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Pharmacology

April Dawn Rallos-Lucero, MD


What is Pharmacology?
The body of knowledge concerned with the action of chemicals on
biologic systems.
Reference
Basic Principles
Part I
Part I: Basic Principles
1. Introduction
2. Pharmacodynamics
3. Pharmacokinetics
4. Drug Metabolism
5. Drug Evaluation & Regulation
Introduction
Pharmacology

Medical
Toxicology
Pharmacology

Medical Pharmacology: the area of pharmacology concerned with the use of chemicals in the prevention,
diagnosis, and treatment of disease, especially in humans.

Toxicology: is the area of pharmacology concerned with the undesirable effects of chemicals on biologic
systems.
What is the difference between
pharmacokinetics &
pharmacodynamics?
Pharmacokinetics
• Describes the effects of the body on drugs
• Example: absorption, excretion

Pharmacodynamics
• Denotes the actions of the drug on the body
• Example: mechanism of action, toxic effects
The Nature of Drugs
Composition:
➢inorganic ions
➢nonpeptide organic molecules
➢small peptides and proteins
➢nucleic acids
➢lipids
➢carbohydrates

Source: plants or animals, but many are partially or completely


synthetic
The Nature of Drugs

Size & Molecular Weight


➢ Most weigh between 100 and 1000

➢ Smaller than MW 100 → rarely sufficiently selective in their actions

➢ Larger than MW 1000 → often poorly absorbed & poorly distributed in the
body
Pharmacodynamics
High-Yield Terms
Receptor A molecule to which a drug binds to bring about a
change in function of the biologic system
Inert binding molecule A molecule to which a drug may bind without
or site changing any function
Receptor site Specific region of the receptor molecule to which
the drug binds
Effector Component of a system that accomplishes the
biologic effect after the receptor is activated by an
agonist; often a channel or enzyme molecule, may
be part of the receptor molecule
Agonist A drug that activates its receptor upon binding
High-Yield Terms
Pharmacologic A drug that binds without activating its receptor
antagonist and thereby prevents activation by an agonist
Competitive A pharmacologic antagonist that can be overcome
antagonist by increasing the concentration of agonist
Irreversible antagonist A pharmacologic antagonist that cannot be
overcome by increasing agonist concentration
Physiologic antagonist A drug that counters the effects of another by
binding to a different receptor and causing
opposing effects
Chemical antagonist A drug that counters the effects of another by
binding the agonist drug (not the receptor)
High-Yield Terms
Allosteric agonist, A drug that binds to a receptor molecule without
antagonist interfering with normal agonist binding but alters the
response to the normal agonist
Partial agonist A drug that binds to its receptor but produces a smaller
effect at full dosage than a full agonist
Graded dose-response A graph of increasing response to increasing drug
curve concentration or dose
Quantal dose-response A graph of the fraction of a population that shows a
curve specified response at progressively increasing doses. The
median effective (ED50), median toxic (TD50), and (in
animals) median lethal (LD50) doses are derived from
experiments carried out in this manner.
High-Yield Terms
Efficacy, maximal The maximal effect that can be achieved with a
efficacy particular drug, regardless of dose
Potency The amount of drug needed to produce a given
effect.
Therapeutic Index Is the ratio of the TD50 (or LD50) to the ED50.
Represents an estimate of the safety of a drug. A
very safe drug might be expected to have a very
large toxic dose and a much smaller effective dose.
Therapeutic Window A more clinically useful index of safety. Describes
the dosage range between the minimum effective
therapeutic concentration or dose, and the
minimum toxic concentration or dose.
Drug-receptor Activation of
AGONIST
binding receptor

Drug-receptor Inhibition of
ANTAGONIST
binding receptor
Sugammadex is a new drug that reverses the action of
rocuronium and certain other skeletal muscle-relaxing agents. It
appears to interact directly with the rocuronium molecule and
not at all with the rocuronium receptor. Which of thefollowing
terms best describes sugammadex?

