PharmacologyTier 1Medical Sciences concept

Vasopressin receptor antagonists (tolvaptan) - mechanism

Core concept

Vaptans block the V2 receptor on the collecting duct principal cell
- Normally: ADH -> V2 (Gs) -> cAMP -> aquaporin-2 insertion into the apical membrane -> water reabsorption
- Blockade -> AQP2 removed -> free water excretion without solute loss = aquaresis
Aquaresis, not diuresis - urine osmolality falls, sodium and potassium excretion barely change
- -> serum sodium rises because water is lost in excess of solute
Contrast with a loop diuretic (loses Na and water) and with fluid restriction (limits intake)
Tolvaptan - oral, selective V2; conivaptan - IV, mixed V1a/V2

Indications
- SIADH and hypervolaemic hyponatraemia where fluid restriction has failed - euvolaemic or hypervolaemic only
- ADPKD - slows eGFR decline and cyst growth (TEMPO 3:4, REPRISE), at high dose
Dosing and safety
- Start 15 mg daily, in hospital, with the fluid restriction lifted
- Monitor sodium at 6, 12 and 24 hours
- Correction limits: <=8-10 mmol/L in 24 h, and <=8 mmol/L/24 h in high-risk patients (alcohol, malnutrition, hypokalaemia, liver disease, chronic hyponatraemia)
- Overcorrection -> osmotic demyelination syndrome - locked-in state, quadriparesis, days later, often irreversible
- Rescue: stop tolvaptan, give 5% dextrose +/- desmopressin to re-lower the sodium
Hepatotoxicity - the reason for restricted use and monthly LFTs in ADPKD; contraindicated in liver disease including cirrhosis
Thirst and polyuria are expected and are the main tolerability issue
Do not use in hypovolaemic hyponatraemia (the problem is volume, not water excess), or in anuria

SIADH management ladder: treat the cause -> fluid restrict to 800-1000 mL -> add oral sodium chloride and/or frusemide -> urea 15-30 g/day -> tolvaptan
- Urea is cheap, effective and safer; tolvaptan is expensive and PBS-restricted (ADPKD indication)
Acute symptomatic hyponatraemia (seizure, coma) is treated with hypertonic 3% saline boluses, not tolvaptan - vaptans are for chronic management
ADPKD: tolvaptan for rapidly progressive disease (Mayo class 1C-1E, or documented rapid eGFR loss) with normal LFTs and specialist supervision
Demeclocycline is an older alternative (induces nephrogenic DI) - slow, nephrotoxic, now rarely used
Watch for co-prescribed CYP3A4 inhibitors - tolvaptan is a substrate and levels rise sharply

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