolism

 Species variation  Species variation

 Quantitative  Human beings metabolize amphetamine by  Substrate competition
 Qualitative deamination; rats and dogs metabolize the drug  Two or more drugs competing for the same
by aromatic hydroxylation enzyme can affect the metabolism of each other;
 Guinea pigs have very little sulfotransferase the substrate for which the enzyme has the
activity, humans have substantial activity greater affinity would be preferentially metabolized
 Guinea pigs do not N-hydroxylate substrates;
mice, rabbits, dogs do
 Hexobarbital is metabolized at different rates by
different species

27
 Mechanism of drug interaction
Increasing risk of death DRUG-DRUG INTERACTION MAY ALTER DRUG
EFFECT BY • Pharmacokinetic interactions
– Absorption
7 6 5 4 2 – Distribution
1 in 10 1 in 10 1 in 10 1 in 10 1 in 103 1 in 10 – Biotransformation***
Additive effect : 1 + 1 =2 – Excretion
Synergistic effect : 1 +1 > 2 • Pharmacodynamic interactions
– Receptor interaction
Potentiation effect : 1 + 0 =2 – Receptor sensitivity
– Neurotransmitter release/Drug transportation
Lightning Antagonism : 1-1 = 0 – Electrolyte balance

Murder
• Physiological interactions
Plane crash • Pharmaceutical interactions
Auto-cash

Fatal, unexpected
drug reaction

Drug metabolism interaction

Pharmacodynamic interactions Physiological interactions
Enzyme inducers : increase metabolism of
concomitant drug therefor increase drug elimination
and decrease drug effect • Receptor interaction
Drug A and Drug B bind to different receptors on
– Competitive
Barbiturate, Rifampin, Phenytoin the same tissue but give opposite or similar
– Non-competitive
effect
Enzyme inhibitors : decresae metabolism of • Sensitivity of receptor
– Number of receptor Aspirin (anti-platelet)
concomitant drug therefor decrease drug – Affinity of receptor +Warfarin/Coumarin (anticoagulant)
excretion and increase drug effect
• Alter neurotransmitter release /drug transportation
Cimetidine, Ketoconazole, Erythromycin, • Alter water/electrolyte balance
Clarithromycin, Chloramphenicol, Quinidine, Increase bleeding
Sulphaphenazole

28
 DRUG-HERB INTERACTIONS
Pharmaceutical interactions Drug-Food interactions
Ginko biloba

 Chemical or physiological interactions

 Vitamin C + amphotericin B
 Pennicilin + Vitamin C

 Grapefruit juice and Terfenadine

 Grapefruit juice and cyclosporin
 Grapefruit juice and felodipine
 Grapefruit contains : furanocoumarin compounds that can
selectively inhibit CYP3 A4

DRUG FEATURES ASSOCIATED WITH

St. John’s wort: CYP3A4 inducer POTENTIAL INTERACTIONS
LIST OF DRUG THE MOST COMMON
Narrow therapeutic index :
INTERACTING DRUG
– Phenytoin
– Cyclosporine •Antacids
– Theophylline
Sharp response curve: •Cimetidine
– Phenytoin •Digoxin
– Aminoglycoside •Warfarin
– Vancomycin
•Theophylline
Dose dependent (Michaelis-Menten) kinetic
–Phenytoin •Ketoconazole

29
 Sources of drug
Drug tablet
Pharmacogenetics variability
Problem in medical practice Pharmacogenomics
Release

same complaints
Drug in gut
Pharmacokinetics
same finding
Pharmacology + Genetics/Genomics Absorpti
same diagnosis on
Drug in blood
same treatment
• The study of how individual’s genetic Distribution
but differential effect ????
inheritance affects the body’s response to
Drug in tissues
•Possible reasons drugs (efficacy & toxicity) Drug in urine/bile
• Physiological factors Drug metabolites
• Pathological factors • The use of genetic content of humans for
Drug at receptor
• Food drug discovery Pharmacodynamics
•Drug interaction
•Genetic
Desired response No response Unwanted response

Genetic variations in drug response and Adrenergic Agents

drug toxicity may result from

•Variation in drug •Variation in drug  Drugs that stimulate the sympathetic

transporters nervous system (SNS)
metabolizing enzymes
• P-glycoprotien
DRUGS AFFECTING THE
• Cytochromes P450
• Thiopurine S- AUTONOMIC NERVOUS SYSTEM
methyltransferase • Variation in disease
•Variation in drug targets modifying genes
• Beta2-adrenergic • Apolipoprotein (APOE)
receptor Adrenergic Agents and Adrenergic-Blocking
• ACE
• Dopamine receptor Agents

30
Adrenergic Agents Adrenergic Agents Adrenergic Receptors

Also known as
Mimic the effects of the SNS neurotransmitters:  Located throughout the body
 adrenergic agonists or sympathomimetics
 norepinephrine (NE) and epinephrine (EPI)  Are receptors for the sympathetic
neurotransmitters
Alpha-adrenergic receptors: respond to NE
Beta-adrenergic receptors: respond to EPI

Alpha-Adrenergic Receptors Alpha1-Adrenergic Receptors Alpha2-Adrenergic Receptors

 Divided into alpha1 and alpha2 receptors  Located on postsynaptic effector cells  Located on presynaptic nerve terminals
 Differentiated by their location on nerves (the cell, muscle, or organ that the nerve (the nerve that stimulates the effector cells)
stimulates)  Control the release of neurotransmitters

31
The predominant alpha-
adrenergic agonist responses
are:
 Vasoconstriction and CNS stimulation
Beta-Adrenergic Receptors The beta-adrenergic agonist
response results in:
All are located on postsynaptic effector cells  Bronchial, GI, and uterine smooth muscle
 Beta1-adrenergic receptors—located primarily relaxation
in the heart
 Glycogenolysis
 Beta2-adrenergic receptors—located in smooth muscle
of the bronchioles, arterioles, and visceral organs  Cardiac stimulation

Dopaminergic Receptors Adrenergic Receptor Responses Adrenergic Receptor Responses

to Stimulation to Stimulation
 An additional adrenergic receptor LOCATION RECEPTOR RESPONSE LOCATION RECEPTOR RESPONSE
 Stimulated by dopamine Cardiovascular Gastrointestinal
 Causes dilation of the following blood Blood vessels alpha1 and beta2 Constriction / Muscle beta2 Decreased
dilation motility
vessels, resulting in INCREASED blood flow
Cardiac muscle beta1 Increased Sphincters alpha1 Constriction
 Renal contractility
 Mesenteric AV Node beta1 Increased
 Coronary heart rate
 Cerebral SA Node beta1 Increased
heart rate

32
 Adrenergic Receptor Responses Adrenergic Receptor Responses Catecholamines
to Stimulation to Stimulation
LOCATION RECEPTOR RESPONSE LOCATION RECEPTOR RESPONSE Substances that can produce a sympathomimetic
Genitourinary Respiratory response
Bladder alpha1 Constriction Bronchial beta2 Dilation/relaxation
sphincter muscles
Endogenous:
 epinephrine, norepinephrine,dopamine
Penis alpha1 Ejaculation
Uterus alpha1 and beta2 Contraction/
relaxation Synthetic:
 isoproterenol, dobutamine, phenylephrine

Adrenergic Agents Adrenergic Agents Adrenergic Agents

Mechanism of Action Mechanism of Action
Direct-acting sympathomimetic: Indirect-acting sympathomimetic:
 Binds directly to the receptor and causes a physiologic  Causes the release of catecholamine from the storage
response sites (vesicles) in the nerve endings
 The catecholamine then binds to the receptors and
causes a physiologic response
Mechanism of Action
Mixed-acting sympathomimetic:
 Directly stimulates the receptor by binding
to it
AND
 Indirectly stimulates the receptor by causing
the release of stored neurotransmitters from
the vesicles in the nerve endings

33
Drug Effects of Adrenergic
Agents
Stimulation of alpha-adrenergic receptors on
smooth muscles results in:
 Vasoconstriction of blood vessels
 Relaxation of GI smooth muscles
 Contraction of the uterus and bladder
 Male ejaculation
 Decreased insulin release
 Contraction of the ciliary muscles of the eye
(dilated pupils)
Drug Effects of Adrenergic Drug Effects of Adrenergic
Agents Agents
Stimulation of beta2-adrenergic receptors on Stimulation of beta1-adrenergic receptors on
the airways results in: the myocardium, AV node, and SA node
 Bronchodilation (relaxation of the bronchi) results in CARDIAC STIMULATION:
 Uterine relaxation  Increased force of contraction
 Glycogenolysis in the liver (positive inotropic effect)
 Increased heart rate
(positive chronotropic effect)
 Increased conduction through the AV node
(positive dromotropic effect)

Adrenergic Agents: Adrenergic Agents: Adrenergic Agents:

Therapeutic Uses Therapeutic Uses Therapeutic Uses
 Anorexiants: adjuncts to diet in the Bronchodilators: treatment of asthma and  Reduction of intraocular pressure and
short-term management of obesity bronchitis mydriasis (pupil dilation): treatment of
Examples: benzphetamine  Agents that stimulate beta2-adrenergic receptors open-angle glaucoma
phentermine of bronchial smooth muscles causing relaxation
Examples: epinephrine and dipivefrin
dextroamphetamine Examples:
Dexedrine albuterol ephedrine epinephrine
isoetharine isoproterenol levalbuterol
metaproterenol salmeterol terbutaline
 These agents may also affect uterine and vascular
smooth muscles.

34
Adrenergic Agents: Adrenergic Agents: Adrenergic Agents:
Therapeutic Uses Therapeutic Uses Therapeutic Uses
Ophthalmic Vasoactive sympathomimetics (pressors,
Nasal decongestant:
 Topical application to the eye surface affects inotropes), also called cardioselective
 Intranasal (topical) application causes constriction
of dilated arterioles and reduction of nasal blood the vasculature of the eye, stimulating alpha sympathomimetics
flow, thus decreasing congestion. receptors on small arterioles, thus relieving  Used to support the heart during cardiac failure
or shock.
Examples: conjunctival congestion.
epinephrine ephedrine naphazoline Examples:
Examples: epinephrine naphazoline
phenylephrine tetrahydrozoline dobutamine dopamine ephedrine
phenylephrine tetrahydrozoline
epinephrine fenoldopam isoproterenol
methoxamine norepinephrine
phenylephrine

Adrenergic Agents: Side Adrenergic Agents: Side Adrenergic Agents:

Effects Effects Interactions
Alpha-Adrenergic Effects Beta-Adrenergic Effects  Anesthetic agents
 CNS:
 CNS:  Tricyclic antidepressants
 headache, restlessness, excitement, insomnia,
 mild tremors, headache, nervousness, dizziness
euphoria  MAOIs
 Cardiovascular:  Antihistamines
 Cardiovascular:
 increased heart rate, palpitations (dysrhythmias),
 palpitations (dysrhythmias), tachycardia,  Thyroid preparations
fluctuations in BP
vasoconstriction, hypertension
 Antihypertensives
 Other:
 Other:  Will directly antagonize another adrenergic
 sweating, nausea, vomiting, muscle cramps
 anorexia, dry mouth, nausea, vomiting, taste agent, resulting in reduced effects
changes (rare)

35
Adrenergic Agents: Adrenergic Agents: Adrenergic Agents:
Nursing Implications Nursing Implications Nursing Implications
 Assess for allergies and history of hypertension, IV administration: With chronic lung disease:
cardiac dysrhythmias, or other cardiovascular
disease.  Check IV site often for infiltration  Instruct patients to avoid factors that exacerbate their
 Use clear IV solutions condition.
 Assess renal, hepatic, and cardiac function
before treatment.  Use an infusion device/IV pump  Encourage fluid intake
(up to 3000 mL per day) if permitted.
 Perform baseline assessment of vital signs,  Infuse agent slowly to avoid dangerous cardiovascular
effects  Educate about proper dosing and
peripheral pulses, skin color, temperature, and equipment care.
capillary refill. Include postural blood pressure  Monitor cardiac rhythm
and pulse.
Salmeterol is indicated for PREVENTION
 Follow administration guidelines carefully. of bronchospasms, not management
of acute symptoms.

Adrenergic Agents: Adrenergic Agents: Adrenergic Agents:

Nursing Implications Nursing Implications Nursing Implications
 Overuse of nasal decongestants may cause rebound Monitor for therapeutic effects
Monitor for therapeutic effects (asthma):
nasal congestion or ulcerations. (cardiovascular uses):
 Return to normal respiratory rate
 Avoid OTC or other medications because of possible  Decreased edema
 Improved breath sounds, fewer rales
interactions.  Increased urinary output
 Increased air exchange
 Administering two adrenergic agents together may  Return to normal vital signs
 Decreased cough
precipitate severe cardiovascular effects such as  Improved skin color and temperature
 Less dyspnea
tachycardia or hypertension.  Increased LOC
 Improved blood gases
 Inform patients taking inhaled isoproterenol that
 Increased activity tolerance
their sputum or saliva may turn pink.

36
Adrenergic-Blocking Agents
 Bind to adrenergic receptors, but inhibit or
block stimulation of the sympathetic nervous
system (SNS)
Adrenergic Blocking Agents
Classified by the type of adrenergic receptor
they block
 Alpha1 and alpha2 receptors
 Beta1 and beta2 receptors
Adrenergic Blocking Agents
 Have the opposite effect of adrenergic agents
 Also known as
 adrenergic antagonists or sympatholytics
Adrenergic-Blocking Agents:
Drug Effects and Therapeutic
Uses
Ergot Alkaloids (Alpha-Blockers)
 Constrict dilated arteries going to the brain
(carotid arteries)
 Used to treat vascular headaches (migraines)
 Stimulate uterine contractions by inducing
vasoconstriction
 Used to control postpartum bleeding
Adrenergic Blocking Agents
 Sympatholytics inhibit—or LYSE—
sympathetic neurotransmitters
(norepinephrine and epinephrine)
Adrenergic-Blocking Agents:
Drug Effects and Therapeutic
Uses
Alpha-Blockers
 Cause both arterial and venous dilation, reducing
peripheral vascular resistance and BP
 Used to treat hypertension
 Effect on receptors on prostate gland and bladder
decreased resistance to urinary outflow, thus reducing
urinary obstruction and relieving effects
of BPH
37
Adrenergic-Blocking Agents: Adrenergic-Blocking Agents: Adrenergic-Blocking Agents:
Drug Effects and Therapeutic Side Effects Side Effects
Uses Alpha Blockers Alpha Blockers
Alpha-Blockers Body System Side/Adverse Effects Body System Side/Adverse Effects
 Phentolamine Cardiovascular Palpitations, orthostatic Gastrointestinal Nausea, vomiting, diarrhea,
 Quickly reverses the potent vasoconstrictive effects of hypotension, tachycardia, constipation, abdominal pain
extravasated vasopressors such as norepinephrine or edema, dysrhythmias, chest pain
epinephrine.
 Restores blood flow and prevents tissue necrosis.
Other Incontinence, nose bleeding,
CNS Dizziness, headache, drowsiness, tinnitus, dry mouth, pharyngitis,
anxiety, depression, vertigo, rhinitis
weakness, numbness, fatigue

Beta Blockers Beta Receptors Beta Receptors

 Block stimulation of beta receptors in Beta1 Receptors Beta2 Receptors

the SNS  Located primarily on the heart  Located primarily on smooth muscles
 Compete with norepinephrine and  Beta blockers selective for these receptors of bronchioles and blood vessels
are called cardioselective beta blockers
epinephrine
 Selective and nonselective beta blockers

38
Nonspecific Beta Blockers Beta Blockers: Mechanism of Beta Blockers: Mechanism of
Action Action
 Beta blockers that block both beta1 and Cardioselective (Beta1) Nonspecific (Beta1 and Beta2)
beta2 receptors  Decreases heart rate  Effects on heart: Same as cardioselective
 Prolongs SA node recovery  Bronchioles: Constriction, resulting in
 Slows conduction rate through the AV node narrowing of airways and
shortness of breath
 Decreases myocardial contractility, thus
decreasing myocardial oxygen demand  Blood vessels: Vasoconstriction

Beta Blockers: Therapeutic Beta Blockers: Therapeutic Beta Blockers: Side Effects
Uses Uses
 Anti-angina: decreases demand for  Antihypertensive
myocardial oxygen Body System Side/Adverse Effects
 Treatment of migraine headaches Blood Agranulocytosis, thrombocytopenia
 Cardioprotective: inhibits stimulation by
circulating catecholamines  Glaucoma (topical use)
Cardiovascular AV block, bradycardia, congestive
 Class II antidysrhythmic
heart failure, peripheral vascular
insufficiency

CNS Dizziness, mental depression,

lethargy, hallucinations

39
Adrenergic-Blocking Agents: Adrenergic Blocking Agents: Adrenergic Blocking Agents:
Side Effects Nursing Implications Nursing Implications
Beta Blockers  Assess for allergies and history of COPD,  Remember that alpha blockers may
Body System Side/Adverse Effects hypotension, cardiac dysrhythmias, precipitate hypotension.
Gastrointestinal Nausea, dry mouth, vomiting, bradycardia, CHF, or other cardiovascular  Remember that beta blockers may
diarrhea, cramps, ischemic colitis problems precipitate bradycardia, hypotension,
heart block, CHF, and bronchoconstriction.
Other Impotence, rash, alopecia, Any preexisting condition that might be
bronchospasms exacerbated by the use of these agents might
be a CONTRAINDICATION to their use.

Adrenergic Blocking Agents: Adrenergic Blocking Agents: Adrenergic Blocking Agents:

Nursing Implications
 Avoid OTC medications because of possible
interactions.
 Possible drug interactions may occur with:
 Antacids (aluminum hydroxide type)
 Antimuscarinics/anticholinergics
 Diuretics and cardiovascular drugs
 Neuromuscular blocking agents
 Oral hypoglycemic agents
Nursing Implications
 Encourage patients to take medications
as prescribed.
 These medications should never be
stopped abruptly.
 Report constipation or the development of
any urinary hesitancy or bladder distention.
Nursing Implications
 Teach patients to change positions slowly to
prevent or minimize postural hypotension.
 Avoid caffeine (excessive irritability).
 Avoid alcohol ingestion and hazardous
activities until blood levels become stable.
 Patients should notify their physician if
palpitations, dyspnea, nausea, or vomiting
occur.

40
Beta Blocking Agents: Beta Blocking Agents: Adrenergic Blocking Agents:
Nursing Implications Nursing Implications Nursing Implications
 Rebound hypertension or chest pain may occur if this Patients should report the following to Monitor for side effects, including:
medication is discontinued abruptly.
their physician: Hypotension Fatigue
 Patients should notify their physician if they become ill
and unable to take medication.  Weight gain of more than 2 pounds (1 kg) Tachycardia (alpha blockers) Lethargy
within a week Bradycardia Depression
 Inform patients that they may notice a decrease in their
tolerance for exercise; dizziness and fainting may occur  Edema of the feet or ankles Heart block Insomnia
with increased activity. Notify the physician if these  Shortness of breath CHF Vivid nightmares
problems occur.  Excessive fatigue or weakness
Increased airway resistance
 Syncope or dizziness

Adrenergic Blocking Agents: Cholinergic Agents

Nursing Implications
Monitor for therapeutic effects  Drugs that stimulate the
 Decreased chest pain in patients with angina parasympathetic nervous system (PSNS)
 Return to normal BP and P
DRUGS AFFECTING THE
 The PSNS is the opposing system to
 Other specific effects, depending on the use AUTONOMIC NERVOUS SYSTEM the SNS

Cholinergic Agents and

Cholinergic Blocking Agents

41
Cholinergic Agents Cholinergic Agents Cholinergic Receptors

Also known as  Mimic the effects of the PSNS Two types, determined by:
 cholinergic agonists neurotransmitter  Location
 Acetylcholine (ACh)  Action once stimulated
or
 parasympathomimetics
Nicotinic receptors and Muscarinic receptors

Nicotinic Receptors Muscarinic Receptors Adrenergic Agents:

 Located in the ganglia of both the
PSNS and SNS
 Named “nicotinic” because can be stimulated
by the alkaloid nicotine
Mechanism of Action
 Located postsynaptically:  Direct-acting (agonist)
 Smooth muscle  Bind to cholinergic receptors, causing stimulation
 Cardiac muscle
 Glands of parasympathetic fibers
 Effector organs of cholinergic sympathetic fibers

 Named “muscarinic” because can be

stimulated by the alkaloid muscarine

42
Adrenergic Agents: Indirect-Acting Cholinergic Drug Effects of Cholinergic
Mechanism of Action Agents (Cholinesterase Agents
 Indirect-acting Inhibitors)
 Reversible  Effects seen when the PSNS is stimulated.
 Inhibit the enzyme “cholinesterase”  Bind to cholinesterase for a period of  The PSNS is the “rest and digest” system.
minutes to hours
Result: more ACh is available at the receptors  Irreversible
 Bind to cholinesterase and form a permanent
covalent bond
 The body must make new cholinesterase

Drug Effects of Cholinergic Drug Effects of Cholinergic Drug Effects of Cholinergic

Agents Agents Agents
“SLUDGE”  Stimulate intestine and bladder  Cardiovascular effects
 Salivation  Increased gastric secretions  Decreased heart rate
 Increased gastrointestinal motility  Vasodilation
 Lacrimation
 Increased urinary frequency
 Urinary incontinence  Respiratory effects
Diarrhea  Bronchial constriction, narrowed airways
  Stimulate pupil
 Gastrointestinal cramps  Constriction (miosis)
 Emesis  Reduced intraocular pressure

 Increased salivation and sweating

43
Drug Effects of Cholinergic Drug Effects of Cholinergic Cholinergic Agents:
Agents Agents Therapeutic Uses
 At recommended doses, the cholinergics  DESIRED EFFECTS: from muscarinic Direct-Acting Agents
primarily affect the MUSCARINIC receptors. receptor stimulation  Reduce intraocular pressure
 At high doses, cholinergics stimulate the  Many undesirable effects are due to  Useful for glaucoma and intraocular surgery
NICOTINIC receptors. stimulation of the nicotinic receptors Examples: acetylcholine, carbachol, pilocarpine

Topical application due to poor oral absorption

Cholinergic Agents: Cholinergic Agents: Cholinergic Agents:

Therapeutic Uses Therapeutic Uses Therapeutic Uses
Direct-Acting Agent—bethanechol Indirect-Acting Agents Indirect-Acting Agent—donepezil (Aricept)
 Increases tone and motility of bladder and GI tract  Cause skeletal muscle contractions  Used in the treatment of mild to moderate Alzheimer’s
 Relaxes sphincters in bladder and GI tract, allowing them  Used for diagnosis and treatment of disease.
to empty myasthenia gravis  Helps to increase or maintain memory and
 Helpful for postsurgical atony of the bladder  Used to reverse neuromuscular blocking agents learning capabilities.
and GI tract  Used to reverse anticholinergic poisoning (antidote)
Examples: physostigmine, pyridostigmine
Oral dose or SC injection

44
Cholinergic Agents: Side Cholinergic Agents: Side Cholinergic Agents:
Effects Effects Interactions
Side effects are a result of overstimulation Side effects are a result of  Anticholinergics, antihistamines,
of the PSNS.
overstimulation of the PSNS. sympathomimetics
 Cardiovascular:
 Respiratory:  Antagonize cholinergic agents, resulting
 Bradycardia, hypotension, conduction
abnormalities (AV block and cardiac arrest)  Increased bronchial secretions, bronchospasms in decreased responses
 CNS:  Other:

 Headache, dizziness, convulsions  Lacrimation, sweating, salivation, loss of binocular

accommodation, miosis
 Gastrointestinal:
 Abdominal cramps, increased secretions,
nausea, vomiting

Cholinergic Agents: Cholinergic Agents: Cholinergic Agents:

Nursing Implications
 Keep in mind that these agents will stimulate
the PSNS and mimic the action of ACh.
 Assess for allergies, presence of GI or GU
obstructions, asthma, peptic ulcer disease,
or coronary artery disease.
 Perform baseline assessment of VS and
systems overview.
Nursing Implications
 Medications should be taken as ordered
and not abruptly stopped.
 The doses should be spread evenly apart
to optimize the effects of the medication.
 Overdosing can cause life-threatening
problems. Patients should not adjust the
dosages unless directed by the physician.
Nursing Implications
 Encourage patients with myasthenia gravis to
take medication 30 minutes before eating to
help improve chewing and swallowing.
 When donepezil is prescribed for Alzheimer’s
disease, be honest with caregivers and
patients that the drug is for management
of symptoms, not for a cure.
 Therapeutic effects of donepezil may not
occur for up to 6 weeks.

45
Cholinergic Agents: Cholinergic Agents:
Nursing Implications Nursing Implications
 Atropine is the antidote for cholinergics. Monitor for side effects, including:
It should be available in the patient’s room for Increased respiratory
immediate use if needed. secretions
 Patients should notify their physician if they Bronchospasms
experience muscle weakness, abdominal Difficulty breathing
cramps, diarrhea, or difficulty breathing. Nausea and vomiting
Diarrhea
Increase in frequency and
urgency of voiding patterns
Cholinergic Agents:
Nursing Implications
Monitor for therapeutic effects:
Abdominal cramping  Alleviated signs and symptoms of myasthenia gravis
 In postoperative patients with decreased GI peristalsis, look
for:
Dysrhythmias
 Increased bowel sounds
Hypotension
 Passage of flatus
Bradycardia
 Occurrence of bowel movements
Increased sweating  In patients with urinary retention/hypotonic bladder,
urination should occur within 60 minutes of bethanecol
administration

Cholinergic Blocking Agents Cholinergic Blocking Agents: Cholinergic Blocking Agents:

 Drugs that block or inhibit the actions of
acetylcholine (ACh) in the parasympathetic
nervous system (PSNS)
Mechanism of Action Mechanism of Action
 Competitive antagonists
 Compete with ACh  Once these drugs bind to receptors, they
 Block ACh at the muscarinic receptors inhibit nerve transmission at these receptors.
in the PSNS
 As a result, ACh is unable to bind to the
receptor site and cause a cholinergic effect.

46
Cholinergic Blocking Agents: Drug Effects of Drug Effects of
Chemical Class Cholinergic Blocking Agents Cholinergic Blocking Agents
Natural Synthetic/Semisynthetic  Cardiovascular  Eye
atropine anisotropine clidinium  Small doses: decrease heart rate  Dilated pupils (mydriasis)
belladonna dicyclomine glycopyrrolate  Large doses: increase heart rate  Decreased accommodation due to paralysis
hyoscyamine hexocyclium homatropine  CNS of ciliary muscles (cycloplegia)
scopolamine ipratropium isopropamide  Small doses: decrease muscle rigidity  Gastrointestinal
oxybutynin propantheline and tremors  Relax smooth muscle tone of GI tract
tolterodine tridihexethyl  Large doses: drowsiness, disorientation,  Decrease intestinal and gastric secretions
hallucinations  Decrease motility and peristalsis

Drug Effects of Cholinergic Blocking Agents: Cholinergic Blocking Agents:

Cholinergic Blocking Agents Therapeutic Uses Therapeutic Uses
 Genitourinary
 Relaxed detrusor muscle
CNS Cardiovascular
 Increased constriction of internal sphincter Decreased muscle rigidity and muscle tremors Affect the heart’s conduction system
 Result: urinary retention  Parkinson’s disease  Low doses: slow the heart rate
 Glandular  High doses: block inhibitory vagal effects on
 Drug-induced extrapyramidal reactions
 Decreased bronchial secretions, salivation, sweating
the SA and AV node pacemaker cells
 Result: increased heart rate
 Respiratory
 Decreased bronchial secretions
 Dilated bronchial airways

47
Cholinergic Blocking Agents: Cholinergic Blocking Cholinergic Blocking Agents:
Therapeutic Uses Agents: Therapeutic Uses Therapeutic Uses
Respiratory Respiratory agents are used to treat:
Atropine
Blocking the cholinergic stimulation of the PSNS  Exercise-induced bronchospasms
Used primarily for cardiovascular disorders allows unopposed action of the SNS.  Chronic bronchitis
 Sinus node dysfunction  Results:  Asthma
 Symptomatic second-degree heart block  Decreased secretions from nose, mouth,  Chronic obstructive pulmonary disease
 Sinus bradycardia with hemodynamic compromise pharynx, bronchi
(advanced life support)  Relaxed smooth muscles in bronchi
and bronchioles
 Decreased airway resistance
 Bronchodilation

Cholinergic Blocking Agents: Cholinergic Blocking Agents: Cholinergic Blocking Agents:

Therapeutic Uses Therapeutic Uses Therapeutic Uses
Gastrointestinal agents are used to treat:
Gastrointestinal Genitourinary
 Peptic ulcer disease
PSNS controls gastric secretions and smooth  Irritable bowel disease
 Relaxed detrusor muscles of the bladder
muscles that produce gastric motility.  GI hypersecretory states  Increased constriction of the internal
 Blockade of PSNS results in: sphincter
 Decreased secretions  Reflex neurogenic bladder
 Relaxation of smooth muscle
 Incontinence
 Decreased GI motility and peristalsis

48
Cholinergic Blocking Agents:
Side Effects
Body System Side/Adverse Effects
Cardiovascular Increased heart rate,
dysrhythmias
CNS CNS excitation, restlessness,
irritability, disorientation,
hallucinations, delirium
Cholinergic Blocking Agents: Cholinergic Blocking Agents:
Side Effects Side Effects
Body System Side/Adverse Effects Body System Side/Adverse Effects
Eye Dilated pupils, decreased Genitourinary Urinary retention
visual accommodation,
Glandular Decreased sweating
increased intraocular pressure
Respiratory Decreased bronchial secretions
Gastrointestinal Decreased salivation,
decreased gastric secretions,
decreased motility

Cholinergic Blocking Agents: Cholinergic Blocking Agents: Cholinergic Blocking Agents:

Interactions
 Antihistamines, phenothiazines,
tricyclic antidepressants, MAOIs
 When given with cholinergic blocking
agents, cause ADDITIVE cholinergic
effects, resulting in increased effects
Nursing Implications
 Keep in mind that these agents will block
the action of ACh in the PSNS.
 Assess for allergies, presence of BPH,
glaucoma, tachycardia, MI, CHF, hiatal
hernia, and GI or GU obstruction.
 Perform baseline assessment of VS
and systems overview.
Nursing Implications
 Medications should be taken exactly as prescribed
to have the maximum therapeutic effect.
 Overdosing can cause life-threatening problems.
 Blurred vision may cause problems with driving
or operating machinery.
 Patients may experience sensitivity to light and
may want to wear dark glasses or sunglasses.

