化合物信息

Drug Groups

approved; investigational

Description

Conivaptan is a non-peptide inhibitor of antidiuretic hormone (vasopressin). It was approved in 2004 for hyponatremia (low blood sodium levels) caused by syndrome of inappropriate antidiuretic hormone (SIADH). Conivaptan inhibits both isotypes of the vasopressin receptor (V1a and V2).

Indication

For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients.

Pharmacology

Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V_1A and V₂ receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V₂ receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular _1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V₂ antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V_1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality.

Toxicity

Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses.

Affected Organisms

Biotransformation

CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V_1a and V₂ receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively.

Half Life

5 hours

Protein Binding

99%

References

External Links