A. Chemical antagonist D. Pharmacologic antagonist


B. Noncompetitive antagonistE. Physiologic antagonist
C. Partial agonist
Answer: A
• Interacts directly with the drug, not the receptor.
Which of the following statements about
these results is correct?

(A) Drug X is safer than drug Y


(B) Drug Y is more effective than drug X
(C) The 2 drugs act on the same receptors
(D) Drug X is less potent than drug Y
(E) The therapeutic index of drug Y is 10
Answer: D
• No information is presented regarding the safety of these drugs.

• No information on efficacy (maximal effect) is presented.

• Although both drugs are said to be producing a therapeutic effect, no information


on their receptor mechanisms is given.

• Since no data on toxicity are available, the therapeutic index cannot be


determined.
Inert Binding Sites
• Drugs bind to these nonregulatory molecules in the body → no
discernible effect
• Albumin: an important plasma protein with significant drug-binding
capacity
Pharmacokinetics
High-Yield Terms
Volume of distribution The ratio of the amount of drug in the body to the drug
(apparent) concentration in the plasma or blood
Half-life The time required for the amount of drug in the body or
blood to fall by 50%.
For drugs eliminated by first-order kinetics, this number
is a constant regardless of the concentration
Bioavailability The fraction (or percentage) of the administered dose of
drug that reaches the systemic circulation
Peak and trough The maximum and minimum drug concentrations
concentrations achieved during repeated dosing cycles
What is the half-life of drug X?

A. 8 am: 100 mg

B. 10 am: 75 mg

C. 12 pm: 50 mg

D. 2 pm: 25 mg
Half-life: 4 hours
High-Yield Terms
Minimum effective The plasma drug concentration below which a patient’s
concentration response is too small for clinical benefit
(MEC)
First-pass effect, The elimination of drug that occurs after administration
presystemic but before it enters the systemic circulation (eg, during
elimination passage through the gut wall, portal circulation, or liver
for an orally administered drug)
Steady state In pharmacokinetics, the condition in which the average
total amount of drug in the body does not change over
multiple dosing cycles (ie, the condition in which the
rate
of drug elimination equals the rate of administration)
The Movement of Drugs in the
Body
A. PERMEATION
Permeation

The movement of drug molecules into & within the biologic


environment.

1. Aqueous diffusion

2. Lipid diffusion

3. Transport by special carriers

4. Endocytosis, pinocytosis
Aqueous Diffusion
Movement of molecules through the watery extracellular & intracellular
spaces

Membranes of most capillaries have small water-filled pores


→Permit diffusion of molecules up to the size of small proteins between
the blood & the extravascular space

Passive process

The capillaries in the brain, testes, and some other organs lack aqueous
pores
→ less exposed to some drugs
Lipid Diffusion

• The passive movement of molecules through membranes and other


lipid structures.
Transport by Special Carriers

• For drugs that do not readily diffuse through membranes.


• Examples:
➢transporters for ions (eg, Na+/K+ ATPase)
➢…for neurotransmitters (eg, transporters for serotonin,
norepinephrine)
➢…for metabolites (eg, glucose, amino acids)
➢…for foreign molecules (xenobiotics) such as anticancer drugs
Endocytosis, Pinocytosis

Endocytosis
Molecule binds to receptor on cell membrane →infolding of that
area of the membrane → internalization → intracellular vesicle →
contents of vesicle released into cytoplasm of cell

Permits very large or very lipid-insoluble chemicals to enter cells


Can be quite selective
Endocytosis, Pinocytosis

Endocytosis
Example:

1. Proteins may enter cell through endocytosis

2. Smaller, polar substances such as vitamin B12 and iron combine


with special proteins (B12 with intrinsic factor and iron with
transferrin) → the complexes enter cells by this mechanism
Endocytosis, Pinocytosis

Exocytosis
is the reverse process, that is, the expulsion of material that is
membrane-encapsulated inside the cell from the cell.

Most neurotransmitters are released by exocytosis.


