Tolvaptan: A Selective Vasopressin V2-Receptor Antagonist
Tolvaptan is a selective vasopressin V2-receptor antagonist that increases free water excretion, resulting in increased serum sodium concentrations, and is primarily used for the treatment of hyponatremia in specific clinical conditions including SIADH, heart failure, and cirrhosis. 1
Mechanism of Action
Tolvaptan works by:
- Selectively antagonizing vasopressin V2-receptors with an affinity 1.8 times that of native arginine vasopressin (AVP) and 29 times greater affinity for V2 than V1a receptors 2
- Causing an increase in urine water excretion (aquaresis)
- Decreasing urine osmolality
- Increasing serum sodium concentrations without significantly affecting urinary excretion of sodium and potassium 2
Approved Indications
In the United States: Approved for hypervolemic and euvolemic hyponatremia (serum sodium <125 mmol/L) associated with:
- Cirrhosis
- Heart failure
- Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) 1
In Europe: Approved only for SIADH (not for cirrhosis-related hyponatremia) 1
In China and Japan: Low doses (7.5-15 mg/day) are approved to control ascites, with a warning about potential liver dysfunction 3
Dosage and Administration
- Initial dose: 15 mg once daily, without regard to meals 1
- Titration: May be increased to 30 mg after at least 24 hours, and to a maximum of 60 mg once daily as needed 1
- Formulation: Available in 15 mg and 30 mg oral tablets 1, 2
- Administration: Can be taken with or without food 2
Clinical Efficacy
Tolvaptan has demonstrated efficacy in:
- Improving serum sodium concentration in 45-82% of hyponatremic patients with cirrhosis and ascites 1
- Significantly improving serum sodium levels compared to placebo in clinical trials (SALT-1 and SALT-2) 4
- Increasing serum sodium levels in patients with both mild (serum sodium <135 mmol/L) and marked (serum sodium <130 mmol/L) hyponatremia 4, 5
- Improving mental component summary scores on health surveys in patients with cirrhosis 5
Safety Considerations and Monitoring
Important Precautions
- Rate of correction: Aim for sodium increase of no more than 8-10 mEq/L per day to avoid osmotic demyelination syndrome 1
- Initiation: Treatment should be started in hospital with close monitoring of serum sodium levels 1
- Liver function: Monthly liver function tests are recommended due to potential liver injury 1
- Fluid restriction: Should be avoided during the first 24 hours of treatment to prevent overly rapid correction of hyponatremia 6
Contraindications
- Patients unable to sense or respond to thirst
- Hypovolemic hyponatremia
- Patients taking strong CYP3A inhibitors
- Anuria
- Hypersensitivity to tolvaptan 1
Adverse Effects
Drug Interactions
- CYP3A inhibitors (ketoconazole, grapefruit juice, clarithromycin): May increase tolvaptan exposure
- CYP3A inducers (rifampin, barbiturates, phenytoin): May decrease effectiveness 1
Special Populations
- Elderly: No overall differences in safety or effectiveness observed, though greater sensitivity in some older individuals cannot be ruled out 2
- Hepatic impairment: Moderate and severe hepatic impairment do not affect exposure to a clinically relevant extent, but use should be avoided in patients with underlying liver disease 2
- Renal impairment: No dose adjustment necessary based on renal function, but not recommended in patients with CrCl <10 mL/min or who are anuric 2
Duration of Effect and Discontinuation
- Onset of aquaretic and sodium-increasing effects occurs within 2-4 hours post-dose 2
- Peak effect observed between 4-8 hours post-dose 2
- About 60% of peak effect on serum sodium is sustained at 24 hours post-dose 2
- Hyponatremia typically recurs within 7 days after discontinuation of tolvaptan 5
Tolvaptan represents an important therapeutic option for managing hyponatremia, particularly in hospitalized patients where fluid restriction alone may be ineffective, but requires careful monitoring and appropriate patient selection due to its potential adverse effects and specific contraindications.