Conivaptan, sold under the brand name Vaprisol, is a non-peptide inhibitor of the receptor for anti-diuretic hormone, also called vasopressin. It was approved in 2004 for hyponatremia (low blood sodium levels). Additionally, conivaptan is used for the treatment of syndrome of inappropriate antidiuretic hormone secretion.
Conivaptan inhibits two of the three subtypes of the vasopressin receptor (V<sub>1A</sub> and V<sub>2</sub>). Effectively, it causes iatrogenic nephrogenic diabetes insipidus.
Conivaptan has not been approved by the US Food and Drug Administration (FDA) for the treatment of decompensated congestive heart failure. However, in theory, vasopressin receptor antagonism would be particularly useful in this setting, and an initial study shows that it has some promise.
Medical uses
Conivaptan is most commonly used in the hospital in cases of euvolemic and hypervolemic hyponatremia, conditions where the sodium level in the blood falls significantly below normal. In the United States, hyponatremia affects about four percent of hospitalized patients. Although many patients do not show symptoms, extreme cases may result in brain swelling, respiratory arrest and even death. Hypervolemic hyponatremia specifically is when the body’s serum sodium levels fall below the total body water increase, which results in edema. This is associated with congestive heart failure, liver disease and kidney failure.
Pharmacology
Conivaptan hydrochloride is an arginine vasopressin (AVP) receptor antagonist with affinity for human V<sub>1A</sub> and V<sub>2</sub> receptors in the nanomolar range in vitro. AVP levels in blood are crucial for water and electrolyte regulation and balance. V<sub>2</sub> receptors maintain plasma osmolality and are coupled to aquaporin channels in the collecting ducts of kidneys where they regulate AVP levels.
Conivaptan hydrochloride functions by antagonizing V<sub>2</sub> receptors in the renal collecting ducts and thus causing aquaresis or water secretion. Typical pharmacodynamic effects of the drug are an increase in net fluid loss, increase in urine output, and decrease in the osmolality of urine.
Conivaptan inhibits its own metabolism in the body, displaying non-linear pharmacokinetics. About 99% of conivaptan found is bound to human plasma proteins over the range of 10 ng/mL to 1000 ng/mL. The mean half-life of the drug is 5 hours and mean clearance is 15.2 L/hr.
Chemistry
Conivaptan hydrochloride is an off-white or a pale yellow power with a solubility of 0.25 mg/mL in water at 23 °C. The injectable formulation consists of 20 mg conivaptan hydrochloride, 0.4 g ethanol, 1.2 g propylene glycol and water.
On 2 March 2007, vaprisol also gained FDA approval for the treatment of hypervolemia hyponatremia. On 22 October 2008, Vaprisol further gained approval as a 5% Dextrose premixed formulation for the treatment of hyponatremia. In 2014 Cumberland pharmaceuticals bought Vaprisol from Astellas and took full responsibility of all development and marketing of the drug.
Cumberland Pharmaceuticals is a pharmaceutical company based in Nashville, Tennessee. In addition to Vaprisol, Cumberland produces Acetadote, Caldolor, Kristalose, Omeclamox, and Ethyol. Hepatoren, Boxban, Vasculan, and currently in phase II clinical trials. Protaban, Methotrexate, and Totect are waiting for pre-approval.