49
Cholinergic Blocking Agents:
Nursing Implications
 When giving ophthalmic solutions, apply pressure to the
inner canthus to prevent systemic absorption.
 Dry mouth may occur; can be handled by chewing gum,
frequent mouth care, and hard candy.
 Check with physician before taking any other
medication, including OTC medications.
 ANTIDOTE for atropine is physostigmine salicylate
(Antilirium).
Cholinergic Blocking Agents:
Nursing Implications
 Anticholinergics may lead to higher risk for
heat stroke due to effects on heat-regulating
mechanisms.
 Teach patients to limit physical exertion, and
avoid high temperatures and strenuous
exercise.
 Emphasize the importance of adequate fluid
and salt intake.
Cholinergic Blocking Agents:
Nursing Implications
 Patients should report the following to their
physician: urinary hesitancy and/or retention,
constipation, palpitations, tremors,
confusion, sedation or amnesia, excessive dry
mouth (especially if they have chronic lung
infections or disease), or fever

Cholinergic Agents: Cholinergic Blocking Agents:

Nursing Implications Nursing Implications
 Monitor for therapeutic effects: Monitor for side effects, including:
 For patients with Parkinson’s disease: Constipation Tachycardia
fewer tremors and decreased salivation Tremors Confusion OPIOID ANALGESIC AGENTS
and drooling Hallucinations Sedation
Urinary retention Hot, dry skin
 For patients with peptic ulcer disease:
Fever
decreased abdominal pain
CNS depression (occurs with large doses of atropine)

50
Analgesics Classification of Pain Classification of Pain
By Onset and Duration
 Somatic
 Medications that relieve pain without causing  Acute pain
 Visceral
loss of consciousness  Sudden in onset
 Superficial
 Painkillers  Usually subsides once treated
 Vascular
 Referred
 Chronic pain  Neuropathic
 Persistent or recurring  Phantom
 Often difficult to treat  Cancer
 Psychogenic
 Central

Classification of Pain By Pain Transmission Gate Pain Transmission

Source Theory
Vascular pain  Most common and well-described Tissue injury causes the release of:
 Possibly originates from vascular or  Uses the analogy of a gate to describe how  Bradykinin
perivascular tissues  Histamine
impulses from damaged tissues are sensed in
the brain  Potassium
Neuropathic pain
 Prostaglandins
 Results from injury to peripheral nerve fibers or damage
to the CNS  Serotonin
These substances stimulate nerve endings,
Superficial pain starting the pain process.
 Originates from skin or mucous membranes

51
Pain Transmission Pain Transmission Pain Transmission

There are two types of nerves stimulated: “A” Fibers “C” Fibers  Types of pain related to proportion of
 “A” fibers Myelin sheath No myelin sheath “A” to “C” fibers in the damaged areas
and Large fiber size Small fiber size
 “C” fibers Conduct fast Conduct slowly
Inhibit pain Facilitate pain transmission
transmission
Sharp and Dull and
well-localized nonlocalized

Pain Transmission Pain Transmission Pain Transmission

 These pain fibers enter the spinal cord
and travel up to the brain.
 The point of spinal cord entry is the
DORSAL HORN.
 The DORSAL HORN is the location
of the “GATE.”
 This gate regulates the flow of sensory  Activation of large “A” fibers CLOSES gate
impulses to the brain.  Inhibits transmission to brain
 Closing the gate stops the impulses.  Limits perception of pain
 If no impulses are transmitted to higher
centers in the brain, there is NO pain
perception.

52
Pain Transmission Pain Transmission Pain Transmission

 Activation of small “B” fibers OPENS gate
 Allows impulse transmission to brain
 Pain perception
 Gate innervated by nerve fibers from brain,
allowing the brain some control over gate
 Allows brain to:
 Evaluate, identify, and localize the pain
 Control the gate before the gate is open
“T” cells
 Cells that control the gate have a threshold
 Impulses must overcome threshold to be sent
to the brain

Pain Transmission Pain Transmission Opioid Analgesics

 Body has endogenous neurotransmitters
 Enkephalins
 Endorphins
 Produced by body to fight pain
 Bind to opioid receptors
 Inhibit transmission of pain by closing gate
Rubbing a painful area with massage or
liniment stimulates large sensory fibers
 Result:
 GATE closed, recognition of pain REDUCED
 Same pathway used by opiates
 Pain relievers that contain opium,
derived from the opium poppy
or
 chemically related to opium
Narcotics: very strong pain relievers

53
Opioid Analgesics Opioid Analgesics Opioid Analgesics: Site of
action
 codeine sulfate Three classifications based on their actions:  Large “A” fibers
 meperidine HCl (Demerol)  Agonist  Dorsal horn of spinal cord
 Agonist-antagonist
 methadone HCl (Dolophine)
 Partial agonist
 morphine sulfate
 propoxyphene HCl

Opioid Analgesics: Opioid Analgesics: Opioid Analgesics: Therapeutic

Mechanism of Action
 Bind to receptors on inhibitory fibers,
stimulating them
 Prevent stimulation of the GATE
 Prevent pain impulse transmission
to the brain
Mechanism of Action Uses
Three types of opioid receptors: Main use: to alleviate moderate to severe pain
 Mu  Opioids are also used for:
 Kappa  Cough center suppression
 Delta  Treatment of constipation

54
Opioid Analgesics: Side
Effects
 Euphoria
 Nausea and vomiting
 Respiratory depression
 Urinary retention
 Diaphoresis and flushing
 Pupil constriction (miosis)
 Constipation
Opiates: Physical Dependence
 The physiologic adaptation of the body to
the presence of an opioid
Opiate Antagonists
naloxone (Narcan)
naltrexone (Revia)
 Opiate antagonists
 Bind to opiate receptors and prevent a response
Used for complete or partial reversal of
opioid-induced respiratory depression
Opiates: Psychological
Dependence (addiction)
 A pattern of compulsive drug use
characterized by a continued craving for
an opioid and the need to use the opioid
for effects other than pain relief
Opiates: Opioid Tolerance
 A common physiologic result of chronic
opioid treatment
 Result: larger dose of opioids are required
to maintain the same level of
analgesia
Opiates
 Opioid tolerance and physical dependence
are expected with long-term opioid
treatment and should not be confused with
psychological dependence (addiction).
55
Opiates
 Misunderstanding of these terms leads to
ineffective pain management and contributes
to the problem of undertreatment.
Opioid Analgesics:
Nursing Implications
 Before beginning therapy, perform a
thorough history regarding allergies, use of
other medications,health history, and
medical history.
 Obtain baseline vital signs and I & O.
 Assess for potential contraindications and
drug interactions.
Opiates
 Physical dependence on opioids is seen when
the opioid is abruptly discontinued or when
an opioid antagonist is administered.
 Narcotic withdrawal
 Opioid abstinence syndrome
Opioid Analgesics:
Nursing Implications
 Perform a thorough pain assessment,
including nature and type of pain,
precipitating and relieving factors, remedies,
and other pain treatments.
 Assessment of pain is now being considered
a “fifth vital sign.”
Opiates
Narcotic Withdrawal Opioid Abstinence
Syndrome
 Manifested as:
 anxiety, irritability, chills and hot flashes, joint
pain, lacrimation, rhinorrhea, diaphoresis, nausea,
vomiting, abdominal cramps, diarrhea
Opioid Analgesics:
Nursing Implications
 Be sure to medicate patients before the pain
becomes severe as to provide adequate
analgesia and pain control.
 Pain management includes pharmacologic
and nonpharmacologic approaches. Be sure
to include other interventions as indicated.
56
Opioid Analgesics:
Nursing Implications
 Oral forms should be taken with food to
minimize gastric upset.
 Ensure safety measures, such as keeping side
rails up, to prevent injury.
 Withhold dose and contact physician if there
is a decline in the patient’s condition or if VS
are abnormal—especially if respiratory rate is
below 12 breaths/minute.
Opioid Analgesics:
Nursing Implications
 Follow proper administration guidelines for
IM injections, including site rotation.
 Follow proper guidelines for IV
administration, including dilution, rate of
administration, and so forth.
CHECK DOSAGES CAREFULLY
Opioid Analgesics:
Nursing Implications
 Constipation is a common side effect and
may be prevented with adequate fluid and
fiber intake.
 Instruct patients to follow directions for
administration carefully, and to keep a
record of their pain experience and
response to treatments.
 Patients should be instructed to change positions
slowly to prevent possible
orthostatic hypotension.

Opioid Analgesics: Opioid Analgesics: Opioid Analgesics:

Nursing Implications
 Patients should not take other medications or
OTC preparations without checking with their
physician.
 Instruct patients to notify physician for signs
of allergic reaction or adverse effects.
Nursing Implications
Monitor for side effects:
 Should VS change, patient’s condition decline,
or pain continue, contact physician immediately.
 Respiratory depression may be manifested by respiratory
rate of less than 12/min, dyspnea, diminished breath
sounds, or shallow breathing.
Nursing Implications
Monitor for therapeutic effects:
 Decreased complaints of pain
 Increased periods of comfort
 With improved activities of daily living, appetite,
and sense of well-being

57
 Psychotherapeutics Psychotherapeutics

 The therapy of emotional and mental  Anxiety

disorders
PSYCHOTHERAPEUTIC AGENTS  Grief
 Depression

Antidepressants are normal human emotions

and Antipsychotics

Psychotherapeutics Psychotherapeutics Psychotherapeutics

 The ability to cope with these emotions can Three main emotional and mental disorders:
 When these emotions significantly affect an
range from occasional depression or anxiety  Psychoses
individual’s ability to carry out normal daily
to constant emotional distress to the point  Affective disorders
functions, treatment with a
ofinterfering with the ability to carry on  Anxiety
psychotherapeutic drug is a possible option.
normal daily living.

58
Psychotherapeutics Psychotherapeutics Psychotherapeutics

Psychosis Affective Disorders Affective Disorders

 A major emotional disorder that impairs the mental
function of the affected individual to the point that the
individual cannot participate in everyday life.
 Hallmark: loss of contact with reality
 Major emotional disorders that impair the
mental function of the affected individual to
the point that the individual cannot
participate in everyday life.
 Mania: abnormally pronounced emotions
 Depression: abnormally reduced emotions
 Bipolar affective disorder: exhibits both mania and
depression

Psychotherapeutics Psychotherapeutics Psychotherapeutics

Pathophysiology Pathophysiology Pathophysiology

Biochemical Imbalance Biochemical Imbalance Biochemical Imbalance
 Mental disorders are associated with abnormal levels of  Brain levels of certain catecholamines play an important  Other biochemicals are necessary for normal
endogenous chemicals, such as neurotransmitters, in the role in maintaining mental health. mental function.
brain.  Dopamine  GABA
 Serotonin  acetylcholine
 Histamine  lithium

59
Etiology of Depression Affective Disorders Antidepressants

Biogenic Amine Hypothesis Drug Categories Cyclic antidepressants

 Depression and mania are due to an alteration in  Antidepressants  tricyclics
neuronal and synaptic catecholamine concentration at  tricyclics, tetracyclics, SSRIs, MAOIs  tetracyclics
adrenergic receptor sites in the brain.
 Antimanic Agents
 Depression: deficiency of catecholamine,  Monoamine oxidase inhibitors (MAOIs)
 lithium
especially norepinephrine  Second-generation antidepressants
 Mania: excess amines and SSRIs

Cyclic Antidepressants Cyclic Antidepressants Cyclic Antidepressants

 Tricyclic antidepressants—primary:
amitriptyline (Elavil), doxepin (Sinequan),
imipramine (Tofranil)
 Tricyclic antidepressants—secondary:
desipramine (Norpramin), nortriptyline
(Aventyl), protriptyline (Vivactil)
 Tetracyclic antidepressants:
amoxapine (Asendin), maprotiline (Ludiomil)
Mechanism of Action Mechanism of Action—Drug
 Block reuptake of neurotransmitters, causing Effects
Blockade of norepinephrine:
accumulation at the nerve endings.
 antidepressant, tremors, tachycardia, additive
 It is thought that increasing concentrations of pressor effects with sympathomimetic drugs
neurotransmitters will correct the abnormally Blockade of serotonin:
low levels that lead to depression.  antidepressant, nausea, headache, anxiety,
sexual dysfunction

60
Cyclic Antidepressants Cyclic Antidepressants Tricyclic Antidepressants
Therapeutic Uses Side Effects Overdose
 Depression  Sedation  Lethal—70 to 80% die before reaching
the hospital
 Childhood enuresis (imipramine)  Impotence
 CNS and cardiovascular systems are
 Obsessive-compulsive disorders  Orthostatic hypotension mainly affected
(clomipramine)  Older patients:  Death results from seizures or dysrhythmias
 Adjunctive analgesics  dizziness, postural hypotension, constipation,  No specific antidote
 Trigeminal neuralgia delayed micturation, edema, muscle tremors  Decrease drug absorption with activated charcoal
 Speed elimination by alkalinizing urine
 Manage seizures and dysrhythmias
 Basic life support

Antidepressants Antidepressants: MAOIs Antidepressants: MAOIs

Monoamine Oxidase Inhibitors: MAOIs
 Highly effective
 Considered second-line treatment for
depression not responsive to cyclics
 Disadvantage: potential to cause
hypertensive crisis when taken with tyramine
Mechanism of Action
 phenelzine (Nardil)  Inhibit the MAO enzyme system in the CNS
 tranylcypromine (Parnate)  Amines (dopamine, serotonin,
 isocarboxazid (Marplan) norepinephrine) are not broken down,
resulting in higher levels in the brain
 Result: alleviation of symptoms of
depression

61
Antidepressants: MAOIs Antidepressants: MAOIs Antidepressants: MAOIs
Therapeutic Uses Side Effects Overdose
 Depression, especially types characterized by  Few side effects—orthostatic hypotension  Symptoms appear 12 hours after ingestion
reverse vegetative symptoms such as most common  Tachycardia, circulatory collapse,
increased sleep and appetite Tachycardia Palpitations seizures, coma
 Depression that does not respond to other Dizziness Drowsiness  Treatment: protect brain and heart,
agents such as tricyclics Insomnia Headache eliminate toxin
Anorexia Nausea
 Gastric lavage
Blurred vision Impotence
 Urine acidification
 Hemodialysis

Antidepressants: MAOIs Antidepressants: MAOIs Second-Generation

Hypertensive Crisis and
Tyramine
 Ingestion of foods and/or drinks with
the amino acid TYRAMINE leads to
hypertensive crisis, which may lead
to cerebral hemorrhage, stroke,
coma, or death
Hypertensive Crisis and
Tyramine
Avoid foods that contain tyramine!
 Aged, mature cheeses (cheddar, blue, Swiss)
 Smoked/pickled or aged meats, fish, poultry (herring,
sausage, corned beef, salami, pepperoni, paté)
 Yeast extracts
 Red wines (Chianti, burgundy, sherry, vermouth)
 Italian broad beans (fava beans)
Antidepressants
 Newer
 Fewer side effects than tricyclics, but not
superior in overall efficacy or onset of action
 trazodone (Desyrel)
 bupropion (Wellbutrin, Zyban)
 selective serotonin reuptake inhibitors (SSRIs)

62
Second-Generation Second-Generation Second-Generation
Antidepressants and SSRIs Antidepressants Therapeutic Antidepressants Side Effects
Mechanism of Action Uses Body System Effects
 Used for depression—very few serious side effects
 Selectively inhibit serotonin reuptake  Bipolar affective disorder CNS Headache, dizziness,
 Little or no effect on norepinephrine or  Obesity
tremor, nervousness,
dopamine reuptake insomnia, fatigue
 Eating disorders
GI Nausea, diarrhea,
 Results in increased serotonin  Obsessive-compulsive disorder
constipation, dry mouth
concentrations at nerve endings  Panic attacks
Other Sweating, sexual
Advantage over tricyclics and MAOIs:  Myoclonus
dysfunction
 Treatment of various substance abuse problems (bupropion
Little or no effect on cardiovascular system [Zyban] is used for smoking cessation treatment)

Second-Generation Antipsychotics Antipsychotics

Antidepressants Drug
Interactions
 Highly bound to plasma proteins
 Compete with other protein-binding drugs,
resulting in more free, unbound drug to cause
a more pronounced drug effect
 Drugs used to treat serious mental illness
 Behavioral problems or psychotic disorders
 Thioxanthenes: chlorprothixene, thiothixene
(Navane)
 Butyrophenones: haloperidol (Haldol)
 Dihydroindolones: molindone (Moban)
 Dibenzoxazepine: loxapine (Loxitane)
 Phenothiazines: three structural groups

63
Antipsychotics Antipsychotics Antipsychotics: Mechanism of
Phenothiazine Structural Groups Atypical Antipsychotics Action
 Aliphatic: chlorpromazine (Thorazine),  clozapine (Clozaril)  Block dopamine receptors in the brain (limbic
triflupromazine (Vesprin)  risperidone (Risperdal) system, basal ganglia)—areas associated with
 Piperidine: mesoridazine (Serentil),  olanzapine (Zyprexa)
emotion, cognitive function, motor function
thioridazine (Mellaril)  quetiapine (Seroquel)  Dopamine levels in the CNS are decreased
 Piperazine: fluphenazine (Prolixin),  Result: tranquilizing effect in psychotic
perphenazine (Trilafon), prochlorperazine patients
(Compazine), trifluoperazine (Stelazine)
Largest group of psychotropic agents

Antipsychotics: Mechanism of Antipsychotics: Drug Antipsychotics: Therapeutic

Action
 The newer, atypical antipsychotics also block
specific serotonin receptors (serotonin-2
[5HT2] receptors).
 This is responsible for their improved efficacy
and safety profiles.
Effects Uses
 Block dopamine receptors in CNS  Treatment of serious mental illnesses:
 Block alpha receptors (causing hypertension,  Bipolar affective disorder
other cardiovascular effects)  Depressive and drug-induced psychoses
 Block histamine receptors (causing  Schizophrenia
anticholinergic effects)  Autism

 Block serotonin  Movement disorders (such as Tourette’s

syndrome)
 Also function as antiemetics
 Some medical conditions
 Antianxiety effects  Nausea, intractable hiccups

64
Antipsychotics: Side Effects
Body System Effects
CNS Sedation, delirium
Cardiovascular Orthostatic hypotension,
syncope, dizziness,
ECG changes
Dermatologic Photosensitivity, skin rash,
hyperpigmentation, pruritus
Antipsychotics: Side Effects Psychotherapeutic Agents:
Nursing Implications
Body System Effects  Before beginning therapy, assess both the
GI Dry mouth, constipation physical and emotional status of patients
GU Urinary hesitancy or  Obtain baseline VS, including postural BP
retention, impaired erection
Hematologic Leukopenia and
readings
agranulocytosis  Obtain liver and renal function tests (and
Metabolic/endocrine Galactorrhea, irregular baseline platelet levels for MAOIs)
menses
increased appetite,
polydipsia

Psychotherapeutic Agents: Psychotherapeutic Agents: Psychotherapeutic Agents:

Nursing Implications
 Assess for possible contraindications to
therapy, cautious use, and potential drug
interactions
 Assess LOC, mental alertness, potential
for injury to self and others
 Check the patient’s mouth to make sure
oral doses are swallowed
Nursing Implications
 Provide simple explanations about the drug,
its effects, and the length of time before
therapeutic effects can be expected
 Abrupt withdrawal should be avoided
 Advise patients to change positions slowly
to avoid postural hypotension and possible
injury
Nursing Implications
 The combination of drug therapy and
psychotherapy is emphasized because
patients need to learn and acquire more
effective coping skills
 Only small amounts of medications should be
dispensed at a time to minimize the risk of
suicide attempts
 Simultaneous use of these agents with
alcohol or other CNS depressants can
be fatal

65
Psychotherapeutic Agents: Psychotherapeutic Agents: Psychotherapeutic Agents:
Nursing Implications Nursing Implications Nursing Implications
Antidepressants Antidepressants Antidepressants
 Many cautions, contraindications, and interactions exist  Sedation often occurs with tricyclic therapy; notify  Tricyclics may need to be weaned and discontinued
pertaining to the use of antidepressants. physician if this lasts more than 2 weeks. before undergoing surgery to avoid interactions with
 Inform patients that it may take 1 to 3, even 4, weeks to  Assist elderly or weakened patients with ambulation and anesthetic agents.
see therapeutic effects. other activities as falls may occur due to drowsiness or  Monitor for side effects and discuss with patients.
 Monitor patients closely during this time and postural hypotension.  Encourage patients to wear medication ID badges
provide support. naming the agent being taken.

Psychotherapeutic Agents: Psychotherapeutic Agents: Psychotherapeutic Agents:

Nursing Implications
Antidepressants
 Caffeine and cigarette smoking may decrease
effectiveness of medication therapy
 Instruct patients and family regarding tyramine-
containing foods and signs and symptoms of
hypertensive crisis
Nursing Implications Nursing Implications
Antipsychotics—Phenothiazines Antipsychotics—Phenothiazines
 Instruct patients to wear sunscreen due to  Long-term haloperidol therapy may result in tremors,
photosensitivity nausea, vomiting, or uncontrollable shaking of small
 Avoid taking antacids or antidiarrheal preparations muscle groups; these symptoms should be reported to
within 1 hour of a dose the physician
 Do not take alcohol or other CNS depressants  Oral forms may be taken with meals to decrease
with these medications GI upset
 These agents may cause drowsiness, dizziness, or
fainting; instruct patients to change positions slowly

66
Psychotherapeutic Agents:
Nursing Implications
Monitor for therapeutic effects:
 Monitor mental alertness, cognition, affect,
mood,ability to carry out activities of daily
living, appetite, and sleep patterns
 Monitor the patient’s potential for self-injury
during the delay between the start of therapy
and symptomatic improvement
Psychotherapeutic Agents:
Nursing Implications
Monitor for therapeutic effects
 For antidepressants:
 Improved sleep patterns and nutrition, increased
feelings of self-esteem, decreased feeling of
hopelessness, increased interest in self and
appearance, increased interest in daily activities,
fewer depressive manifestations or suicidal
thoughts or ideations
Psychotherapeutic Agents:
Nursing Implications
Monitor for therapeutic effects
 For antipsychotics:
 Improved mood and affect, alleviation of
psychotic symptoms and episodes
 Decrease in hallucinations, paranoia, delusions,
garbled speech, inability to cope

CNS Depressants CNS Depressants

Sedatives Hypnotics
 Drugs that have an inhibitory effect on the  Calm or soothe the CNS to the point that they
CNS to the degree that they reduce: cause sleep
CENTRAL NERVOUS SYSTEM  Nervousness
 Excitability
DEPRESSANTS  Irritability
 without causing sleep

67
CNS Depressants Sedative-Hypnotics: Sedative-Hypnotics:
Barbiturates Barbiturates
Sedative-Hypnotics—dose dependent:  First introduced in 1903, standard agents Four categories:
 At low doses, calm or soothe the CNS without inducing for insomnia and sedation  Ultrashort
sleep  mephobexital, thiamylal, thiopental
 Habit-forming
 At high doses, calm or soothe the CNS  Short
 Only a handful commonly used today due  pentobarbital, secobarbital
 to the point of causing sleep
in part to the safety and efficacy of:  Intermediate
BENZODIAZEPINES  aprobarbital, butabarbital
 Long
 phenobarbital

Sedative-Hypnotics: Sedative-Hypnotics: Sedative-Hypnotics:

Barbiturates Barbiturates Barbiturates
Barbiturates have a very narrow therapeutic index. Mechanism of Action Drug Effects
 Site of action:  Low doses: Sedative effects
Therapeutic Index  Brain stem (reticular formation)
 Dosage range within which the drug is effective  Cerebral cortex  High doses: Hypnotic effects
but above which is rapidly toxic.  By inhibiting GABA, nerve impulses traveling in (also lowers respiratory rate)
the cerebral cortex are also inhibited.
Notorious enzyme inducers

68
Sedative-Hypnotics: Sedative-Hypnotics: Sedative-Hypnotics:
Barbiturates Barbiturates Barbiturates
Therapeutic Uses Side Effects Side Effects
 Hypnotics Body System Effects Body System Effects
 Sedatives CNS Drowsiness, lethargy, vertigo GI Nausea, vomiting, diarrhea
 Anticonvulsants mental depression, coma
 Surgical procedures Other Agranulocytosis,
Respiratory Respiratory depression, apnea, vasodilation, hypotension,
bronchospasms, cough Stevens-Johnson syndrome

Sedative-Hypnotics: Sedative-Hypnotics: CNS Depressants:

Barbiturates Barbiturates Benzodiazepines
Toxicology Drug Interactions Most frequently prescribed sedative-hypnotics
 Overdose frequently leads to respiratory depression, and  Additive effects:  Most commonly prescribed drug classes
subsequently, respiratory arrest.  ETOH, antihistamines, benzodiazepines,  Favorable side effects
 Can be therapeutic: narcotics, tranquilizers  Efficacy
 Anesthesia induction  Inhibited metabolism:  Safety
 Uncontrollable seizures: “phenobarbital coma”  MAOIs will prolong effects of barbiturates
 Increased metabolism:
 Reduces anticoagulant response, leading to
possible clot formation

69
CNS Depressants: CNS Depressants: CNS Depressants:
Benzodiazepines Benzodiazepines Benzodiazepines
Classified as either: Sedative-Hypnotic Type Anxiolytic Type
 Sedative-hypnotic or Anxiolytic  Long-Acting:  alprazolam (Xanax)
 flurazepam (Dalmane), quazepam (Doral)  chloridiazepoxide (Librium)

(Medication that relieves anxiety)  diazepam (Valium)

 Short-Acting:
 lorazepam (Ativan)
 estazolam (Prosom), temazepam (Restoril),
 midazolam (Versed)
 triazolam (Halcion)

zolpidem (Ambien) and zaleplon (Sonata)

(nonbenzodiazepine hypnotic agents, share characteristics)

CNS Depressants: CNS Depressants: CNS Depressants:

Benzodiazepines Benzodiazepines Benzodiazepines
Mechanism of Action Drug Effects Therapeutic Uses
 Sedation
 Depress CNS activity  Calming effect on the CNS
 Sleep induction
 Affect hypothalamic, thalamic, and limbic
 Useful in controlling agitation and anxiety  Skeletal muscle relaxation
systems of the brain
 Anxiety relief
 Benzodiazepine receptors  Treatment of alcohol withdrawal
 Agitation
 Depression
 Epilepsy
 Balanced anesthesia

70
CNS Depressants: CNS Depressants: CNS Depressants:
Benzodiazepines Nursing Implications Nursing Implications
Side Effects  Before beginning therapy, perform a  Give 15 to 30 minutes before bedtime for
thorough history regarding allergies, use maximum effectiveness in inducing sleep.
 Mild and infrequent of other medications,health history, and  Most benzodiazepines (except flurazepam)
Headache Drowsiness Dizziness medical history. cause REM rebound and a tired feeling the
Vertigo Lethargy  Obtain baseline vital signs and I & O, next day; use with caution in the elderly.
Paradoxical excitement
including supine and erect BPs.  Patients should be instructed to avoid alcohol
(nervousness) “Hangover effect”  Assess for potential disorders or conditions and other CNS depressants.
that may be contraindications, and for
potential drug interactions.

CNS Depressants: CNS Depressants: CNS Depressants:

Nursing Implications Nursing Implications Nursing Implications
 Check with physician before taking any other  Safety is important  Monitor for therapeutic effects
medications, including OTC medications.  Increased ability to sleep at night
 Keep side rails up
 It may take 2 to 3 weeks to notice improved  Fewer awakenings
sleep when taking barbiturates.  Do not permit smoking  Shorter sleep induction time
 Abruptly stopping these medications,  Assist patient with ambulation  Few side effects, such as hangover effects
especially barbiturates, may cause rebound (especially the elderly)  Improved sense of well-being because of
insomnia. improved sleep
 Keep call light within reach

 Monitor for side effects

71
 Hypertension Classification of Blood
Pressure
Category Systemic BP (mm Hg) Diastolic BP (mm Hg)
High blood pressure
 Normal: Systolic < 130 mm Normal <130 <85

ANTIHYPERTENSIVE AGENTS Hg Diastolic < 85 mm Hg High normal 130-139 85-89

Hypertension
Stage 1 140-159 90-99
Stage 2 160-169 100-109
Stage 3 180-209 110-119
Stage 4  210  120

Classification of Blood Blood Pressure = CO x SVR Antihypertensive Agents

Pressure
Primary Hypertension
 CO = Cardiac output  Medications used to treat hypertension
 Specific cause unknown
 90% of the cases  SVR = Systemic vascular resistance
 Also known as essential or idiopathic hypertension

Secondary Hypertension
 Cause is known (such as eclampsia of pregnancy, renal
artery disease, pheochromocytoma)
 10% of the cases

72
Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:
Categories Categories Mechanism of Action
 Adrenergic agents  Adrenergic Agents Adrenergic Agents
 Angiotensin-converting enzyme inhibitors  Alpha1 blockers Alpha1 Blockers (peripherally acting)
 Angiotensin II receptor blockers  Beta blockers (cardioselective and nonselective)  Block the alpha1-adrenergic receptors
 Centrally acting alpha blockers  The SNS is not stimulated
 Calcium channel blockers
 Combined alpha-beta blockers Result: DECREASED blood pressure
 Diuretics
 Peripheral-acting adrenergic agents
 Vasodilators  Stimulation of alpha1-adrenergic receptors
causes HYPERtension
 Blocking alpha1-adrenergic receptors causes decreased
blood pressure

Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:

Mechanism of Action
Adrenergic Agents Adrenergic Agents Adrenergic Agents
Alpha1 Blockers Central-Acting Adrenergics Central-Acting Adrenergics
 doxazosin (Cardura)  Stimulate alpha2-adrenergic receptors  clonidine (Catapres)
 prazosin (Minipress)  Sympathetic outflow from the CNS is decreased  methyldopa (Aldomet)
 terazosin (Hytrin) (drug of choice for hypertension in pregnancy)
Result: decreased blood pressure

73
Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:
Mechanism of Action Adrenergic Agents
Adrenergic Agents Adrenergic Agents Therapeutic Uses
Adrenergic Neuronal Blockers Adrenergic Neuronal Blockers  Alpha1 blockers (peripherally acting)

(peripherally acting) (peripherally acting)  Treatment of hypertension

 reserpine  Relief of symptoms of BPH
 Inhibit release of norepinephrine
 guanadrel (Hylorel)  Management of of severe CHF when used
 Also deplete norepinephrine stores with cardiac glycosides and diuretics
 guanethidine (Ismelin)
 SNS (peripheral adrenergic nerves) is not stimulated

Result: decreased blood pressure

Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:

Adrenergic Agents Adrenergic Agents Adrenergic Agents
Therapeutic Uses Therapeutic Uses Side Effects
 Central-Acting Adrenergics  Adrenergic neuronal blockers Most common: dry mouth drowsiness
 Treatment of hypertension, either alone or (peripherally acting) sedation constipation
with other agents  Treatment of hypertension, either alone or with Other: headaches sleep disturbances
 Usually used after other agents have failed other agents nausea rash
due to side effects cardiac disturbances (palpitations)
 Seldom used because of frequent side effects
 Also may be used for treatment of severe
dysmenorrhea, menopausal flushing, glaucoma HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION
 Clonidine is useful in the management of
withdrawal symptoms in opioid- or nicotine-
dependent persons

74
Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:
Categories Mechanism of Action Mechanism of Action
Angiotensin-Converting Enzyme Inhibitors ACE Inhibitors ACE Inhibitors
(ACE Inhibitors)  Aldosterone stimulates water and sodium resorption.
 Large group of safe and effective drugs RAAS: Renin Angiotensin-Aldosterone System  Result: increased blood volume, increased preload, and
increased B
 Often used as first-line agents for CHF  When the enzyme angiotensin I is converted to
and hypertension angiotensin II, the result is potent vasoconstriction and
 May be combined with a thiazide diuretic stimulation of aldosterone
or calcium channel blocker
 Result of vasoconstriction: increased systemic vascular
resistance and increased afterload

 Therefore, increased BP

Antihypertensive Agents: Antihypertensive Agents Antihypertensive Agents:

Mechanism of Action Therapeutic Uses
ACE Inhibitors
ACE Inhibitors ACE Inhibitors
 captopril (Capoten)
 ACE Inhibitors block the angiotensin-converting enzyme,  Hypertension
thus preventing the formation of angiotensin II.  Short half-life, must be dosed more frequently
than others  CHF (either alone or in combination with diuretics
 Also prevent the breakdown of the vasodilating or other agents)
 enalapril (Vasotec)
substance, bradykinin  Slows progression of left ventricular hypertrophy after an
 The only ACE inhibitor available in oral and parenteral forms
MI
Result: decreased systemic vascular resistance (afterload),  lisinopril (Prinivil and Zestril) and quinapril (Accupril)
vasodilation, and therefore, decreased blood pressure
 Renal protective effects in patients with diabetes
 Newer agents, long half-lives, once-a-day dosing Drugs of choice in hypertensive patients with CHF
 Several other agents available

75
Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:
Side Effects Categories Mechanism of Action
ACE Inhibitors Angiotensin II Receptor Blockers (A II Blockers Angiotensin II Receptor Blockers
 Fatigue Dizziness or ARBs)  Allow angiotensin I to be converted to angiotensin II, but
 Headache Mood changes  Newer class block the receptors that receive angiotensin II

 Impaired taste  Well-tolerated  Block vasoconstriction and release of aldosterone

 Do not cause coughing
Dry, nonproductive cough, reverses when therapy is stopped

NOTE: first-dose hypotensive effect may occur!!

Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:

Therapeutic Uses Side Effects
Angiotensin II Receptor Blockers Angiotensin II Receptor Blockers Angiotensin II Receptor Blockers
 losartan (Cozaar)  Hypertension  Upper respiratory infections
 eposartan (Teveten)  Adjunctive agents for the treatment of CHF  Headache
 valsartan (Diovan)  May be used alone or with other agents such  May cause occasional dizziness, inability to sleep,
 irbesartan (Avapro) as diuretics diarrhea, dyspnea, heartburn, nasal congestion, back
pain, fatigue
 candesartan (Atacand)
 telmisartan (Micardis)

76
Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents
Categories Mechanism of Action
Calcium Channel Blockers Calcium Channel Blockers Calcium Channel Blockers
 Benzothiazepines  Cause smooth muscle relaxation by blocking the binding  Benzothiazepines:
 Dihydropyridines of calcium to its receptors, preventing muscle
 diltiazem (Cardizem, Dilacor)
contraction
 Phenylalkylamines
 This causes decreased peripheral smooth muscle tone,  Phenylalkamines:
decreased systemic vascular resistance  verapamil (Calan, Isoptin)
 Result: decreased blood pressure  Dihydropyridines:
 amlodipine (Norvasc), bepridil (Vascor),
nicardipine (Cardene)
 nifedipine (Procardia), nimodipine (Nimotop)

Antihypertensive Agents: Antihypertensive Agents: Antihypertensive Agents:

Therapeutic Uses Side Effects Diuretics
Calcium Channel Blockers Calcium Channel Blockers  Decrease the plasma and extracellular fluid volumes
 Angina  Cardiovascular  Results: decreased preload
 Hypertension  hypotension, palpitations, tachycardia decreased cardiac output
 Dysrhythmias decreased total peripheral resistance
 Migraine headaches  Gastrointestinal
 constipation, nausea  Overall effect: decreased workload of the heart,
and decreased blood pressure
 Other
 rash, flushing, peripheral edema, dermatitis

77
Antihypertensive Agents: Antihypertensive Agents Antihypertensive Agents:
Mechanism of Action Therapeutic Uses
Vasodilators Vasodilators Vasodilators
 diazoxide (Hyperstat)  Treatment of hypertension
 Directly relaxes arteriolar smooth muscle
 hydralazine HCl (Apresoline)  May be used in combination with other agents
 Result: decreased systemic vascular response,  minoxidil (Loniten, Rogaine)  Sodium nitroprusside and diazoxide IV are reserved for
decreased afterload, and  sodium nitroprusside (Nipride, Nitropress) the management of hypertensive emergencies
PERIPHERAL VASODILATION

Antihypertensive Agents: Side Antihypertensive Agents: Antihypertensive Agents:

Effects Nursing Implications Nursing Implications
Vasodilators  Before beginning therapy, obtain a thorough  Educate patients about the importance of not missing a
dose and taking the medications exactly as prescribed.
 Hydralazine: health history and head-to-toe physical
examination.  Patients should never double up on doses if a dose is
 dizziness, headache, anxiety, tachycardia, nausea missed; check with physician for instructions on what to
and vomiting, diarrhea, anemia, do if a dose is missed.
dyspnea, edema, nasal congestion  Assess for contraindications to specific
antihypertensive agents.  Monitor BP during therapy. Instruct patients to
keep a journal of regular BP checks.
 Sodium nitroprusside:
 Assess for conditions that require cautious
 bradycardia, hypotension, possible use of these agents.
cyanide toxicity

78
Antihypertensive Agents:
Nursing Implications
 Instruct patients that these drugs should not be stopped
abruptly, as this may cause a rebound hypertensive crisis,
and perhaps lead to CVA.
 Oral forms should be given with meals so that absorption
is more gradual and effective.
 Administer IV forms with extreme caution and
use an IV pump.
Antihypertensive Agents:
Nursing Implications
 Men taking these agents may not be aware that
impotence is an expected effect. This may influence
compliance with drug therapy.
 If patients are experiencing serious side effects,
or believe that the dose or medication needs to
be changed, they should contact their physician
immediately.
Antihypertensive Agents:
Nursing Implications
 Remind patients that medications is only part of therapy.
Encourage patients to watch their diet, stress level,
weight, and alcohol intake.
 Patients should avoid smoking and eating foods high in
sodium.
 Encourage supervised exercise.
Antihypertensive Agents:
Nursing Implications
 Hot tubs, showers, or baths; hot weather; prolonged
sitting or standing; physical exercise; and alcohol
ingestion may aggravate low blood pressure, leading to
fainting and injury. Patients should
sit or lie down until symptoms subside.
 Patients should not take any other medications,
including OTC drugs, without first getting the approval of
their physician.
Antihypertensive Agents:
Nursing Implications
 Instruct patients to change positions slowly to avoid
syncope from postural hypotension.
 Patients should report unusual shortness of breath;
difficulty breathing; swelling of the feet, ankles, face, or
around the eyes; weight gain or loss; chest pain;
palpitations; or excessive fatigue.
Antihypertensive Agents:
Nursing Implications
 Monitor for side/adverse effects
(dizziness, orthostatic hypotension, fatigue)
and for toxic effects.
 Monitor for therapeutic effects
 Blood pressure should be maintained at less
than 140/90 mm Hg
79
 Diuretic Agents Sodium

 Drugs that accelerate the rate of urine
formation.
DIURETIC AGENTS  Result: removal of sodium and water
 Where sodium goes, water follows.
 20 to 25% of all sodium is reabsorbed
into the bloodstream in the loop of Henle,
5 to 10% in the distal tubules, and 3%
in collecting ducts.
 If it is not absorbed, it is excreted with
the urine.

Diuretic Agents Carbonic Anhydrase Carbonic Anhydrase Inhibitors:

Inhibitors Mechanism of Action
(CAIs)  The enzyme carbonic anhydrase helps to make
 Carbonic anhydrase inhibitors H+ ions available for exchange with sodium and water in
 acetazolamide (Diamox)
 Loop diuretics the proximal tubules.
 methazolamide
 Osmotic diuretics  dichlorphenamide  CAIs block the action of carbonic anhydrase, thus
 Potassium-sparing diuretics preventing the exchange of H+ ions with sodium
and water.
 Thiazide and thiazide-like diuretics

80
Carbonic Anhydrase Inhibitors: Carbonic Anhydrase Inhibitors:
Mechanism of Action Therapeutic Uses
 Inhibition of carbonic anhydrase reduces H+ ion  Adjunct agents in the long-term management
concentration in renal tubules. of open-angle glaucoma
 As a result, there is increased excretion of bicarbonate,  Used with miotics to lower intraocular pressure before
sodium, water, and potassium. ocular surgery in certain cases
 Also useful in the treatment of:
 Resorption of water is decreased and urine
 Glaucoma
volume is increased.
 Edema
Carbonic Anhydrase Inhibitors:
Therapeutic Uses
 Acetazolamide is used in the management of
edema secondary to CHF when other diuretics
are not effective.
 CAIs are less potent diuretics than loop diuretics
or thiazides—the metabolic acidosis they induce reduces
their diuretic effect in 2 to 4 days.

 Epilepsy
 High-altitude sickness

Carbonic Anhydrase Inhibitors: Loop Diuretics Loop Diuretics:

Side Effects Mechanism of Action
Metabolic acidosis Drowsiness  bumetanide (Bumex)  Act directly on the ascending limb of the
Anorexia Paresthesias  ethacrynic acid (Edecrin) loop of Henle to inhibit sodium and chloride
resorption.
Hematuria Urticaria  furosemide (Lasix)
Photosensitivity Melena  Increase renal prostaglandins, resulting in the
dilation of blood vessels and reduced peripheral
vascular resistance.

81
Loop Diuretics: Drug Loop Diuretics: Loop Diuretics: Side
Effects Therapeutic Uses Effects
 Potent diuresis and subsequent loss of fluid  Edema associated with CHF or hepatic Body System Effect
 Decreased fluid volume causes: or renal disease CNS Dizziness, headache,
 Reduced BP
 Control of hypertension tinnitus, blurred vision
 Reduced pulmonary vascular resistance
 Reduced systemic vascular resistance
GI Nausea, vomiting,
 Reduced central venous pressure
diarrhea
 Reduced left ventricular end-diastolic pressure

 Potassium depletion

Loop Diuretics: Side Effects Osmotic Diuretics Osmotic Diuretics:

Mechanism of Action
Body System Effect  mannitol (Resectisol, Osmitrol)  Work in the proximal tubule
Hematologic Agranulocytosis,  Nonabsorbable, producing an osmotic effect
neutropenia,  Pull water into the blood vessels and
thrombocytopenia nephrons from the surrounding tissues
Metabolic Hypokalemia,
hyperglycemia,
hyperuricemia

82
Osmotic Diuretics: Drug
Effects
 Reduced cellular edema
 Increased urine production, causing diuresis
 Rapid excretion of water, sodium, and other
electrolytes, as well as excretion of toxic
substances from the kidney
 Reduces excessive intraocular pressure
Potassium-Sparing Diuretics
 amiloride (Midamor)
 spironolactone (Aldactone)
 triamterene (Dyrenium)
Osmotic Diuretics: Osmotic Diuretics: Side
Therapeutic Uses Effects
 Used in the treatment of patients in the early,  Convulsions
oliguric phase of ARF  Thrombophlebitis
 To promote the excretion of toxic substances  Pulmonary congestion
 Reduction of intracranial pressure
 Treatment of cerebral edema Also headaches, chest pains, tachycardia,
blurred vision, chills, and fever
Potassium-Sparing Diuretics: Potassium-Sparing Diuretics:
Mechanism of Action Drug Effects
 Work in collecting ducts and distal  Prevent potassium from being pumped into
convoluted tubules the tubule, thus preventing its secretion
 Interfere with sodium-potassium exchange
 Competitively bind to aldosterone receptors  Competitively block the aldosterone
receptors and inhibit its action
 Block the resorption of sodium and water
usually induced by aldosterone
 The excretion of sodium and water
is promoted
83
Potassium-Sparing Diuretics: Potassium-Sparing Diuretics: Potassium-Sparing Diuretics:
Therapeutic Uses Side Effects Side Effects
spironolactone and triamterene Body System Effect spironolactone
 Hyperaldosteronism  gynecomastia, amenorrhea, irregular menses
CNS Dizziness, headache
 Hypertension
 Reversing the potassium loss caused by GI Cramps, nausea,
vomiting, diarrhea
 potassium-losing drugs
Other Urinary frequency,
amiloride weakness
**hyperkalemia
 Treatment of CHF

Thiazide and Thiazide-Like Thiazide and Thiazide-Like Thiazide and Thiazide-Like

Diuretics
 hydrochlorothiazide (Esidrix, HydroDIURIL)
 chlorothiazide (Diuril)
 trichlormethiazide (Metahydrin)
Diuretics: Mechanism of Action
 Inhibit tubular resorption of sodium and chloride ions
 Action primarily in the ascending loop of Henle and
early distal tubule
Diuretics: Drug Effects
 Lowered peripheral vascular resistance
 Depletion of sodium and water

 Thiazide-like  Result: water, sodium, and chloride are excreted

 chlorthalidone (Hygroton)  Potassium is also excreted to a lesser extent

 metolazone (Mykrox, Zaroxolyn)

 Dilate the arterioles by direct relaxation

84
 Thiazide and Thiazide-Like Thiazide and Thiazide-Like Thiazide and Thiazide-Like
Diuretics: Therapeutic Uses Diuretics: Side Effects Diuretics: Side Effects
 Hypertension Body System Effect Body System Effect
(one of the most prescribed group of agents for this) CNS Dizziness, headache, GU Impotence
blurred vision, paresthesias, Integumentary Urticaria, photosensitivity
 Edematous states decreased libido
Metabolic Hypokalemia, glycosuria,
 Idiopathic hypercalciuria
GI Anorexia, nausea, vomiting, hyperglycemia
diarrhea
 Diabetes insipidus

 Adjunct agents in treatment of CHF, hepatic cirrhosis

Diuretic Agents: Diuretic Agents: Diuretic Agents:

Nursing Implications Nursing Implications Nursing Implications
 Perform a thorough patient history and physical  Instruct patients to take in the morning as much as  Teach patients to maintain proper nutritional and fluid
examination. possible to avoid interference with sleep patterns. volume status.

 Assess baseline fluid volume status, intake and output,
serum electrolyte values, weight, and vital signs.
 Assess for disorders that may contraindicate the use of,
or necessitate cautious use of, these agents.
 Monitor serum potassium levels during therapy.
 Potassium supplements are usually not recommended
when potassium levels exceed
3.0 mEq/L.
 Teach patients to eat more potassium-rich foods when
taking any but the potassium-sparing agents.
 Foods high in potassium include bananas, oranges,
dates, raisins, plums, fresh vegetables, potatoes, meat,
and fish.

85
Diuretic Agents: Diuretic Agents: Diuretic Agents: Nursing
Nursing Implications Nursing Implications Implications
 Patients taking diuretics along with a digitalis  Teach patients to change positions slowly, and to rise  Patients who have been ill with nausea, vomiting, and/or
preparation should be taught to monitor for slowly after sitting or lying to prevent dizziness and diarrhea should notify their physician as fluid loss may be
digitalis toxicity. possible fainting related to orthostatic hypotension. dangerous.

 Diabetic patients who are taking thiazide and/or
loop diuretics should be told to monitor blood glucose
and watch for elevated levels.
 Encourage patients to keep a log of their  Signs and symptoms of hypokalemia include muscle
daily weight. weakness, constipation, irregular pulse rate, and overall
feeling of lethargy.
 Encourage patients to return for follow-up visits
and lab work.

Diuretic Agents: Diuretic Agents: Diuretic Agents:

Nursing Implications
 Instruct patients to notify the physician immediately if
they experience rapid heart rates or syncope (reflects
hypotension or fluid loss).
 A weight gain of 2 or more pounds a day
or 5 or more pounds a week should be
reported immediately.
Nursing Implications Nursing Implications
Monitor for adverse effects:  Monitor for therapeutic effects:
 metabolic alkalosis, drowsiness, lethargy, hypokalemia,  Reduction in edema, fluid volume overload, CHF
tachycardia, hypotension, leg  Reduction of hypertension
cramps, restlessness, decreased mental alertness
 Return to normal intraocular pressures

86
 Antianginal Agents Angina Pectoris (Chest Pain)

 Nitrates  When the supply of oxygen and nutrients in

 Beta blockers the blood is insufficient to meet the demands
ANTIANGINAL AGENTS  Calcium channel blockers
of the heart, the heart muscle aches.
 The heart demands a large supply of oxygen
to meet the demands placed on it.

Types of Angina Antianginal Agents: Antianginal Agents:

 Chronic stable angina Therapeutic Objectives Therapeutic Objectives

(also called classic or effort angina)
 Unstable angina
(also called preinfarction or crescendo angina)
 Vasospastic angina
(also called Prinzmetal’s or variant angina)
 Increase blood flow to ischemic heart muscle
and/or
 Decrease myocardial oxygen demand
 Minimize the frequency of attacks and decrease the
duration and intensity of anginal pain
 Improve the patient’s functional capacity with as few side
effects as possible
 Prevent or delay the worst possible outcome, MI

87
Antianginal Agents: Antianginal Agents: Antianginal Agents: Nitrates
Nitrates Nitrates
Available forms:  Cause vasodilation due to relaxation of Nitroglycerin
Sublingual Ointments smooth muscles  Prototypical nitrate
Buccal Transdermal patches  Large first-pass effect with PO forms
Chewable tablets Inhalable sprays  Potent dilating effect on coronary arteries  Used for symptomatic treatment of ischemic heart
Capsules Intravenous solutions conditions (angina)
 Used for prophylaxis and treatment  IV form used for BP control in perioperative
of angina hypertension, treatment of CHF, ischemic pain,
and pulmonary edema associated with acute MI

Antianginal Agents: Nitrates Antianginal Agents: Nitrates Antianginal Agents: Beta

Blockers
 isosorbide dinitrate Side Effects  atenolol (Tenormin)
(Isordil, Sorbitrate, Dilatrate SR)
 Headache  metoprolol (Lopressor)
 isosorbide mononitrate
 Usually diminish in intensity and frequency
(Imdur, Monoket, ISMO)  propranolol (Inderal)
with continued use
Used for:  Tachycardia, postural hypotension
 nadolol (Corgard)
 Acute relief of angina  Tolerance may develop
 Prophylaxis in situations that may provoke angina
 Long-term prophylaxis of angina

88
 Antianginal Agents: Beta Antianginal Agents: Beta Antianginal Agents: Beta
Blockers Blockers Blockers
Mechanism of Action Therapeutic Uses Side Effects
 Decrease the HR, resulting in decreased myocardial  Antianginal Body System Effects
oxygen demand and increased oxygen delivery to the  Antihypertensive Cardiovascular bradycardia, hypotension
heart second- or third-degree heart block
 Cardioprotective effects, especially after MI
 Decrease myocardial contractility, helping to conserve heart failure
energy or decrease demand Metabolic Altered glucose and lipid
metabolism

Antianginal Agents: Beta Antianginal Agents: Antianginal Agents:

Blockers Calcium Channel Blockers Calcium Channel Blockers
 verapamil (Calan) Mechanism of Action
Side Effects
 diltiazem (Cardizem)  Cause peripheral arterial vasodilation
Body System Effects  Reduce myocardial contractility
CNS dizziness, fatigue,  nifedipine (Procardia)
(negative inotropic action)
mental depression, lethargy,
 Result: decreased myocardial oxygen demand
drowsiness, unusual dreams
Other impotence
wheezing, dyspnea

89
Antianginal Agents:
Calcium Channel Blockers
Therapeutic Uses
 First-line agents for treatment of angina, hypertension,
and supraventricular tachycardia
 Short-term management of atrial fibrillation and flutter
 Several other uses
Antianginal Agents:
Nursing Implications
 Patients should not take any medications,
including OTC medications, without checking
with the physician.
 Patients should report blurred vision,
persistent headache, dry mouth, dizziness,
edema, fainting episodes, weight gain of
2 pounds in 1 day or 5 or more pounds in
1 week, pulse rates under 60, and any
dyspnea.
Antianginal Agents:
Calcium Channel Blockers
Side Effects
 Very acceptable side effect and safety profile
 May cause hypotension, palpitations, tachycardia
or bradycardia, constipation, nausea, dyspnea
Antianginal Agents:
Nursing Implications
 Alcohol consumption and hot baths or spending
time in jacuzzis, hot tubs, or saunas will result in
vasodilation, hypotension, and the possibility of fainting.
 Teach patients to change positions slowly to avoid
postural BP changes.
 Encourage patients to keep a record of their anginal
attacks, including precipitating factors, number of pills
taken, and therapeutic effects.
Antianginal Agents:
Nursing Implications
 Before administering, perform a complete
health history to determine presence of
conditions that may be contraindications
for use or call for cautious use.
 Obtain baseline VS, including respiratory
patterns and rate.
 Assess for drug interactions.
Antianginal Agents:
Nitroglycerin
Nursing Implications
 Instruct patients in proper technique and guidelines for
taking sublingual NTG for anginal pain.
 Instruct patients never to chew or swallow the
SL form.
 Instruct patients that a burning sensation felt with
SL forms indicates that the drug is still potent.
90
Antianginal Agents: Antianginal Agents: Antianginal Agents:
Nitroglycerin Nitroglycerin Nitroglycerin
Nursing Implications Nursing Implications Nursing Implications
 Instruct patients to keep a fresh supply of NTG on hand;  Instruct patients in the proper application of nitrate  Instruct patients to take prn nitrates at the first hint
potency is lost in about 3 months after the bottle has topical ointments and transdermal forms, including site of anginal pain.
been opened. rotation and removal of old medication.  If experiencing chest pain, the patient taking SL NTG
 Medications should be stored in an airtight, dark glass  To reduce tolerance, the patient may be instructed to should be lying down to prevent or decrease dizziness
bottle with a metal cap and no cotton filler remove topical forms at bedtime, and apply new doses in and fainting that may occur due to hypotension.
to preserve potency. the morning, allowing for a nitrate-free period.  Monitor VS frequently during acute exacerbations
of angina and during IV administration.

Antianginal Agents: Antianginal Agents: Antianginal Agents: Beta

Nitroglycerin
Nursing Implications
 IV forms of NTG must be contained in glass IV bottles
and must be given with infusion pumps.
 Discard parenteral solution that is blue, green,
or dark red.
 Follow specific manufacturer’s instructions for IV
administration. Use special IV tubing provided or non-
PVC tubing.
Calcium Channel Blockers Blockers
Nursing Implications Nursing Implications
 Blood levels should be monitored to ensure they  Patients taking beta blockers should monitor pulse rate
are therapeutic. daily and report any rate lower than 60 beats per minute.
 Oral CCBs should be taken before meals and  Dizziness or fainting should also be reported.
as ordered.  Constipation is a common problem. Instruct patients to
 Patients should be encouraged to limit take in adequate fluids and eat high-fiber foods.
caffeine intake.

91
Antianginal Agents: Beta Antianginal Agents:
Blockers Nursing Implications
Nursing Implications  Monitor for adverse reactions
 These medications should never be abruptly  Allergic reactions, headache, light-headedness,
discontinued due to risk of rebound hypertensive crisis. hypotension, dizziness ANTIDYSRHYTHMIC AGENTS
 Inform patients that these medications are for
long-term prevention of angina, not for  Monitor for therapeutic effects
immediate relief.
 Relief of angina, decreased BP, or both

Antidysrhythmics Cardiac Cell Resting Membrane Potential:

RMP
Dysrhythmia  Inside the cardiac cell, there exists a net  This difference in the electronegative charge.
 Any deviation from the normal rhythm of the heart negative charge relative to the outside of  Results from an uneven distribution of ions
the cell. (sodium, potassium, calcium) across the cell
Antidysrhythmics membrane.
 Drugs used for the treatment and prevention of  An energy-requiring pump is needed to
disturbances in cardiac rhythm
maintain this uneven distribution of ions.
 Sodium-potassium ATPase pump

92
Action Potential Action Potential Vaughan Williams
Classification
 A change in the distribution of ions causes Four Phases  System commonly used to classify
cardiac cells to become excited.  The SA node and the Purkinje cells each have separate antidysrhythmic drugs
action potentials.
 The movement of ions across the cardiac
cell’s membrane results in the propagation
of an electrical impulse.

 This electrical impulse leads to contraction

of the myocardial muscle.

Vaughan Williams Vaughan Williams Vaughan Williams

Classification Classification Classification
 Class 1 Class I Class I
 Class Ia
 Class Ib
 Membrane-stabilizing agents moricizine
 Class Ic  Fast sodium channel blockers  General Class I agent
 Class II  Divided into Ia, Ib, and Ic agents, according  Has characteristics of all three subclasses
 Class III to effects  Used for symptomatic ventricular and life-threatening
 Class IV dysrhythmias
 Other

93
Vaughan Williams Vaughan Williams Vaughan Williams
Classification Classification Classification
Class Ia Class Ib Class Ic
quinidine, procainamide, disopyramide tocainide, mexiletine, phenytoin, lidocaine encainide, flecainide, propafenone
 Block sodium channels  Block sodium channels  Block sodium channels (more pronounced effect)
 Delay repolarization  Accelerate repolarization  Little effect on APD or repolarization
 Increase the APD  Decrease the APD  Used for severe ventricular dysrhythmias
 Used for atrial fibrillation, premature atrial  Used for ventricular dysrhythmias only  May be used in atrial fibrillation/flutter
contractions, premature ventricular contractions, (premature ventricular contractions, ventricular
ventricular tachycardia, Wolff-Parkinson-White tachycardia, ventricular fibrillation)
syndrome

Vaughan Williams Vaughan Williams Vaughan Williams

Classification
Class II
Beta blockers: atenolol, esmolol, petaprolol,
propranolol
 Reduce or block sympathetic nervous system
stimulation, thus reducing transmission of impulses in
the heart’s conduction system
 Depress phase 4 depolarization
 General myocardial depressants for both
supraventricular and ventricular dysrhythmias
Classification Classification
Class III Class IV
amiodarone, bretylium, sotalol, ibutilide verapamil, diltiazem
 Increase APD  Calcium channel blockers
 Prolong repolarization in phase 3  Depress phase 4 depolarization
 Used for dysrhythmias that are difficult to treat  Used for paroxysmal supraventricular tachycardia; rate
 Life-threatening ventricular tachycardia or fibrillation, control for atrial fibrillation and flutter
atrial fibrillation or flutter—resistant to other drugs
 Sustained ventricular tachycardia

94
Vaughan Williams Antidysrhythmics Antidysrhythmics
Classification
Other Antidysrhythmics Digoxin adenosine (Adenocard)
digoxin, adenosine  Cardiac glycoside  Slows conduction through the AV node
 Have properties of several classes and are not placed into  Inhibits the sodium-potassium ATPase pump  Used to convert paroxysmal supraventricular tachycardia
one particular class to sinus rhythm
 Positive inotrope—improves the strength of cardiac
contraction  Very short half-life
 Only administered as fast IV push
 Allows more calcium to be available for contraction
 May cause asystole for a few seconds
 Used for CHF and atrial dysrhythmias
 Other side effects minimal
 Monitor potassium levels, drug levels, and
for toxicity

Antidysrhythmics: Side Antidysrhythmics: Antidysrhythmics:

Effects Nursing Implications Nursing Implications
 Obtain a thorough drug and medical history.  Assess for conditions that may be
ALL antidysrhythmics can cause dysrhythmias!!
 Measure baseline BP, P, I & O, and contraindications for use of specific agents.
 Hypersensitivity reactions
 Nausea cardiac rhythm.  Assess for potential drug interactions.
 Vomiting  Measure serum potassium levels before  Instruct patients regarding dosing schedules
 Diarrhea initiating therapy. and side effects to report to physician.
 Dizziness
 Blurred vision
 Headache

95
Antidysrhythmics:
Nursing Implications
 During therapy, monitor cardiac rhythm,
heart rate, BP, general well-being, skin color,
temperature, heart and breath sounds.
 Assess plasma drug levels as indicated.
 Monitor for toxic effects.
Antidysrhythmics:
Nursing Implications
 Patients taking propranolol, digoxin, and
other agents should be taught how to take
their own radial pulse for 1 full minute, and to
notify their physician if the pulse is less than
60 beats/minute before taking the next dose
of medication.
Antidysrhythmics: Antidysrhythmics:
Nursing Implications Nursing Implications
 Instruct patients to take medications as  For class I agents, monitor ECG for QT
scheduled and not to skip doses or double up intervals prolonged more than 50%.
for missed doses.  IV infusions should be administered with
 Patients who miss a dose should contact their an IV pump.
physician for instructions if a dose is missed.
 Instruct patients not to crush or chew any oral
sustained-release preparations.
Antidysrhythmics:
Nursing Implications
 Monitor for therapeutic response:
 Decreased BP in hypertensive patients
 Decreased edema ANTILIPEMIC AGENTS
 Regular pulse rate or
 Pulse rate without major irregularities, or
 Improved regularity of rhythm
96
Antilipemics Triglycerides and Types of Lipoproteins
Cholesterol
 Drugs used to lower lipid levels  Two primary forms of lipids in the blood Lipid Protein
Content Lipoprotein Classification Content
 Water-insoluble fats that must be bound to
Most chylomicron Least
apoproteins, specialized lipid-carrying
proteins  very-low density lipoprotein
 Lipoprotein is the the combination of (VLDL) 
triglyceride or cholesterol with apoprotein
 Intermediate-density lipoprotein
(IDL) 
Least High-density lipoprotein (HDL) Most

