Clozapine causes agranulocytosis as a serious adverse effect. The mechanism most accepted for this idiosyncratic toxicity involves:

• A Direct toxic effect of the parent drug on granulocyte precursors in bone marrow
• B Inhibition of G-CSF receptors on bone marrow stem cells
• C Immune-mediated destruction of granulocytes triggered by a reactive nitrenium ion metabolite of clozapine ✓
• D Competitive antagonism of folate in granulocyte precursors

Explanation

Clozapine is oxidized by myeloperoxidase in neutrophils to a reactive nitrenium ion intermediate. This metabolite acts as a hapten, triggering an immune-mediated reaction that destroys granulocytes. The risk is highest in the first 18 weeks, which is why mandatory ANC monitoring is required throughout therapy. G-CSF is sometimes used to treat clozapine-induced agranulocytosis. The mechanism is distinct from direct bone marrow suppression.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.