Pharmacology UG-Course Touqeer Ahmed PhD 27th February, 2015 Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology

Agonists (Types) Agonist: An agonist binds to a receptor and produces a biologic response. An agonist may mimic the response of the endogenous ligand on the receptor, or it may elicit a different response from the receptor and its transduction mechanism. Full agonists: If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand (e.g. phenylephrine is an agonist at α1-adrenoceptors) Partial agonists Partial agonists have efficacies (intrinsic activities) greater than zero but less than that of a full agonist. Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist. (e.g. aripiprazole, used to treat schizophrenia) A unique feature of these drugs is that, under appropriate conditions, a partial agonist may act as an antagonist of a full agonist. Inverse agonists: Some receptors show a spontaneous conversion from R to R* in the absence of agonist (that is, they can be active without the presence of agonist). These receptors, thus, show a constitutive activity that is part of the baseline response measured in the absence of drug. Inverse agonists, unlike full agonists, stabilize the inactive R form. (some scientist categorize these along with antagonist)

Agonists (Quantifying Agonism) Drugs have two observable properties in biological systems: Potency Potency is controlled by four factors: Receptor density in a tissue Efficiency of the stimulus-response mechanisms present by default in the tissue Affinity of the drug for its receptor Efficacy Efficacy/Magnitude of effect (when a biological response is produced) The advantage of using efficacy is that this property depends solely on efficacy, whereas potency is a mixed function of both affinity and efficacy

Comparison of Efficacy and Potency

Antagonism Antagonists are drugs that decrease or oppose the actions of another drug or endogenous ligand. An antagonist has no effect if an agonist is not present. Antagonism may occur in several ways. Many antagonists act on the identical receptor macromolecule as the agonist. Antagonists, however, have no intrinsic activity and, therefore, produce no effect by themselves. Although antagonists have no intrinsic activity, they are able to bind avidly to target receptors because they possess strong affinity.

Antagonism (Quantifying Antagonism) A. Competitive antagonism B. If the antagonist binds to the same site as the agonist but does so irreversibly or pseudo-irreversibly (competitive but irreversible) C . Allosteric effect occur when the ligand I binds to a site, where agonist does not bind on the receptor, and inhibit response. (non-competitive) D. or potentiate response e.g. interaction of benzodiazepines with the GABAA

Antagonism (Types) A. Competitive antagonists B. Irreversible antagonists C. Functional and chemical antagonism An antagonist may act at a separate receptor, initiating effects that are functionally opposite those of the agonist. A classic example is the functional antagonism by epinephrine to histamine induced bronchoconstriction. Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at β2-adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax. This functional antagonism is also known as “physiologic antagonism.” A chemical antagonist prevents the actions of an agonist by modifying or sequestering the agonist so that it is incapable of binding to and activating its receptor. For example, protamine sulfate is a chemical antagonist for heparin. It is a basic (positively charged) protein that binds to the acidic heparin (negatively charged), rapidly preventing its therapeutic as well as toxic effects. Chelation of the drugs in GIT is another example

Therapeutic Index Therapeutic index of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals

Pharmacokinetics Pharmacokinetics refers to what the body does to a drug Absorption: First, drug absorption from the site of administration permits entry of the therapeutic agent (either directly or indirectly) into plasma. Distribution: Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intra cellular fluids. Metabolism: Third, the drug may be biotransformed by metabolism by the liver, or other tissues. Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Pharmacokinetic parameters allow the clinician