• (A) Aqueous diffusion • (D) Lipid diffusion
• (B) Aqueous hydrolysis • (E) Special carrier transport
• (C) Endocytosis
• Endocytosis is an important mechanism for transport of very large
molecules across membranes.
• Aqueous diffusion is not involved in transport across the lipid barrier of
cell membranes.
• Lipid diffusion and special carrier transport are common for smaller
molecules.
• Hydrolysis has nothing to do with the mechanisms of permeation; rather,
hydrolysis is one mechanism of drug metabolism.
B. Fick’s Law of Diffusion
Fick’s Law of Diffusion
• predicts the rate of movement of molecules across a barrier
• concentration gradient (C1 − C2) and permeability coefficient for
the drug and the area and thickness of the barrier membrane are
used to compute the rate as follows:
Where will drug absorption be faster
according to Fick’s Law of Diffusion?

➢ small intestine or stomach?


➢ lungs or skin?
Fick’s Law of Diffusion

• Drug absorption is faster from organs with large surface areas, such
as the small intestine, than from organs with smaller absorbing areas
(the stomach).

• Drug absorption is faster from organs with thin membrane barriers


(eg, the lung) than from those with thick barriers (eg, the skin).
C. Water & Lipid Solubility
Solubility
• The aqueous solubility of a drug is often a function of the electrostatic charge
(degree of ionization, polarity) of the molecule
➢ water molecules behave as dipoles and are attracted to charged drug molecules, forming an
aqueous shell around them

• The lipid solubility of a molecule is inversely proportional to its charge.


Solubility
• Many drugs are weak bases or weak acids.
• For such molecules, the pH of the medium determines the fraction of
molecules charged (ionized) versus uncharged (nonionized).
• If the pKa of the drug and the pH of the medium are known, the fraction
of molecules in the ionized state can be predicted by means of the
Henderson-Hasselbalch equation:

• “Protonated” means associated with a proton (a hydrogen ion); this form


of the equation applies to both acids and bases.
Ionization of Weak acids & Bases

• Weak bases are ionized—and therefore more polar and more water-
soluble—when

• they are protonated.

• Weak acids are not ionized—and so are less water-soluble—when


they are protonated.
• Most drugs are freely filtered at the glomerulus, but lipid-soluble drugs can be
rapidly reabsorbed from the tubular urine.

• If a patient takes an overdose of a weak acid drug, for example, aspirin, the
excretion

• of this drug is faster in alkaline urine.


• → a drug that is a weak acid dissociates to its charged, polar form in alkaline
solution, and this form cannot readily diffuse from the renal tubule back into the
blood; that is, the drug is trapped in the tubule.
• Conversely, excretion of a weak base (eg, pyrimethamine, amphetamine) is
faster in acidic urine
ABSORPTION
Absorption of Drugs
1. Routes of Administration
•The amount absorbed into the systemic circulation divided by the amount
of drug administered constitutes its bioavailability by that route.

2. Blood flow
IM & SC sites, & in shock, the GIT as well

3. Concentration

Fick’s law: concentration is a major determinant


Common Routes of Drug Administration
• Oral (swallowed) PO
convenient, slower absorption, subject to first-pass effect
The next routes avoid the first-pass metabolism:
• Buccal & sublingual (not swallowed) SL
direct absorption into the systemic venous circulation
• Intravenous (IV)
instant & complete absorption; more dangerous
Common Routes of Drug Administration
(The next routes avoid the first-pass metabolism: )
• Intramuscular (IM)
often faster and more complete than with oral
• Subcutaneous (SC)
slower absorption than IM
• “First-pass effect” is the term given to elimination of a drug before it
enters the systemic circulation (ie, on its first pass through the portal
circulation and liver).

• The first-pass effect is usually, but not always, due to metabolism in


the gut, the portal blood, or the liver.
Intravenous
Common Routes of Drug Administration
• Rectal (suppository)
• partial avoidance of the first-pass effect; drugs with
unpleasant taste
• Inhalation
• offers delivery closest to respiratory tissues(eg, for asthma)
• usually very rapid absorption (eg, for anesthetic gases)
Common Routes of Drug Administration
• Topical
•application to the skin or to the mucous membrane of the
eye, ear, nose, throat, airway, or vagina for local effect
• Transdermal
•application to the skin for systemic effect
•Absorption usually occurs very slowly (because of the
thickness of the skin), but the first-pass effect is avoided
Rectal
Inhalation
Topical
Transdermal
A 60-year-old patient with severe cancer pain is given 10
mg of morphine by mouth. The plasma concentration is
found to be only 30% of that found after intravenous
administration of the same dose. Which of the following
terms describes the process by which the amount of
active drug in the body is reduced after administration but
before entering the systemic circulation?

