Vasopressin-2 receptor antagonist


Tolvaptan (Samsca®) is indicated in Europe for the treatment of patients with hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH). In the US, tolvaptan is also indicated for hypervolemic and euvolemic hyponatremia (sodium concentration

Symptomatic hyponatremia can accompany heart failure, SIADH and liver cirrhosis. Increased levels of vasopressin (also known as antidiuretic hormone, ADH) contribute via overstimulation of vasopressin-2 (V2) receptors in renal collecting ducts. Consequently, the synthesis and transport of aquaporin channels is enhanced, water is retained and plasma osmolality decreases as drinking continues (due to dietary habit rather than to thirst), urine volume is reduced but urinary Na+ excretion continues.Tolvaptan is the first orally active, specific V2-receptor antagonist to be licensed for use in man. It counteracts the actions of vasopressin by blocking the V2-receptor, thereby decreasing the expression

of the aquaporin channels. This causes: 1) an increase in free water clearance, 2) a decrease in urine osmolality, and 3) an increase in serum sodium concentration.

The starting dose for tolvaptan is 15 mg. This may be increased up to 60 mg daily depending on serum sodium concentration and volume status.

The water diuresis results in thirst, polyuria and dry mouth in up to 5% of the treated patients. In some cases (mainly in heart failure patients) dehydration occurred. Serious effects, such as cardiogenic shock, and pulmonary embolism were slightly more frequent in tolvaptan-treated patients compared to placebo. Tolvaptan has teratogenic effects in animal models and is therefore contraindicated during pregnancy and breastfeeding.

EPAR of tolvaptan.