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Receptor regulation in pharmacology.pptx
- 1. Receptor Regulation Dr. Usman Ali, Ph.D. Pharmacology
- 2. Revision
- 5. Therapeutic Index Is the ratio of the LD50 to ED50 Represent an estimate of the safety of a drug.
- 8. Efficacy describes ability of drug-bound receptor to produce a response. Potency is the amount of drug needed to produce a certain response. Affinity describes strength of drug binding with receptor. Intrinsic activity – capacity to induce a functional change in the receptor.
- 11. Receptors A receptor is that component (macromolecule) of a cell (on or inside the cell) that interacts with the drug, and this interaction leads to a chain of events that alter the activity of the cell. Important: Drug binds to the receptors to illicit a biological response (toxic/therapeutic). Effectors Effectors are molecules that act in response to the drug (or more precisely, the drug-receptor complex) and participate in the aforementioned chain of intracellular events leading to the drug’s effects.
- 17. Upregulation Upregulation (i.e., increase in the number) of receptors occurs when the activity of the receptor is lower than usual (e.g., due to long-term administration of an antagonist). For example, administration of beta- blockers upregulates β adrenoreceptors. Thus, if β-blockers are abruptly stopped, it can cause rebound hypertension because of the sudden stimulation of a large number of β adrenoreceptors.
- 18. • Chronic decrease in the concentration of hormone and in response the target cell increase the no of receptor to and normalize/regularize the normal physiological activities. • Hypersensitivity • Why? To cause effective stimulation • Two method • 1 activate inactivated receptor • 2. Over production of receptors via message to nucleus
- 19. Downregulation Downregulation (i.e., decrease in number) is the inverse of upregulation. It occurs due to repeated or long-term administration of an agonist. Along with downregulation, desensitization of the receptor to the drug may also occur. This is a physicochemical alteration in the receptor which makes it unresponsive to the drug; this is also called tachyphylaxis and is seen in chronic drug use, for example. Important: The process is useful in the prevention of cell damage due to the high concentration of an agonist.
- 20. • Chronic increase in the concentration of hormone and the target cell decrease the receptors to and normalize/regularize the physiological activities. • Hyposensitivity ( sensitivity to ligand is decreased) • Why? To stop over stimulation
- 23. Agonists • Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are termed agonists. • 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 agonists bind to a different region on the receptor referred to as an allosteric site.
- 24. Antagonist • 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) • Physical antagonist binds to the drug and prevents its absorption like charcoal binds to alkaloids and prevents their absorption. • Chemical antagonist combines with a substance chemically like chelating agents binds with the metals. • Physiological antagonist produces an action opposite to a substance but by binding to the different receptors e.g. adrenaline is a physiological antagonist of histamine because adrenaline causes bronchodilatation by binding to β2 receptors, which is opposite to bronchoconstriction caused by histamine through H1 receptors. • Pharmacological antagonists produce no effect , shows no intrinsic activity.
- 25. • Partial agonists -Agents that are only partly as effective as agonists regardless of the concentration employed. • Inverse agonists -Many receptors exhibit some constitutive activity in the absence of a regulatory ligand; drugs that stabilize such receptors in an inactive conformation are termed inverse agonists (produce effect opposite to that of agonist).
- 26. POTENCY The amount of the drug needed to produce a given effect. potency is determined by the affinity of the receptor for the drug. The dose causing 50% from the maximal effect (EC50) can be obtained from graded dose-response curve. In quantal dose response curve, ED50, TD50 and LD50 are potency variables.
- 27. Repeated administration of a drug results in diminished effect “Tolerance”. Tachyphylaxis: is a type of tolerance which occurs very rapidly. Desensitization: decreased response to the agonist after its repeated injection in small doses. May be due to 1- Masking or internalization of the receptors. 2- Loss of receptors (down regulation)- decreased synthesis or increased destruction. 3- Exhaustion of mediators (depletion of catecholamine).
Editor's Notes
- The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.
- Selectivity, specificity, agonist, antagonist
- From
- feedback mechanism to protect against both acute and chronic receptor over-stimulation
- The anti-obesity drugs rimonabant and taranabant are inverse agonists at the cannabinoid CB1 receptor and though they produced significant weight loss, both were withdrawn owing to a high incidence of depression and anxiety, which are believed to relate to the inhibition of the constitutive activity of the cannabinoid receptor.