How does clozapine toxicity differ mechanistically and clinically from that of other atypical antipsychotics?
Clozapine is an atypical antipsychotic. Mechanistically, clozapine works by antagonizing the dopamine (D1, D2, and D4,), alpha (α1 and α2), serotonin (5-HT1A, 5HT2A, and 5HT1C), muscarinic (M1, M2-5), and GABA (GABAA) receptors, and blocks the reuptake of norepinephrine. Clozapine exerts the most activity at the M1 muscarinic receptor. In comparison to other antipsychotics, clozapine has relatively weak affinity for the DA2 receptor. Distinctive clinical effects associated with clozapine at therapeutic and toxic doses includes tachycardia, orthostatic hypotension, gastrointestinal symptoms, sedation, agranulocytosis, sialorrhea, seizures, reflex tachycardia, myocarditis, and QTc prolongation.
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Contributed by: Cedric White, PharmD (Cedric.White@bmc.org) with oversight from Natalija Farrell, PharmD, BCPS, DABAT (Natalija.Farrell@bmc.org)