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

TachyphylaxisWhen desensitization occurs rapidly c/d

tachyphylaxis (Acute tolerance)ToleranceMore gradual d/c in responsiveness to drug

(days or weeks)

RefractorinessLoss 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 receptorsReceptors coupled to ionic

channel=rapid desensitizatione.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 (3rd 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