Conivaptan antagonists

Conivaptan Antagonist at Via and V2 ADH receptors Reduces water reabsorption, increases plasma Na concentration Hyponatremia IV Only Toxicity Infusion site reactions... 

Conivaptan Antagonist of vasopressin (and V2) receptors Vasodilation Potential use in hypertension and heart failure hyponatremia... 

Conivaptan Antagonist of vasopressin Vla and V2 receptors Reduced renal excretion of water in conditions associated with increased vasopressin Hyponatremia in hospitalized patients IV infusion Toxicity Infusion site reactions... 

Several nonpeptidic, orally active vasopressin receptor antagonists have been developed. The dual V1A/V2R antagonist conivaptan is used in the treatment of hyponatraemia and could also become useful for diseases such as congestive heart failure, in which increased peripheral resistance and dilutional hyponatremia both are present [4]. Side effects of conivaptan include headache, injection site reactions, vomiting, diarrhoea, constipation and thirst. 

Several selective V2R antagonists have also been developed (tolvaptan, lixivaptan, OPC-31260, Satavaptan, RWJ-351647). These substances, together with conivaptan, are also known as aquaretic agents . 

Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan is a pharmacologic antagonist at Via and V2 receptors. Both lithium and demeclocycline appear to reduce the formation of cyclic adenosine monophosphate (cAMP) in response to ADH. 

Antidiuretic hormone antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, or in the hospital when large quantities of intravenous fluid are needed for other purposes. Lithium carbonate has been used to treat this syndrome, but the response is unpredictable. Demeclocycline, in dosages of 600-1200 mg/d, yields a more predictable result and is less toxic. Appropriate plasma levels (2 mcg/mL) should be maintained by monitoring. Unlike demeclocycline, conivaptan is administered by IV injection, so it is not suitable for chronic use in outpatients. Lixivaptan and tolvaptan should soon be available for oral use. 

A group of nonpeptide antagonists of vasopressin receptors is being investigated for use in patients with hyponatremia or acute heart failure, which is often associated with elevated concentrations of vasopressin. Conivaptan has high affinity for both Vla and V2 receptors. Tolvaptan has a 30-fold higher affinity for V2 than for Vi receptors. In several clinical trials,... 

Vasopressin receptor antagonists, such as relcovaptan (an antagonist at Vla receptors), lixivaptan and tolvaptan (V2), and conivaptan (mixed V a/V2), are also under development (1). 

Udelson JE, Smith WB, Hendrix GH, Painchaud CA, Ghazzi M, Thomas I, Ghah JK, Selaru P, Chanoine F, Pressler ML, Konstam MA. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001 104(20) 2417-23. 

Ghali JK, Koren MJ, Taylor JR, Brooks-Asplund E, Fan K, Long WA, Smith N. Efficacy and safety of oral conivaptan a V1A/v2 vasopressin receptor antagonist, assessed in a... 

As Of 2009, conivaptan HCl (1) is one of three vasopressin receptor antagonists approved for use in the treatment of hyponatremia worldwide. The U.S. approval of 1 was preceded by the 2006 approval of mozavaptan hydrochloride (2) in Japan. In 2009, tolvaptan (3) joined 1 as an FDA-approved agent for the treatment of hyponatremia. In this chapter, the pharmacological profile and synthesis of conivaptan hydrochloride (1) is examined in detail. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

Conivaptan HCl (1) is a potent dual Vla and V2 vasopressin receptor antagonist that increases water excretion without significant electrolyte depletion. 

VASOPRESSIN RECEPTOR ANTAGONISTS [SEDA-34, 713 SEDA-35, 797] Conivaptan... 

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