• (A) Excretion • (D) Metabolism


• (B) First-order elimination • (E) Pharmacokinetics
• (C) First-pass effect
• “First-pass effect” is the term given to elimination of a drug before it enters the
systemic circulation (ie, on its first pass through the portal circulation and liver).

• The first-pass effect is usually, but not always, due to metabolism in the gut, the
portal blood, or the liver.
Distribution of Drugs
Determinants of Distribution

1. Size of the organ

2. Blood flow

well-perfused tissues (eg, brain, heart, kidneys, and splanchnic


organs) usually achieve high tissue concentrations sooner than
poorly perfused tissues (eg, fat, bone).
Determinants of Distribution

3. Solubility
•If the drug is very soluble in the cells, the concentration in the perivascular
extracellular space will be lower and diffusion from the vessel into the
extravascular tissue space will be facilitated.
•Example: brain has a high lipid content → dissolve a high concentration
of lipid-soluble agents rapidly
4. Binding

•Warfarin: strongly bound to plasma albumin → restricts warfarin’s


diffusion out of the vascular compartment.
•Chloroquine: strongly bound to extravascular tissue proteins → marked
reduction in its plasma concentration
Metabolism of Drugs
High-Yield Terms
Phase I reactions Reactions that convert the parent drug to a more
polar (water-soluble) or more reactive product by
unmasking or inserting a polar functional group
such as —OH, —SH, or —NH2
Phase II reactions Reactions that increase water solubility by
conjugation of the drug molecule with a polar
moiety such as glucuronate, acetate, or sulfate
CYP isozymes Cytochrome P450 enzyme species (eg, CYP2D and
CYP3A4) that are responsible for much of drug
metabolism. Many isoforms of CYP have been
recognized
Enzyme induction Stimulation of drug-metabolizing capacity; usually
manifested in the liver by increased synthesis of
smooth endoplasmic reticulum (which contains high
concentrations of phase I enzymes)
Types of Metabolic Reactions
Phase I Reactions
• Include:
1. Oxidation
- especially by the cytochrome P450 group of enzymes, a.k.a.
mixed-function oxidases
2. Reduction
3. Deamination
4. Hydrolysis
Phase I Reactions

• These enzymes are found in high concentrations in the smooth


endoplasmic reticulum of the liver.
• They are not highly selective in their substrates, so a relatively small
number of P450 isoforms are able to metabolize thousands of drugs.
• Of the drugs metabolized by phase I cytochrome P450s,
approximately 75% are metabolized by just two:
➢ CYP3A4
➢ CYP2D6
Phase II Reactions

• Synthetic reactions that involve addition (conjugation) of subgroups


to —OH, —NH2, and —SH functions on the drug molecule.
• Most of these groups are relatively polar and make the product less
lipid-soluble than the original drug molecule.
• Like phase I enzymes, phase II enzymes are not very selective.
• Drugs that are metabolized by both routes may undergo phase II
metabolism before or after phase I.
Where are drugs metabolized?
What is the most important organ for drug metabolism?
Sites of Drug Metabolism
• The most important organ for drug metabolism is the liver.

• The kidneys play an important role in the metabolism of some drugs.

