Conivaptan hyponatremia

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. 

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... 

Non-peptide vasopressin receptor antagonists include relcovaptan (an antagonist at Vla receptors), lixivaptan, satavaptan, and tolvaptan (V2), and conivaptan (mixed Via/v2)- They have been used in the treatment of hyponatremia. 

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. 

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. 

Conivaptan hydrochloride (1) represents the first FDA-approved agent for the treatment of hyponatremia to modulate electrolyte-free water reabsorption in the renal collecting ducts by antagonizing the action of AVP on vasopressin receptors. As such, 1 represents a novel approach toward the treatment of hyponatremia that could significantly affect the pharmacotherapy of a range of diseases characterized by abnormal water retention. 

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). 

On the basis of these studies, conivaptan HCl (1) has been approved by the FDA for the treatment of hospitalized patients with euvolemic and hypervolemic hyponatremia but is not currently indicated for the treatment of congestive heart failure.28 Due to its aquaretic effects, conivaptan use is contraindicated in patients with hypovolemic... 

A 24-year-old woman with a subependymoma in the fourth ventricle was given conivaptan 25 mg for acute hyponatremia her serum sodium increased by 16 mmol/1 over 8.5 hours without any deterioration in symptoms. 

In 84 adults with hyponatremia (euvole-mic or hypervolemic) who were randomized to a bolus of conivaptan 20 mg followed by a 4-day continuous infusion of 40 mg/day (n = 29) or 80 mg/day (n = 26) compared with placebo (n = 29), the main adverse reactions were infusion site reactions [41 ]. 

Buckley MS, Patel SA, Hatlrup AE, Kazem NH, Jacobs SC, Culver M A. Conivaptan for treatment of hyponatremia in neurologic and neurosurgical adults. Ann Pharmacother 2013 47(9) 1194—200. 

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