Smoking cessation and clozapine — MRCPsych Paper A MCQ

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ModeratePsychopharmacologySmoking cessation and clozapineMRCPsych Paper A

A 40-year-old man who regularly smokes cigarettes is admitted to a smoke-free psychiatric ward. His established clozapine dose is continued unchanged. Seven days later, he develops excessive sedation and worsening hypersalivation. What is the most likely pharmacokinetic explanation?

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Correct answer: D — Reduced CYP1A2 induction increases clozapine concentration

Explanation lettering: B = shown as A · D = shown as B · A = shown as C · C = shown as D

C is correct. Polycyclic aromatic hydrocarbons in tobacco smoke induce hepatic CYP1A2, an important pathway in clozapine metabolism. Abrupt smoking cessation removes this induction, reducing clozapine clearance and increasing its plasma concentration. The onset after one week and the dose-related adverse effects—sedation and hypersalivation—support clozapine toxicity. Nicotine is not responsible for CYP1A2 induction, so nicotine withdrawal does not alter protein binding and nicotine replacement would not prevent this interaction. Clozapine is extensively hepatically metabolised, making reduced renal clearance an inadequate explanation. CYP2D6 is only a minor metabolic pathway, and the presentation is not caused by selective norclozapine accumulation. Smoking-status changes therefore require clinical review and clozapine-level monitoring.

Reference: electronic Medicines Compendium. Clozapine Viatris 100 mg Tablets, Summary of Product Characteristics, sections 4.4, 4.5 and 5.2. Updated 13 March 2026. https://www.medicines.org.uk/emc/product/15498/smpc