• A few drugs are metabolized in many tissues (eg, liver, blood, intestinal wall)
because of the wide distribution of their enzymes.
Determinants of Biotransformation Rate

A. Genetic Factors
- e.g., abnormal plasma cholinesterase, slow acetylators

- determines rate of phase I oxidation

B. Effect of Other Drugs

- coadministration
1. Enzyme Induction

2. Enzyme Inhibition
Enzyme Induction
• Induction: increased rate and extent of metabolism
• usually results from increased synthesis of cytochrome P450-
dependent drug-oxidizing enzymes in the liver as well as the cofactor,
heme.
• Several days are usually required to reach maximum induction; a
similar amount of time is required to regress after withdrawal of the
inducer.
• The most common strong inducers of drug metabolism are:
• carbamazepine, phenobarbital, phenytoin, and rifampin.
Drugs that significantly induce P450-mediated drug metabolism in humans
CYP Family Important Inducers Drugs whose metabolism is Induced
Induced
1A2 Benzo[a]pyrene (from tobacco smoke), Acetaminophen, clozapine, haloperidol, theophylline, tricyclic
carbamazepine, phenobarbital, rifampin, antidepressants, (R)-warfarin
omeprazole
2C9 Barbiturates, especially phenobarbital, Barbiturates, celecoxib, chloramphenicol, doxorubicin,
phenytoin, primidone, rifampin ibuprofen, phenytoin, chlorpromazine, steroids, tolbutamide,
(S)-warfarin
2C19 Carbamazepine, phenobarbital, phenytoin, Diazepam, phenytoin, topiramate, tricyclic antidepressants,
rifampin (R)-warfarin

2E1 Ethanol, isoniazid Acetaminophen, enflurane, ethanol (minor), halothane

3A4 Barbiturates, carbamazepine, corticosteroids, Antiarrhythmics, antidepressants, azole antifungals,


efavirenz, phenytoin, rifampin, pioglitazone, benzodiazepines, calcium channel blockers, cyclosporine,
St. John’s wort delavirdine, doxorubicin, efavirenz, erythromycin, estrogens,
HIV protease inhibitors, nefazodone, paclitaxel, proton pump
inhibitors, HMG-CoA reductase inhibitors, rifabutin, rifampin,
sildenafil, SSRIs, tamoxifen, trazodone, vinca alkaloids
Enzyme Inhibition
• The inhibitors of drug metabolism most likely to be involved in serious
drug interactions are amiodarone, cimetidine, furanocoumarins
present in grapefruit juice, azole antifungals, and the HIV protease
inhibitor ritonavir.
Drugs that significantly inhibit P450-mediated drug metabolism in humans
CYP Family Inhibitors Drugs whose metabolism is Inhibited
Inhibited
1A2 Cimetidine, fluoroquinolones, grapefruit juice, Acetaminophen, clozapine, haloperidol, theophylline, tricyclic
macrolides, isoniazid, zileuton antidepressants, (R)-warfarin

2C9 Amiodarone, chloramphenicol, cimetidine, Barbiturates, celecoxib, chloramphenicol, doxorubicin, ibuprofen,


isoniazid, phenytoin, chlorpromazine, steroids, tolbutamide, (S)-warfarin
metronidazole, SSRIs, zafirlukast
2C19 Fluconazole, omeprazole, SSRIs Diazepam, phenytoin, topiramate, (R)-warfarin

2D6 Amiodarone, cimetidine, quinidine, SSRIs Antiarrhythmics, antidepressants, beta-blockers, clozapine,


flecainide, lidocaine, mexiletine, opioids

3A4 Amiodarone, azole antifungals, cimetidine, Antiarrhythmics, antidepressants, azole antifungals,


clarithromycin, cyclosporine, diltiazem, benzodiazepines,
erythromycin, fluoroquinolones, grapefruit juice, calcium channel blockers, cyclosporine, delavirdine, doxorubicin,
HIV protease inhibitors, metronidazole, quinine, efavirenz,
SSRIs, tacrolimus erythromycin, estrogens, HIV protease inhibitors, nefazodone,
paclitaxel,
proton pump inhibitors, HMG-CoA reductase inhibitors, rifabutin,
rifampin, sildenafil, SSRIs, tamoxifen, trazodone, vinca alkaloids
Drug Metabolism → Termination of Drug
Action
• Drugs metabolized to inactive derivatives → action terminated prior
to excretion
• Example: sympathomimetics, phenothiazines
• Form of elimination
Drug Metabolism → Drug Activation
• Prodrugs: inactive upon administration → metabolized to become
active
• Example: levodopa, minoxidil
Drug Elimination Without Metabolism
• Some drugs are not modified by the body
• They continue to act until they are excreted
• Example: lithium
Elimination of Drugs
Elimination of Drugs

• Along with the dosage, the rate of elimination following the last dose
(disappearance of the active molecules from the site of action, the
bloodstream, and the body) determines the duration of action for most
drugs.

