Tolvaptan, a vasopressin V2 receptor antagonist (vaptans), is used in hyponatraemia due to SIADH and in autosomal dominant polycystic kidney disease (ADPKD). In SIADH, its mechanism of correcting hyponatraemia is:

• A It blocks aldosterone binding in the collecting duct, causing sodium retention
• B It stimulates ENaC sodium channels in the collecting duct via a separate pathway
• C It blocks V2 receptor-mediated insertion of aquaporin-2 channels into the collecting duct apical membrane, causing excretion of free water (aquaresis) without sodium loss ✓
• D It inhibits proximal tubular sodium-glucose cotransporter causing osmotic diuresis

Explanation

ADH (vasopressin) binds V2 receptors on principal cells of the collecting duct, activating adenylyl cyclase → cAMP → PKA-mediated phosphorylation → insertion of aquaporin-2 (AQP2) channels into the apical membrane, promoting water reabsorption. Tolvaptan competitively blocks this V2 receptor, preventing AQP2 membrane insertion and impairing free water reabsorption. The resulting free water excretion ('aquaresis') — urinary loss of water without proportional solute loss — gradually raises plasma sodium in SIADH. Unlike hypertonic saline, tolvaptan selectively corrects hyponatraemia without risk of sodium overload, but requires careful monitoring to prevent too-rapid correction (risk of osmotic demyelination syndrome).

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

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Written and medically reviewed by the StethoPrep medical team.