From the Guidelines
Tolvaptan decreases urine osmolality by blocking vasopressin receptors in the kidney, leading to increased free water excretion and production of more dilute urine with lower osmolality. As a selective V2 receptor antagonist, tolvaptan prevents antidiuretic hormone (ADH) from binding to its receptors in the collecting ducts of the kidney, reducing water reabsorption and increasing solute-free water excretion 1. This mechanism is supported by the most recent and highest quality study, which found that tolvaptan treatment resulted in a significant reduction in urine osmolality and an increase in solute-free water excretion 1.
Key Points
- Tolvaptan is typically dosed at 15-60 mg once daily for conditions like hyponatremia associated with SIADH (Syndrome of Inappropriate Antidiuretic Hormone secretion) or heart failure.
- When administering tolvaptan, it's essential to monitor serum sodium levels closely to prevent overly rapid correction of hyponatremia, which could lead to osmotic demyelination syndrome.
- Patients should have unrestricted access to water to prevent dehydration, and the medication should be taken in the morning to minimize nighttime urination.
- The physiological mechanism involves disrupting the normal insertion of aquaporin-2 water channels into the apical membrane of collecting duct cells, which would otherwise allow water reabsorption in response to vasopressin.
Clinical Considerations
- Tolvaptan treatment should be interrupted in situations causing volume depletion or an inability to compensate for the aquaresis.
- Patients should be counseled to drink liquids without sugar or fat, and to adopt a low-sodium intake, because low osmolar intake reduces polyuria.
- Individual adjustments should include adapting the schedule, timing, and doses of tolvaptan to the person’s activities.
From the FDA Drug Label
When taken orally, 15 to 60 mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium concentrations.
Tolvaptan decreases urine osmolality by increasing urine water excretion, which results in an increase in free water clearance (aquaresis) 2. This effect is due to the drug's mechanism of action as a selective vasopressin V2-receptor antagonist, which antagonizes the effect of vasopressin and leads to an increase in urine water excretion 2.
- Key points:
- Tolvaptan decreases urine osmolality
- This effect is due to increased urine water excretion
- The drug's mechanism of action is as a selective vasopressin V2-receptor antagonist
From the Research
Effect of Tolvaptan on Urine Osmolality
- Tolvaptan, a vasopressin receptor antagonist, has been shown to decrease urine osmolality in various studies 3, 4, 5, 6, 7.
- In a study of hospitalized hyponatremic patients, tolvaptan decreased urine osmolality in all patients, with a significant decrease in patients with the syndrome of inappropriate antidiuretic hormone (SIADH) 3.
- Another study found that tolvaptan decreased urinary osmolarity from 547 mosmol/L to 90 mosmol/L in a pediatric patient with nephrotic syndrome 4.
- A double-blind, randomized, placebo-controlled, crossover study of calcium urinary stone formers found that tolvaptan decreased urinary osmolality from 529 ± 213 mOsm/kg to 204 ± 96 mOsm/kg 5.
- A prospective, observational cohort study of patients with autosomal dominant polycystic kidney disease (ADPKD) found that tolvaptan decreased urine osmolality immediately after initiation, with a mean decrease from 351.8 ± 142.2 mOsm/kg H2O to 97.6 ± 23.8 mOsm/kg H2O 6.
- A subanalysis of the K-STAR study found that tolvaptan added to furosemide resulted in a greater decrease in urine osmolality compared to increased furosemide in patients with heart failure and chronic kidney disease stages G3b-5 7.
Mechanism of Action
- Tolvaptan works by blocking the action of vasopressin, a hormone that regulates water reabsorption in the kidneys 3, 4, 5, 6, 7.
- By blocking vasopressin, tolvaptan increases water excretion and decreases urine osmolality, making it an effective treatment for hyponatremia and other conditions characterized by excessive water retention 3, 4, 5, 6, 7.
Clinical Implications
- The decrease in urine osmolality caused by tolvaptan can be used as a predictor of the drug's effectiveness in treating hyponatremia and other conditions 3, 4, 5, 6, 7.
- Tolvaptan's ability to decrease urine osmolality also makes it a potential treatment for conditions such as nephrotic syndrome and autosomal dominant polycystic kidney disease (ADPKD) 4, 6.