DR. SHABAN ALI

Desensitization & Tachphylaxis Reduction of effect of a drug after its continuous administration Diminished response of a drug in person after its continuous use b/c body adapts the continuous presence of drug Desensitization & tachyphylaxis= Synonymous

Tachyphylaxis When desensitization occurs rapidly c/d tachyphylaxis (Acute tolerance) Tolerance More gradual d/c in responsiveness to drug (days or weeks) Refractoriness Loss of therapeutic efficacy

Drug resistance Loss of effectiveness of antimicrobial or antitumour drugs

Mechanisms of Desensitization Change in receptors Loss of receptors Exhaustion of mediators Increased metabolic degradation Physiological adaptation Active extrusion of drug from cells (mainly relevant in chemotherapy)

Change in receptors Conformational change in receptors Receptors coupled to ionic channel=rapid desensitization e.g., NMJ (ion channel)= confirm.change  tight binding of agonist (un opening of channel) β -adrenoceptors (GPCR) =not activate adenylate cyclase although still bound to receptor cont.

Mechanism for change in receptors Phosphorylation of specific residue (3 rd cytoplasmic loop) in receptor protein Phosphorylated receptor is less efficient at activating G-protein and also exhibits lower affinity for agonists

Receptor desensitization

Loss of receptors Prolonged exposure to agonists results in a gradual d/c in no of receptors Receptors taken into cell by endocytosis E.g., β -adrenoceptors  studies of cell culture receptor d/c in presence of ISOP Receptors of various peptides, hormones

Exhaustion of mediators Depletion of essential intermediate subs. e.g., amphetamine = tachyphylaxis b/c of depletion of stores of NA

Increased metabolic degradation Tolerance to some drugs b/c of repeated administration of same dose result in low plasma conc. b/c of more metabolic degradation (by metabolic enzyme induction) Modest tolerance e.g., barbiturates & ethanol

Physiological Adaptation Diminution of drug effect b/c of nullification by homeostatic response (unknown mech ) E.g., thiazide diuretics = hypotensive effect d/c b/c of stimulation of renin-angiotensin system Side effect (nausea, sleepiness) subside even drug is continued