Vasopressin Receptor Antagonists

Vasopressin receptor antagonists (vaptans) block the V2 receptor and promote free water excretion (aquaresis). They treat euvolaemic and hypervolaemic hyponatraemia, including SIADH and heart failure, and slow kidney growth in polycystic kidney disease.

Mechanism. Blockade of V2 receptors in the collecting duct prevents aquaporin 2 insertion, causing dilute urine, a rise in serum sodium and weight loss without sodium or potassium loss. Conivaptan also blocks V1a.

Pharmacokinetics. Tolvaptan is oral, absorbed rapidly, with a half-life of 6 to 12 hours; sodium rises within 2 to 4 hours. It is metabolised by CYP3A4 and is a P-glycoprotein substrate.

Tolvaptan. Oral. For hyponatraemia: start 15 mg once daily in hospital; increase after 24 hours to 30 mg, then 60 mg daily by sodium response. For autosomal dominant polycystic kidney disease: 45 mg in the morning with 15 mg 8 hours later, increased to 60 mg and 30 mg, then 90 mg and 30 mg as tolerated.

Conivaptan. Intravenous: 20 mg loading dose over 30 minutes, then 20 mg continuous infusion over 24 hours, up to 40 mg daily for a maximum of 4 days. Limited availability.

Alternatives for hyponatraemia. Fluid restriction, oral urea 15 to 30 g daily, and hypertonic saline in severe symptomatic cases.

• Hyponatraemia (SIADH, heart failure, cirrhosis): after fluid restriction and treatment of the cause fail, and when there is no hypovolaemia. Start in hospital.
• Rate of correction: the serum sodium rise must not exceed 8 to 10 mmol/L in 24 hours; use 8 mmol/L as the limit in patients at high risk of osmotic demyelination (sodium under 120 mmol/L, hypokalaemia, alcohol use, liver disease, malnutrition). Check sodium every 6 to 8 hours for the first 24 hours.
• Fluid: do not restrict fluid in the first 24 hours of tolvaptan, and allow free water access in the presence of thirst.
• Overcorrection: stop the drug, give 5% dextrose, and consider desmopressin 2 micrograms intravenously to lower the sodium again.
• Duration: a short course of days; tolvaptan for hyponatraemia is not used for more than 30 days.

Special groups. Pregnancy: avoid. Breastfeeding: avoid. Children: not licensed. Older adults: higher risk of dehydration and overcorrection. Kidney impairment: not effective at very low eGFR (under 10 mL/min); anuria is a contraindication. Liver impairment: avoid in cirrhosis because of liver injury and bleeding. Regional: cost and availability are limited in East Africa, so urea and fluid restriction are the usual options.

Adverse effects. Thirst, dry mouth, polyuria, nocturia, hypernatraemia, dehydration, hypotension, osmotic demyelination (with overcorrection), hepatotoxicity (especially tolvaptan in polycystic kidney disease), and hyperkalaemia.

Contraindications. Hypovolaemic hyponatraemia, hypernatraemia, anuria, inability to sense or respond to thirst, concurrent strong CYP3A4 inhibitors, and use in autosomal dominant polycystic kidney disease with liver disease.

Interactions. Ketoconazole and clarithromycin raise tolvaptan exposure. Rifampicin lowers it. Avoid hypertonic saline and diuretics that cause rapid sodium change. Digoxin levels rise.

Monitoring. Sodium every 6 to 8 hours for 24 to 48 hours, then daily; fluid balance and weight; liver enzymes and bilirubin before starting in polycystic kidney disease, then at 2 and 4 weeks, monthly for 18 months and every 3 months afterwards.

Referral and escalation. All patients are started in hospital. Overcorrection, neurological symptoms, jaundice or liver enzymes over 3 times the upper limit.