The mechanism underlying clozapine-induced agranulocytosis is BEST explained by:

• A Clozapine's active metabolite norclozapine directly suppresses G-CSF signalling
• B Reactive nitrenium ion formed by neutrophil myeloperoxidase-mediated oxidation of clozapine, haptenating neutrophil proteins and triggering immune destruction ✓
• C Clozapine directly inhibiting DNA topoisomerase II in granulocyte precursors
• D HLA-DQB1*02:01 allele binding clozapine and presenting it to cytotoxic T cells

Explanation

Clozapine undergoes oxidation by neutrophilic myeloperoxidase to a reactive nitrenium ion intermediate, which covalently binds (haptenates) neutrophil proteins. This modified self-protein is recognised as foreign, triggering an immune-mediated destruction of neutrophils. This mechanism explains the idiosyncratic and delayed onset, and the lack of dose-dependence. Norclozapine (option A) does not suppress G-CSF. Option D (HLA allele) is the pharmacogenomic risk factor for carbamazepine-induced SJS, not clozapine agranulocytosis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.