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Tolvaptan, A Selective Oral Vasopressin V2-receptor Antagonist for Hyponatremia

« Back to Volume 23, Issue 2, June 2007 - Table of Contents

Hyponatremia due to increased secretion of antidiuretic hormone (ADH) may be due to the syndrome of inappropriate secretion of ADH (SIADH) related to an insult to the central nervous secretion (or rarely in children—ectopic secretion of ADH), heart failure, or hepatic cirrhosis. Pathogenetically, it is the result of excessive and inappropriate reabsorption of free water in the renal collecting ducts in response to ADH signaling through the V2 receptor (OMIM 300538, chromosome Xq28), a G-protein coupled receptor that stimulates adenylyl cyclase and generation of cyclic AMP. ADH is a cyclical 9 amino acid peptide derived from a larger parent protein that also contains within its structure neurophysin—a carrier of ADH—and a glycoprotein. Parenterally administered non-peptide antagonists to ADH have been developed to block the action of ADH in the renal collecting tubule by binding to the V2 receptor and increasing the urinary excretion of free water (Figure 1).1 In a randomized, double-blind, placebo-controlled, out-patient study in which fluid intake was not monitored, the investigators ascertained the efficacy and safety of the oral administration of one such agent, tolvaptan, in 171 adults (>18 years of age) with hyponatremia (120-134 mEq/L), 91 of whom had SIADH. Compared to placebo, tolvaptan rapidly and safely increased and maintained serum sodium concentrations into the low normal range over a 30-day interval of treatment (Figure 2). One week after discontinuation of tolvaptan, serum sodium levels declined to values seen in the group that received the placebo. As anticipated, tolvaptan increased urine output initially. The drug was well tolerated. The authors concluded that orally administered tolvaptan is a clinically effective V2 -receptor antagonist in adults with hyponatremia of diverse etiology.

Figure 1.
Figure 1. Structure of the Oral Vasopressin-Receptor Antagonists Conivaptan and Tolvaptan. Reprinted with permission from: Hays RM. Vasopressin antagonists -progress and promise. N Engl J Med. 2006;355:2146-8. Copyright © MMS. 2006. All rights reserved.
Figure 2.
Figure 2. Mean serum sodium concentrations attained with tolvaptan (circles) and placebo (squares). Reprinted with permission from: Schrier RW, et al. N Engl J Med. 2006;355:2099-112. Copyright © MMS. 2006. All rights reserved.

Schrier RW, Gross P, Gheorghiade M, et al. Tolvaptan, a selective oral vasopressin V 2-receptor antagonist, for hyponatremia. N Engl J Med. 2006;355:2099-112.

Editor’s Comment

Management of SIADH in children is primarily accomplished by fluid restriction. In critical situations slow intravenous infusion of 3% saline may be considered in an amount calculated to increase the serum sodium concentration to values that ameliorate symptoms (approximately 125 mEq/L) while carefully monitoring urine output.2 Very rapid increase in serum sodium concentrations may lead to central pontine myelinolysis. The non-peptide antagonists of the V2 receptor have not been examined or approved for use in children as yet, but would appear to be promising therapeutic agents that have been termed “aquaretics.” In addition to the renal V2 receptor, there are V1a and V1b receptors that mediate the vasoconstrictive and adrenocorticotropin-releasing properties of ADH.

Allen W. Root, MD

References - (linked to Pubmed Links)

  1. Hays RM. Vasopressin antagonists -progress and promise. N Engl J Med. 2006;355:2146-8.
  2. Robertson GL. Clinical disorders of the posterior pituitary. In Pescovitz PH, Eugster EA, eds. Pediatric Endocrinology: Mechanisms, Manifestations, and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:90-107.

 

 

 

« Back to Volume 23, Issue 2, June 2007 - Table of Contents


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