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PHARMACO-DYNAMICS:
MOLECULAR MECHANISMS OF
DRUG ACTION

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 Pharmaco-Dynamics is the study of the biochemical and
physiological effects of drug and their mechanisms of
action.

 Understanding pharmaco-dynamics can provide the basis

for the rational therapeutic use of a drug and the design of
new and superior therapeutic agents.

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DRUG RECEPTOR / DRUG TARGET

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 The term drug receptor or drug target denotes the cellular
macromolecule or macromolecular complex with which the
drug interacts to elicit a cellular response, i.e., a change in
cell function.

 Drugs commonly alter the rate or magnitude of an intrinsic

cellular response rather than create new responses.

 Drug receptors are often located on the surface of cells, but

may also be located in specific intracellular compartments
such as the nucleus.
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PHYSIOLOGICAL RECEPTORS

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Drug receptors consists of proteins that normally serve as
receptors for endogenous regulatory ligands. These drug
targets are termed physiological receptors like endogenous
receptor for dopamine is dopamine receptors.

Many drugs act on physiological receptors and are

particularly selective because physiological receptors have
evolved to recognize and respond to individual signaling
molecules with great selectivity.

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Agonists
Drugs that bind to physiological receptors and mimic the
regulatory effects of the endogenous signaling compounds are

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termed agonists.

Primary agonist
If the drug binds to the same recognition site as the endogenous
agonist (the primary or orthosteric site on the receptor) the drug is
said to be a primary agonist.

Allosteric (allotopic) agonists

Allosteric (allotopic) agonists bind to a different region on the
receptor referred to as an allosteric or allotopic site, i.e;
‐Epigallocatechin‐3‐gallate is example at GABAa receptors
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ANTAGONISM

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Drugs that block or reduce the action of an agonist are termed
antagonists.
Antagonism most commonly results from:
 competition with an agonist for the same or overlapping site on the
receptor (a syntopic interaction) i.e. propranolol, an adrenaline beta-
adrenergic receptor antagonist, and cimetidine, a histamine H2-
receptor antagonist
 by interacting with other sites on the receptor (allosteric
antagonism); i.e. Cyclothiazide has been shown to act as antagonist
of mGluR1 receptor.

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 By combining with the agonist (chemical antagonism), i.e.
protamine sulfate is a positively charged substance that when given
i.v. will bind to heparin, a strongly negatively charged anticoagulant
drug. Protamine sulfate is “antidote” for heparin overdose, because
once heparin binds to protamine sulfate, it cannot exert its
anticoagulant effects.

 Functional antagonism by indirectly inhibiting the cellular or

physiological effects of the agonist. phenobarbital-induced enzyme
induction increases the metabolism of the anticoagulant warfarin

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Partial agonists
Agents that are only partly as effective as agonists regardless

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of the concentration employed are termed partial agonists, i.e.
buprenorphine are used to treat opiate dependence.

Inverse agonists
Receptors that exhibit some constitutive activity in the
absence of a regulatory ligand; drugs that stabilize such
receptors in an inactive conformation are termed inverse
agonists, i.e. rimonabant is inverse agonist for cannabinoid
receptor.

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Regulation of the activity of a receptor with conformation-selective
drugs.
DRUG SPECIFICITY

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 Dissociation constant is measure of the strength of the
reversible interaction between a drug and its receptor or the
affinity of one for the other.
 The chemical structure of a drug contributes to the drug’s
specificity as both the affinity of a drug for its receptor and its
intrinsic activity are determined by its chemical structure.

 A drug that interacts with a single type of receptor that is

expressed on only a limited number of differentiated cells
will exhibit high specificity.
 An example of such a drug is ranitidine, an H 2 receptor
antagonist used to treat ulcers. 10
 If a receptor is expressed ubiquitously on a variety of cells
throughout the body, drugs acting on such a widely expressed
receptor will exhibit widespread effects, and could produce

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serious side effects or toxicities if the receptor serves important
functions in multiple tissues.

