Vasopressin Antagonists

Vasopressin (antidiuretic hormone, ADH) is made in the hypothalamus and stored in the posterior pituitary. In the kidney it binds V2 receptors on the principal cells of the collecting duct. That raises cyclic AMP (cAMP), and aquaporin-2 water channels are inserted into the membrane, so water is reabsorbed and the urine is concentrated.

Tolvaptan is a selective V2-receptor antagonist: its affinity for the V2 receptor is 1.8 times that of native vasopressin and 29 times its affinity for the V1a receptor. Blocking V2 lowers cAMP, keeps the aquaporin-2 vesicles from fusing with the membrane, and increases free-water clearance — aquaresis — with a fall in urine osmolality and a rise in serum sodium. Urinary sodium and potassium excretion are not significantly changed: the kidney loses water, not salt.

Conivaptan is the class’s intravenous member: a dual V1a and V2 vasopressin antagonist labeled to raise serum sodium in hospitalized patients with euvolemic and hypervolemic hyponatremia. The WHO stem -vaptan marks vasopressin receptor antagonists. Desmopressin, the drug that stimulates V2 receptors, is on the Endocrine › Pituitary ADH Agents page.

Samsca treats clinically significant euvolemic or hypervolemic hyponatremia, including hyponatremia from heart failure and SIADH. It is not for a patient who needs sodium raised urgently because of serious neurologic symptoms, and raising sodium with it has not been shown to improve symptoms. It is contraindicated in hypovolemic hyponatremia and in anyone who cannot sense or respond to thirst.

The boxed warning sets the rules. Samsca is started and restarted only in a hospital where serum sodium can be monitored closely, because too-rapid correction of hyponatremia (the label’s example is more than 12 mEq/L in 24 hours) can cause osmotic demyelination — dysarthria, mutism, dysphagia, lethargy, spastic quadriparesis, seizures, coma and death. People with severe malnutrition, alcoholism or advanced liver disease may need slower correction, and SIADH or a very low starting sodium raises the risk of correcting too fast. Fluid restriction during the first 24 hours makes overly rapid correction more likely and is generally avoided; patients keep drinking in response to thirst.

Tolvaptan can also injure the liver. Samsca therapy is limited to 30 days, it is avoided in underlying liver disease (including cirrhosis), and the same box states that tolvaptan is not used for ADPKD outside the FDA-approved REMS.

In autosomal dominant polycystic kidney disease (ADPKD), cAMP drives cyst growth and fluid secretion into the cysts. By blocking vasopressin at the V2 receptor, tolvaptan lowers the intracellular cAMP that would otherwise stimulate cystic proliferation and growth. Jynarque is indicated to slow kidney function decline in adults at risk of rapidly progressing ADPKD.

Its boxed warning is about the liver. Tolvaptan can cause serious and potentially fatal liver injury, and acute liver failure requiring transplantation has been reported. ALT, AST and bilirubin are measured before starting, at 2 and 4 weeks, monthly for the first 18 months and every 3 months after that, and Jynarque is available only through a restricted program, the Tolvaptan for ADPKD Shared System REMS, in which prescribers, patients and pharmacies enroll.

The constant water loss is the main burden. The most common reactions are thirst, polyuria, nocturia, pollakiuria and polydipsia, and aquaretic effects were the most common reason patients stopped. Patients drink water whenever they are thirsty, through the day and at night if awake.