Conivaptan

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 . 

Note, if asymptomatic, just restrict fluid to between 1000 and 1200 mL/d +/- high protein diet +/- sodium chloride (NaCl) tablets ° Conivaptan may be utilized in carefully selected patients... 

Conivaptan and demeclocycline have half-lives of 5-10 hours. 

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. 

Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in congestive heart failure. When treatment by volume replacement is not desirable, hyponatremia may result. As for SIADH, water restriction is often the treatment of choice. In patients with congestive heart failure, this approach is often unsuccessful in view of increased thirst and the large number of oral medications being used. In these patients, conivaptan may be particularly useful because it has been found that... 

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... 

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,... 

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... 

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). 

In 142 patients with symptomatic heart failure (New York Heart Association classes III and IV) randomized to double-blind, placebo-controlled short-term treatment with a single intravenous dose of conivaptan 10, 20, or 40 mg, conivaptan significantly reduced pulmonary capillary wedge pressure and right atrial pressure and increased urine output (1). 

In a 5-day, double-blind, randomized, placebo-con-trolled study in 74 patients with euvolemic or hypervolemic hyponatremia, oral conivaptan (40 or 80 mg/day) significantly increased serum sodium concentrations (2). The most common adverse events were headache, hypotension, nausea, constipation, and postural hypotension. 

In 84 patients with euvolemic or hypervolemic hyponatremia randomized to intravenous placebo or conivaptan 20 mg over 30 minutes followed by a 96-hour infusion of either 40 or 80 mg/day, conivaptan increased serum sodium concentrations (3). Infusion site reactions led to withdrawal of one and four of the patients who were given conivaptan 40 and 80 mg/day respectively. 

Intravenous conivaptan had no effects on the electrocardiogram in a randomized, single-blind, placebo- and positive-controlled, parallel-group study, in which an intravenous loading dose of conivaptan of 20 mg was followed by a continuous infusion of 40 or 80 mg/day for 4 days or moxifloxacin 400 mg/day for 4 days (9). 

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... 

Zeltser D, Rosansky S, van Rensburg H, Verbalis JG, Smith N Conivaptan Study Group. Assessment of the efficacy and safety of intravenous conivaptan in euvolemic and hypervolemic hyponatremia. Am J Nephrol 2007 27(5) 447-57. 

Lasseter KC, Dilzer SC, Smith N. Intravenous conivaptan effects on the QTC interval and other electrocardiographic parameters in healthy volunteers. Adv Ther 2007 24(2) 310-8. 

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