 The examples include the inotropic drug digoxin, which

inhibits the ubiquitously expressed enzyme Na+,K+-ATPase.

 The antifolate anticancer drugs such as methotrexate that

inhibit dihydrofolate reductase, an enzyme required by all cells
for the synthesis of purines and thymidylate .

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 Lidocaine (Na+ channel blocker) has local anesthetic
effects when administered locally to prevent or relieve
pain, but can also have cardiac and CNS effects if it
reaches the systemic circulation.

 Immunosuppressant drugs that specifically inhibit cells

of the immune system; their use is limited by the risk of
opportunistic systemic infections.

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Drugs that act locally but have global effects are diuretics
that act on cells in the kidney to alter serum electrolytes
such as K+. However, the hypokalemia that a diuretic such
as furosemide can cause can significantly increase the risk
of skeletal muscle cramps and cardiac arrhythmias.

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 Many clinically important drugs exhibit a broad specificity because
the drug is able to interact with multiple receptors in different
tissues.

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 Such broad specificity might enhance the clinical utility of a drug,
but also contribute to a spectrum of adverse side effects due to off-
target interactions.
 Amiodarone, an agent used to treat cardiac arrhythmias. In cardiac
muscle, amiodarone inhibits Na+, Ca2+, and K+ channels, and
noncompetitively inhibits β adrenergic receptors.
 All of these drug-receptor interactions may contribute to its
therapeutic efficacy and widespread use to treat many forms of
arrhythmia.
 However, amiodarone also has a number of serious toxicities, some
of which are due to the drug’s structural similarity to thyroid
hormone and its ability to interact with nuclear thyroid receptors
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 Some drugs are administered as racemic mixtures of
stereoisomers. The stereoisomers can exhibit different
pharmacodynamic as well as pharmacokinetic properties.

 The anti-arrhythmic drug sotalol is prescribed as a

racemic mixture; the d- and l-enantiomers are equipotent
as K+ channel blockers, but the l-enantiomer is a much
more potent β adrenergic antagonist

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 The pharmacological properties of many drugs differ
depending upon whether the drug is used acutely or
chronically.

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 In some cases, chronic administration of a drug causes a down-
regulation or desensitization of receptors that can require dose
adjustments to maintain adequate therapy.

 Chronic administration of nitrovasodilators to treat angina

results in the rapid development tachyphylaxis.

 To avoid tachyphylaxis, it is necessary to interrupt

nitrovasodilator therapy every night for at least 18 hours.
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 Some drug effects do not occur by means of macromolecular
receptors, such as the therapeutic neutralization of gastric

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acid by the antacid bases aluminum and magnesium
hydroxide.

 Drugs such as mannitol act according to colligative

properties to increase the osmolarity of various body fluids
and cause changes in the distribution of water to promote
diuresis, expansion of circulating volume in the vascular
compartment, or reduction of cerebral edema.

 The oral administration of cholesterol-binding agents (e.g.,

cholestyramine resin) is used to decrease serum cholesterol
by limiting absorption of dietary cholesterol from the 17
intestine.
STRUCTURE–ACTIVITY RELATIONSHIPS
AND DRUG DESIGN

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 A significant number of clinically useful drugs were developed in an
era when drug discovery primarily involved screening compounds
for their capacity to elicit salutary effects in patients or an animal
disease model.

 The receptors responsible for the clinical effects of many drugs have
yet to be identified, although significant efforts are devoted toward
identifying their mechanisms of action.

 The endogenous and exogenous ligands for these putative receptors

are still unknown, these are referred to as orphan receptors. Orphan
receptors are still found in the G–protein coupled receptor and
nuclear hormone receptor families. 18
 The relationship between chemical structure of drug, its affinity
for receptor and intrinsic activity is quite stringent.

