Pharmacodynamic

Objectives
• Receptor theory
• Relation between Drug concentration
and response
• Drug potency & efficacy
• Antagonists – competitive and
unsurmountable
• Partial and full agonists
• Spare Receptors
• Receptor-mediated signaling systems
• Receptor-desensitization
• Quantal dose-effect curves
• Therapeutic index
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Receptor Theory
The existence of receptors was first inferred from observations of the
chemical and physiological specificity of drug effects.
Now receptors have been isolated biochemically and genes encoding
receptor proteins have been cloned and sequenced.
Receptors determine the quantitative relationship between drug dose and
pharmacologic effect
Receptors are responsible for the selectivity of drug action
Receptors mediate the actions of pharmacologic agonists and antagonists
What are Drug Receptors?
Cell surface or intracellular regulatory proteins – mediate the effects
of endogenous chemical signals such as neurotransmitters and
hormones. e.g. adrenoreceptors, steroid receptors, acetylcholine
receptors.
Enzymes – cell surface, membrane-spanning or intracellular proteins
inhibited (or less commonly activated) by the binding of a drug. e.g. Na+K
+ATPase is the cell surface receptor for cardiac glycosides such as
digitalis
Structural proteins – extra- or intracellular proteins inhibited (or less
commonly activated) by the binding of a drug. e.g.tubulin is the receptor
for colchicine - an anti-inflammatory agent
General Classes of Antagonists
Chemical Antagonists
One drug may antagonize the action of a second by binding to and
inactivating the second drug. e.g. protamine (a positively charged protein at physiologic
pH) binds (sequesters) heparin (a negatively charged anticoagulant) making it
unavailable for interactions with proteins involved in the formation of blood clots.
Physiological Antagonists
Physicians often prescribe drugs that take advantage of physiologic
antagonism between endogenous regulatory pathways. Thus the catabolic actions of
glucocorticoids lead to increased blood sugar - an effect opposed by insulin. While
glucocorticoids and insulin act on quite different pathways, insulin is sometimes
administered to oppose the hyperglycemic action of glucocorticoid hormone - whether
resulting from increased endogenous synthesis (e.g. a tumor of the adrenal cortex) or
as a result of glucocorticoid therapy.
Pharmacological Antagonists
Drugs that bind to receptors but do not act like agonists and, therefore, do not
alter receptor function. These antagonists may block the ability of agonists to bind to the
receptor by competing for the same receptor site or may bind to another site on the
receptor that blocks the action of the agonist. In both cases, the biological actions of the
agonist are prevented.
Partial and Full Agonists
Agonists may differ in how tightly they bind to their receptors (potency) and in
the effect they produce (efficacy). Some drugs may bind very tightly (are
highly potent) but produce only a modest effect (low efficacy).
Low efficacy drugs are termed “partial agonists” while the structurally related
drugs which produce a full effect are called “full agonists”.Therapeutic Index
Quantal dose effect curves permit an analysis of the margin of safety (or
selectivity in response) for a specific drug. In animal studies, the therapeutic
index is defined as the ratio of the TD50 to ED50.
Thus if TD50 = 500 mg and ED50 = 5 mg, the drug is 100-fold more selective
for the desired response and the therapeutic index is 100.
The therapeutic index in humans is never known with great precision. Drug
trials and accumulated clinical experience indicate a range of effective doses
and a different (but sometimes overlapping) range of possibly toxic doses.
Clinically acceptable risk depends on the severity of the disease being
treated. e.g. dose range of a drug for relief from headache should be much
lower than the dose range that produces toxicity even if only a small % of
individuals show toxic effect. With a lethal disease such as Hodgkin s
lymphoma, the acceptable difference between therapeutic and toxic doses
may be smaller.40
Summary
• Receptor theory
• Relation between Drug concentration
and response
• Drug potency & efficacy
• Partial and full agonists
• Spare Receptors
• Quantal dose-effect curves
• Therapeutic index
receptors mediate drug actions
Michaelis-Menten (saturation) curves
EC50 vs Maximum response
reversible binding to agonist site and irreversible/
reversible binding to non-agonist sites
incomplete and complete mimics of
natural agonist
Full response at subsaturating
[agonist]
quantity of drug required for a specific
magnitude of effect in a large population
the ratio of the TD50 to ED50
• Antagonists – competitive and
unsurmountable