The 'anticonvulsant hypersensitivity syndrome' occurring with aromatic antiepileptics (phenytoin, carbamazepine, phenobarbitone) is thought to be mediated by toxic accumulation of:

• A Free valproic acid metabolites causing mitochondrial dysfunction
• B Reactive nitrogen species from nitric oxide synthase induction
• C Arene oxide intermediates due to CYP450 epoxide hydroxylase deficiency ✓
• D Glucuronide conjugates accumulating in hepatocytes

Explanation

Aromatic antiepileptics are metabolised via CYP450 to reactive arene oxide intermediates. In susceptible individuals, deficiency or saturation of epoxide hydroxylase (the enzyme that detoxifies these intermediates) leads to their accumulation, causing multi-organ hypersensitivity reactions — fever, rash, lymphadenopathy, and hepatitis. This cross-reactivity explains why all three aromatic AEDs can precipitate the syndrome. Valproate toxicity (pancreatitis, hepatotoxicity) has a different metabolic basis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.