Tolvaptan is a vasopressin V2-receptor antagonist (aquaretic) used in hyponatraemia due to SIADH. The risk of osmotic demyelination syndrome (ODS) with tolvaptan is most pronounced when:

• A The drug is used in patients with hepatic cirrhosis, because portal hypertension impairs tolvaptan clearance causing supratherapeutic plasma levels
• B Tolvaptan is combined with loop diuretics, which further reduce free water clearance causing paradoxical hyponatraemia
• C Serum sodium corrects by more than 8 mEq/L in 24 hours or 18 mEq/L in 48 hours, particularly in patients with severe chronic hyponatraemia (Na+ <120 mEq/L) for >48 hours ✓
• D Tolvaptan is discontinued abruptly, leading to a rebound in ADH-mediated water retention and rapid hyponatraemia

Explanation

Overly rapid correction of chronic hyponatraemia (present >48 hours) leads to osmotic demyelination syndrome (ODS), previously called central pontine myelinolysis. When the brain has adapted to hypo-osmolality by extruding organic osmolytes, rapid re-introduction of sodium creates a large osmotic gradient driving water out of oligodendrocytes, causing demyelination. The safe correction rate is ≤8–10 mEq/L in 24 hours (maximum 18 mEq/L in 48 hours), and even more conservative (<8 mEq/L/24h) in the highest-risk patients (malnourished, alcoholic, liver transplant). Because tolvaptan is highly effective at raising sodium rapidly, patients need hourly sodium monitoring initially. Tolvaptan is contraindicated in hepatic cirrhosis due to hepatotoxicity (TEMPO 3:4 trial).

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

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Written and medically reviewed by the StethoPrep medical team.