tolvaptan

2 min read Updated 2026-03-15
cardiology nephrology pharmacology hyponatraemia
Contents
tolvaptan

Selective V2 receptor antagonist — produces aquaresis (free water) without natriuresis. Does not decongest heart failure — EVEREST (2007): symptom improvement, no mortality benefit. Water without sodium does not resolve oedema. Primary role: SIADH hyponatraemia and ADPKD.

mechanism

Blocks vasopressin V2 receptor in the collecting duct → prevents aquaporin-2 insertion → free water excretion (aquaresis). No natriuresis — sodium excretion unchanged. Selective for V2 (no V1a/V1b effects at therapeutic doses).

dosing

SIADH hyponatraemia

  • Start 15 mg PO daily; titrate to 30 mg, then 60 mg at ≥ 24h intervals
  • Must initiate in hospital — risk of overcorrection
  • Do not fluid-restrict during first 24h — allow thirst-driven intake
  • Limit Na⁺ correction ≤ 8 mmol/L per 24h (osmotic demyelination prevention)
  • Max 30 days (hepatotoxicity risk)

ADPKD

  • 45/15 mg split dosing → titrate to 90/30 mg; long-term with REMS monitoring

key points

aquaresis ≠ natriuresis

Oedema is sodium-driven — water follows sodium. Tolvaptan removes water without sodium → hypernatraemia and dehydration without decongestion. This is why EVEREST showed no mortality benefit in HF.

  • Contraindicated in hypovolaemic hyponatraemia — these patients need saline, not aquaresis
  • Contraindicated if patient cannot perceive or respond to thirst (obtunded, intubated without IV free water)
  • CYP3A4 substrate — contraindicated with strong inhibitors (ketoconazole, clarithromycin, ritonavir)
  • Hepatotoxicity: FDA boxed warning; LFTs monthly for 18 months (ADPKD); limit ≤ 30 days for hyponatraemia

adverse effects

  • Thirst, dry mouth, polyuria (expected — aquaresis)
  • Hypernatraemia (overcorrection)
  • Hepatotoxicity (idiosyncratic; boxed warning — rare fatal cases)
  • Osmotic demyelination — if Na⁺ corrected too rapidly in chronic hyponatraemia

evidence

  • EVEREST (2007) — n=4133; tolvaptan in ADHF: improved weight and dyspnoea short-term; no mortality or hospitalisation benefit
  • SALT-1/SALT-2 (2006) — tolvaptan raised Na⁺ in SIADH and HF-related hyponatraemia
  • TEMPO 3:3 (2012) — tolvaptan slowed kidney growth and eGFR decline in early ADPKD

Key references