Coronary Heart Disease Antilipemics Antilipemics: Bile Acid

 The risk of CHD in patients with cholesterol
levels of 300 mg/dL is 3 to 4 times greater
than that in patients with levels less than
300 mg/dL
 Bile acid sequestrants
 HMG-CoA reductase inhibitors
(HMGs or statins)
 Fibric acid derivatives
 Niacin (nicotinic acid)
Sequestrants
 cholestyramine (Questran)
 colestipol hydrochloride (Colestid)
 Also called bile acid-binding resins and
ion-exchange resins

97
Antilipemics: Bile Acid Antilipemics: Bile Acid Antilipemics: Bile Acid
Sequestrants Sequestrants Sequestrants
Mechanism of Action Therapeutic Uses Side Effects
 Prevent resorption of bile acids from small intestine  Type II hyperlipoproteinemia  Constipation
 Bile acids are necessary for absorption  Relief of pruritus associated with partial biliary  Heartburn, nausea, belching, bloating
of cholesterol obstruction (cholestyramine)
These adverse effects tend to disappear over time

Antilipemics: HMG-CoA Antilipemics: Antilipemics:

Reductase Inhibitors (HMGs HMG-CoA Reductase Inhibitors HMG-CoA Reductase Inhibitors
or statins) Mechanism of Action Therapeutic Uses
 Inhibit HMG-CoA reductase, which is used by the liver to  Treatment of type IIa and IIb hyperlipidemias
 lovastatin (Mevacor) produce cholesterol  Reduce LDL levels by 30 to 40%
 pravastatin (Pravachol)  Lower the rate of cholesterol production  Increase HDL levels by 2 to 15%
 Reduce triglycerides by 10 to 30%
 simvastatin (Zocor)
 atorvastatin (Lipitor)
 cerivastatin (Baycol)
 fluvastatin (Lescol)
 Most potent LDL reducers

98
Antilipemics: Antilipemics: Fibric Acid Antilipemics: Fibric Acid
HMG-CoA Reductase Inhibitors Derivatives Derivatives
 clofibrate Mechanism of Action
Side Effects
 Mild, transient GI disturbances  gemfibrozil (Lopid)  Believed to work by activating lipase, which
 Rash  fenofibrate (Tricor) breaks down cholesterol
 Headache  Also suppress release of free fatty acid from
 Myopathy (muscle pain) the adipose tissue, inhibit synthesis of
 Elevations in liver enzymes triglycerides in the liver, and increase the
secretion of cholesterol in the bile

Antilipemics: Fibric Acid Antilipemics: Fibric Acid Antilipemics: Niacin

Derivatives Derivatives (Nicotinic Acid)
Therapeutic Uses Side Effects  Vitamin B3
 Treatment of type IV and V hyperlipemias  Abdominal discomfort  Lipid-lowering properties require much
 Diarrhea higher doses than when used as a vitamin
 Treatment of type III, IV, and V
 Nausea
hyperlipidemias  Effective, inexpensive, often used in
 Blurred vision
combination with other lipid-lowering agents
Decrease the triglyceride levels and increase  Increased risk of gallstones
HDL by as much as 25%  Prolonged prothrombin time
 Liver studies may show increased function

99
Antilipemics: Niacin Antilipemics: Niacin Antilipemics: Niacin
(Nicotinic Acid) (Nicotinic Acid) (Nicotinic Acid)
Mechanism of Action Therapeutic Uses Side Effects
 Thought to increase activity of lipase, which breaks down  Effective in lowering triglyceride, total serum  Flushing (due to histamine release)
lipids cholesterol, and LDL levels  Pruritus
 Reduces the metabolism or catabolism of cholesterol  Increases HDL levels  GI distress
and triglycerides  Effective in the treatment of types IIa, IIb, III, IV,
and V hyperlipidemias

Antilipemics: Nursing Antilipemics: Nursing Antilipemics: Nursing

Implications
 Before beginning therapy, obtain a thorough
health and medication history.
 Assess dietary patterns, exercise level,
weight, height, VS, tobacco and alcohol
use, family history.
 Assess for contraindications, conditions that
require cautious use, and drug interactions.
Implications
 Contraindications include biliary obstruction,
liver dysfunction, active liver disease.
 Obtain baseline liver function studies.
 Patients on long-term therapy may need
supplemental fat-soluble vitamins (A, D, K).
 Take with meals to decrease GI upset.
Implications
 Patient must be counseled concerning diet and nutrition
on an ongoing basis.
 Instruct on proper procedure for taking the medications.
 Powder forms must be taken with a liquid, mixed
thoroughly but not stirred, and NEVER taken dry.
 Other medications should be taken 1 hour before
or 4 to 6 hours after meals to avoid interference
with absorption.

100
Antilipemics: Nursing
Implications
 Clofibrate often causes constipation; instruct
patients to increase fiber and fluid intake to
offset this effect.
 To minimize side effects of niacin, start on
low initial dose and gradually increase it,
and take with meals.
 Small doses of aspirin or NSAIDs may be
taken 30 minutes before niacin to minimize
cutaneous flushing.
Antilipemics: Nursing Antilipemics: Nursing
Implications Implications
 Inform patients that these agents may take  Monitor for side effects, including increased
several weeks to show effectiveness. liver enzyme studies.
 Instruct patients to report persistent GI upset,  Monitor for therapeutic effects:
constipation, abnormal or unusual bleeding,  Reduced cholesterol and triglyceride levels
and yellow discoloration of the skin.

Acid-Related Pathophysiology Glands of the Stomach

ANTACIDS AND The stomach secretes:  Cardiac

ACID-CONTROLLING AGENTS  Hydrochloric acid (HCl)  Pyloric
 Bicarbonate
 Gastric*
 Pepsinogen
 Intrinsic factor
Antacids *The gastric glands are the largest in number
 Mucus
H2 Antagonists
 Prostaglandins
Proton Pump Inhibitors

101
Cells of the Gastric Gland Cells of the Gastric Gland Cells of the Gastric Gland

 Parietal Parietal Cells Chief Cells

 Chief  Produce and secrete HCl  Secrete pepsinogen, a proenzyme
 Primary site of action for many acid-controller drugs  Pepsinogen becomes PEPSIN when activated by
 Mucoid
exposure to acid
 Pepsin breaks down proteins (proteolytic)

Cells of the Gastric Gland Hydrochloric Acid Acid-Related Diseases

Mucoid Cells
 Mucus-secreting cells (surface epithelial cells)
 Provide a protective mucous coat
 Protects against self-digestion by HCl
 Secreted by the parietal cells  Caused by imbalance of the three cells of the
 Maintains stomach at a pH of 1 to 4 gastric gland and their secretions
 Most common: Hyperacidity
 Secretion stimulated by:
 Large, fatty meals  Most harmful: Peptic ulcer disease (PUD)
 Excessive amounts of alcohol  Lay terms for overproduction of HCl by the
 Emotional stress parietal cells: indigestion, sour stomach,
heartburn, acid stomach

102
Antacids: Mechanism of Antacids: Mechanism of Antacids: Drug Effects
Action Action
 Antacids DO NOT prevent the
Promote the gastric mucosal defense Reduction of pain associated with acid-related
overproduction of acid.
mechanisms disorders
 Secretion of:  Acids DO neutralize the acid once it’s in  Raising gastric pH from 1.3 to 1.6 neutralizes 50% of the
 Mucus: Protective barrier against HCl the stomach. gastric acid.
 Bicarbonate: Helps buffer acidic properties of  Raising gastric pH 1 point (1.3 to 2.3) neutralizes90% of
HCl the gastric acid.

 Prostaglandins: Prevent activation of proton

pump

Antacids Antacids Antacids

 OTC formulations available as:  Aluminum salts Aluminum Salts

Capsules and tablets Powders  Magnesium salts  Forms: carbonate, hydroxide, phosphate
 Have constipating effects
Chewable tablets Suspensions  Calcium salts
Effervescent granules and tablets  Often used with magnesium to counteract constipation
 Sodium bicarbonate
Example: aluminum carbonate (Basaljel)

Used alone or in combination

103
Antacids Antacids Antacids

Magnesium Salts Calcium Salts Sodium Bicarbonate

 Forms: carbonate, hydroxide, oxide, trisilicate
 Commonly cause a laxative effect
 Usually used with other agents to counteract this effect
 Dangerous when used with renal failure—the failing
kidney cannot excrete extra magnesium, resulting in
accumulation
Examples: magnesium hydroxide (MOM); combination
products such as Maalox, Mylanta (aluminum and
magnesium)
 Forms: many, but carbonate is most common
 May cause constipation
 Their use may result in kidney stones
 Long duration of acid action may cause increased gastric
acid secretion (hyperacidity rebound)
 Often advertised as an extra source of dietary calcium
Example: Tums (calcium carbonate)
 Highly soluble
 Quick onset, but short duration
 May cause metabolic alkalosis
 Sodium content may cause problems in patients with
CHF, hypertension, or renal insufficiency

Antacids and Antiflatulents Antacids and Antiflatulents Antacids: Side Effects

 Antiflatulents: used to relieve the painful OTC Antiflatulents Minimal, and depend on the compound used
symptoms associated with gas  activated charcoal  Aluminum and calcium
 Several agents are used to bind or alter  simethicone  Constipation
intestinal gas, and are often added to antacid  Alters elasticity of mucus-coated bubbles, causing  Magnesium
combination products. them to break.  Diarrhea
 Used often, but there are limited data to support  Calcium carbonate
effectiveness.  Produces gas and belching; often combined
with simethicone

104
Antacids: Drug Interactions Antacids: Drug Interactions Antacids: Nursing
Implications
 Chelation Increased stomach pH  Assess for allergies and preexisting
 Chemical binding, or inactivation, of another drug  Increased absorption of basic drugs conditions that may restrict the use of
 Chemical inactivation  Decreased absorption of acidic drugs antacids, such as:
 Produces insoluble complexes Increased urinary pH Fluid imbalances Renal disease CHF
 Increased excretion of acidic drugs Pregnancy GI obstruction
 Result: reduced drug absorption
 Decreased excretion of basic drugs  Patients with CHF or hypertension should use
low-sodium antacids such as Riopan, Maalox,
or Mylanta II.

Antacids: Nursing Antacids: Nursing Antacids: Nursing

Implications
 Use with caution with other medications due
to the many drug interactions.
 Most medications should be given 1 to 2
hours after giving an antacid.
 Antacids may cause premature dissolving of
enteric-coated medications, resulting in
stomach upset.
Implications
 Be sure that chewable tablets are chewed
thoroughly, and liquid forms are shaken well
before giving.
 Administer with at least 8 ounces of water to
enhance absorption (except for the “rapid
dissolve” forms).
 Caffeine, alcohol, harsh spices, and black
pepper may aggravate the underlying GI
condition.
Implications
 Monitor for side effects:
 Nausea, vomiting, abdominal pain, diarrhea
 With calcium-containing products: constipation,
acid rebound
 Monitor for therapeutic response:
 Notify heath care provider if symptoms are not
relieved.

105
Histamine Type 2 (H2) H2 Antagonists
Antagonists
 Reduce acid secretion
 All available OTC
 Most popular drugs for treatment of acid-
related disorders
cimetidine (Tagamet)
nizatidine (Axid)
H2 Antagonists:
Mechanism of Action
 Block histamine (H2) at the receptors of acid-
producing parietal cells
 Production of hydrogen ions is reduced,
resulting in decreased production of HCl
famotidine (Pepcid)
ranitidine (Zantac)

H2 Antagonists: Drug Effect H2 Antagonists: Therapeutic H2 Antagonists: Side

Uses Effects
 Suppressed acid secretion in the stomach  Shown to be effective for:  Overall, less than 3% incidence of side effects
Gastric ulcer Gastroesophageal reflux  Cimetidine may induce impotence and
disease (GERD)
gynecomastia
Upper GI Duodenal ulcer (with or
bleeding without H. pylori)
 May be effective for:
 Stress ulcers Peptic esophagitis
 Prevention and management of allergic
conditions, when used with H1 blockers

106
H2 Antagonists: Drug H2 Antagonists: Drug H2 Antagonists: Nursing
Interactions Interactions Implications
 Cimetidine  SMOKING has been shown to decrease  Assess for allergies and impaired renal or liver
 Binds with P-450 microsomal oxidase system in the effectiveness of H2 blockers function.
the liver, resulting in inhibited oxidation of many  Use with caution in patients who are
drugs and increased drug levels
confused, disoriented, or elderly.
 All H2 antagonists may inhibit the absorption of
drugs that require an acidic GI environment for  Take 1 hour before or after antacids.
absorption.  Ranitidine may be given intravenously; follow
administration guidelines.

Proton Pump Inhibitors Proton Pump Inhibitors Proton Pump Inhibitors:

 The parietal cells release positive hydrogen
ions (protons) during HCl production.
 This process is called the “proton pump.”
 H2 blockers and antihistamines do not stop
the action of this pump.
Mechanism of Action
Irreversibly bind to H+/K+ ATPase enzyme.
 This bond prevents the movement of hydrogen ions
from the parietal cell into the stomach.
 Result: Achlorhydria—ALL gastric acid secretion
is blocked.
 In order to return to normal acid secretion, the
parietal cell must synthesize new H+/K+ ATPase.

107
Proton Pump Inhibitors: Proton Pump Inhibitors: Proton Pump Inhibitors: Side
Drug Effect Therapeutic Uses Effects
 Total inhibition of gastric acid secretion  GERD maintenance therapy  Safe for short-term therapy
lansoprazole (Prevacid) omeprazole (Prilosec)  Erosive esophagitis  Incidence low and uncommon
rabeprazole (Aciphex) pantoprazole (Protonix)  Short-term treatment of active duodenal and
esomeprazole (Nexium) benign gastric ulcers
 Zollinger-Ellison syndrome
 Treatment of H. pylori-induced ulcers

Proton Pump Inhibitors: Proton Pump Inhibitors: Other Drugs

Nursing Implications Nursing Implications
 Assess for allergies and history of liver Instruct the patient taking omeprazole:  sucralfate (Carafate)
disease  It should be taken before meals.  misoprostol (Cytotec)
 Pantoprazole is the only proton pump  The capsule should be swallowed whole, not crushed,
opened or chewed.
inhibitor available for parenteral
 It may be given with antacids.
administration, and can be used for patients
 Emphasize that the treatment will be short-term.
who are unable to take oral medications
 May increase serum levels of diazepam,
phenytoin, and cause increased chance for
bleeding with warfarin

108
Sucralfate (Carafate)
 Cytoprotective agent
 Used for stress ulcers, erosions, PUD
 Attracted to and binds to the base of ulcers
and erosions, forming a protective barrier
over these areas
 Protects these areas from pepsin, which
normally breaks down proteins (making
ulcers worse)
misoprostol (Cytotec)
 Used for prevention of NSAID-induced gastric
ulcers
 Doses that are therapeutic enough to treat
duodenal ulcers often produce abdominal
cramps, diarrhea
Sucralfate (Carafate)
 Little absorption from the gut
 May cause constipation, nausea, and dry
mouth
 May impair absorption of other drugs,
especially tetracycline
 Binds with phosphate; may be used in chronic
renal failure to reduce phosphate levels
 Do not administer with other medications
DRUGS AFFECTING THE
GASTROINTESTINAL SYSTEM
Antidiarrheals and Laxatives
misoprostol (Cytotec)
 Synthetic prostaglandin analogue
 Prostaglandins have cytoprotective activity:
 Protect gastric mucosa from injury by enhancing
local production of mucus or bicarbonate
 Promote local cell regeneration
 Help to maintain mucosal blood flow
Diarrhea
 Abnormal frequent passage of loose stools
or
 Abnormal passage of stools with increased
frequency, fluidity, and weight, or with
increased stool water excretion
109
Diarrhea Diarrhea Causes of Diarrhea

Acute Diarrhea Chronic Diarrhea Acute Diarrhea Chronic Diarrhea

 Sudden onset in a previously healthy person  Lasts for over 3 to 4 weeks Bacteria Tumors
 Lasts from 3 days to 2 weeks Viral Diabetes
 Associated with recurring passage of
 Self-limiting Drug-induced Addison’s disease
diarrheal stools, fever, loss of appetite,
 Resolves without sequelae hyperthyroidism
nausea, vomiting, weight loss, and chronic
Nutritional Irritable bowel syndrome
weakness
Protozoal

Antidiarrheals: Mechanism Antidiarrheals: Mechanism Antidiarrheals: Mechanism of

of Action of Action Action
Adsorbents Anticholinergics Intestinal Flora Modifiers
 Coat the walls of the GI tract  Decrease intestinal muscle tone and peristalsis of GI tract  Bacterial cultures of Lactobacillus organisms
 Bind to the causative bacteria or toxin, which  Result: slowing the movement of fecal matter through work by:
are then eliminated through the stool the GI tract  Supplying missing bacteria to the GI tract
 Suppressing the growth of diarrhea-causing bacteria
Examples: bismuth subsalicylate (Pepto-Bismol), Examples: belladonna alkaloids (Donnatal),
kaolin-pectin, activated charcoal, atropine, hyoscyamine
Examples: Lactobacillus acidophilus (Lactinex)
attapulgite (Kaopectate)

110
Antidiarrheals: Mechanism Antidiarrheal Agents: Side Antidiarrheal Agents: Side
of Action Effects Effects
Opiates Anticholinergics Opiates
 Decrease bowel motility and relieve rectal spasms  Urinary retention, hesitancy, impotence  Drowsiness, sedation, dizziness, lethargy
 Decrease transit time through the bowel, allowing more  Headache, dizziness, confusion, anxiety, drowsiness  Nausea, vomiting, anorexia, constipation
time for water and electrolytes to be absorbed  Dry skin, rash, flushing  Respiratory depression
 Blurred vision, photophobia, increased  Bradycardia, palpitations, hypotension
Examples: paregoric, opium tincture, codeine, intraocular pressure
loperamide, diphenoxylate
 Urinary retention
 Flushing, rash, urticaria

Antidiarrheal Agents: Antidiarrheal Agents: Antidiarrheal Agents:

Interactions
 Adsorbents decrease the absorption of many
agents, including digoxin, clindamycin,
quinidine, and hypoglycemic agents
 Adsorbents cause increased bleeding times
when given with anticoagulants
 Antacids can decrease effects of
anticholinergic antidiarrheal agents
Nursing Implications
 Obtain thorough history of bowel patterns,
general state of health, and recent history of
illness or dietary changes, and assess for
allergies.
 DO NOT give bismuth subsalicylate to
children under age 16 or teenagers with
chicken pox because of the risk of Reye’s
syndrome.
Nursing Implications
 Use adsorbents carefully in elderly patients or
those with decreased bleeding time, clotting
disorders, recent bowel surgery,
or confusion.
 Anticholinergics should not be administered
to patients with a history of glaucoma, BPH,
urinary retention, recent bladder surgery,
cardiac problems, or myasthenia gravis.

111
Antidiarrheal Agents:
Nursing Implications
 Teach patients to take medications exactly as
prescribed and to be aware of their fluid
intake and dietary changes.
 Assess fluid volume status; intake and output;
and mucous membranes before, during, and
after initiation of treatment.
Antidiarrheal Agents:
Nursing Implications
 Teach patients to notify their physician
immediately if symptoms persist.
LAXATIVES
Monitor for therapeutic effect.

Constipation Causes of Constipation Causes of Constipation

 Abnormally infrequent and difficult passage
of feces through the lower GI tract.
 Symptom, not a disease
 Disorder of movement through the colon
and/or rectum
 Can be caused by a variety of diseases
or drugs
Metabolic and endocrine disorders
 Diabetes, hypothyroidism, pregnancy
Neurogenic
 Autonomic neuropathy, multiple sclerosis, spinal cord
lesions, Parkinson’s disease, CVA
Adverse drug effects
 Analgesics, anticholinergics, iron supplements, opiates,
aluminum antacids, calcium antacids
Lifestyle
 Poor bowel movement habits: voluntary refusal to
defecate resulting in constipation
 Diet: poor fluid intake and/or low-residue (roughage)
diet, or excessive consumption of dairy products
 Physical inactivity
 Psychological factors: stress, anxiety, hypochondria

112
Laxatives: Laxatives: Mechanism of Laxatives: Mechanism of
Action Action
Mechanisms of Action Bulk-Forming Emollient
 Bulk-forming  High fiber  Stool softeners and lubricants
 Emollient  Absorbs water to increase bulk  Promote more water and fat in the stools
 Hyperosmotic  Distends bowel to initiate reflex bowel activity  Lubricate the fecal material and intestinal walls
 Saline
 Stimulant Examples: psyllium (Metamucil), methylcellulose (Citrucel), Examples: Stool softeners: docusate salts (Colace, Surfak)
polycarbophil Lubricants: mineral oil

Laxatives: Mechanism of Laxatives: Mechanism of Laxatives: Mechanism of

Action Action Action
Hyperosmotic Saline Stimulant
 Increase fecal water content  Increase osmotic pressure within the intestinal tract,  Increases peristalsis via intestinal nerve stimulation
 Result: bowel distention, increased peristalsis, causing more water to enter the intestines
and evacuation  Result: bowel distention, increased peristalsis, and Examples: castor oil, senna, cascara, bisacodyl
evacuation
Examples: polyethylene glycol (GoLYTELY), sorbitol,
glycerin, lactulose (Chronulac) Examples: magnesium sulfate (Epsom salts)
magnesium hydroxide (MOM),
magnesium citrate
sodium phosphate (Fleet Phospho-Soda)

113
 Laxatives: Therapeutic Uses Laxatives: Therapeutic Uses Laxatives: Therapeutic Uses
Laxative Group Use Laxative Group Use Laxative Group Use
Bulk-forming Acute and chronic Hyperosmotic Chronic constipation Stimulant Acute constipation
constipation
Diagnostic and surgical preps Diagnostic and surgical
Irritable bowel syndrome bowel preps
Saline Constipation
Diverticulosis
Diagnostic and surgical preps
Emollient Acute and chronic
constipation Removal of helminths
and parasites
Softening of fecal impaction
Facilitation of BMs in
anorectal conditions

Laxatives: Therapeutic Uses Laxatives: Therapeutic Uses Laxatives: Side Effects

Laxative Group Use Laxative Group Use  All laxatives can cause electrolyte
imbalances!!!
Bulk-forming Impaction and fluid overload Saline Magnesium toxicity (with
renal insufficiency),
Emollient Skin rashes cramping, diarrhea,
increased thirst
Decreased absorption
of vitamins Stimulant Nutrient malabsorption, skin
rashes, gastric irritation,
Hyperosmotic Abdominal bloating, rectal irritation
rectal irritation

114
Laxatives: Nursing Laxatives: Nursing
Implications Implications
 Obtain a thorough history of presenting  A healthy, high-fiber diet and increased
symptoms, elimination patterns, and fluid intake should be encouraged as an
allergies. alternative to laxative use.
 Long-term use of laxatives often results in
 Assess fluid and electrolytes before decreased bowel tone and may lead to
initiating therapy. dependency.
Laxatives: Nursing
Implications
 Patients should take all laxative tablets with 6
to 8 ounces of water.
 Patients should take bulk-forming laxatives
as directed by the manufacturer with at least
240 mL (8 ounces) of water.

 Patients should not take a laxative or  All laxative tablets should be swallowed
cathartic if they are experiencing nausea, whole, not crushed or chewed, especially
vomiting, and/or abdominal pain. if enteric-coated.

Laxatives: Nursing Laxatives: Nursing

Implications Implications DRUGS AFFECTING THE
 Bisacodyl and cascara sagrada should be  Monitor for therapeutic effect.
given with water due to interactions with
RESPIRATORY SYSTEM
milk, antacids, and H2 blockers.

 Patients should contact their physician if they

experience severe abdominal pain, muscle Antihistamines,
Decongestants,
weakness, cramps, and/or dizziness, which Antitussives,
may indicate possible fluid or electrolyte loss. and
Expectorants

115
Understanding the Common
Cold
 Most caused by viral infection
(rhinovirus or influenza virus—the “flu”)
Treatment of the Common Cold
 Involves combined use of antihistamines,
nasal decongestants, antitussives, and
expectorants.
 Treatment is SYMPTOMATIC only, not
curative.
 Symptomatic treatment does not eliminate
the causative pathogen.
Understanding the Common
Cold
 Virus invades tissues (mucosa) of upper
respiratory tract, causing upper respiratory
infection (URI).
 Excessive mucus production results from the
inflammatory response to this invasion.
 Fluid drips down the pharynx into the
esophagus and lower respiratory tract,
causing cold symptoms: sore throat,
coughing, upset stomach.
Treatment of the Common Cold
 Difficult to identify whether cause is viral or
bacterial.
 Treatment is “empiric therapy,” treating the
most likely cause.
 Antivirals and antibiotics may be used, but
viral or bacterial cause may not be easily
identified.
Understanding the Common
Cold
 Irritation of nasal mucosa often triggers the
sneeze reflex.
 Mucosal irritation also causes release of
several inflammatory and vasoactive
substances, dilating small blood vessels in the
nasal sinuses and causing nasal congestion.
Antihistamines
Drugs that directly compete with histamine
for specific receptor sites.
 Two histamine receptors:
 H1 histamine-1
 H2 histamine-2
116
Antihistamines
H2 Blockers or H2 Antagonists
 Used to reduce gastric acid in PUD
 Examples: cimetidine (Tagamet),
ranitidine (Zantac), or
famotidine (Pepcid)
Antihistamines: Mechanism of
Action
 The binding of H1 blockers to the histamine
receptors prevents the adverse consequences
of histamine stimulation:
 Vasodilation
 Increased gastrointestinal and respiratory
secretions
 Increased capillary permeability
Antihistamines
H1 antagonists are commonly referred
to as antihistamines
 Antihistamines have several effects:
 Antihistaminic
 Anticholinergic
 Sedative
Antihistamines: Mechanism of
Action
 More effective in preventing the actions of
histamine rather than reversing them
 Should be given early in treatment, before
all the histamine binds to the receptors
Antihistamines: Mechanism of
Action
BLOCK action of histamine at the receptor
sites
 Compete with histamine for binding at unoccupied
receptors.
 CANNOT push histamine off the receptor if already
bound.
Histamine vs. Antihistamine
Effects
Cardiovascular (small blood vessels)
 Histamine effects:
 Dilation and increased permeability
(allowing substances to leak into tissues)
 Antihistamine effects:
 Prevent dilation of blood vessels
 Prevent increased permeability
117
Histamine vs. Antihistamine Histamine vs. Antihistamine Antihistamines: Other
Effects Effects Effects
Smooth Muscle (on exocrine glands) Immune System Skin:
 Histamine effects: (Release of substances commonly  Block capillary permeability, wheal-and-flare formation,
itching
 Stimulate salivary, gastric, lacrimal, and associated with allergic reactions)
bronchial secretions  Histamine effects: Anticholinergic:
 Antihistamine effects:  Mast cells release histamine and other  Drying effect that reduces nasal, salivary, and lacrimal
 Prevent salivary, gastric, lacrimal, and gland secretions (runny nose, tearing, and itching eyes)
substances, resulting in allergic reactions.
bronchial secretions  Antihistamine effect: Sedative:
 Binds to histamine receptors, thus preventing  Some antihistamines cause drowsiness
histamine from causing a response.

Antihistamines: Therapeutic Antihistamines Antihistamines: Therapeutic

Uses Uses
10 to 20% of general population is sensitive
Management of: to various environmental allergies. Also used to relieve symptoms associated
 Nasal allergies
 Histamine-mediated disorders: with the common cold:
 Allergic rhinitis  Sneezing, runny nose
 Seasonal or perennial allergic rhinitis (hay fever, mold and dust allergies)
 Palliative treatment, not curative
(hay fever)  Anaphylaxis
 Angioneurotic edema
 Allergic reactions
 Drug fevers
 Motion sickness  Insect bite reactions
 Sleep disorders  Urticaria (itching)

118
Antihistamines: Side Antihistamines: Two Types Antihistamines:
effects
 Anticholinergic (drying) effects, most
Traditional
common:  Traditional  Older
 Dry mouth
or  Work both peripherally and centrally
 Difficulty urinating
 Nonsedating/Peripherally Acting  Have anticholinergic effects, making them more
 Constipation effective than nonsedating agents in some cases
 Changes in vision Examples: diphenhydramine (Benadryl)
 Drowsiness chlorpheniramine (Chlor-Trimeton)
 (Mild drowsiness to deep sleep)

Antihistamines: Nursing Implications: Nursing Implications:

Antihistamines Antihistamines
 Gather data about the condition or allergic reaction that
Nonsedating/Peripherally Acting required treatment; also, assess for drug allergies.
 Instruct patients to report excessive
 Developed to eliminate unwanted side effects,
 Contraindicated in the presence of acute asthma
sedation, confusion, or hypotension.
mainly sedation attacks and lower respiratory diseases.  Avoid driving or operating heavy machinery,
 Work peripherally to block the actions of histamine;
 Use with caution in increased intraocular pressure, and do not consume alcohol or other CNS
thus, fewer CNS side effects cardiac or renal disease, hypertension, asthma, COPD, depressants.
 Longer duration of action (increases compliance) peptic ulcer disease, BPH, or pregnancy.
Examples: fexofenadine (Allegra)
 Do not take these medications with other
loratadine (Claritin)
prescribed or OTC medications without
checking with prescriber.

119
Nursing Implications: Nasal Congestion
Antihistamines
 Best tolerated when taken with meals—  Excessive nasal secretions
reduces GI upset.
DECONGESTANTS  Inflamed and swollen nasal mucosa
 If dry mouth occurs, teach patient to
perform frequent mouth care, chew gum, or  Primary causes:
suck on hard candy (preferably sugarless) to
 Allergies
ease discomfort.
 Upper respiratory infections (common cold)
 Monitor for intended therapeutic effects.

