A 35-year-old woman with bipolar disorder is started on valproate. After 3 weeks she develops vomiting, confusion, and her serum ammonia is markedly elevated. Liver function tests are normal. This adverse effect of valproate is most likely due to:
- A Valproate-induced hepatic necrosis causing reduced urea synthesis
- B Inhibition of carbamoyl phosphate synthetase I by valproate or its metabolites, impairing urea cycle function ✓
- C Valproate-induced renal tubular acidosis causing ammonia retention
- D Increased intestinal ammonia production due to gut flora alteration by valproate
Correct answer: B. Inhibition of carbamoyl phosphate synthetase I by valproate or its metabolites, impairing urea cycle function
Explanation
Valproate-induced hyperammonaemia with normal liver function (non-hepatic) occurs because valproate and its metabolite (propionate) inhibit carbamoyl phosphate synthetase I (CPS-I), the rate-limiting enzyme of the urea cycle in mitochondria, thereby impairing ammonia detoxification. It may also deplete carnitine, further disrupting mitochondrial function. This can cause encephalopathy even without hepatotoxicity and is treated with L-carnitine supplementation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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