Pharmacodynamics-2 Antagonists: USMLE1

Antagonist : Drugs that interact with receptors to interfere with their activation by agonists.

Can be classified as:

·         Competitive

·         Non competitive

Can be classified as:

·         Pharmacologic : same receptors

·         Physiologic : diff receptors

·         Chemical

·         Competitive antagonists cause a parallel shift to the right and can be reversed completely by increasing the dose of agonist drug.

In effect ,such antagonists appear to decrease the potency of the agonist drug.

Most receptor antagonists used in medicine are competitive.

Examples include atropine blocksà acetylcholine at M receptors and propranolol blocksànor epinephrine at beta receptors.

·         Noncompetitive/Irreversible  antagonists cause a nonparallel shift to the right and can be reversed only partially by increasing the dose of agonist drug.

Such antagonists appear to decrease both the potency and efficacy of agonists.

One example is phenoxybenzamine , which irreversibly blocks the effects of nor epinephrine at alpha receptors by the formation of covalent bond. Phenoxybenzamine makes a co-valent bond with alpha receptor in the vasculatures.

Diazoxide binds with alpha receptors.

Pharmacologic antagonism (same receptor)

·         An agonist and antagonist compete for a single receptor type.

Ach + M receptor= effects

Atropine + M receptor= blocks the effect of ACH on M receptor

Physiologic antagonism (Different Receptors).

·         Occurs when an agonist response mediated through one receptor is antagonized by an opposing agonist action at different receptor.

·         E.g. acetylcholine causes àbradycardia through M receptor activation, which  may be antagonized by NE via beta receptor activation.

Histamine H1 receptorà bronchospasm

Epinephrine beta 2 receptorà bronchodilatation

Chemical antagonism:

·         Occurs when drug effect is antagonized by the formation of a complex between the effector drug and another compound.

E.g. protamine binds to heparin to reverse its actions.

Dimercaprol, a chelator of lead poisoning

·         In this case, a given quantal effect (a condition that can be expressed only as occurring or not occurring) is chosen , and the concentration of the drug is plotted against the percentage of a specific population in which the drug produces the effect.

·         These curves plot the percentage of a population responding to a specified drug effect versus dose.

Use to estimate ED50, TD50, LD50

·         ED50 (median effective dose) : The amount of a drug required to produce a response in 50% of the subjects to whom the drug is given.

 ·         TD50 (median toxic dose):  the dose that produces a toxic effect in 50 per cent of the population.

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LLD50 (median lethal dose) the quantity of an agent/drug that will kill 50 per cent of the test subjects/population

Toxicity and the Therapeutic Index:

·         Comparisons between ED 50 and TD 50 values permit evaluation of the relative safety of a drug (the therapeutic index)

·         TI = TD50/ED50

·         Also comparison between ED50 and LD50 if the latter is known.

·         TI = LD50/ED50