A patient on clozapine for treatment-resistant schizophrenia develops a WBC count of 2800/mm³. The mechanism of clozapine-induced agranulocytosis involves:
- A Direct suppression of granulopoiesis through D4 receptor blockade in bone marrow
- B Oxidative stress from H4R blockade depleting glutathione in neutrophil precursors
- C Formation of reactive nitrenium ion metabolites that haptenize neutrophil proteins triggering immune-mediated destruction ✓
- D Competitive inhibition of G-CSF receptor reducing neutrophil maturation
Correct answer: C. Formation of reactive nitrenium ion metabolites that haptenize neutrophil proteins triggering immune-mediated destruction
Explanation
Clozapine is oxidized by myeloperoxidase in neutrophils to a reactive nitrenium ion intermediate that covalently modifies neutrophil proteins. This creates drug-protein adducts (haptens) that trigger an immune-mediated destruction of neutrophils and their precursors. This idiosyncratic reaction is not dose-related and requires weekly CBC monitoring. The risk is highest during the first 18 weeks of therapy.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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