Decongestants Decongestants Oral Decongestants

Two main types are used: Two dosage forms:  Prolonged decongestant effects,
 Adrenergics (largest group)  Oral but delayed onset
 Corticosteroids  Inhaled/topically applied to the nasal membranes  Effect less potent than topical
 No rebound congestion
 Exclusively adrenergics
 Examples: phenylephrine
pseudoephedrine (Sudafed)

120
Topical Nasal Decongestants Topical Nasal Decongestants Nasal Decongestants:
Mechanism of Action
 Both adrenergics and steroids  Adrenergics: Site of action: blood vessels surrounding
 Prompt onset ephedrine (Vicks) naphazoline (Privine) nasal sinuses
oxymetazoline (Afrin) phenylephrine  Adrenergics
 Potent
(Neo Synephrine)  Constrict small blood vessels that supply
 Sustained use over several days causes URI structures
 Intranasal Steroids:
rebound congestion, making the condition  As a result, these tissues shrink and nasal
beclomethasone dipropionate
worse secretions in the swollen mucous membranes
(Beconase, Vancenase)
are better able to drain
flunisolide (Nasalide)
 Nasal stuffiness is relieved

Nasal Decongestants: Nasal Decongestants: Drug Nasal Decongestants:

Mechanism of Action
Site of action: blood vessels surrounding
nasal sinuses
 Nasal steroids
 Anti-inflammatory effect
 Work to turn off the immune system cells
involved in the inflammatory response
 Decreased inflammation results in decreased
congestion
 Nasal stuffiness is relieved
Effects Therapeutic Uses
 Shrink engorged nasal mucous membranes Relief of nasal congestion associated with:
 Relieve nasal stuffiness  Acute or chronic rhinitis
 Common cold
 Sinusitis
 Hay fever
 Other allergies
May also be used to reduce swelling of the nasal passage and
facilitate visualization of the nasal/pharyngeal membranes before
surgery or diagnostic procedures.

121
Nasal Decongestants: Side Nursing Implications: Nursing Implications:
Effects Nasal Decongestants Decongestants
Adrenergics Steroids
 Decongestants may cause hypertension,  Patients should avoid caffeine and caffeine-
nervousness local mucosal dryness
and irritation
palpitations, and CNS stimulation—avoid in containing products.
insomnia
patients with these conditions.  Report a fever, cough, or other symptoms
palpitations  Assess for drug allergies. lasting longer than a week.
tremors  Monitor for intended therapeutic effects.
(systemic effects due to adrenergic stimulation of the
heart, blood vessels, and CNS)

Cough Physiology Two Basic Types of Cough

Respiratory secretions and foreign objects are  Productive Cough

naturally removed by the  Congested, removes excessive secretions
ANTITUSSIVES
 cough reflex  Nonproductive Cough
 Induces coughing and expectoration  Dry cough
 Initiated by irritation of sensory receptors in the
respiratory tract

122
Coughing Antitussives Antitussives: Mechanism of
Action
Most of the time, coughing is beneficial Drugs used to stop or reduce coughing Opioid
 Removes excessive secretions  Opioid and nonopioid  Suppress the cough reflex by direct action on the cough
 Removes potentially harmful foreign substances center in the medulla.
(narcotic and non-narcotic)
In some situations, coughing can be harmful, Examples: codeine (Robitussin A-C, Dimetane-DC)
Used only for NONPRODUCTIVE coughs!
hydrocodone
such as after hernia repair surgery

Antitussives: Mechanism of Antitussives: Therapeutic Antitussives: Side Effects

Action
Nonopioid
 Suppress the cough reflex by numbing the stretch
receptors in the respiratory tract and preventing the
cough reflex from being stimulated.
Examples: benzonatate (Tessalon)
dextromethorphan (Vicks Formula 44,
Robitussin-DM)
Uses
 Used to stop the cough reflex when the
cough is nonproductive and/or harmful
Benzonatate
 Dizziness, headache, sedation
Dextromethorphan
 Dizziness, drowsiness, nausea
Opioids
 Sedation, nausea, vomiting, lightheadedness, constipation

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Nursing Implications: Nursing Implications:
Antitussive Agents Antitussive Agents
 Perform respiratory and cough assessment,  Report any of the following symptoms to the caregiver:
 Cough that lasts more than a week
and assess for allergies.
 A persistent headache EXPECTORANTS
 Instruct patients to avoid driving or  Fever
operating heavy equipment due to possible  Rash

sedation, drowsiness, or dizziness.  Antitussive agents are for NONPRODUCTIVE coughs.

 Monitor for intended therapeutic effects.
 If taking chewable tablets or lozenges,
do not drink liquids for 30 to 35 minutes
afterward.

Expectorants Expectorants: Mechanisms of Expectorants: Mechanism of

Action Action
 Drugs that aid in the expectoration  Direct stimulation Direct stimulation:
(removal) of mucus
or  The secretory glands are stimulated directly to increase
 Reduce the viscosity of secretions their production of respiratory tract fluids.
 Reflex stimulation
 Disintegrate and thin secretions Examples: terpin hydrate, iodine-containing
products such as iodinated glycerol and
Final result: thinner mucus that is easier to remove potassium iodide (direct and indirect
stimulation)

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Expectorants: Mechanism of Expectorants: Drug Effects Expectorants: Therapeutic
Action Uses
Reflex stimulation:  By loosening and thinning sputum and Used for the relief of nonproductive coughs
 Agent causes irritation of the GI tract. bronchial secretions, the tendency to cough associated with:
 Loosening and thinning of respiratory tract secretions is indirectly diminished. Common cold Pertussis
occur in response to this irritation. Bronchitis Influenza
Examples: guaifenesin, syrup of ipecac Laryngitis Measles
Pharyngitis
Coughs caused by chronic paranasal sinusitis

Expectorants: Common Side Nursing Implications:

Effects Expectorants
 Expectorants should be used with caution in
guaifenesin terpin hydrate
the elderly, or those with asthma or
Nausea, vomiting Gastric upset respiratory insufficiency. BRONCHODILATORS AND
Gastric irritation (Elixir has high alcohol
content)
 Patients taking expectorants should receive OTHER RESPIRATORY AGENTS
more fluids, if permitted, to help loosen and
liquefy secretions.
 Report a fever, cough, or other symptoms
lasting longer than a week.
 Monitor for intended therapeutic effects.

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Drugs Affecting Bronchodilators: Xanthine Bronchodilators: Xanthine
the Respiratory System Derivatives Derivatives
 Bronchodilators  Plant alkaloids: caffeine, theobromine, and Mechanism of Action
 Xanthine derivatives theophylline  Increase levels of energy-producing cAMP*
 Beta-agonists  Only theophylline is used as a bronchodilator  This is done competitively inhibiting
 Anticholinergics Examples: aminophylline phosphodiesterase (PDE), the enzyme that
 Antileukotriene agents dyphilline breaks down cAMP
 Corticosteroids oxtriphylline  Result: decreased cAMP levels, smooth
theophylline (Bronkodyl, Slo-bid, muscle relaxation, bronchodilation, and
 Mast cell stabilizers increased airflow
Theo-Dur,Uniphyl)
*cAMP = cyclic adenosine monophosphate

Bronchodilators: Xanthine Bronchodilators: Xanthine Bronchodilators: Xanthine

Derivatives Derivatives Derivatives
Drug Effects Therapeutic Uses Side Effects
 Cause bronchodilation by relaxing smooth muscles of
the airways.
 Dilation of airways in asthmas, chronic  Nausea, vomiting, anorexia
 Result: relief of bronchospasm and greater airflow into
bronchitis, and emphysema  Gastroesophageal reflux during sleep
and out of the lungs.  Mild to moderate cases of asthma  Sinus tachycardia, extrasystole, palpitations,
 Also causes CNS stimulation.  Adjunct agent in the management of COPD ventricular dysrhythmias
 Also causes cardiovascular stimulation: increased force
of contraction and increased HR, resulting in increased
 Adjunct therapy for the relief of pulmonary  Transient increased urination
cardiac output and increased blood flow to the kidneys edema and paroxysmal nocturnal edema in
(diuretic effect). left-sided heart failure

126
Bronchodilators: Beta- Bronchodilators: Beta- Bronchodilators: Beta-
Agonists Agonists Three types Agonists Mechanism of Action
 Large group, sympathomimetics  Nonselective adrenergics  Begins at the specific receptor stimulated
 Stimulate alpha1, beta1 (cardiac), and beta2 (respiratory)
 Used during acute phase of asthmatic attacks receptors.  Ends with the dilation of the airways
 Quickly reduce airway constriction and Example: epinephrine
 Nonselective beta-adrenergics
restore normal airflow  Stimulate both beta1 and beta2 receptors.
Activation of beta2 receptors activate cAMP, which
relaxes smooth muscles of the airway and results
 Stimulate beta2 adrenergic receptors Example: isoproterenol (Isuprel)
in bronchial dilation and increased airflow.
throughout the lungs  Selective beta2 drugs
 Stimulate only beta2 receptors.
Example: albuterol

Bronchodilators: Beta- Bronchodilators: Beta- Respiratory Agents:

Agonists Therapeutic Uses Agonists General Nursing Implications
 Relief of bronchospasm, bronchial asthma,
bronchitis, and other pulmonary disease. Side Effects
Alpha-Beta Beta1 and Beta2 Beta2  Encourage patients to take measures that
(epinephrine) (isoproterenol) (albuterol) promote a generally good state of health in
 Useful in treatment of acute attacks as well
order to prevent, relieve, or decrease
as prevention.
insomnia cardiac stimulation hypotension symptoms of COPD.
 Used in hypotension and shock. restlessness tremor vascular  Avoid exposure to conditions that precipitate bronchospasms
 Used to produce uterine relaxation to prevent headache (allergens, smoking, stress, air pollutants)
anorexia anginal pain tremor  Adequate fluid intake
premature labor.
cardiac stimulation vascular headache tremor  Compliance with medical treatment
 Hyperkalemia—stimulates potassium to shift into vascular headache
 Avoid excessive fatigue, heat, extremes in temperature, caffeine
the cell.

127
Respiratory Agents:
General Nursing Implications
 Encourage patients to get prompt treatment
for flu or other illnesses, and to get
vaccinated against pneumonia or flu.
 Encourage patients to always check with
their physician before taking any other
medication, including OTC.
Respiratory Agents: Respiratory Agents:
General Nursing Implications General Nursing Implications
 Perform a thorough assessment before  Teach patients to take bronchodilators
beginning therapy, including: exactly as prescribed.
 Skin color  Ensure that patients know how to use
 Baseline vital signs
inhalers, MDIs, and have the patients
 Respirations (should be <12 or >24 breaths/min)
demonstrate use of devices.
 Respiratory assessment, including PO2
 Monitor for side effects.
 Sputum production
 Allergies
 History of respiratory problems
 Other medications

Respiratory Agents: Bronchodilators: Nursing Bronchodilators: Nursing

Nursing Implications Implications Implications
 Monitor for therapeutic effects Xanthine Derivatives Xanthine Derivatives
 Decreased dyspnea  Contraindications: history of PUD or  Report to physician:
 Decreased wheezing, restlessness, and anxiety GI disorders
Palpitations Nausea Vomiting
 Improved respiratory patterns with return to
 Cautious use: cardiac disease Weakness Dizziness Chest pain
normal rate and quality
 Improved activity tolerance  Timed-release preparations should not be Convulsions
crushed or chewed (causes gastric irritation)
 Decreased symptoms and increased
ease of breathing

128
Bronchodilators: Nursing
Implications
Xanthine Derivatives
 Be aware of drug interactions with:
cimetidine, oral contraceptives,
allopurinol
 Large amounts of caffeine can have
deleterious effects.
Anticholinergics:
Mechanism of Action
 Acetylcholine (ACh) causes bronchial
constriction and narrowing of the airways.
 Anticholinergics bind to the ACh receptors,
preventing ACh from binding.
 Result: bronchoconstriction is prevented,
airways dilate.
Bronchodilators: Nursing Bronchodilators: Nursing
Implications Implications
Beta-Agonist Derivatives Beta-Agonist Derivatives
 Albuterol, if used too frequently, loses its  Patients should take medications exactly
beta2-specific actions at larger doses. as prescribed, with no omissions or double
 As a result, beta1 receptors are stimulated, doses.
causing nausea, increased anxiety,  Patients should report insomnia, jitteriness,
palpitations, tremors, and increased restlessness, palpitations, chest pain, or
heart rate. any change in symptoms.
Anticholinergics Anticholinergics: Side
Effects
 Ipratropium bromide (Atrovent) is the only Dry mouth or throat Gastrointestinal distress
anticholinergic used for respiratory disease. Headache Coughing
Anxiety
 Slow and prolonged action
 Used to prevent bronchoconstriction No known drug interactions
 NOT used for acute asthma exacerbations!
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Antileukotrienes
 Also called leukotriene receptor antagonists
(LRTAs)
 New class of asthma medications
 Three subcategories of agents
Antileukotrienes Antileukotrienes:
Mechanism of Action
Currently available agents:  Leukotrienes are substances released when a
 montelukast (Singulair) trigger, such as cat hair or dust, starts a series
 zafirlukast (Accolate) of chemical reactions in the body.
 zileuton (Zyflo)  Leukotrienes cause inflammation,
bronchoconstriction, and mucus production.
 Result: coughing, wheezing, shortness
of breath

Antileukotrienes: Antileukotrienes: Drug Antileukotrienes:

Mechanism of Action
 Antileukotriene agents prevent leukotrienes
from attaching to receptors on cells in the
lungs and in circulation.
 Inflammation in the lungs is blocked, and
asthma symptoms are relieved.
Effects
By blocking leukotrienes:
 Prevent smooth muscle contraction of the
bronchial airways
 Decrease mucus secretion
 Prevent vascular permeability
 Decrease neutrophil and leukocyte infiltration
to the lungs, preventing inflammation
Therapeutic Uses
 Prophylaxis and chronic treatment of asthma
in adults and children over age 12
 NOT meant for management of acute
asthmatic attacks
 Montelukast is approved for use in children
age 2 and older

130
Antileukotrienes: Side Antileukotrienes: Antileukotrienes:
Effects Nursing Implications Nursing Implications
zileuton zafirlukast  Ensure that the drug is being used for chronic  Check with physician before taking any
Headache Headache management of asthma, not OTC or prescribed medications—many
Dyspepsia Nausea acute asthma. drug interactions.
Nausea Diarrhea
 Teach the patient the purpose of the therapy.  Assess liver function before beginning
Dizziness Liver dysfunction
 Improvement should be seen in about therapy.
Insomnia
Liver dysfunction 1 week.  Medications should be taken every night on a
continuous schedule, even if symptoms
montelukast has fewer side effects improve.

Corticosteroids Corticosteroids: Inhaled Corticosteroids

 Anti-inflammatory
 Used for CHRONIC asthma
 Do not relieve symptoms of acute
asthmatic attacks
 Oral or inhaled forms
 Inhaled forms reduce systemic effects
 May take several weeks before full
effects are seen
Mechanism of Action
 Stabilize membranes of cells that release  beclomethasone dipropionate
harmful bronchoconstricting substances. (Beclovent, Vanceril)
 These cells are leukocytes, or white  triamcinolone acetonide
blood cells. (Azmacort)
 Also increase responsiveness of bronchial  dexamethasone sodium phosphate
smooth muscle to beta-adrenergic (Decadron Phosphate Respihaler)
stimulation.
 flunisolide (AeroBid)

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Inhaled Corticosteroids:
Therapeutic Uses
 Treatment of bronchospastic disorders
that are not controlled by conventional
bronchodilators.
 NOT considered first-line agents for
management of acute asthmatic attacks
or status asthmaticus.
Inhaled Corticosteroids: Inhaled Corticosteroids:
Side Effects Nursing Implications
 Pharyngeal irritation  Contraindicated in patients with psychosis,
 Coughing fungal infections, AIDS, TB.
 Dry mouth  Cautious use in patients with diabetes,
 Oral fungal infections glaucoma, osteoporosis, PUD, renal disease,
CHF, edema.
Systemic effects are rare because of the low
doses used for inhalation therapy.  Teach patients to gargle and rinse the mouth
with water afterward to prevent the
development of oral fungal infections.

Inhaled Corticosteroids: Mast Cell Stabilizers Mast Cell Stabilizers

Nursing Implications
 Abruptly discontinuing these medications can
lead to serious problems.
 If discontinuing, should be weaned for a
period of 1 to 2 weeks, and only if
recommended by physician.
 REPORT any weight gain of more than 5
pounds a week or the occurrence of chest
pain.
 cromolyn (Nasalcrom, Intal)
 nedocromil (Tilade)
 Indirect-acting agents that prevent the
release of the various substances that
cause bronchospasm
 Stabilize the cell membranes of
inflammatory cells (mast cells, monocytes,
macrophages), thus preventing release of
harmful cellular contents
 No direct bronchodilator activity
 Used prophylactically

132
Mast Cell Stabilizers: Mast Cell Stabilizers: Side Mast Cell Stabilizers:
Therapeutic Uses Effects Nursing Implications
 Adjuncts to the overall management Coughing Taste changes  For prophylactic use only
of COPD
Sore throat Dizziness  Contraindicated for acute exacerbations
 Used solely for prophylaxis, NOT for Rhinitis Headache  Not recommended for children under age 5
acute asthma attacks
Bronchospasm  Therapeutic effects may not be seen for up to
 Used to prevent exercise-induced 4 weeks
bronchospasm
 Teach patients to gargle and rinse the mouth
 Used to prevent bronchospasm associated with water afterward to minimize irritation to
with exposure to known precipitating factors,
such as cold, dry air or allergens the throat and oral mucosa

Antibiotics Antibiotics
ANTI-INFECTIVE AGENTS
Antibiotics:  Medications used to treat bacterial infections  Empiric therapy: treatment of an infection
before specific culture information has been
Sulfonamides
Penicillins
Cephalosporins
 Ideally, before beginning antibiotic therapy,
Tetracyclines
Aminoglycosides the suspected areas of infection should be reported or obtained
cultured to identify the causative organism  Prophylactic therapy: treatment with
Quinolones
Macrolides

and potential antibiotic susceptibilities. antibiotics to prevent an infection, as in intra-

abdominal surgery

133
Antibiotics Antibiotics: Sulfonamides Sulfonamides: Mechanism of
Action
 Bactericidal: kill bacteria One of the first groups of antibiotics  Bacteriostatic action
 Bacteriostatic: inhibit growth of susceptible  sulfadiazine  Prevent synthesis of folic acid required for
bacteria, rather than killing them immediately;  sulfamethizole synthesis of purines and nucleic acid
will eventually lead to bacterial death  sulfamethoxazole  Does not affect human cells or certain
 sulfisoxazole bacteria—they can use preformed folic acid

Sulfonamides: Sulfonamides: sulfisoxazole Sulfonamides: Side Effects

sulfamethoxazole Therapeutic Therapeutic Uses
Azo-Gantanol
Uses Azo-Gantrisin Body System Effect
 Combined with phenazopyridine  Combined with phenazopyridine Blood Hemolytic and aplastic
(an analgesic-anesthetic that affects the mucosa anemia, thrombocytopenia
of the urinary tract).  Used for UTIs
Integumentary Photosensitivity, exfoliative
 Used to treat urinary tract infections (UTIs) and to reduce dermatitis, Stevens-Johnson
the pain associated with UTIs. Pediazole syndrome, epidermal
Bactrim  Combined with erythromycin necrolysis

 Combined with trimethoprim.  Used to treat otitis media

 Used to treat UTIs, Pneumocystis carinii pneumonia, ear
infections, bronchitis, gonorrhea, etc.

134
Sulfonamides: Side Effects Antibiotics: Penicillins Antibiotics: Penicillins

Body System Effect  Natural penicillins Natural penicillins

GI Nausea, vomiting, diarrhea,  Penicillinase-resistant penicillins  penicillin G, penicillin V potassium
pancreatitis
 Aminopenicillins
Other Convulsions, crystalluria,
 Extended-spectrum penicillins Penicillinase-resistant penicillins
toxic nephrosis, headache,
peripheral neuritis, urticaria  cloxacillin, dicloxacillin, methicillin, nafcillin, oxacillin

Antibiotics: Penicillins Antibiotics: Penicillins Antibiotics: Penicillins

Aminopenicillins  First introduced in the 1940s  Bacteria produce enzymes capable of

 amoxicillin, ampicillin, bacampicillin  Bactericidal: inhibit cell wall synthesis destroying penicillins.
 Kill a wide variety of bacteria
Extended-spectrum penicillins  These enzymes are known as
 Also called “beta-lactams” beta-lactamases.
 piperacillin, ticarcillin, carbenicillin, mezlocillin

 As a result, the medication is not effective.

135
Antibiotics: Penicillins Antibiotics: Penicillins Penicillins: Mechanism of
Action
 Penicillins enter the bacteria via the cell wall.
 Chemicals have been developed to inhibit  Penicillin-beta-lactamase inhibitor
these enzymes: combination drugs:  Inside the cell, they bind to penicillin-binding protein.
 clavulanic acid
 ampicillin + sulbactam = Unasyn  Once bound, normal cell wall synthesis is disrupted.
 tazobactam
 sulbactam  amoxicillin + clavulanic acid = Augmentin  Result: bacteria cells die from cell lysis.
 These chemicals bind with beta-lactamase
and prevent the enzyme from breaking  ticarcillin + clavulanic acid = Timentin  Penicillins do not kill other cells in the body.
down the penicillin  piperacillin + tazobactam = Zosyn

Penicillins: Therapeutic Penicillins: Adverse Penicillins: Side Effects

Uses
 Prevention and treatment of infections
caused by susceptible bacteria, such as:
 gram-positive bacteria
 Streptococcus, Enterococcus, Staphylococcus
species
Effects
 Allergic reactions occur in 0.7% – 8% of  Common side effects:
treatments
 urticaria, pruritus, angioedema  nausea, vomiting, diarrhea, abdominal pain
 10% of allergic reactions are life-threatening
 Other side effects are less common
and
 10% of these are fatal

136
Antibiotics: Cephalosporins Antibiotics: Cephalosporins Cephalosporins: First
Generation
 First Generation  Semisynthetic derivatives from a fungus  cefadroxil
 Second Generation  Structurally and pharmacologically related
 cephalexin
 cephradine
 Third Generation to penicillins
 cefazolin
 Fourth Generation  Bactericidal action  cephalothin
 Broad spectrum  cephapirin
 Divided into groups according to their  Good gram-positive coverage
 Poor gram-negative coverage
antimicrobial activity

Cephalosporins: First Cephalosporins: Second Cephalosporins: Second

Generation Generation Generation
cefazolin cephalexin  cefaclor • cefonicid Cefoxitin cefuroxime
(Ancef and Kefzol) (Keflex and Keftab)  cefprozil • ceforanide (Mefoxin) (Kefurox and Ceftin)
IV and PO PO IV and IM PO
 cefamandole • cefmetazole
 cefoxitin • cefotetan Used prophylactically for Surgical prophylaxis
used for surgical prophylaxis, URIs, otitis media abdominal or colorectal
 cefuroxime
surgeries Does not kill
 Good gram-positive coverage
Also kills anaerobes anaerobes
 Better gram-negative coverage than first generation

137
 Cephalosporins: Third Cephalosporins: Third Cephalosporins: Third
Generation Generation Generation
 cefixime • ceftizoxime cefixime (Suprax) ceftazidime (Ceptaz, Fortaz, Tazidime, Tazicef)
 Only oral third-generation agent
 cefpodoxime proxetil • ceftriaxone
 Best of available oral cephalosporins against  IV and IM
 cefoperazone • ceftazidime gram-negative
 Tablet and suspension  Excellent gram-negative coverage
 cefotaxime • moxalactam
 Most potent group against gram-negative  Used for difficult-to-treat organisms such as Pseudomonas spp.
 Less active against gram-positive
ceftriaxone (Rocephin)
 IV and IM, long half-life, once-a-day dosing  Eliminated renally instead of biliary route
 Easily passes meninges and diffused into CSF  Excellent spectrum of coverage
to treat CNS infections

Cephalosporins: Fourth Cephalosporins: Side Antibiotics: Tetracyclines

Generation Effects
cefepime (Maxipime)  similar to penicillins  demeclocycline (Declomycin)
 Newest cephalosporin agents.  oxytetracycline
 Broader spectrum of antibacterial activity than  tetracycline
third generation, especially against gram-positive
bacteria.  doxycycline (Doryx, Doxy-Caps, Vibramycin)
 minocycline

138
Antibiotics: Tetracyclines Antibiotics: Tetracyclines Tetracyclines: Therapeutic
Uses
 Natural and semi-synthetic  Bind to Ca2+ and Mg2+ and Al3+ ions to  Wide spectrum:
 Obtained from cultures of Streptomyces form insoluble complexes  gram-negative, gram-positive, protozoa,
 Thus, dairy products, antacids, and iron Mycoplasma, Rickettsia, Chlamydia, syphilis,
 Bacteriostatic—inhibit bacterial growth
Lyme disease
 Inhibit protein synthesis salts reduce absorption of tetracyclines
 Demeclocycline is also used to treat SIADH,
 Stop many essential functions of the bacteria and pleural and pericardial effusions

Tetracyclines: Side Effects Tetracyclines: Side Effects Tetracyclines: Side Effects

Strong affinity for calcium Alteration in intestinal flora may result in: May also cause:
 Discoloration of permanent teeth and tooth  Superinfection (overgrowth of nonsusceptible organisms  Vaginal moniliasis
enamel in fetuses and children such as Candida)  Gastric upset
 May retard fetal skeletal development if taken  Diarrhea  Enterocolitis
during pregnancy  Pseudomembranous colitis  Maculopapular rash

139
Antibiotics: Aminoglycosides Aminoglycosides
Aminoglycosides
 gentamicin (Garamycin)  Natural and semi-synthetic  Used to kill gram-negative bacteria such as
 kanamycin  Produced from Streptomyces Pseudomonas spp., E. coli, Proteus spp.,
 neomycin  Poor oral absorption; no PO forms Klebsiella spp., Serratia spp.
 streptomycin
 Very potent antibiotics with serious toxicities  Often used in combination with other
 tobramycin
 Bactericidal antibiotics for synergistic effect.
 amikacin (Amikin)
 netilmicin  Kill mostly gram-negative; some
gram-positive also

Aminoglycosides Aminoglycosides: Side Antibiotics: Quinolones

Effects
 Three most common (systemic): gentamicin, Ototoxicity and nephrotoxicity are  ciprofloxacin (Cipro)
tobramycin, amikacin the most significant
 Headache  enoxacin (Penetrex)
 Cause serious toxicities:  Paresthesia  lomefloxacin (Maxaquin)
 Neuromuscular blockade
 Nephrotoxicity (renal failure)
 norfloxacin (Noroxin)
 Dizziness
 Vertigo  ofloxacin (Floxin)
 Ototoxicity (auditory impairment and vestibular
 Skin rash
[eighth cranial nerve])
 Fever
 Must monitor drug levels to prevent toxicities  Superinfections

140
Quinolones Quinolones: Mechanism of Quinolones: Therapeutic
Action Uses
 Excellent oral absorption  Bactericidal  Lower respiratory tract infections
 Absorption reduced by antacids  Effective against gram-negative organisms  Bone and joint infections
 First oral antibiotics effective against and some gram-positive organisms  Infectious diarrhea
gram-negative bacteria  Alter DNA of bacteria, causing death  Urinary tract infections
 Do not affect human DNA  Skin infections
 Sexually transmitted diseases

Quinolones: Side Effects Quinolones: Side Effects Antibiotics: Macrolides

Body System Effects Body System Effects  erythromycin

CNS headache, dizziness, fatigue,
depression, restlessness
GI nausea, vomiting, diarrhea,
constipation, thrush,
increased liver function studies
Integumentary rash, pruritus, urticaria,
flushing, photosensitivity
(with lomefloxacin)
Other fever, chills, blurred vision,
tinnitus
 azithromycin (Zithromax)
 clarithromycin (Biaxin)
 dirithromycin
 troleandomycin
 bactericidal action

141
 Macrolides: Therapeutic Macrolides: Side Effects Antibiotics: Nursing
Uses Implications
Strep infections
GI effects, primarily with erythromycin:  Before beginning therapy, assess drug allergies;
 Streptococcus pyogenes hepatic, liver, and cardiac function; and other lab
(group A beta-hemolytic streptococci) studies.
 nausea, vomiting, diarrhea, hepatotoxicity,
Mild to moderate URI flatulence, jaundice, anorexia  Be sure to obtain thorough patient health history,
 Haemophilus influenzae including immune status.
 Newer agents, azithromycin and clarithromycin: fewer
side effects, longer duration of action,  Assess for conditions that may be contraindications to
Spirochetal infections better efficacy, better tissue penetration antibiotic use, or that may indicate cautious use.
 Syphilis and Lyme disease
 Assess for potential drug interactions.
Gonorrhea, Chlamydia, Mycoplasma

Antibiotics: Nursing Antibiotics: Nursing Antibiotics: Nursing

Implications
 It is ESSENTIAL to obtain cultures from
appropriate sites BEFORE beginning
antibiotic therapy.
Implications Implications
 Patients should be instructed to take antibiotics exactly  For safety reasons, check the name of the
as prescribed and for the length of time prescribed; they medication carefully since there are many
should not stop taking the medication early when they
feel better. agents that sound alike or have similar
spellings.
 Assess for signs and symptoms of superinfection: fever,
perineal itching, cough, lethargy, or any unusual
discharge.

142
Antibiotics: Nursing Antibiotics: Nursing Antibiotics: Nursing
Implications Implications Implications
 Each class of antibiotics has specific side Sulfonamides Penicillins
effects and drug interactions that must be  Should be taken with at least 2400 mL of fluid  Any patient taking a penicillin should be carefully
carefully assessed and monitored. per day, unless contraindicated. monitored for an allergic reaction for at least 30 minutes
 Due to photosensitivity, avoid sunlight and after its administration.
 The most common side effects of antibiotics tanning beds.
are nausea, vomiting, and diarrhea.  The effectiveness of oral penicillins is decreased when
 These agents reduce the effectiveness of taken with caffeine, citrus fruit, cola beverages, fruit
oral contraceptives. juices, or tomato juice.
 All oral antibiotics are absorbed better if
taken with at least 6 to 8 ounces of water.

Antibiotics: Nursing Antibiotics: Nursing Antibiotics: Nursing

Implications
Cephalosporins
 Orally administered forms should be given with food to
decrease GI upset, even though this will delay
absorption.
 Some of these agents may cause an Antabuse-like
reaction when taken with alcohol.
Implications
Tetracyclines
 Milk products, iron preparations, antacids, and other
dairy products should be avoided because of the
chelation and drug-binding that occurs.
 All medications should be taken with 6 to 8 ounces of
fluid, preferably water.
 Due to photosensitivity, avoid sunlight and
tanning beds.
Implications
Aminoglycosides
 Monitor peak and trough blood levels of these agents to
prevent nephrotoxicity and ototoxicity.
 Symptoms of ototoxicity include dizziness, tinnitus, and
hearing loss.
 Symptoms of nephrotoxicity include urinary casts,
proteinuria, and increased BUN and serum creatinine
levels.