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 Minor modifications in the drug molecule may result in major
changes in its pharmacological properties based on altered
affinity for one or more receptors.

 It is sometimes possible to develop a congener with a more

favorable ratio of therapeutic to adverse effects, enhanced
selectivity among different cells or tissues, or more acceptable
secondary characteristics than those of the parent drug.

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For example,
 Addition of a phosphate ester at the N3 position
in the antiseizure drug phenytoin, produces a
prodrug (FOSPHENYTOIN) that is more soluble
in intravenous solutions than its parent.

 This modification results in far more reliable

distribution in the body and a drug that must be
cleaved by esterase to become active.

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QUANTITATIVE ASPECTS OF DRUG
INTERACTIONS WITH RECEPTORS

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Dose-response/concentration-response curve is a representation of
the observed effect of a drug as a function of its concentration in the
receptor compartment.

y axis shows a percentage of maximal response) expressed as a function of the

concentration of drug present at the receptor. The concentration of drug that
produces 50% of the maximal response quantifies drug activity and is referred to as21
the EC50 (effective concentration for 50% response).
AFFINITY, EFFICACY, AND POTENCY.
In general, the drug-receptor interaction is characterized by

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 binding of drug to receptor

 generation of a response in a biological system, as illustrated in

Equation where the ligand is denoted as L and the inactive
receptor as R.

 The reversible formation of the ligand-receptor complex LR, is

governed by the chemical property of affinity. The second reaction
shown in Equation is the reversible formation of the active ligand-
receptor complex, LR*.

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 where LR* is produced in proportion to [LR] and leads to a
response.

 This relationship illustrates the affinity of the ligand (L) with

receptor (R) on both the forward or association rate (k+1) and
the reverse or dissociation rate (k−1).

 The ability of a drug to activate a receptor and generate a

cellular response is a reflection of its efficacy.

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 When the response of an agonist is measured in a simple
biological system, the apparent dissociation constant, Kapp, is
a macroscopic equilibrium constant that reflects both the

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ligand binding equilibrium and the subsequent equilibrium
that results in the formation of them active receptor LR*.

 The equilibrium dissociation constant (KD) is then described by

ratio of the off and on rate constants (k−1/k+1).

 The affinity constant or equilibrium association constant (KA)

is the reciprocal of the equilibrium dissociation constant (i.e.,
KA = 1/KD); thus a high-affinity drug has a low KD and will
bind a greater number of a particular receptor at a low 24
concentration
THE FRACTIONAL OCCUPANCY (F) OF
RECEPTORS

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QUANTIFYING AGONISM

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 When the relative potency of two agonists of equal
efficacy is measured in the same biological system, the
comparison yields a relative measure of the affinity and
efficacy of the two agonists.
 Agonist response can be describe by determining the
half-maximally effective concentration (EC50) for
producing a given effect.
 Thus, measuring agonist potency by comparison of EC50
values measure the capability of different agonists to
induce a response in a test system.

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When two drugs produce equivalent responses, the drug whose dose-
response curve lies to the left of the other (i.e., the concentration producing
a half-maximal effect [EC50] is smallest) is said to be the more potent.

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QUANTIFYING ANTAGONISM

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Competitive antagonism
 a drug with affinity for a receptor but lacking intrinsic
efficacy competes with the agonist for the primary
binding site on the receptor.
 The characteristic pattern of such antagonism is the
concentration-dependent production of a parallel shift to
the right of the agonist dose-response curve with no
change in the maximal response.
 The magnitude of the rightward shift of the curve
depends on the concentration of the antagonist and its
affinity for the receptor.
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 A partial agonist similarly can compete with a “full” agonist for
binding to the receptor.

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 However, increasing concentrations of a partial agonist will inhibit
response to a finite level.
 Partial agonists thus can be used therapeutically to buffer a
response by inhibiting excessive receptor stimulation without
totally abolishing receptor stimulation.
 Pindolol, a β antagonist with slight intrinsic agonist activity, will
prevent overstimulation of the heart by blocking effects of
endogenous catecholamines
 and assure slight receptor stimulation in patients over sensitive to
the negative inotropic and negative chronotropic effects of β
blockade).

