Толваптан

Описание

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-proteincoupled receptor subtypes:V₁-vascular types a and b, V₂-renal, and V₃-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135 mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V₂receptor promotes water excretion without perturbing electrolyte balance making it an appealing target for preventing disease progression. Following the introduction of the dual AVP V_1a/V₂ receptor antagonist conivaptan, tolvaptan has recently been launched as a nonpeptide, selective V₂ receptor antagonist with potent aquaretic attributes for the treatment of hypervolemic and euvolemic hyponatremia (serum sodium concentration of <125 mmol/L or less distinct hyponatremia that is symptomatic and has resisted correction with fluid restriction). As a more potent and selective V₂ receptor antagonist, tolvaptan is a follow-up to mozavaptan, which possesses weak V₁ receptor antagonism and was approved for the treatment of SIADH in Japan. .

Химические свойства

White Solid

Использование

Labelled Tolvaptan s, and the syndrome of inappropriate antidiuretic hormone (SIADH).

Клиническое использование

Tolvaptan, also known as OPC-41061, is a selective, competitive arginine vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH). Otsuka Pharmaceutical licensed tolvaptan under the trade name Samsca after the FDA approved the drug in May 2009. Tolvaptan has also shown efficacy against polycystic kidney disease. In a 2004 trial, tolvaptan administered with traditional diuretics was noted to increase excretion of excess fluids and improve blood sodium levels in patients with heart failure without producing side effects such as hypotension (low blood pressure) or hypokalemia (decreased blood levels of potassium). The drug also exhibited no adverse effect on kidney function.

Побочные эффекты

The most common adverse events were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. The recommended starting dose is 15 mg daily with a daily 15-mg adjustment to a maximum of 60 mg daily to raise serum sodium concentration. Initiation should be in a hospital setting where serum sodium and volume status may be monitored since too rapid correction of hyponatremia (>12 mEq/L/24 h) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, spastic quadriparesis, seizures, coma, and death. In addition to avoiding concomitant use of strong CYP3A4 inhibitors, tolvaptan is contraindicated in settings of urgent need to raise serum sodium acutely, in patients with an inability to sense or appropriately respond to thirst, in hypovolemic hyponatremia conditions, and in anuric patients.