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Antibiotics: Nursing Antibiotics: Nursing Antibiotics: Nursing
Implications Implications Implications
Quinolones Macrolides Monitor for therapeutic effects:
 Should be taken with at least 3 L of fluid per day, unless  These agents are highly protein-bound and will cause  Disappearance of fever, lethargy, drainage,
otherwise specified severe interactions with other protein-bound drugs.
and redness
 The absorption of oral erythromycin is enhanced when
taken on an empty stomach, but because
of the high incidence of GI upset, many agents
are taken after a meal or snack.

Understanding Viruses Understanding Viruses

Viral Replication Viruses are difficult to kill because they live

 A virus cannot replicate on its own. inside our cells.
ANTIVIRAL AGENTS  It must attach to and enter a host cell.  Any drug that kills a virus may also kill our cells.
 It then uses the host cell’s energy to synthesize protein,
DNA, and RNA.

144
Viral Infections Antivirals Antivirals
Competent immune system:
Key characteristics of antiviral drugs: Viruses killed by current antiviral therapy:
 Best response to viral infections
 Able to enter the cells infected with virus.  cytomegalovirus (CMV)
 A well-functioning immune system will eliminate
or effectively destroy virus replication  herpes simplex virus (HSV)
 Interfere with viral nucleic acid synthesis and/or
regulation.  human immunodeficiency virus (HIV)
Immunocompromised patients have frequent viral  influenza A (the “flu”)
 Some agents interfere with ability of virus
infections to bind to cells.  respiratory syncytial virus (RSV)
 Cancer patients, especially leukemia or lymphoma
 Some agents stimulate the body’s immune system.
 Transplant patients, due to pharmacological therapy
 AIDS patients, disease attacks immune system

Antivirals: Mechanism of Antivirals Antivirals: Purine

Action Synthetic Purine Nucleoside Nucleosides
Inhibit viral replication Analogues Agent Antiviral Activity
 Inhibit viral attachment Two types of nucleosides: guanines
 Prevent genetic copying of virus acyclovir HSV 1 & 2, VZV
Purine nucleosides
 Prevent viral protein production  guanine
ganciclovir (DHPG) CMV retinitis and systemic
CMV infection
 adenosine
ribavirin (RTCD) Influenza types A and B,
RSV, LV, HV
Pyrimidine nucleosides adenosines
 thymine didanosine (ddl) HIV
 cytosine vidarabine (Ara-A) HSV, herpes zoster

145
Antivirals: Pyrimidine Other Antivirals Antivirals: Side Effects
Nucleosides
Agent Antiviral Activity amantadine acyclovir
cytosines (Symmetrel) and rimantadine (Flumadine)  Burning when topically applied, nausea, vomiting,
lamivudine (3TC) HIV diarrhea, headache
zalcitabine (ddC) HIV  influenza A
amantadine and rimantadine
thymine foscarnet (Foscavir)  Anticholinergic effects, insomnia, lightheadedness,
idoxuridine (IDU) HSV anorexia, nausea
 CMV (retinitis and systemic)
stavudine (d4T) HIV
trifluridine HSV Neuraminidase Inhibitors: oseltamivir (Tamiflu) didanosine (ddl)
zidovudine (AZT) HIV and zanamivir (Relenza)  Pancreatitis, peripheral neuropathies, seizures
 influenza types A and B

Antivirals: Side Effects Antivirals: Nursing Antivirals: Nursing

Implications
zidovudine (AZT)  Before beginning therapy, thoroughly
 Bone marrow suppression, nausea, headache assess underlying disease and medical
history, including allergies.
foscarnet (Foscavir)  Assess baseline VS and nutritional status.
 Headache, seizures, acute renal failure, nausea,  Assess for contraindications, conditions
vomiting, diarrhea
that may indicate cautious use, and potential
ganciclovir (Cytovene) drug interactions.
 Bone marrow toxicity, nausea, anorexia, vomiting
Implications
 Be sure to teach proper application technique
for ointments, aerosol
powders, etc.
 Emphasize hand washing before and after
administration of medications to prevent site
contamination and spread of infection.
 Patients should wear a glove or finger cot
when applying ointments or solutions to
affected areas.

146
Antivirals: Nursing Antivirals: Nursing Antivirals: Nursing
Implications Implications Implications
 Instruct patients to consult their physician  Instruct patients on the importance of taking Monitor for side effects:
before taking any other medication, including these medications exactly as prescribed and  effects are varied and specific to each agent
OTC medications. for the full course of treatment.
 Emphasize the importance of good hygiene.  With zidovudine:
 Inform patients that hair loss MAY occur so
 Inform patients that antiviral agents are not
that they are prepared for this rare adverse
cures, but do help to manage symptoms. reaction.
 This medication should be taken on an
empty stomach.

Antivirals: Nursing Protozoal Infections

Implications
Monitor for therapeutic effects: Parasitic protozoa: live in or on humans
 effects will vary depending on the type of viral infection  malaria
 Effects range from delayed progression of AIDS
ANTIMALARIAL,  leishmaniasis
and ARC to decrease in flu-like symptoms, decreased
frequency of herpes-like flare-ups,
ANTIPROTOZOAL, AND  amebiasis
 giardiasis
or crusting over of herpetic lesions. ANTIHELMINTIC AGENTS  trichomoniasis

147
Malaria Malarial Parasite Plasmodium Life Cycle
(plasmodium)
 Caused by the plasmodium protozoa. Two Interdependent Life Cycles Asexual cycle: two phases
 Four different plasmodium species.  Sexual cycle: in the mosquito  Exoerythrocytic phase: occurs “outside”
 Asexual cycle: in the human the erythrocyte
 Cause: the bite of an infected adult
 Knowledge of the life cycles is essential in  Erythrocytic phase: occurs “inside”
mosquito. the erythrocyte
understanding antimalarial drug treatment.
 Can also be transmitted by infected  Drugs are only effective during the asexual cycle. Erythrocytes = RBCs
individuals via blood transfusion,
congenitally, or via infected needles by drug
abusers.

Antimalarial Agents Antimalarials: Antimalarials: Mechanism of

Mechanism of Action Action
Attack the parasite during the asexual phase, 4-aminoquinoline derivatives chloroquine 4-aminoquinoline derivatives quinine and
when it is vulnerable and hydroxychloroquine mefloquine
 Erythrocytic phase drugs: chloroquine,  Bind to parasite nucleoproteins and interfere with protein  Alter pH within the parasite.
hydroxychloroquine, quinine, mefloquine synthesis.
 Interfere with parasite’s ability to metabolize and use
 Exoerythrocytic phase drug: primaquine  Prevent vital parasite-sustaining substances from being erythrocyte hemoglobin.
formed.
 Effective only during the erythrocytic phase.
 Alter pH within the parasite.
May be used together for synergistic or additive killing power.
 Interfere with parasite’s ability to metabolize and
use erythrocyte hemoglobin.
 Effective only during the erythrocytic phase

148
Antimalarials: Mechanism of Antimalarials: Mechanism of Antimalarials: Drug Effects
Action Action
diaminophyrimidines pyrimethamine and primaquine  Kill parasitic organisms.
trimethoprim  Only exoerythrocytic drug.  Chloroquine and hydroxychloroquine also
 Inhibit dihydrofolate reductase in the parasite.  Binds and alters DNA. have antiinflammatory effects.
 This enzyme is needed by the parasite to make essential
substances. sulfonamides, tetracyclines, clindamycin
 Also blocks the synthesis of tetrahydrofolate.  Used in combination with antimalarials to increase
protozoacidal effects
These agents may be used with sulfadoxine or dapsone
for synergistic effects.

Antimalarials: Therapeutic Antimalarials: Side Effects Antiprotozoals

Uses
 Used to kill plasmodium organisms, the  Many side effects for the various agents  atovaquone (Mepron)
parasites that cause malaria.  Primarily gastrointestinal: nausea, vomiting,  metronidazole (Flagyl)
 The drugs have varying effectiveness on diarrhea,anorexia, and abdominal pain  pentamidine (Pentam)
the different malaria organisms.  iodoquinol (Yodoxin, Di-Quinol)
 Some agents are used for prophylaxis against  paromomycin (Humatin)
malaria.
 Chloroquine is also used for rheumatoid
arthritis and lupus.

149
Protozoal Infections Protozoal Infections Antiprotozoals: Mechanism of
Action
 amebiasis Transmission and Uses atovaquone (Mepron)
 giardiasis  Person-to-person
 Ingestion of contaminated water or food  Protozoal energy comes from the
 pneumocystosis mitochondria
 Direct contact with the parasite
 toxoplasmosis  Atovaquone: selective inhibition of
 Insect bite (mosquito or tick)
 trichomoniasis mitochondrial electron transport
 Result: no energy, leading to cellular death

Used to treat mild to moderate P. carinii

Antiprotozoals: Mechanism of Antiprotozoals: Mechanism Antiprotozoals: Mechanism of

Action and Uses metronidazole Action
of Action and Uses
 Disruption of DNA synthesis as well as nucleic  Inhibits DNA and RNA and Uses iodoquinol
 “Luminal” (Yodoxin, Di-
or “contact” amebicide
pentamidine Quinol)
acid synthesis  Binds to and aggregates ribosomes  Acts primarily in the intestinal lumen of the
 Bactericidal, amebicidal, trichomonacidal infected host
 Directly lethal to Pneumocystis carinii
 Directly kills the protozoa
Used for treatment of trichomoniasis, amebiasis,  Inhibits glucose metabolism, protein and
giardiasis, anaerobic infections, and antibiotic- RNA synthesis, and intracellular amino acid Used to treat intestinal amebiasis
associated pseudomembranous colitis transport

Mainly used to treat P. carinii pneumonia

and other protozoal infections

150
Antiprotozoals: Mechanism Antiprotozoals: Side Antiprotozoals: Side
of Action and Uses Effects Effects
 “Luminal” or “contact” amebicide atovaquone pentamidine
paromomycin  nausea, vomiting, diarrhea, anorexia
 Kills by inhibiting protein synthesis  bronchospasms, leukopenia, thrombocytopenia, acute
pancreatitis, acute renal failure, increased liver function
metronidazole studies
Used to treat amebiasis and intestinal protozoal
infections, and also adjunct therapy in  metallic taste, nausea, vomiting, diarrhea,
management of hepatic coma abdominal cramps paromomycin
 nausea, vomiting, diarrhea, stomach cramps
iodoquinol
 nausea, vomiting, diarrhea, anorexia, agranulocytosis

Antihelmintics Antihelmintics Antihelmintics

 diethylcarbamazine (Hetrazan)  Drugs used to treat parasitic worm infections:  It is VERY IMPORTANT to identify the
 mebendazole (Vermox) helmintic infections causative worm
 niclosamide (Niclocide)  Unlike protozoa, helminths are large and  Done by finding the parasite ova or larvae in
 oxamniquine (Vansil)
have complex cellular structures feces, urine, blood, sputum, or tissue
 Drug treatment is very specific  cestodes (tapeworms)
 piperazine (Vermizine)
 nematodes (roundworms)
 praziquantel (Biltricide)  trematodes (flukes)
 pyrantel (Antiminth)
 thiabendazole (Mintezol)

151
Antihelmintics: Mechanism Antihelmintics: Mechanism Antihelmintics: Mechanism
of Action and Uses of Action of Action
diethylcarbamazine (Hetrazan) piperazine (Vermizine) and pyrantel (Antiminth) mebendazole (Vermox)
 Blocks acetylcholine at the neuromuscular junction,  Inhibits uptake of glucose and other nutrients, leading to
 Inhibits rate of embryogenesis resulting in paralysis of the worms, which are then autolysis and death of the parasitic worm
expelled through the GI tract
thiabendazole (Mintezol) Used to treat cestodes and nematodes
Used to treat nematodes (giant worm and pinworm)
 Inhibits the helminth-specific enzyme, fumarate reductase

Both used for nematodes

(tissue and some roundworms)

Antihelmintics: Mechanism Antihelmintics: Mechanism Antihelmintics: Side

of Action of Action Effects
niclosamide (Niclocide) oxamniquine (Vansil) and praziquantel niclosamide, oxamniquine, praziquantel,
 Causes the worm to become dislodged
(Biltricide) thiabendazole, piperazine, pyrantel
from the GI wall  Cause paralysis of worms’ musculature and  nausea, vomiting, diarrhea, dizziness, headache
 They are then digested in the intestines immobilization of their suckers
and expelled  Cause worms to dislodge from mesenteric veins
to the liver, then killed by host tissue reactions mebendazole
Used to treat cestodes  diarrhea, abdominal pain, tissue necrosis
Used to treat trematodes, cestodes
(praziquantel only)

152
Antimalarial, Antiprotozoal,
Antihelmintic Agents: Nursing
Implications
 Before beginning therapy, perform a
thorough health history and medication
history, and assess for allergies.
 Check baseline VS.
 Check for conditions that may contraindicate
use, and for potential drug interactions.
Antimalarial Agents:
Nursing Implications
 Instruct patient to notify physician
immediately if ringing in the ears, hearing
decrease, visual difficulties, nausea, vomiting,
profuse diarrhea, or abdominal pain occur.
 Alert patients to the possible recurrence of
the symptoms of malaria so that they will
know to seek immediate treatment.
Antimalarial, Antiprotozoal, Antimalarial Agents:
Antihelmintic Agents: Nursing Nursing Implications
Implications  Assess for presence of malarial symptoms.
 Some agents may cause the urine to have an  When used for prophylaxis, these agents
asparagus-like odor, or cause an unusual skin should be started 2 weeks before potential
odor, or a metallic taste; be sure to warn the exposure to malaria, and for 8 weeks after
patient ahead of time. leaving the area.
 Administer ALL agents as ordered and for the  Medications are taken weekly, with 8 ounces
prescribed length of time. of water.
 Most agents should be taken with food to
reduce GI upset.
Antimalarial, Antiprotozoal,
Antihelmintic Agents: Nursing
Implications
Monitor for side effects:
 Ensure that patients know the side effects that should be
ANTIFUNGAL AGENTS
reported.
 Monitor for therapeutic effects and adverse effects with
long-term therapy.
153
Antifungal Agents Fungi Yeasts

Drugs used to treat infections caused by fungi  Also known as mycoses  Single-cell fungi
 Systemic and topical  Very large and diverse group of  Reproduce by budding
microorganisms  Very useful organisms
 Broken down into yeasts and molds  Baking
 Alcoholic beverages

Molds Mycotic Infections Mycotic Infections

 Multicellular Four General Types Candida albicans

 Characterized by long, branching filaments  Cutaneous  Due to antibiotic therapy, antineoplastics,
 Subcutaneous or immunosuppressants
called hyphae
 Superficial  May result in overgrowth and systemic infections
 Systemic*
*Can be life-threatening
*Usually occur in immunocompromised host

154
Mycotic Infections Mycotic Infections Antifungal Agents

In the mouth: Vaginal candidiasis:

Systemic
 Oral candidiasis or thrush  “Yeast infection”
 Examples: amphotericin B, fluconazole,
 Newborn infants and immunocompromised patients  Pregnancy, diabetes mellitus, oral contraceptives ketoconazole, itraconazole

Topical
 Examples: clotrimazole, miconazole, nystatin

Antifungal Agents Antifungal Agents: Antifungal Agents:

Mechanism of Action Mechanism of Action
Broken down into four major groups based Polyenes: amphotericin B and nystatin flucytosine
on their chemical structure  Bind to sterols in cell membrane lining  Also known as 5-fluorocytosine (antimetabolite)
 Polyenes: amphotericin B and nystatin  Allow K+ & Mg++ to leak out, altering fungal cell  Taken up by fungal cells and interferes with DNA
 Flucytosine metabolism synthesis
 Imidazoles: ketoconazole, miconazole, clotrimazole,  Result: fungal cell death  Result: fungal cell death
fluconazole
 Griseofulvin

155
 Antifungal Agents: Antifungal Agents: Antifungal Agents: Side
Mechanism of Action Mechanism of Action Effects
Imidazoles griseofulvin amphotericin B
ketoconazole, miconazole, clotrimazole, fluconazole  Disrupts cell division “Shake and Bake”
 Result: inhibited fungal mitosis (reproduction) fever chills headache anorexia
 Inhibit an enzyme, resulting in cell membrane malaise nausea hypotension tachycardia
leaking muscle and joint pain
 Lead to altered cell membrane lowered potassium and magnesium levels

 Result: fungal cell death *renal toxicity

*neurotoxicity: seizures and paresthesias

Antifungal Agents: Side Antifungal Agents: Antifungal Agents:

Effects Nursing Implications
fluconazole  Before beginning therapy, assess for
 nausea, vomiting, diarrhea, abdominal pain, hypersensitivity, possible contraindications,
 increased liver function studies and conditions that require cautious use.
 Obtain baseline VS, CBC, liver function
flucytosine studies, and ECG.
 nausea, vomiting, anorexia  Assess for other medications used (prescribed
and OTC) in order to avoid
griseofulvin drug interactions.
 rash, urticaria, headache, nausea, vomiting, anorexia
Nursing Implications
 Follow manufacturer’s directions carefully
for reconstitution and administration.
 Monitor VS of patients receiving IV infusions
every 15 to 30 minutes.
 During IV infusions, monitor I & O and
urinalysis findings to identify adverse
renal effects.

156
Antifungal Agents:
Nursing Implications
amphotericin B
 To reduce the severity of the infusion-related reactions,
pretreatment with an antipyretic (acetaminophen),
antihistamines, and antiemetics may be given.
 A test dose of 1 mg per 20 mL 5% dextrose in
water infused over 30 minutes should be given.
 Use IV infusion pumps and the most distal
veins possible.
Antifungal Agents:
Nursing Implications
 Tissue extravasation of fluconazole at the IV
site may lead to tissue necrosis—monitor IV
site carefully.
 Oral forms of griseofulvin should be given
with meals to decrease GI upset.
 Monitor carefully for side/adverse effects.
Antifungal Agents:
Nursing Implications
Monitor for therapeutic effects:
 Easing of the symptoms of infection
 Improved energy levels
 Normal vital signs, including temperature

Antitubercular Agents Mycobacterium Infections

 Tuberculosis, “TB” Common Infection Sites

ANTITUBERCULAR AGENTS  Caused by Mycobacterium tuberculosis  lung (primary site)
 brain
 Antitubercular agents treat all forms of
 bone
mycobacterium
 liver
 kidney

157
Mycobacterium Infections Mycobacterium Infections Antitubercular Agents

 Aerobic bacillus  Tubercle bacilli are conveyed by droplets. Primary Agents Secondary Agents
 Passed from infected:  Droplets are expelled by coughing or sneezing, isoniazid* capreomycin
 Humans then gain entry into the body
ethambutol cycloserine
by inhalation.
 Cows (bovine) pyrazinamide (PZA) ethionamide
 Tubercle bacilli then spread to other body organs
 Birds (avian) rifampin kanamycin
via blood and lymphatic systems.
 Tubercle bacilli may become dormant, or walled streptomycin para-aminosalicyclic acid
off by calcified or fibrous tissue. (PSA)
*most frequently used

Antitubercular Agents: Antitubercular Agents:

Mechanism of Action Mechanism of Action
Three Groups isoniazid
 Drug of choice(INH)
for TB
 Protein wall synthesis inhibitors streptomycin,
kanamycin, capreomycin, rifampin, rifabutin
 Resistant strains of mycobacterium emerging ANTITUBERCULAR AGENTS:
 Metabolized in the liver through
 Cell wall synthesis inhibitors cycloserine, ethionamide,
acetylation—watch for “slow acetylators” THERAPEUTIC
Used for the prophylaxis USES
isoniazid
 Other mechanisms of action or treatment of TB

158
Antitubercular Therapy
Effectiveness depends upon:
 Type of infection
 Adequate dosing
 Sufficient duration of treatment
 Drug compliance
 Selection of an effective drug combination
Antitubercular Agents:
Nursing Implications
Patient education is CRITICAL:
 Therapy may last for up to 24 months.
 Take medications exactly as ordered,
at the same time every day.
 Emphasize the importance of strict compliance
to regimen for improvement of condition or cure.
Antitubercular Agents: Side
Effects
 INH
peripheral neuritis, hepatotoxicity
 ethambutol
retrobulbar neuritis, blindness
 rifampin
hepatitis, discoloration of urine, stools
Antitubercular Agents:
Nursing Implications
Patient education is CRITICAL:
 Remind patients that they are contagious during
the initial period of their illness—instruct in proper
hygiene and prevention of the spread of infected
droplets.
 Emphasize to patients to take care of themselves,
including adequate nutrition and rest.
Antitubercular Agents:
Nursing Implications
 Obtain a thorough medical history and assessment.
 Perform liver function studies in patients
who are to receive isoniazid or rifampin
(especially in elderly patients or those who use alcohol
daily).
 Assess for contraindications to the various agents,
conditions for cautious use, and potential drug
interactions.
Antitubercular Agents:
Nursing Implications
 Patients should not consume alcohol while on these
medications nor take other medications, including OTC,
unless they check with their physician.
 Diabetic patients taking INH should monitor their blood
glucose levels because hyperglycemia may occur.
 INH and rifampin cause oral contraceptives to become
ineffective; another form of birth control
will be needed.
159
Antitubercular Agents:
Nursing Implications
 Patients who are taking rifampin should be told that their
urine, stool, saliva, sputum, sweat, or tears may become
reddish-orange; even contact lenses may be stained.
 Vitamin B6 may is needed to combat peripheral neuritis
associated with INH therapy.
Antitubercular Agents:
Nursing Implications
Monitor for side effects
 Instruct patients on the side effects that should be
reported to the physician immediately.
 These include fatigue, nausea, vomiting, numbness and
tingling of the extremities, fever, loss of appetite,
depression, jaundice.
Antitubercular Agents:
Nursing Implications
Monitor for therapeutic effects:
 Decrease in symptoms of TB, such as cough
and fever
 Lab studies (culture and sensitivity tests)
and CXR should confirm clinical findings
 Watch for lack of clinical response to therapy, indicating
possible drug resistance

NSAIDs NSAIDs: Mechanism of Action

 Large and chemically diverse group of drugs  Activation of the arachidonic acid
ANTIINFLAMMATORY AGENTS with the following properties: pathway causes:
 Analgesic  pain
AND NONSTEROIDAL  Antiinflammatory  headache
ANTIINFLAMMATORY DRUGS  Antipyretic
 fever
(NSAIDS)  inflammation

160
NSAIDs: Mechanism of Action NSAIDs: Mechanism of Action NSAIDs: Mechanism of Action

Analgesia—treatment of headaches and pain Antipyretic: reduce fever Relief of inflammation

 Block the undesirable effects of prostaglandins, which  Inhibit prostaglandin E2 within the area of the brain that  Inhibit the leukotriene pathway, the prostaglandin
cause headaches controls temperature pathway, or both

NSAIDs NSAIDs: Acetic Acid NSAIDs: Carboxylic Acids

Six structurally related groups:  diclofenac sodium (Voltaren) Acetylated

 Acetic acids  diclofenac potassium (Cataflam)  aspirin (ASA)
 Carboxylic acids  choline magnesium salicylate (Trilisate)
 etodolac (Lodine)
 Propionic acids  diflunisal (Dolobid)
 Enolic acids
 indomethacin (Indocin)
 Fenamic acids  sulindac (Clinoril) Nonacetylated
 Nonacidic compounds  tolmetin (Tolectin)  salicylamide
 salsalate (Disalcid)
 sodium salicylate

161
NSAIDs: Propionic Acids NSAIDs: Other Agents NSAIDs: Other Agents

 fenoprofen (Nalfon) Enolic acids COX-2 Inhibitors

 flurbiprofen (Ansaid)
 ibuprofen (Motrin, others)
 ketoprofen (Orudis)
 ketorolac (Toradol)
 naproxen (Naprosyn)
 oxaprozin (Daypro)
 phenylbutazone (Butazolidin)  celecoxib (Celebrex)
 piroxicam (Feldene)
 rofecoxib (Vioxx)
Fenamic acids
 meclofenamic acid (Meclomen)
 mefenamic acid (Ponstel)
Nonacidic compounds
 nabumetone (Relafen)

NSAIDs: Drug Effects NSAIDs: Therapeutic Uses NSAIDs: Specific Agents

 Analgesic (mild to moderate)  Relief of mild to moderate pain salicylates (aspirin)

 Acute gout
 Antigout  More potent effect on platelet aggregation and thermal
 Various bone, joint, and muscle pain regulatory center in the brain
 Antiinflammatory
 Osteoarthritis  analgesic
 Antipyretic  antipyretic
 Rheumatoid arthritis
 Relief of vascular headaches  antiinflammatory
 Juvenile rheumatoid arthritis
 Platelet inhibition (ASA)  Antithrombotic effect: used in the treatment of MI and
 Dysmenorrhea other thromboembolic disorders
 Fever

162
NSAIDs: Specific Agents NSAIDs: Side Effects NSAIDs: Side Effects

phenylbutazone (Butazolidin) Gastrointestinal Renal

 Greater effects on uric acid production and excretion, in
addition to antiinflammatory effects
 More commonly used for treatment of gout
 dyspepsia, heartburn, epigastric distress, nausea  reductions in creatinine clearance
**GI bleeding  acute tubular necrosis with renal failure
**mucosal lesions (erosions or ulcerations)
 Misoprostol (Cytotec) can be used to reduce these
dangerous effects.

NSAIDs: Side Effects NSAIDs: Salicylate Toxicity NSAIDs: Nursing

Cardiovascular  Adults: tinnitus and hearing loss
 noncardiogenic pulmonary edema  Children: hyperventilation and CNS effects
 Effects arise when serum levels exceed
300g/mL.
 Metabolic acidosis and respiratory alkalosis
may be present.
Implications
 Before beginning therapy, assess for
conditions that may be contraindications to
therapy, especially:
 GI lesions or peptic ulcer disease
 Bleeding disorders
 Assess also for conditions that require
cautious use.
 Perform lab studies as indicated (cardiac,
renal, liver studies, CDC, platelet count).

163
NSAIDs: Nursing NSAIDs: Nursing NSAIDs: Nursing
Implications Implications Implications
 Perform a medication history to assess for  Salicylates are NOT to be given to children  Educate patients about the various side
potential drug interactions.
under age 12 because of the risk of Reye’s effects of NSAIDs, and to notify their
 Several serious drug interactions exist:
syndrome. physician if these effects become severe
 alcohol
 Because these agents generally cause GI or if bleeding or GI pain occur.
 heparin
distress, they are often better tolerated if  Patients should watch closely for the
 phenytoin
taken with food, milk or an antacid to avoid occurrence of any unusual bleeding,
 oral anticoagulants
GI irritation. such as in the stool.
 steroids
 sulfonamides  Explain to patients that therapeutic effects  Enteric-coated tablets should not be
may not be seen for 3 to 4 weeks. crushed or chewed.

NSAIDs: Nursing Steroids: the worst drugs for

Implications adverse effects
 Monitor for therapeutic effects, which vary
according to the condition being treated:
CORTICOSTEROIDS
decrease in swelling, pain, stiffness,
and tenderness of a joint or muscle area

164
 Corticosteroids History
History Uses: 1855 – Addison's disease
Synthesis – Therapeutic 1856 – Adrenal glands essential for life
Pharmacological – Diagnostic
Actions Adverse reactions 1930 – Cortex > medulla
Pharmacokinetics Contraindications 1932 – Cushing’s syndrome
Preparations Precautions during 1949 – Hench et al (Steroids in rheumatoid arthritis)
Therapeutic principles therapy
Glucocorticoid
1952 – Aldosterone
Dosage schedule &
Steroid withdrawal antagonists

Basal secretions
Group Hormone Daily
secretions
Glucocorticoids • Cortisol 5 – 30 mg
• Corticosterone 2 – 5 mg
Mineralocorticoids • Aldosterone 5 – 150 μg
• 11- deoxycorticosterone Trace

Sex Hormones
•Androgen • DHEA 15 – 30 mg
•Progestogen • Progesterone 0.4 – 0.8 mg
•Oestrogen • Oestradiol Trace

From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

165
 Cholesterol ACTH
Pharmacological Actions
Pharmacological Actions
Oestriol
Pregnenolone 17-α- Hydroxy
pregnenolone
Dehydro-epi
androsterone
 Direct (Intended) Actions  Negative feedback mechanism.
 Steroids and drugs designed to mimic them are
Anti-inflammatory directly gene-active.
Progesterone 17- Hydroxy Andro-
Oestrone
progesterone stenedione Anti-allergy  Glucocorticoids (e.g., prednisolone) used to
11-Desoxy- 21,β hydroxylase
Anti-immunity suppress inflammation, allergy and immune
corticosterone responses.
11- Desoxy-
cortisol
 Permissive Actions  Anti-inflammatory therapy is used in many illnesses
Corticosterone • Lipolytic effects (e.g., RA, UC, BA, eye and skin inflammations).
11,β hydroxylase
18-Hydroxy- • Effect on bp -Useful in, say, tissue transplantation and
corticosterone lymphopoiesis (leukemias and lymphomas).
• Effect on bronchial muscles
 Striking improvements can be obtained, but severe
ALDOSTERONE CORTISOL TESTOSTERONE OESTRADIOL  (e.g.,sympathomimetic amine) adverse, but highly predictable, effects are ensue.

Hypothalamopituitary adrenal (HPA) axis: Negative

Immune
Stress Feedback system:
Circadian altered
rhythm Hypothalamus
Muscle:
CRH Net loss of amino
Posterior Acids (glucose)
Anterior Pituitary Gland
Pituitary Gland Liver:
(-) Deamination of
proteins into amino
ACTH acids,
gluconeogenesis
Glucocorticoids,
Adrenals Catecholamines, (glucose)
etc.. Fat Cells:
Free fatty
acid
Kidney mobilization

Heart rate:
Increased

166
 Pharmacological Actions
Corticosteroids are Gene-Active
 For most clinical purposes, synthetic
glucocorticoids are used because they have a
higher affinity for the receptor, are less activated
and have little or no salt-retaining properties.
 Hydrocortisone used for: orally for replacement
therapy, i.v. for shock and asthma, topically for
eczema (ointment) and enemas (ulcerative
colitis).
 Prednisolone the most widely used drug given
orally in inflammation and allergic diseases.
Pharmacological Actions
 Betamethasone and dexamethasone: very
potent, w/o salt-retaining properties; thus, very
useful for high-dose therapies (e.g., cerebral
edemas).
 Beclometasone, diproprionate, budesonide:
pass membranes poorly; more active when
applied topically (severe eczema for local anti-
inflammatory effects) than orally; used in
asthma, (aerosol).
 Triamcinolone: used for severe asthma and for
local joint inflammation (intra-articular inj.).