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 An antagonist may dissociate so slowly from the receptor that
its action is exceedingly prolonged, as with the opiate partial

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agonist buprenorphine and the Ca2+ channel blocker
amlodipine.
 In the presence of a slowly dissociating antagonist, the
maximal response to the agonist will be depressed at some
antagonist concentrations ,this is referred to as noncompetitive
antagonism.
 An antagonist may also interact irreversibly (covalently) with
a receptor and compete for same binding site as do the α
adrenergic antagonist phenoxybenzamine, to produce
relatively irreversible effects.

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 Noncompetitive antagonism can also be produced by another
type of drug, referred to as an allosteric or allotopic
antagonist.

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 This type of drug produces its effect by binding to a site on
the receptor distinct from that of the primary agonist, thereby
changing the affinity of the receptor for the agonist. In the
case of an allosteric antagonist, the affinity of the receptor for
the agonist is decreased by the antagonist.

 In contrast, a drug binding at an allosteric site could potentiate

the effects of primary agonists; such a drug would be referred
to as an allosteric agonist or co-agonist.

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 The affinity of a competitive antagonist (Ki) for its receptor can be
determined in radioligand binding assays or by measuring the
functional response of a system to a drug in the presence of the

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antagonist.

 Concentration curves are run with the agonist plus an effective

concentration of the antagonist.

 As more antagonist (I) is added, a higher concentration of the agonist

(A) is needed to produce an equivalent response (the half-maximal or
50%, response is a convenient and accurately determined level of
response).

 If the antagonist binds to the same site as the agonist but does so
irreversibly or pseudo-irreversibly (slow dissociation but no covalent
bond), it causes a shift of the dose-response curve to the right, with
further depression of the maximal response.
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 The extent of the rightward shift of the concentration-
dependence curve is a measure of the affinity of the inhibitor.
 Higher-affinity inhibitor will cause a greater rightward shift

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than a lower-affinity inhibitor at the same inhibitor
concentration.
 Mathematical expressions of fractional occupancy (f) of the
receptor by agonist can be written as:
 for the agonist alone

 Agonist in the presence of inhibitor

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 PHARMACODYNAMIC VARIABILITY:
INDIVIDUAL AND POPULATION PHARMACO-
DYNAMICS

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 Individuals vary in the magnitude of their response to the
same concentration of a similar drug, and a given
individual may not always respond in the same way to
the same drug concentration.

 Receptors are dynamic, and their concentration and

function may be up- or down-regulated by endogenous
and exogenous factors.

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 Therapeutic index (LD50/ED50 ratio), describe how
selective the drug is in producing its desired effects
versus its adverse effects.

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 The therapeutic window, is the range of steady-state
concentrations of drug that provides therapeutic
efficacy with minimal toxicity.

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 Population therapeutic window expresses a range of concentrations at
which the likelihood of efficacy is high and the probability of adverse
effects is low.
 It does not guarantee either efficacy or safety. Therefore, use of the

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population therapeutic window to adjust dosage of a drug should be
complemented by monitoring appropriate clinical and surrogate markers
for drug effect(s).

The relation of the therapeutic window of drug concentrations to the

therapeutic and adverse effects in the population.
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FACTORS MODIFYING DRUG ACTION

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 Many factors can influence the therapeutic efficacy and
safety of a drug in an individual patient and give rise to
inter-individual variability in the dose required to obtain
optimal therapeutic effect with minimal adverse effects.

 Pharmacokinetics factors include disease-related

alterations such as impaired renal and liver clearance,
circulatory failure, altered drug binding to plasma
proteins, impaired GI absorption, and pharmacokinetic
drug interactions.

