Conivaptan: A Dual Receptor Vasopressin V_1a/V₂ Antagonist

Abstract

Several fluid retentive states such as heart failure, cirrhosis of the liver, and syndrome of inappropriate antidiuretic hormone secretion are associated with inappropriate elevation in plasma levels of arginine vasopressin (AVP), a neuropeptide that is secreted by the hypothalamus and plays a critical role in the regulation of serum osmolality and in circulatory homeostasis. The actions of AVP are mediated by three receptor subtypes V 1a , V 2 , and V 1b . The V 1a receptor regulates vasodilation and cellular hypertrophy while the V 2 receptor regulates free water excretion. The V 1b receptor regulates adrenocorticotropin hormone release. Conivaptan is a nonpeptide dual V 1a /V 2 AVP receptor antagonist. It binds with high affinity, competitively, and reversibly to the V 1a /V 2 receptor subtypes; its antagonistic effect is concentration dependent. It inhibits CYP3A4 liver enzyme and elevates plasma levels of other drugs metabolized by this enzyme. It is approved only for short-term intravenous use. Infusion site reaction is the most common reason for discontinuation of the drug. In animals conivaptan increased urine volume and free water clearance. In heart failure models it improved hemodynamic parameters and free water excretion. Conivaptan has been shown to correct hyponatremia in euvolemic or hypervolemic patients. Its efficacy

Use of conivaptan to allow aggressive hydration to prevent tumor lysis syndrome in a pediatric patient with large-cell lymphoma and SIADH

“…Drugs inhibiting the P450 system can increase conivaptan levels. Similarly, conivaptan can increase serum levels of medications metabolized via the P450 system [9]. Although formal pharmacodynamics of chemotherapy agents was not performed in our study, the patient did not have excessive or unexpected side effects from the standard-dose chemotherapy.…”

“…Three oral agents, lixivaptan, tolvaptan, and satavaptan, are selective V2 receptor blockers. However, only conivaptan is available in the United States [9]. By blocking V2 receptors in the renal collecting duct, these agents promote aquaresis without excreting more sodium in the urine.…”

“…Approximately 1% of the IV dose was excreted in urine as intact conivaptan over the first 24 h after dosing. One should apply extra caution when administering conivaptan to patients with impaired hepatic or renal function [9].…”

Hyponatriämie

“…Der kombinierte V1a/V2-Antagonist Conivaptan wurde intravenös in einer Dosierung von 40-80 mg zur Korrektur der akuten Hyponatriämie bei Patienten mit einem erhöhten extrazellulären Volumen bei Herzinsuffizienz eingesetzt [17]. Conivaptan ist ein potenter Hemmer von CYP3A4 und interagiert darüber mit einer Reihe von Arzneimitteln.…”

Hyponatremia: Clinical Associations, Prognosis, and Treatment in Cirrhosis

“…[82][83][84] In general, conivaptan was well tolerated with the most common adverse reaction being infusion-site reactions. 82,85 Conivaptan has been assessed in randomized double-blinded placebo-controlled clinical trials, only 1 of which used IV conivaptan. 83,[86][87][88] Zeltser and associates used a small cohort of 84 patients with euvolemic or hypervolemic hyponatremia and randomly assigned them to 40 mg/d, 80 mg/d of IV conivaptan, or placebo, with outcomes measures including net increase in sodium levels and time from initial dose to ≥ 4 mEq/L increase.…”