Stress and The Adrenal Glands Actions: Carbohydrate and protein metabolism
Pharmacological Actions
Negative nitrogen balance and hyperglycemia

1. Carbohydrate 8. Stomach
 Gluconeogenesis
2. Protein 9. Blood  Peripheral actions (mobilize aas and glucose and glycogen)
10. Anti-inflammatory  Hepatic actions
3. Lipid
4. Electrolyte and H2O 11. Immunosuppressant
 Peripheral utilization of glucose
5. CVS 12. Respiratory system

6. Skeletal Muscle 13. Growth and Cell Division

 Glycogen deposition in liver
7. CNS 14. Calcium metabolism (activation of hepatic glycogen synthase)

167
 Actions: Electrolyte and water balance
Actions: Cardiovascular system
Actions: Lipid metabolism
 Aldosterone is more important
 Restrict capillary permeability
 Act on DT and CD of kidney
Na+ reabsorption  Maintain tone of arterioles
 Redistribution of Fat 

 Buffalo hump  Urinary excretion of K+ and H+  Myocardial contractility

 Moon face  Addison’s disease ??

 Promote adipokinetic agents activity • Na+ loss Mineralocorticoid induced hypertension ??

(glucagon, growth hormone, adrenaline, thyroxine) • Shrinkage of ECF
• Cellular hydration
• Hypodynamic state of CVS Na+ sensitize blood vessels to the action of
• Circulatory collapse, catecholamines & angiotensin
renal failure, death

Actions: Skeletal Muscles Actions: CNS

Pseudotumor cerebri
Needed for maintaining the normal function of Skeletal
muscle  Direct: (Intracranial hypertension)
 Mood
Addison's disease: weakness and fatigue is due to  Glucocorticoids
 Behaviour
inadequacy of circulatory system  Mineralocorticoids
 Brain excitability
Prolonged use:  Amiodarone
 Indirect:
Steroid myopathy  maintain glucose, circulation and electrolyte  Vitamin A
balance  Oral contraceptives
 Tetracyclines
ICP (pseudotumor cerebri) - Rare

From Harrison. 15th edition, volume 1, page 435

168

Actions: Stomach
Aggravate peptic ulcer. May be due to:
 Acid and pepsin secretion
 immune response to H.Pylori
Actions: Anti-inflammatory
Actions: Blood
 Recruitment of WBC and monocyte-
macrophage into affected area & elaboration
RBC: Hb and RBC content of chemotactic substances
(erythrophagocytosis )  Lipocortin
 ELAM1 and ICAM-1 in endothelial cells
WBC: Lymphocytes, eosinophils,  TNF from phagocytic cells
monocytes, basophils
 IL1 from monocyte-macrophage
Polymorphonucleocytes
 Formation of Plasminogen Activator
 Action of MIF and fibroblastic activity
 Expression of COX II

Corticosteroids Anti-inflammatory actions of corticosteroids

Immunosuppressive and anti-allergic actions
Corticosteroid inhibitory effect
Lipocortin  Suppresses all types of hypersensitivity and
Phospholipids allergic phenomenon
 At High dose: Interfere with all steps of
Phospholipase A2
immunological response
Arachidonic acids  Causes greater suppression of Cell-mediated
immunity (graft rejection and delayed
hypersensitivity)
lipoxygenase Cycylooxygenase  Transplant rejection: antigen expression from
grafted tissues, delay revascularization,
sensitisation of T lymphocytes etc.
Prostaglandins,
Leukotriene Thromboxane
PAF by Prostacyclins
lipocortin

169
 Actions: Growth and Cell division Actions: Calcium metabolism

 Intestinal absorption
 Inhibit cell division or synthesis of DNA
 Delay the process of healing
 Renal excretion
 Retard the growth of children

 Excessive loss of calcium from spongy bones

(e.g., vertebrae, ribs, etc)

Preparations
Actions: Respiratory system Drug Anti-inflam. Salt retaining Topical
Preparations
Cortisol 1 1.0 1
 Not bronchodilators Drug Anti-inflam. Salt retaining Topical
Cortisone 0.8 0.8 0
 Most potent and most effective anti-inflammatory Long acting
Prednisone 4 0.8 0
 Effects not seen immediately (delay 6 or more hrs) Betamethasone 25-40 0 10
Prednisolone 5 0.3 4
 Inhaled corticosteroids are used for long term control Dexamethasone 30 0 10
Methylpredni- 5 0 5
solone Mineralocorticoids
Fludrocortisone 10 250 10
Intermediate acting
DOCA 0 20 0
Triamcinolone 5 0 5
Paramethasone 10 0 -
Fluprednisolone 15 0 7

170
Synthesis Diabetes Mellitus
Stimuli Part Principal
product  The incidence of diabetes is increasing at an
Angiotensin II Zona alarming rate in the US.
Aldosterone
glomerulosa
ACTH Zona fasiculata Cortisol
& reticularis Adrenal androgens
Sympathetic Adrenaline &
nervous Medulla Nor-adrenaline ANTI-DIABETIC DRUGS
system

Pancreatic axis  Glucose homeostasis Normal

Body
cells
Insulin take up more
glucose Insulin
 Insulin Beta cells

 β cells secrete due to

of pancreas stimulated
to release insulin into
the blood Glycerol
high blood glucose
Liver takes Blood glucose level

High blood
up glucose
and stores it as
declines to a set point;
stimulus for insulin Lipolysis
levels glucose level glycogen release diminishes

 Glucose uptake into STIMULUS:

Rising blood glucose

tissues increases
level (e.g., after eating
a carbohydrate-rich
meal) Homeostasis: Normal blood glucose level
Free fatty acids
STIMULUS:
(about 90 mg/100 mL)
Triglyceride
 Glucagon
Declining blood
glucose level
(e.g., after
Synthesis
skipping a meal)
 α cells secrete when Free fatty acids
blood glucose is low Blood glucose level
rises to set point; Alpha
stimulus for glucagon
 Glucose is released from
cells of
release diminishes pancreas stimulated
to release glucagon
tissues back into blood Liver
into the blood
LPL Glucose
breaks down
glycogen and Glucagon
releases glucose
to the blood
Figure 26.8
Insulin

171
Normal Glucose Control
Diabetes Mellitus
 In the post-absorptive period of a normal individual, low
Diabetes mellitus  This is a disease caused by elevated glucose levels
basal levels of circulating insulin are maintained through  2 Types of diabetes:
constant β cell secretion. This suppresses lipolysis, Type I diabetes (10% of cases)
proteolysis and glycogenolysis. After ingesting a meal a  Type I
burst of insulin secretion occurs in response to elevated  “Childhood” diabetes  Develops suddenly, usually before age 15.
glucose and amino acid levels. When glucose levels return to  Loss of pancreatic β cells  Caused by inadequate production of insulin because T
basal levels, insulin secretion returns to its basal level. cell-mediated autoimmune response destroys beta cells.
 Decreased insulin
 Type I DM: Lack of functional β-cells prevents mitigation of
elevated glucose levels and associated insulin responses.  Type II  Controlled by insulin injections.
The onset and progression of neuropathy, nephropathy and  “Adult” diabetes Type II diabetes (90% of cases)
retinopathy are directly related to episodic hyperglycemia.  Defective signal reception in insulin pathway
 Usually occurs after age 40 and in obese individuals, but
 Type II DM: The pancreas retains some β-cell function but  Decreased insulin
effective insulin response is inadequate for the glucose level. genetics, aging, and peripheral insulin resistance also.
Actual insulin levels may be normal or supra-normal but it is  Both cause hyperglycemia, glycosuria, lipid  Insulin levels are normal or elevated but there is either a
ineffective (insulin resistance). breakdown because tissues are deficient in decrease in number of insulin receptors or the cells
glucose, ketone bodies
cannot take it up.
 Controlled by dietary changes and regular exercise.

Type 2 Diabetes: Pathophysiology

Type 1 Diabetes Mellitus
FOOD

Glycerol Lipolysis
Exxagerated lipolysis
Storage In Fat Depots
Inhibition of Lipolysis
I I
I I
Free fatty acids β Cell Insulin
Triglyceride Insulin
Synthesis
Dysfunction Secretion Insulin
Pancreas Pancreas
Free fatty acids

I Restrain of I
Decreased Glucose HGO Uptake of glucose
Increased Uptake
LPL Glucose splanchnic
glc
output
Insulin Resistance Insulin Effects

172
Insulin and Oral Hypoglycemics Long term complications
The peptide hormones directly involved in responding to and controlling
blood glucose levels are located in the islets of Langerhans in the
pancreas; insulin is secreted by β-cells and glucagon by α2 cells.
 Diabetes is a
Diabetes is a disorder of inadequate insulin activity it is associated with
heterogeneous group of
episodes of both hyper- and hypo-glycemia. It is the episodes of
syndromes
hyperglycemia that are associated with long-term complications.
characterized by the
elevation of glucose
levels due to a relative or
absolute deficiency of
insulin; frequently
inadequate insulin
release is complicated
by excess glucagon
release.

The long term complications of diabetes may be

divided into two large groups:
1. Macrovascular: These complications are
associated with pathology of the large and
medium-sized vessels; this includes CHD, stroke,
PVD
2. Microvascular: These complications are due to
vascular pathology of the small vessels and
include neuropathy, nephropathy, retinopathy

173
Treatment: Insulin secretion:
 Type I: Type 1s depend on exogenous insulin to prevent Insulin secretion is regulated by glucose levels, certain amino
hyperglycemia and avoid ketoacidosis. The goal of type 1 acids, hormones and autonomic mediators.
therapy is to mimic both the basal and reactive secretion of  Secretion is most commonly elicited by elevated glucose
insulin in response to glucose levels avoiding both hyper- levels; increased glucose levels in β-cells results in increased
and hypo-glycemic episodes. ATP levels, this results in a block of K+ channels causing
 Type II: The goal of treatment is to maintain glucose membrane depolarization which opens Ca2+ channels.
concentrations within normal limits to prevent long term  The influx of Ca2+ results in a pulsatile secretion of insulin;
complications. Weight reduction, exercise (independent of continued Ca2+ influx results in activation of transcription
weight reduction) and dietary modification decrease insulin factors for insulin.
resistance and are essential steps in a treatment regimen.  Oral glucose elicits more insulin secretion than IV glucose;
For many this is inadequate to normalize glucose levels, the oral administration elicits gut hormones which augment the
insulin response.
addition of hypoglycemic agents is often required, often
insulin therapy is required.  Insulin is normally catabolized by insulinase produced by the
kidney.

Mechanism of Insulin Release in the

INSULIN
Pancreas
 Insulin is a peptide hormone synthesized as a
precursor (pro-insulin) which undergoes
proteolytic cleavage to form a dipeptide; the
cleaved polypeptide remnant is termed protein
C.
 Both are secreted from the β-cell, normal
individuals secrete both insulin and (but much
less) pro-insulin.
 Type 2s are found to secrete high levels of pro-
insulin (pro-insulin is inactive) measuring the
level of C-protein is a more accurate estimation
of normal insulin secretion in type 2s.
Insulin
 Human insulin consists of 51 aa
in two chains connected by 2
disulfide bridges (a single gene
product cleaved into 2 chains
during post-translational
modification).
 T1/2 ~5-10 minutes, degraded by
glutathione-insulin
transhydrogenase (insulinase)
which cleaves the disulfide links.
 Bovine insulin differs by 3 aas,
pork insulin differs by 1 aa.
 Insulin is stored in a complex
with Zn2+ ions.

174
 Mechanism of Insulin Action The Goal of Insulin Therapy
The synthesis and release of
insulin is modulated by: Administration of insulins are arranged to mimic the normal basal,
1. Glucose (most  Insulin binds to specific high prandial and post-prandial secretion of insulin. Short acting forms
important), AAs, FAs affinity membrane receptors are usually combined with longer acting preparations to achieve
and ketone bodies with tyrosine kinase activity
stimulate release.  Phosphorylation cascade results this effect.
2. Glucagon and in translocation of Glut-4 (and
somatostation inhibit some Glut-1) transport proteins
relases into the plasma membrane.
3. α-Adrenergic  It induces the transcription of
stimulation inhibits several genes resulting in
release (most increased glucose catabolism
important). and inhibits the transcription of
4. β-Adrenergic genes involved in
stimulation promotes gluconeogenesis.
release. Insulin secretion - Insulin secretion in beta cells is triggered
 Insulin promotes the uptake of
by rising blood glucose levels. Starting with the uptake of
5. Elevated intracellular glucose by the GLUT2 transporter, the glycolytic K+ into cells.
Ca2+ promotes release. phosphorylation of glucose causes a rise in the ATP:ADP
ratio. This rise inactivates the potassium channel that
depolarizes the membrane, causing the calcium channel to
open up allowing calcium ions to flow inward. The ensuing
rise in levels of calcium leads to the exocytotic release of

insulin from their storage granule.

Rapid Onset and Ultrashort-acting Intermediate –acting Insulin Prolonged-acting insulin

Preparations
1.Regular insulin: short acting, soluble, crystalline zinc insulin is usually given
subcutaneously; it rapidly lowers glucose levels. All regular insulin is now made Preparations preparations
using genetically engineered bacteria; cow and pig no longer used.
2. Lispro, Aspart & Glulisine preparations are classified as ultrashort acting forms 1. Lente insulin: This is a 1.Ultralente: a suspension
with onset more rapid than regular insulin and a shorter duration. These are less
often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a
amorphous precipitate of insulin of zinc insulin forming Pump vs. Standard
with zinc ion combined with 70% large particles which
meal and has its peak effect 30-90 minutes after injection (vs. 50-120 minutes for
regular insulin).
ultralente insulin. Onset is dissolve slowly, delaying Insulin Therapy
slower but more sustained than onset and prolonging
3. Glulisine can be given anywhere from 15 minutes prior to 20 minutes after regular insulin. It cannot be duration of action.
beginning a meal. given IV ( this has not been
produced since 2005). 2.Insulin glargine:
Precipitation at the
2. Isophane NPH insulin: Neutral injection site extends
protamine Hagedorn insulin is a the duration of action of
suspension of crystalline zinc this preparation.
insulin combined with protamine
(a polypeptide). The conjugation 3. Detemir insulin: has a FA
with protamine delays its onset complexed with insulin
of action and prolongs it resulting in slow
effectiveness. It is usually given dissolution.
in combination with regular
insulin.

175
 Action of Insulin on Various Tissues

 Insulin Preparations and Treatment Insulin Combinations Liver Muscle Adipose

 Various types of insulin are characterized by their  Various premixed ↓ glucose production ↑ Glucose transport ↑ glucose transport
combinations of various
onset and duration of action preparations of insulin are
available to ease ↑ glycolysis ↑ glycolysis ↑ lipogenesis&
administration. Standard lipoprotein lipase
combination use should activity
follow establishment of ↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis
an acceptable regime of
individual preparations.
↑ Protein synthesis ↑ protein synthesis

Adverse Effects of Insulin Oral Hypoglycemics

1. Hypoglycemia may occur due to insulin overdose,
insufficient caloric intake (missed meal, improper meal
content, delayed meal, etc.). Ethanol consumption  These agents are useful in the treatment of type
promotes hypoglycemic response. Symptoms: ↑ HR, 2s who do not respond adequately to non-
diaphoresis, MS changes, anything (diabetics are usually medical interventions (diet, exercise and weight
really good at recognizing hypoglycemic symptoms). loss).
2. Hypokalemia: insulin draws K+ into the cell with glucose  Newly diagnosed Type 2s (less than 5 years)
(hyperglycemia with normal K+). often respond well to oral agents, patients with
3. Anaphylaxis: when sensitized to non-human insulin gets long standing disease (often diagnosed late)
non-human insulin (now rare). often require a combination of agents with or
4. Lipodystrophy at injection site without insulin.
5. Weight gain  The progressive decline in β-cell function often
6. Injection complications necessitates the addition of insulin at some time
in Type II diabetes. Oral agents are never
indicated for Type Is.

176

Sulfonylureas
These agents promote the release of
insulin from β-cells (secretogogues);
tolbutamide, glyburide, glipizide
and glimepiride.
 Mechanism:
 These agents require functioning β-
cells, they stimulate release by
blocking ATP-sensitive K+ channels
resulting in depolarization with Ca2+
influx which promotes insulin
secretion.
 They also reduce glucagon secretion
and increase the binding of insulin to
target tissues.
 They may also increase the number
of insulin receptors
 Pharmacokinetics: These agents
bind to plasma proteins, are
metabolized in the liver and
excreted by the liver or kidney.
Tolbutamide has the shortest
duration of action (6-12 hrs) the
other agents are effective for ~24
hrs.
Insulin Sensitizers
Two classes of oral hypoglycemics work by improving insulin
target cell response; the biguanides and thiazolidinediones.
Biguanides:
 Metformin is classified as an insulin sensitizer, it increases
glucose uptake and utilization by target tissues. It requires
the presence of insulin to be effective but does not promote
insulin secretion. The risk of hypoglycemia is greatly
reduced.
 Mechanism: Metformin reduces plasma glucose levels by
inhibiting hepatic gluconeogenesis. It also slows the
intestinal absorption of sugars. It also reduces
hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL).
Lipid lower requires 4-6 weeks of treatment. Metformin also
decreases appetite. It is the only oral hypoglycemic shown
to reduce cardiovascular mortality. It can be used in
combination with other oral agents and insulin.
 Adverse effects: Hypoglycemia occurs only when combined
with other agents. Rarely severe lactic acidosis is associated
with metformin use particularly in diabetics with CHF. Drug
interactions with cimetidine, furosemide, nifedipine and
Meglitinide analogs
Sulfonylureas
These agents (repaglinide (Prandin) and nateglinide (Starlix))
Adverse Effects: These agents tend to cause weight act as secretogogues.
gain, hyperinsulinemia and hypopglycemia.  Mechanism: These agents bind to ATP sensitive K+channels
Hepatic or renal insufficiency causes like sulfonylureas acting in a similar fashion to promote
accumulation of these agents promoting the risk insulin secretion however their onset and duration of action
of hypoglycemia. There are a number of drug- are much shorter. They are particularly effective at
drug interactions. Elderly patients appear mimicking the prandial and post-prandial release of insulin.
particularly susceptible to the toxicities of these When used in combination with other oral agents they
agents.
produce better control than any monotherapy.
 Tolbutamide is asociated with a 2.5X ↑ in  Pharmacokinetics: These agents reach effective plasma
cardiovascular mortality.
levels when taken 10-30 minutes before meals. These agents
Onset and Duration are metabolized to inactive products by CYP3A4 and
 Short acting: Tolbutamide (Orinase) excreted in bile.
 Intermediate acting: Tolazamide (Tolinase),  Adverse Effects: Less hypoglycemia than sulfonylureas;
Glipizide (Glucotrol), Glyburide (Diabeta) drugs that inhibit CYP3A4 (ketoconozole, fluconazole,
 Long acting: Chloropropamide, Glimerpiride erythromycin, etc.) prolong their duration of effect. Drugs
that promote CYP3A4 (barbiturates, carbamazepine and
rifampin) decrease their effectiveness. The combination of
gemfibrozil and repaglinide has been reported to cause
severe hypoglycemia.
Insulin Sensitizers
Thiazolidinediones
(Glitazones)
 These agents are insulin
sensitizers, they do not
promote insulin
secretion from β-cells
but insulin is necessary
for them to be effective.
Pioglitazone and  Mechanism of Action: These agents act through the activation of
rosigglitazone are the peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for
two agents of this PPAR-γ regulate adipocyte production, secretion of fatty acids and
group. glucose metabolism. Agents binding to PPAR-γ result in increased
insulin sensitivity is adipocytes, hepatocytes and skeletal muscle.
Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all
improved. HDL levels are also elevated. Accumulation of subcutaneous
fat occurs with these agents.
177
 In the liver: ↓glucose output α-Glucosidase Inhibitors
 In muscle: ↑glucose uptake
 In adipose: ↑glucose uptake , ↓FA release This enzyme hydrolyses
 Only pioglitazone may be used in combination with insulin; oligosaccharides to
monosaccharides which are
the insulin dose must be modified. Rosiglitazone may be then absorbed. Acarbose
used with other hypoglycemic but severe edema occurs also inhibits pancreatic
when combined with insulin. amylase. The normal post-
prandial glucose rise is
 Pharmacokinetics: Both are extensively bound to albumin. blunted, glucose levels rise
Both undergo extensive P450 metabolism; metabolites are modestly and remain
slightly elevated for a
excreted in the urine the primary compound is excrete prolonged period, less of an
unchanged in the bile. insulin response is required
and hypoglycemia is
 Adverse Effects: Fatal hepatotoxicity has occurred with avoided; use with other
these agents; hepatic function must be monitored. Oral agents may result in
hypoglycemia. Sucrase is
contraceptives levels are decreased with concomitant also inhibited by these
administration, this has resulted in some pregnancies. drugs.
α-Glucosidase Inhibitors
Acarbose and miglitol are two agents of this class used for
type 2 diabetes.
Mechanism of action: These agents are oligosaccharide derivatives
taken at the beginning of a meal delay carbohydrate digestion by
competitively inhibiting α-glucosidase, a membrane bound
enzyme of the intestinal brush border.
Pharmacokinetics: Acarbose is poorly absorbed remaining in the
intestinal lumen. Migitol is absorbed and excreted by the kidney.
Both agents exert their effect in the intestinal lumen.
Adverse Effects: GUESS (flatulence, diarrhea, cramping). Metformin
bioavailability is severely decreased when used concomitantly.
These agents should not be used in diabetics with intestinal
pathology.

Incretin Therapy
Type 2 Post Prandial Glucose  Incretins are naturally occurring hormones that the gut
releases throughout the day; the level of active incretins
Regulation increases significantly when food is ingested.
 An easy (and over-  Endogenous incretins GLP-1 (glucagon-like peptide 1) and
simplified) way to GIP (glucose-dependent insulinotropic peptide) facilitate
approach type 2 diabetics the response of the pancreas and liver to glucose
is their “glucostat” is set at fluctuations through their action on pancreatic β cells and
α cells.
a higher level. Glucagon
 GIP and GLP-1 are the 2 major incretin hormones in
remains higher than humans: 1
normal to maintain the  GIP is a 42-aa peptide derived from a larger protein
higher glucose level, but (ProGIP) and is secreted by endocrine K cells mainly
the insulin response is less present in the proximal gastrointestinal (GI) tract
pronounced. (duodenum and proximal jejunum).
 GLP-1 is a 30- or 31-aa peptide derived from a larger
protein (proglucagon) and is secreted by L cells located
predominantly in the distal GI tract (ileum and colon). This
protein was first isolated from salivary gland venom of the
Gila monster (investigating how these lizards are able to
tolerate long periods between meals).

178
 These incretins are released from the gut in response to
ingestion of food and collectively contribute to glucose
Incretin Therapy control by:
Stimulating glucose-dependent insulin release from
Januvia (sitagliptin) pancreatic beta cells (GLP-1 and GIP):
Decreasing glucagon production from pancreatic alpha cells
(GLP-1) when glucose levels are elevated.
The combination of increased insulin production and
decreased glucagon secretion reduces hepatic glucose
production when plasma glucose is elevated.
The physiologic activity of incretins is limited by the enzyme
dipeptidyl peptidase-4 (DPP-4), which rapidly degrades
active incretins after their release.
The Incretin Effect Is Diminished in Type 2 Diabetes
Levels of GLP-1 are decreased.
The insulinotropic response to GIP is diminished but not
absent.
Defective GLP-1 release and diminished response to GIP may
be important factors in glycemic dysregulation in type 2
diabetes.

Standard vs. Intensive Symptomatic Hypoglycemia

Treatment  A note on the treatment of hypoglycemia: Oral glucose/carbohydrate
administration results in a more rapid rise in blood glucose than IV
administration; this is due to the involvement of gastrointestinal
hormones.

The trade off between standard and intensive therapy is more frequent
hypoglycemic events (hypoglycemic events, seizures and coma) for a
marked delay in the onset of diabetic complications both microvascular and
macrovascular.
HbA1c = Hemoglobin A1c is a useful measure of glucose control over the
prior 3-6 months, hyperglycemic episodes result in the nonspecific
glycosylation of various proteins.

179
SEX HORMONES AND DRUGS

180
Estrogen Hypothalamus
FEMALE REPRODUCTIVE Testostero Hypothalamic-
Hypothalamic-Pituitary- Hypothalamus
ne Pituitary-Gonadal
GnRH Gonadal Axis (HPG): SYSTEM
Females  HORMONAL REGULATION OF OOGENSIS
GnRH - Axis (HPG): Males
-
AP AND OVULATION Anterior
Pituitary
FS L OVULATION:

H sharp surge in LH Seminferous

H with simulataneous FS
Tonic increase in FSH L H tubules:
LH Inhi (Spermatogenisi
LH H+
surge Meiosis I resumes;
oocyte and surrounding bin s)
cumulus break away and
are extruded
+ PGF2 - Sertoli
oocyte passes into
Progestero a oviduct cells
ne Leydig cells
+
Estroge Male Testostero
ECTOPIC
ns IMPLANTATIONS characteristics ne
+
Growth

Aromatase Inhibitors Receptor Antagonists

 Used to inhibit estrogen-dependent tumors,  Selective Estrogen Receptor Modulators

metastatic breast cancer.
 But, serious estrogen-lacking side-effects:
increased risk of osteoporosis.
 Anastrozole, letrozole, exemestane,
formestane.
(SERMs).
 Are mixed agonists/antagonists.
 ERα and ERβ types are tissue-specific.
 See next slide for how SERMs are tissue-
specific.

181

Adrenal Sex Hormones
 Androgens – male hormones secreted by the
adrenal cortex in both sexes and are responsible
for the physiological effects exerted by adrenal
sex hormones.
 The incr protein synthesis (anabolism), which
incr muscle and bone mass and strength, affect
development of male 2° characteristics. They
incr hair growth and libido in women. Excessive
secretion: masculine effects in women.
 Female sex hormones exert few effects.
Excessive secretion: feminine characteristics in
men.
SERMs
 Tamoxifen – an ER antagonist in breast, but a
partial agonist in endometrium and bone.
 Raloxifene – ER agonist in bone, but an
antagonist in both breast and endometrium.
 Clomifene – used to induce ovulation. Is an
ER antagonist in hypothalamus and ant pit,
but a partial agonist in ovaries.
Drugs Affecting the
Reproductive System
Female hormones:
Estrogen and Progesterone
Example: Oral contraceptives (OCPs)
Estrogen prevents ovulation.
Progesterone prevents implantation of
ovum, decreases amount and increases viscosity
of cervical mucous to impair sperm motility, and
impedes motility of the ova by affecting
peristalsis of the ovaduct.
Androgen Receptor Antagonists
Flutamide and spironolactone – used to treat
metastatic prostate cancer and BPH.
Progesterone Receptor Antagonists
Mifepristone (aka RU-486) – used to induce 1st-
trimester abortion.
Often admin with misoprostol (PG analogue) –
stimulates uterine contractions.
Asoprisnil – does not cause abortion, but inhibits the
growth of tissue derived from the endometrium and
myometrium.
May be used to treat endometriosis and uterine
fibroids.
Infertility
Clomifene and Tamoxifen – anti-estrogens – work by
inhibiting the negative feedback of estrogens in the
hypothalamus  Incr release of LH and FSH.
Gonadotropins – used in women who lack approp pit
function or do not respond to clomifene therapy.
Treatment starts with daily inj of menotrophin (LH =
FSH amts) or urofollitropin (FSH), followed by 1-2
large doses of chorionic gonadotropin (mostly LH)
to induce ovulation.
Adverse Effects…? Multiple births…
In men with hypogonadotrophic hypogonadism, both
LH and FSH are given to stim spermatogenesis and
androgen release.
182
Testosterone
 ~ 2% of test in plasma is free.
 Converted to dihydrotestosterone (DHT) in skin,
prostate, seminal vesicles, and epididymus.
 Androgen deficiency – treated with i.m. injections
of testosterone propionate.
 Effects: At puberty  2° sexual characteristics in
male.
 In adult male, large doses  gonadotrophin release and
atrophy of interstitial tissue and tubules (testes).
 In women, androgens  changes seen in prepubertal
males.
Oral Contraceptives
 Uses: Contraception, menstrual irregularities.
 Adverse Effects: hypertension, diabetes, high
LDL, dizziness, numbness, weight gain, fluid
retention, breast tenderness, breakthrough
bleeding.
 Contraindications: ABSOLUTE:
Thromboplebitis, CVA, breast cancer,
pregnancy, liver disease or impairment, CAD,
> 35, smoker.
Estrogens Progestogens
 The main estrogen released by the ovary.  Used for hormonal contraception and for
 Synthetic estrogens may be more effective following
oral administration. producing long-term ovarian suppression for
 Adverse Effects (see below, oral contracep): other purposes (e.g., dysmenorrhea,
- prolonged administrations  abnormal endometriosis, hirsutism and bleeding
endometrial hyperplasia, abnormal bleeding disorders) when estrogens are contra-
patterns, assoc with incr incidence of endometrial
cancer. indicated
- But this cancer can be prevented it progestogen
accompanies the estrogen.
- Thus, women taking HRT must also take a
progestogen unless they have had a hysterectomy.
Fertilization
Oral Contraceptives
 Combination Pills – contain estrogen:
ethinylestradiol and progestogen, taken for ~
21 days and discontinued for the following 6-
7 days to allow menstruation to occur.
 Progestogen-only Pills – contain low dose of
progestogen, taken continuously.
Copyright © 2010 Pearson Education, Inc.
183
Oral Contraceptives - Mechanism
 Combination pills act by feedback inhibition on the
hypothal to supress GnRH and hence plasma
gonadotropin secretion.
 Produce an endometrium that is unreceptive to
implantation.
 Alter ovaduct motility.
 Change the composition of cervical mucous.
 These latter effects also caused by progestogen-only
pills and appear to be the basis of their contraceptive
actions.
 Block ovulation in only ~ 25% of women.
 Menstruation often stops initially with progestogens,
but usually returns with prolonged use.
 But the length and duration of bleeding – highly
variable.
Oral Contraceptives Oral Contraceptives
 Combination of both E and P – most potent and
3 Delivery systems are available: vaginal ring,
effective way to suppress GnRH, LH, and FSH
secretion. transdermal patches, oral tablets.
 The combined effects on previous slide  >99% Ring contains ethinyl estradiol and a progestin,
efficacy. etonogestrel.
 Ethinyl estradiol or mestranol – the E in the Has zero-order p’kinetics over 21 days.
combination contraceptives.
Dermal patch has ethinyl estradiol and a progestin,
 The progestins – all are potent PR agonists, but
norelgestromin. – Changed weekly for 3 weeks.
also have some androgenic cross-reactivity.
Norgestrel and levonorgestrel > norethindrone
and norethindrone acetate > ethynodiol,
norgestimate, gestodene, and degestrel in
androgenic activity.