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FACTORS THAT INFLUENCE THE RELATIONSHIP BETWEEN
PRESCRIBED DOSAGE AND DRUG EFFECTS

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 PHARMACOGENETICS

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 Pharmacogenetics refers to the genetic and genomic variations
that give rise to variability in both pharmacokinetic and
pharmacodynamic aspects of drug therapy.

 Among the best examples of a drug with significant inter-

individual sensitivity due to genetic factors affecting both
pharmacokinetics and pharmaco-dynamics is the anticoagulant
drug warfarin.

 In order to achieve optimal anticoagulant therapy with minimal

adverse effects, it is necessary to stay within a very narrow
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 There is considerable inter-individual variation in this
optimal dose range, nearly 60% of the variability is due
to genetic variation in the primary metabolizing enzyme
(CYP2C9) and in the drug’s receptor, vitamin K epoxide
reductase complex, subunit 1 (VKORC1).

 Polymorphisms in CYP2C9 increase sensitivity towards

warfarin, whereas coding region polymorphisms in
VKORC1 result in a warfarin-resistant phenotype.

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COMBINATION THERAPY
 Marked alterations in the effects of some drugs can result

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from co-administration with other agents, including
prescription and nonprescription drugs, as well as
supplements and nutraceuticals.
 Drug interactions may be pharmacokinetic (the delivery of a
drug to its site of action is altered by a second drug) or
pharmacodynamic (the response of the drug target is
modified by a second drug).

 There are many examples of pharmacodynamic interactions

that can produce significant adverse effects.

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 Nitrovasodilators produce relaxation of vascular smooth
muscle (vasodilation) via NO-dependent elevation of cyclic

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GMP in vascular smooth muscle.

 The pharmacologic effects of sildenafil, tadalafil, and

vardenafil result from inhibition of the PDE5 (type 5 cyclic
nucleotide phosphodiesterase) that hydrolyzes cyclic GMP to
5′GMP in the vasculature.

 Thus, co-administration of an NO donor (e.g., nitroglycerin)

with a PDE5 inhibitor can cause potentially catastrophic
hypotension.
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 The oral anticoagulant warfarin has a narrow margin is
subject to numerous important pharmacokinetic and

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pharmacodynamic drug interactions.
 Alterations in dietary vitamin K intake may also significantly
affect the pharmaco-dynamics of warfarin and dose changes
may be required if a patient’s diet is inconsistent.

 Similarly, antibiotics that alter the intestinal flora reduce the

bacterial synthesis of vitamin K, thereby enhancing the effect
of warfarin.

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 NSAIDs cause gastric and duodenal ulcers, and their
concurrent administration with warfarin increases the
risk of GI bleeding almost 4-fold compared with
warfarin alone.

 Aspirin increases the incidence of bleeding in warfarin-

treated patients by inhibiting platelet aggregation.

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 NSAIDs, including indomethacin, ibuprofen, piroxicam,
and COX-2 inhibitors, can antagonize anti-hypertensive
therapy, especially with regimens employing ACE
inhibitors, ARBs and β adrenergic receptor antagonists.

 In contrast, aspirin and sulindac produce little, if any,

elevation of blood pressure when used concurrently with
these anti-hypertensive drugs.

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 Anti-arrhythmic drugs such as sotalol and quinidine
that block K + channels can cause the polymorphic
ventricular tachycardia known as torsades de pointes.

 The abnormal repolarization that leads to this

polymorphic ventricular tachycardia is potentiated by
hypokalemia, and diuretics that produce K+ loss
increase the risk of this drug-induced arrhythmia.
 0015712659615…….

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 Most drugs are evaluated in young and middle-aged
adults, and data on their use in children and the
elderly are sparse.

 At the extremes of age, drug pharmacokinetics and

pharmaco-dynamics can be altered, possibly
requiring substantial alteration in the dose or dosing
regimen to safely produce the desired clinical effect.

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Thank you

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