Tolvaptan is a vasopressin V2 receptor antagonist used for hyponatraemia in SIADH. Unlike conventional diuretics, tolvaptan produces 'aquaresis' (electrolyte-free water excretion). The mechanism is:

• A Inhibits Na-K-2Cl cotransporter in the thick ascending limb of Henle, reducing the medullary concentration gradient and impairing water reabsorption from the collecting duct
• B Blocks V2 receptors on renal collecting duct principal cells, preventing cAMP-mediated aquaporin-2 (AQP2) insertion into the apical membrane, thus reducing water reabsorption without affecting sodium excretion ✓
• C Activates V1a receptors in the renal vasculature, causing afferent arteriolar vasoconstriction and reducing GFR-dependent sodium delivery to diluting segments
• D Competitively inhibits ADH binding to collecting duct AQP4 channels, blocking paracellular water flux

Explanation

ADH (vasopressin) binds V2 receptors (Gs-coupled) on collecting duct principal cells, activating adenylyl cyclase, raising cAMP, activating PKA, which phosphorylates AQP2 vesicles and drives their insertion into the apical membrane — greatly increasing water permeability. Tolvaptan competitively blocks V2 receptors, preventing this cascade, so AQP2 channels remain in intracellular vesicles, the collecting duct becomes water-impermeable, and dilute urine is excreted (electrolyte-free water loss). This raises plasma sodium in SIADH without significant natriuresis — unlike loop diuretics which waste sodium along with water. AQP4 is in the brain; V1a is the vasopressor receptor; NKCC2 is furosemide's target.

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

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Written and medically reviewed by the StethoPrep medical team.