A patient with cirrhosis and refractory ascites is started on tolvaptan. The mechanism of action of tolvaptan and the specific contraindication in liver disease relates to:

• A Tolvaptan is a V1a receptor antagonist causing vasodilation; contraindicated because it worsens portal hypertension
• B Tolvaptan inhibits ADH synthesis; contraindicated because it causes DI-like syndrome worsening hyponatraemia
• C Tolvaptan is a selective V2 receptor antagonist causing aquaresis; it is contraindicated in cirrhosis because hepatic CYP3A4 metabolism is impaired, leading to drug accumulation and hepatotoxicity ✓
• D Tolvaptan is a vasopressin receptor agonist; contraindicated because it worsens sodium retention in cirrhosis

Explanation

Tolvaptan is a selective vasopressin V2 receptor antagonist that blocks ADH binding to V2 receptors in the collecting duct, preventing aquaporin-2 insertion and causing electrolyte-free water excretion ('aquaresis') without significant natriuresis. It is effective in hypervolaemic and euvolaemic hyponatraemia. However, in the TEMPO trial for ADPKD, hepatotoxicity was identified; the FDA issued a black box warning against use in cirrhosis due to severe and potentially fatal liver injury. The hepatotoxic risk in cirrhosis relates to pre-existing impaired hepatic function compounded by tolvaptan's CYP3A4 metabolism and possibly direct hepatotoxicity. Despite being pathophysiologically logical for cirrhotic hyponatraemia, it is contraindicated in this context.

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

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Written and medically reviewed by the StethoPrep medical team.