Oral Contraceptives – Adverse Effects

Oral Contraceptives – Adverse
Effects
Non-life
 BreakthroughThreatening
bleeding and irregular menses (most
women who take combo pills).
 Abdominal pain
 Chest pain, cough, dyspnea, dizziness, numbness,
headache, nausea, changes in libido, breast
soreness.
 Eye problems: vision loss or blurred.
 Severe leg pain (calves, thighs).
 Hirsutism, vaginal yeast infections and depression.
 ~ 20-30 % women experience some of these effects.
 Rare.
Serious
 Cholestatic jaundice and thromboembolic disease.
 Thromboembolism (~ 25/10,000 women).
Emergency (morning-after) Contraception –
levenorgestrel – a single high dose can be taken up
to 3 days after unprotected intercourse. Blocks the
LH surge.
Therapeutic Termination of Pregnancy – mifepristone
– a progesterone ant – highly effective in
terminating early pregnancy (up to 63 days’
gestation) when used with a PG-cervical ripening
agent (e.g., gemeprost pessaries). [Recall –
Progesterone supports endometrial implantation of
fertilized ovum].
-Main adverse effect: pain and bleeding.
Male Contraception
 Tried suppressing sperm production.
- Very unsuccessful.
- Most promising to date: testosterone enanthate +
daily oral levonorgestrel; and parenternal
ptestosterone undecanoate + injectable
medroxyprogesterone ascetate. But,…
- Highly variable results from clinical trials  only ~
60% of men became azoospermic.
Significant adverse effects: acne, weight gain,
polycythemia, potential increase in prostate size.
 “back to the drawing board…”

184
Infertility Drugs Oxytoxics Premature Labor Inhibitor

 Example: Clomid  Examples: Pitocin (oxytocin)  Examples: Yutopar (rotodrine)

 Stimulates secretion of FSH and LH, which
stimulates maturation of follicles, ovulation
and development of the corpus luteum.
 Uses: Inadequate ovulation, low sperm count
in males.
 Adverse Effects: Similar to those of OCPs.
Increased incidence of early abortion and
multiple births, pelvic pain.
 Enhances contractile activity of the uterine
smooth muscle.
 Adverse Effects: Uterine rupture, fetal
hypoxia or trauma, hypertension, CVA.
 Uses: Post-partum hemorrhage only.
 Selective β2 adrenergic receptor antagonist
that prevents smooth muscle contractions.
 Uses: Preterm labor if gestation > 20 weeks.
 Adverse Effects: palpitations, tachycardia,
hypotension.

Male Hormones
 Example: Testosterone
 Secreted by the testes.
 Uses: Treatment of low sperm count and impotence caused
by any kind of deficiency.
CANCER CHEMOTHERAPY
Undescended testicles.
Anabolic action in conditions such as osteoporosis, anemia,
and debilitated states. Inoperable breast cancer in
postmenopausal women.
Adverse Effects: Edema, acne, hirsutism, voice deepening,
polycythemia, increased LDL, depression.
Contraindications: Pregnancy, prostate cancer, breast cancer
in males.

185

Normal cells…
•Differentiate, grow, mature, divide
–Regulated, balanced; cell birth=cell death
•Regulation: intracell signaling
–Hyperplasia: new cells prod’d w/ growth
stimulus via hormones, endogenous signals
–Ex: hyperplasia of endometrial tissue
during menstrual cycle is normal and
necessary
Neoplasms
• = Tumors = groups of neoplastic cells
• Two major types: benign, malignant
• Benign – “noncancerous”
– Local; cells cohesive, well-defined borders
– Push adjacent tissue away
– Doesn’t spread beyond original site
– Often has capsule of fibrous connective
tissue
BUT if intense, prolonged
demand …
– Dysplasia: replacement cells disordered in size,
shape
• May  cell structural, functional abnormalities
•Incr’d mitosis rate
– Metaplasia: replacement of one cell type by another •Somewhat reversible, often precancerous
• Thicker cell layer better accommodates irritation – Neoplasia: abnormal growth/invasion of cells
– Ex: bronchial epithelium chronically irritated  •“New growth”
ciliated columnar epithelial cells replaced by sev
•Neoplasm = tumor
layers cuboidal epithelium
» Note: Replacement cells normal, just •Irreversible
different •Cells replicate, grow w/out control
» Reversible
Cancer (Neoplastic) Cells
• Malignant – grow more rapidly; often • May be:
called “cancer” – Well-differentiated = retain normal cell
– Not cohesive; seldom have capsule function
– Irregular shape; disrupted architecture •Mimic normal tissue
•Often benign
– Invade surrounding cells
– Can break away to form second tumor – Poorly differentiated = disorganized
•“Metastasis” from 1o to 2o site •Can’t tell tissue of origin
•“Anaplastic”
186
 Oncogenesis = Process of
Tumor Development
• Probably multi-step process
•  Decr’d ability to differentiate and
control replication and growth
Steps to Cancer
 Initation = impt change introduced into cell
 Probably through DNA alteration
 >1 event probably needed for tumor prod’n
 Reversible unless and until:
 Promotion = biochem event encourages tumor
form’n
 Gen’ly need both initiation and promotion
 Initiators, promoters may be toxins OR radiation OR
viruses)

Genetics vs. Environment Cell Cycle = Growth, Cell Cycle Phases

Division
 Most tumors arise “spontaneously” w/out known
Premitotic synth of
carcinogen exposure, AND
structures, mol’s
 Proto-oncogenes can be inherited (ex: “breast cancer
gene”)
 BUT environmental agents are known to cause DNA
mutations, AND
 Risk factors known (Ex:
 Cigarette smoking  lung cancer
 UV light exposure  skin cancer)
 Theory: “Genetics loads the gun; the environment
Synth DNA precursors,
pulls the trigger”
proteins, etc.

187
 Cdk’s, Cyclins Implement Cycle
Cycle Checkpoints Decisions

Brody 42.1 – G0

G0 Apoptosis Review
 Quiescent phase outside cell cycle
 Most adult cells  In healthy cells, survival factors signal act’n
 Cyclin D in low concent anti-apoptotic mech’s
 Cytokines, hormones, cell contact factors
 Rb prot hypophosph’d
 Inhib’s expression prot’s impt to cycle progression  Programmed cell death
 Binds E2F transcr’n factors  Cascade of proteases initiate process
 Controls genes impt to DNA repl’n  Initiator caspases that act on effector caspases
 Growth factor binding  act’n to G1  Effector caspase act’n may be through Tumor
Necrosis Factor Receptor

188

 Second pathway act’d by intracell signals, e.g.
DNA damage
 Players are p53 gene & prot; mitochondrial
cytochrome c; Apaf-1 (prot); caspase 9
 Effector caspases initiate pathway 
cleavage cell constituents  cluster membr-
bound “entities” (used to be cell) that are
phagocytosed
 Anti-apoptotic genetic lesions nec for dev’t
cancer
 Apoptosis resistance characteristic of cancer cells
Uncontrolled Proliferation
 Result of act’n proto-oncogenes or inact’n
tumor suppressor genes
 Change in growth factors, receptors
 Incr’d growth factors prod’d
 Change in growth factor pathways
 2nd messenger cascades (esp tyr-kinase receptor
cascades)
 Change in cell cycle transducers
 Cyclins, Cdk’s, Cdk inhibitors
Genes Impt to Oncogenesis
 Code for prot’s that regulate cell div/prolif’n when
turned on/off
 Malfunctions, mutations may  oncogenesis
 Changes w/ viruses, chem’s: point mutations, gene
amplifications, chromosome translocations
50.2 Rang
 Two impt routes:
 Proto-Oncogenes – code for prot’s turning cell div ON
 Mutations  overexpression  cancer
 Tumor suppressor genes – code for prot’s turning cell div
OFF
 Mutations  repression  cancer
 Change in apoptotic mech’s Anticancer Drugs are
 Change in telomerase expression Antiproliferative
 Change in local blood vessels  angiogenesis
 Note: Genes controlling any of these  Affect cell division
prot’s/mech’s can be considered proto-  Active on rapidly dividing cells
oncogenes or tumor suppressor genes
 Most effective during S phase of cell cycle
 Note: Dev’t malignant cancer depends on sev  Many cause DNA damage
transform’ns
 Damage DNA  init’n apoptosis
189
 Difficulties in Chemotherapy  Suspended cancer cells (leukemias)
 Side effects greatest in other rapidly-dividing  Killing 99.99% of 1011 cancer cell burden, 107
cells Effectiveness neoplastic cells remain
 Bone marrow toxicity  Can’t rely on host immunological defense to kill
 Solid tumors remaining cancer cells
 Impaired wound healing  Growth rate decr’s as neoplasm size incr’s
 Hair follicle damage
 Diagnosis, treatment difficult if rapidly growing
 Outgrows ability to maintain blood supply AND
 Ex: Burkitt’s lymphoma doubles ~24 h
 Gi epith damage  Not all cells proliferate continuously
 Approx 30 doublings  tumor mass of 2 cm (109
 Growth in children  Compartments
cells)
 Gametes  Dividing cells (may be ~5% tumor volume)
 May be detected, if not in deep organ
 Only pop’n susceptible to most anticancer drugs
 Fetus  Approx 10 add’l doublings  20 cm mass (1012 cells)
 Resting cells (in G0); can be stim’d  G1
– lethal
 May themselves be carcinogenic  Not sensitive to chemotherapy, but act’d when therapy
ends  Therefore, “silent” for first ¾ existence
 Cells unable to divide but add to tumor bulk

Drugs Used in Cancer Alkylating Agents

Chemotherapy
 Cytotoxic Agents
 Alkylating Agents
 Contain chem grps that covalently bind cell
 Antimetabolites
nucleophiles
 Cytotoxic antibiotics Rand 50.3  Impt properties of drugs
 Plant derivatives  Can form carbonium ions
 C w/ 6 electrons highly reactive
 Hormones
 React w/ -NH2, -OH, -SH
 Suppress nat’l hormone secr’n or antagonize
hormone action  Bifunctional (2 reactive grps)
 Allow cross-linking
 Misc (mostly target oncogene products)

190
 Nitrogen Mustards
 Impt targets
 G N7 – strongly nucleophilic
 A N1, A N3, C N3 also targets
 DNA becomes cross-linked w/ agent
 Intra- or inter-strand
  Decr’d transcr’n, repl’n
  Chain scission, so strand breaks Rang 50.4 42-5 structures
  Inappropriate base pairing (alkylated G w/ T)
 Most impt: S phase repl’n (strands unwound,
more susceptible)  G2 block, apoptosis
•Loss Cl  intramolec cyclization of side chain
– Reactive ethylene immonium derivative

Nitrosoureas
Cyclophosphamide
•Also activated in vivo
 Most common •Alkylate DNA BUT alk’n prot’s  toxicity
 Prodrug – liver metab by CYP P450 MFO’s
 Effects lymphocytes 42.6 cyclophosph
 Also immunosuppressant 42.7 nitrosourea
 Oral or IV usually
 SE’s: n/v, bone marrow dpression,
hemorrhagic cystitis
 Latter due to acrolein toxicity; ameliorated w/ SH-
donors

191
 Temozolomide Cisplatin
•Methylates G, A  improper G-T base pairing
Antimetabolites
 Cl- dissoc’s  reactive complex that reacts w/ H2O
and interacts w/ DNA  intrastrand cross-link (G
N7 w/ adjacent G O6)  denaturation DNA  Mimic structures of normal metabolic mol’s
 Nephrotoxic  Inhibit enz’s competitively OR
 Severe n/v ameliorated w/ 5-HT3 antagonists (decr  Inc’d into macromol’s  inappropriate structures
gastric motility)  Kill cells in S phase
 Carboplatin – fewer above SE’s, but more  Three main groups
myelotoxic  Folate antagonists
 Pyr analogs
 Pur analogs

Folic Acid Analogs  Folate  FH4 cat’d by Methotrexate

dihydrofolate
 Folic acid essential for synth purines, and reductase in 2 steps:
thymidylate  Folate  FH2  Higher affinity for enz than does FH2
 FH2  FH4  Add’l H or ionic bond forms
 Folate: pteridine ring + PABA + glutamate
 FH4 serves as methyl   Depletion FH4 in cell  depl’n dTMP 
 In cells, converted to polyglutamates then 
“thymine-less death”
tetrahydrofolate (FH4) grp donor (1-C unit) to
deoxyuridine (dUMP   Inhib’n DNA synth
 dTMP), also  Uptake through folate transport system
regenerating FH2  Resistance through decr’d uptake
 Metabolites (polyglutamate deriv’s) retained for
weeks, months

192
Pyrimidine Analogs
 Gemcitabine
 5-Fluorouracil – dUMP analog also works  Phosph’d  tri-PO4’s  Cytosine arabinoside
through dTMP synthesis pathway  “Fraudulent nucleotide”
 Analog of 2’dC
 Converted  “fraudulent” nucleotide FdUMP   Also inhib’s ribonucleotide reductase  decr’d
 Phosph’d in vivo  cytosine arabinoside
 Competitive inhibitor for thymidylate synthetase nucleotide synth
triphosphate
active site, but can’t be converted to dTMP  Capecitabine is prodrug  Inhibits DNA polymerase
 Covalently binds thymidylate synthetase
 Converted to 5FU in liver, tumor
 Mech action uses all 3routes  decr’d DNA  Gemcitabine – araC analog
 Enz impt to conversion overexpressed in cancer cells
synthesis, also transcr’n/transl’n inhib’n  Fewer SE’s
(?)

 Epirubicin, mitozantrone structurally related

Purine Analogs Cytotoxic Antibiotics
 SE’s: cardiotoxicity (due to free radical prod’n),
bone marrow suppression
 6-Mercaptopurine, 6-Thioguanine
 Converted to “fraudulent nucleotides”  Substances of microbial origin that prevent
 Inhibit enz’s nec for purine synth mammalian cell division
 Fludarabine
 Anthracyclines
 Converted to triphosphate
 Doxorubicin
 Mech action sim to ara-C
 Intercalates in DNA
 Pentostatin
 Inhibits repl’n via action at topoisomerase II Mitozantrone
 Inhibits adenosine deaminase
 Topoisomerase II catalyzes nick in DNA strands
 Catalyzes adenosine  inosine
 Intercalated strand/topoisomerase complex stabilized 
 Interferes w/ purinemetab, cell prolif’n permanently cleaved helix

http://www.geocities.com/lubolahchev/Mitoxa4.gif
http://www.farmakoterapi.uio.no/cytostatika/images/16_1_t.gif

193
  Dactinomycin Vinca Alkaloids
Plant Alkaloids
 Intercalates in DNA minor groove between adjacent GC
pairs
 Interferes w/ RNA polymerase movement  decr’d  Work at mitosis
transcr’n  Effect tubulin, therefore microtubule activity
 Also may work through topoisomerase II   Prevention spindle form’n OR
 Bleomycin  Stabilize (“freeze”) polymerized microtubules
 Glycopeptide
  Arrest of mitosis
 Chelates Fe, which interacts w/ O2
  Gen’n superoxide and/or hydroxyl radicals  Other effects due to tubulin defects
 Radicals degrade DNA  fragmentation, release of free  Phagocytosis/chemotaxis
bases  Axonal transport in neurons
 Most effective in G2, also active against cells in G0
 Little myelosuppression BUT pulmonary fibrosis
http://biotech.icmb.utexas.edu/botany/gifs/vdes.gif

Taxanes: Paclitaxel, Docetaxel

 Etoposide, teniposide
 From mandrake root
 Inhibit mitoch function, nucleoside transport,
topoisomerase II Ironotecan
 Campothecins: irinotecan, topotecan
 Irinotecan requires hydrolysis  active form
 Bind, inhibit topoisomerase II
 Repair is difficult
Topotecan

http://home.caregroup.org/clinical/altmed/interactions/Images/Drugs/docetaxe.gif
http://biotech.icmb.utexas.edu/botany/gifs/tax.gif

194
Hormones  Estrogens  Hormone antagonists
 Tamoxifen impt in breast cancer treatment
 Block androgen effects (ex: fosfestrol)
 Competes w/ endogenous estrogens for receptor
 Used to recruit cells in G0  G1, so better targets
 Tumors der’d from tissues responding to  Inhibits transcr’n estrogen-responsive genes
for cytotoxic drugs
hormones may be hormone-dependent  Flutamide, cyproterone impt in prostate tumors
 Progestogens (ex: megestrol,  Androgen antagonists
 Growth inhib’d by hormone antagonists OR other
hormones w/ opposing actions OR inhibitors of
medroxyprogesterone)  Trilostane, aminoglutethimide inhibit sex
relevant hormone  Used in endometrial, renal tumors hormone synth at adrenal gland
 Formestane inhibits aromatase at adrenal gland
 Glucocorticoids  GnRH analogs (ex: goserelin)
 Inhibitory on lymphocyte prolif’n  Inhibit gonadotropin release  decr’d circulating
 Used against leukemias, lymphomas
estrogens

Americans’ Views of the Seriousness

of Health Problems
(Top 10 of 36 Problems) Two Decades of Neurobiological
Drug abuse 82%
Research Have
% saying “very serious problem”

Cancer
Brought Us A New Understanding
78%

Drunk driving 75%

Heart disease 74% of

HIV/AIDS
Violence
73%

71%
Drug Abuse and Addiction, Their
DRUGS OF ABUSE Child abuse 69% Complexity and their Solutions
Smoking 68%

Alcohol abuse 65%

Stress 65%

Harvard School of Public Health/Robert Wood Johnson Foundation/ICR, August 2000

195
 Dopamine Pathways
For Example… Neuronal structure
We Know That Despite striatum
hippocampus
frontal
Their Many Differences, Virtually cortex (receiving)

All Abused Substances Enhance substantia

Dopamine (neurotransmitter) Activity Functions
nigra/VTA

Serotonin Pathways
(particularly related to pleasure, •reward (motivation)
•pleasure,euphoria nucleus
accumbens Functions
motor, and cognitive function •motor function
(fine tuning) raphe •mood (sending)
•compulsion •memory
• Other pathways also involved! •perserveration processing
•decision making
•sleep

vesicle
stimulation Drug : Neuronal terminal
• cocaine transporter transporter Effects of Drugs on Dopamine Release
• ritalin 1100
1000
Accumbens
AMPHETAMINE
400
Accumbens COCAINE

% of Basal Release

% of Basal Release
900
Vmat Vmat serotonin/ 800 Much greater
DA 300
DA
DOPAC
700 Activity than any
DOPAC
HVA
/serotonin 600
500
HVA
Other drug of abuse 200
400
300
-causes neurotoxicity
200 100
100
0
0 1 2 3 4 5 hr 0
0 1 2 3 4 5 hr
How some drugs of abuse cause dopamine release: • Release DA from vesicles and reverse Time After Amphetamine Time After Cocaine

• opioids narcotics (activate opioid receptors)DA/5HT transporter 250

250
ETHANOL
DA/5HT NICOTINE Accumbens

• nicotine (activate nicotine receptors)

% of Basal Release
200 Accumbens Dose (g/kg ip)

% of Basal Release
200
• marijuana (activate cannabinoid receptors)
Caudate
0.25
Drug Types: 150 0.5
1
• caffeine • Amphetamines 100
150 2.5

• alcohol (activate GABA receptors; an inhibitory transmitter) -methamphetamine

100
-MDMA (Ecstasy) 0
0 1 2 3 hr 0
0 1 2 3 4hr
Time After Nicotine Time After Ethanol
Source: Di Chiara and Imperato

196
 Natural Rewards Elevate Dopamine Addiction and tolerance can be synonymous
Levels Implication:
FOOD SEX

DA Concentration (% Baseline)
200 200
NAc shell

150 150
% of Basal DA Output

Elucidation of the mechanism of

Copulation Frequency
100 100

drug addiction will help to

15

Empty 10
50
Box Feeding
5 understand other addictive and
0
0 60 120 180 ScrScr
ScrScr
BasFemale 1 Present
Scr Scr
Female 2 Present
0
motivational behaviors/disorders
Time (min) Sample 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Number
Mounts
Intromissions
Ejaculations

Source: Di Chiara et al. Source: Fiorino and Phillips

Brain Circuits Involved in

Induction of Tolerance to Morphine Drug Addiction
INHIBITORY PFC
CONTROL ACG
OFC Hipp
SCC
NAc REWARD
MOTIVATION/ c VP
Pharmacodynamic mechanism DRIVE Amyg
MEMORY/
of Tolerance (saliency) LEARNING

197
 • Principles of Behavior Dynamics

Reward Pathways:
HOW DOES ADDICTION
Behavior Tracts Compete for Expression
Role of Opioids OCCUR?
Prefrontal A
Cortex
B
behavior
expressed C
B
C
dopamine initiated
Orbito-
frontal cortex

 Expression is Determined by (i) Dominance of Tracts,

(ii) Strength of Prefrontal Cortex to Select, (iii) Relevance or
saliency (orbitofrontal cortex)
Activation of Dopamine reward pathway initiates a behavior
track
(Miller & Cohen, Annu. Rev. Neurosci. 24 [2001] 167

• Principles of Behavior Dynamics

We Have Generated A Lot of

C AND…
A Evidence Showing That…
Prefrontal
Cortex B
Addiction
BB behavior
B B Prolonged Drug Use Changes We Have Evidence That
expressed
the Brain and These Changes Can Be Both
Orbito-
frontal cortex
In Fundamental Structural and Functional
dopamine
and Long-Lasting Ways
How does a behavior become
an addiction?

198
 BRAIN IMAGING Decreases in Metabolism
in Orbito Frontal Cortex (OFC) METH Suppresses Expression of DAT
Positron Emission Tomography

control cocaine abuser

(note: duration of use/3-20 yrs; abstinent/ 1-4 yrs)
Magnetic Resonance Imaging Volkow et al. Am. J. Psychiatry 148, 621 Source: McCann U.D. et al., The Journal of Neuroscience, 18(20), pp. 8417-8422, October 15, 1998.

Dopamine Transporter Loss After Dependence of Verbal Memory on Striatal

DAT
MOTOR FUNCTION
Heavy Methamphetamine Use
(PET analysis) Interference recall Delayed recall

• Slowed gait
Compromises Cognitive Functions
R = 0.70 R = 0.64
•Impaired balance
p < 0.005 p < 0.01

• Impairment correlates with damage

to dopamine system
Comparison Subject METH Abuser
Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001. Source: Volkow, N.D. et al., Am J. Psychiatry, 158(3), pp. 377-382, 2001.

199
 Reward System in Addiction
Is There Recovery?
Implication: More

• Good News: After 2 years some Cocaine

Brain changes resulting from of the dopamine deficits are Ability to Experience
prolonged use of psychostimulants, recovering METH Rewards Is Damaged
such as methamphetamine
may be reflected in compromised • Bad News: Functional deficits

treated
cognitive and motor functioning persist Alcohol

Less

• What does this mean???

Food

INHERITED FACTORS In General: Inheritability for Drug

(genetic vulnerability-not Abuse Ranges From 40-60%
Their Brains…
inevitability)
• Some Variability Between Drugs
• Some Gender Variability
Get Rewired
by Drug Use • Common strategy to investigate
are Twin Studies

200
 Chromosomal Locations for Substance Abuse
Vulnerability Loci
Complex genetics VULNERABILITY to What?
Starting Drug Use?
Liking Drugs More?
Complex phenotypes (expressions)
Continuing Drug Use?
22
17

(Relation to Risk Factors?) Becoming Addicted?

6
Specific to A Particular Drug?
5 3 samples, > 2
r-SA
labs
r-candidate 4 samples, > 3
Uhl et al Tr Genetics, updated June 03
labs

For Example-
Contribution of Genetic Factors to:
Genetics
Nicotine- Genetics May Influence How
•Liability to initiate=56% Neurobiology Interacts With Gene/
Environment
Interaction
• Transition to dependence=70% Environment
• Smoking persistence= >50% Environment
(Lerman & Berrettine, Amer. J. Med. Gen. 54 (2003) 48)

201
 PET Images: Addictive Disorders Often Co-Exist National Comorbidity
Dopamine Receptor Density with or Predispose to Mental Survey (NCS)
Disorders Nearly half of individuals with a past year
substance use disorder also had a mental
disorder
DSM IV Manual:
Devotes ~ 100 pages to describing Mental disorders found to be most prevalent
More addiction and dependence disorders included affective disorders, anxiety disorders,
likely
personality disorders, and psychotic disorders
to self-
administer
Discusses substance abuse as a
(Note: can we have parity for mental health with-
Cocaine confound to diagnosis and Tx out considering drug abuse?)

Common Underlying Neurobiological Drug Disorder

Factors Can Be: Cocaine and Methamphetamine Schizophrenia, paranoia,
anhedonia, compulsive
behavior
Neurochemical (imbalance of Because of this overlap, drugs of abuse
Stimulants Anxiety, panic attacks,
neurotransmitters) can cause symptoms that mimic mania and sleep disorders
Structural/anatomical (same regions most forms of mental illness
and pathways) LSD, Ecstasy & psychedelics Delusions and hallucinations

Genetic (inherited factors that Alcohol, sedatives, sleepaids Depression and mood
& narcotics disturbances
compromise function)
PCP & Ketamine Antisocial behavior

202
 Serotonin/dopamine synaptic Mechanism of action
terminal
of amphetamine and
transporter
Synaptic vesicle Prozac, cocaine
Ritalin, &
Some drugs of abuse have a Cocaine
block
mechanism of action similar to
that of drugs used as
psychotherapeutic agents
Postsynaptic
Significance: rationale for target

self-administration
Causes an effect
Activate transmitter receptors

People With Comorbid

Mental and Addictive Disorders
Chronic use of some of these drugs of DoubleBrain Disease
Have a Double
abuse may alter the way the brain
functions, making persons particularly Comorbid Role of Stress and Trauma
susceptible to mental illness Mental
Disorders
Addictive
Disorder Disorder

203
 The Stress Hormone Cycle
Anxiety DRUG USE
(Self-Medication) Anxiety RELAPSE

Hypothalamus Prolonged
CRF Stress Responses What Role Does Stress Play CRF What
DRUG Happens When A Person
Stress Responses CRF USE
Pituitary
Gland
Stress
StressResponses
Responses In Initiating Drug Use? Stops
CRFTaking A Drug?

ACTH
CORTISOL
Adrenal
CRF: Glands STRESS Anxiety
Abstinence
Corticotropin
Releasing
Kidneys
Factor

Stress Reliably Reinstates Drug Seeking in Rats CRF1 Receptor Antagonist Attenuates Objectives of Intervention:
* Stress-Induced Reinstatement
Cocaine-trained rats Alcohol-trained rats of Drug Seeking
100 • Rearrange dominance of behavior tracks
Responses

80 Inactive Lever
Active Lever
60
40 *
*
60
Heroin-trained rats
Alcohol-trained rats Cocaine-trained rats
60
 contingency management (vouchers)
Responses (1 hr)

Responses (3 hr)

20 *
No stress
0 45 45 Intermittent Footshock  motivational enhancement
SalineCocaine
Footshock Water
Alcohol
Alcohol
Footshock
30 30
*
*  therapeutic communities
100 Nicotine-trained rats Heroin-trained *rats * *
*
Responses

15 15
80
60 *
* * 0 0
40
20 0 15 30 0 15 30 0 15 30
0 CP-154,526 Dose (mg/kg,
SalineNicotineFootshock SalineHeroin
SalineHeroinFootshock
Footshock SC)
From: Psychopharmacology, 1996, 1998, 1999 ; J. Neurosci. 1996 From: Shaham et al. Psychopharmacology 1998; Le et al. Psychopharmacology, 2000

204
 • Principles of Behavior Dynamics • Principles of Behavior Dynamics

• Strengthen prefrontal cortex influence

Prefrontal A (change thinking process) Prefrontal A
Cortex
B
behavior
expressed C
B  cognitive and cognitive behavioral tx Cortex
B
behavior
expressed C
B
C (unlearn old habits-suppress; learn C
dopamine initiated new skills) dopamine initiated
Orbito- Orbito-
frontal cortex  assertiveness training (suppress and frontal cortex

express)

• Principles of Behavior Dynamics

•Alter function of orbitofrontal • Recovery of function (frontal and obito
(saliency) cortex frontal cortex)
Prefrontal A
 motivational therapy Cortex
B
behavior
C
B  all treatments that keep brain away
expressed

C from drugs for extended time

 family therapies
dopamine initiated
Orbito-
frontal cortex

205
 • Principles of Behavior Dynamics Targets of Medication
• Alleviate underlying psychiatric
disorder • Methadone, LAAM and Buprenorphine
Prefrontal A
Activate opioid receptors
Cortex
B
behavior
expressed C
B  administer: Antidepressants for depression
C • Naloxone
dopamine initiated Ritalin for ADHD Block opioid receptors
Orbito-
frontal cortex

Sedatives for anxiety • Nicotine gum/patch

Activate nicotinic receptors

vesicle Neuronal terminal

stimulation • Principles of Behavior Dynamics
transporter • Psychostimulants
Enhancing GABA-ergic inhibition GABA and cannabinoid
Vmat How some drugs of abuse cause dopamine release: (baclofen-muscle relaxant; anti-seizure systems critical for
• opioids narcotics (activate opioid receptors) Prefrontal A
function
• nicotine (activate nicotine receptors) Tiagabine) Cortex
B
behavior
expressed C
B
Cannabinoid antagonist (rimonabant) C
dopamine initiated
Orbito-
DA frontal cortex

206
 • Relieve stress-related drug abuse
CRF antagonist
Anxiety RELAPSE
No cure
Prolonged
DRUG
USE God Bless!!!
CRF
THANK YOU

Abstinence

207