• Drug elimination ≠ Drug excretion

• A drug may be eliminated by metabolism long before the modified


molecules are excreted from the body.
Elimination of Drugs
• Usually through the kidneys

• A small number of drugs combine irreversibly with their receptors, so that


disappearance from the bloodstream is not equivalent to cessation of drug action: These
drugs may have a very prolonged action.

Example:

Phenoxybenzamine : irreversible inhibitor of α adrenoceptors

eliminated from the bloodstream in less than 1 h after administration

action lasts for 48 h, the time required for turnover of the receptors
Elimination of Drugs

A. First-Order Elimination

B. Zero-Order Elimination
First-Order Elimination
• Implies that the rate of elimination is proportional to the concentration (ie, the
higher the concentration, the greater the amount of drug eliminated per unit
time).

• The result is that the drug’s concentration in plasma decreases exponentially

with time.

• Have a characteristic half-life of elimination that is constant regardless of the


amount of drug in the body.
First-Order Elimination

• The concentration of such a drug in the blood will decrease by 50%


for every half-life.

• Most drugs in clinical use demonstrate first-order kinetics.


Zero-Order Elimination
• Implies that the rate of elimination is constant regardless of
concentration.
• Occurs with drugs that saturate their elimination mechanisms
• the concentrations of these drugs in plasma decrease in a linear
fashion over time
• Examples:
Ethanol
Phenytoin at high therapeutic or toxic concentrations
Aspirin
Clearance
• Clearance (CL) relates the rate of elimination to the plasma
concentration:
Clearance

• For a drug eliminated with first-order kinetics, clearance is a


constant; that is, the ratio of rate of elimination to plasma
concentration is the same regardless of plasma concentration.
• depends on the drug, blood flow, and the condition of the organs of
elimination in the patient
• for drugs eliminated with zero-order kinetics, clearance is not
constant.
Drug Evaluation & Regulation
• The sale and use of drugs are regulated in almost all countries by
governmental agencies.
• Regulation is done by the Food and Drug Administration (FDA).
• New drugs are developed in industrial or academic laboratories.
• Before a new drug can be approved for regular therapeutic use in
humans, a series
• of animal and experimental human studies must be carried out.
FDA ratings of drug safety in pregnancy.
Category Description

A Controlled studies in women fail to demonstrate a risk to the fetus in the first
trimester (and there is no evidence of a risk in
later trimesters), and the possibility of fetal harm appears remote

B Either animal reproduction studies have not demonstrated a fetal risk but there are
no controlled studies in pregnant women,
or animal reproduction studies have shown an adverse effect (other than a decrease
in fertility) that was not confirmed in
controlled studies in women in the first trimester (and there is no evidence of a risk in
later trimesters)
C Either studies in animals have revealed adverse effects on the fetus (teratogenic or
embryocidal or other) and there are no
controlled studies in women, or studies in women and animals are not available.
Drugs should be given only when the
potential benefit justifies the potential risk to the fetus
FDA ratings of drug safety in pregnancy.
Category Description

D There is positive evidence of human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the
risk (eg, if the drug is needed in a life-threatening situation or for a serious disease for
which safer drugs cannot be used or
are ineffective)
X Studies in animals or human beings have demonstrated fetal abnormalities or there is
evidence of fetal risk based on human
experience or both, and the risk of the use of the drug in pregnant women clearly
outweighs any possible benefit. The drug is
contraindicated in women who are or may become pregnant
Further Readings
A. Phases of clinical trials (Phase 1 to Phase 4)
B. Drug patents
C. Generic drugs
D. Orphan drugs