Basic Principles of Drug Action Lecture 2 PDF

 Learning Objectives:  To: Define agonist, antagonist & inverse agonist based on affinity and efficacy of the drug, using two state model of receptor. Identify types of drug antagonism  Drug-Receptor interaction Agonist, antagonist & inverse agonist Drug-Receptor binding m...

 Learning Objectives:  To: Define agonist, antagonist & inverse agonist based on affinity and efficacy of the drug, using two state model of receptor. Identify types of drug antagonism  Drug-Receptor interaction Agonist, antagonist & inverse agonist Drug-Receptor binding may or may not result in receptor activation. Occupation → affinity: tendency of the drug to bind the receptor Activation → efficacy (intrinsic activity): ability of a drug, once bound, to initiate changes → effect.  Two-State Model of Receptor: The receptor exists in resting (R) and activated (R*) states. No ligand → (R). Ligand → (R*) ‘inactive’ R ‘active’ R R R NO A Response R R R R R R ‘inactive’ R A active’ R Agonist: a drug that binds to the receptor” affinity” → activation of the receptor” efficacy”. a. Full agonist: possesses ↑ affinity & efficacy (+1), high % of receptors reside in (R*). Equilibrium shifts to the active state → maximal tissue response ‘inactive’ R ‘active’ R A A A A A Maximal R Response A A A R ‘inactive’ R agonist A active’ R a. Partial agonist: possesses ↑ affinity & intermediate efficacy (0-1) i.e. Some receptors are activated even at 100% occupancy. Partial shift of equilibrium to active R*→ sub-maximal tissue response. They have low intrinsic activity (act as an agonist in the absence of full agonist, or as antagonist if full agonist is present, e.g. Pindolol, acebutolol ‘inactive’ R ‘active’ R R A A R A A Sub-maximal Response R A ‘inactive’ R agonist A active’ R R Affinity  Antagonist: a drug that binds to the receptor “ affinity” without activating the receptor ” zero efficacy” i.e. equal affinity for (R) & (R*). No change in equilibrium. ‘inactive’ R ‘active’ R R R A NO R Response R R R R ‘inactive’ R antagonist A active’ R R  Constitutively active receptor → few % of receptors found in (R*) in the absence of the ligand. i.e. some receptors are ‘active’ even in the absence of the drug. e.g benzodiazebines, cannabinoids, histamine & serotonin receptors ‘inactive’ R ‘active’ R R R A R A R R A R R R ‘inactive’ R A active’ R Inverse agonist: A ligand that reduces the level of constitutive activity of the receptor (-ve efficacy), have strong affinity for (R). i.e. Equilibrium shifts to the inactive R. e.g. antihitamines, famotidine, metoprolol. It induces a response opposite to agonist response ‘inactive’ R ‘active’ R R R R A R R R R Inverse agonist  Spare receptors Spare receptors (reserve) are present when tissue maximal response is produced by agonist at very low occupancy. i.e. Spare receptors are said to exist if the maximal drug response (Emax) is obtained at less than maximal occupation of the receptors They are not hidden or in any way different from other receptors.  It occurs with drugs elicit smooth muscle contraction, e.g. Ach Common with receptors that bind hormones and neurotransmitters They increase sensitivity of tissues to the drug. ↓ conc. of hormones & neurotransmitters can produce biological response.  Drug antagonism Is the case where the effect of agonist is diminished or completely abolished in the presence of antagonist.  Types: 1. Chemical antagonism: Does not involve receptors. It occurs in solutions e.g. plasma, GIT fluids. Ex. Protamine (+ve) with heparin (-ve) Dimercaprol with heavy metals (lead) Calcium disodium edetate with arsenic/lead 2. Pharmacokinetic antagonism: The antagonist effectively reduces plasma concentration of the agonist by ↑ metabolism, ↑renal excretion or ↓ absorption of the agonist. Absorption: Tetracycline absorption is reduced by metal ions (Ca+2, iron, Al+3). Cholestyramine reduces absorption of digoxin Metabolism: Phenobarbitone (↑metabolism) reduces warfarin effect. Excretion: Na bicarbonate reduces aspirin effect (↑excretion). 3. Competitive antagonism (pharmacological): Antagonist competes with the agonist for the same receptor binding site.  Characters: a. Reversible: (Surmountable) b. Shift the agonist dose-response curve to the right (↑ EC50 →↓potency) without changing the slope & Emax (it doesn't change efficacy) e.g. Propranolol antagonizes isoprenaline effect. Atropine antagonizes Ach Naloxone antagonizes morphine effect A In the presence of antagonist  Irreversible antagonist binds (covalently) to the same binding site of the agonist. e.g phenoxybenzamine (irreversible alfa blocker).  Characters: 1. Effect of irreversible antagonist is non- surmountable (covalent bond) 2. Reduces Emax (↓ efficacy, but it doesn’t change potency).  Advantages & disadvantages of irreversible antagonists: Advantages: Antagonism occurs even in the presence of high conc. of agonist. e.g. phenoxybenzamine treats hypertension due to pheochromocytoma. Disadvantages: In over-dose case, the blockade can not be overcome by increasing the agonist conc. 4. Non-competitive antagonism: A non-competitive antagonist (allosteric antagonist): binds to an allosteric site (site that distinct from the agonist binding site) to prevent activation of the receptor. It reduces Emax & slope of the agonist dose-response curve (↓ efficacy). B In the presence of antagonist 5. Physiological antagonism: Two agents act on different targets, and produce opposite physiological effect. e.g. omeprazole (acts on proton pump) antagonizes histamine effect (acts on H2 receptors). insulin (insulin receptor) antagonizes hyperglycemic effect of glucocorticoids (steroid receptor). Bradycardia caused by Ach is treated with - adrenoceptor agonist (isoprenaline) Glucagon (glucagon receptor) antagonizes hypoglycemic effect of insulin (insulin receptor).