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DR. SHABAN ALI

DENSENSITIZATION & TACHYPHYLAXIS. 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

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DR. SHABAN ALI

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  1. DENSENSITIZATION & TACHYPHYLAXIS DR. SHABAN ALI

  2. 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

  3. 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

  4. Drug resistance • Loss of effectiveness of antimicrobial or antitumour drugs

  5. 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)

  6. Change in receptors • Conformational change in receptors • Receptorscoupled 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 receptorcont.

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

  8. Receptor desensitization

  9. 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

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

  11. 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

  12. 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

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