Vasopressin Antagonists

Posted by • June 5th, 2015

A new review in the Disorders of Fluids and Electrolytes series summarizes the salient discoveries that culminated in the development of vasopressin antagonists, focusing on their actions, side effects, emerging safety concerns, and important gaps in data. The review also considers how and when to use these agents.

Ample evidence is available to implicate vasopressin, a small polypeptide that is synthesized in the hypothalamus and secreted from the posterior pituitary, in the pathogenesis of many hyponatremic disorders. As the most common electrolyte disorder, hyponatremia is consistently associated with increased mortality and morbidity. The treatment of hyponatremia has been plagued by a paucity of controlled studies and by a lack of reliable and safe approaches. Therefore, the regulatory approval of vasopressin antagonists represents a milestone in the field.

Clinical Pearls

Describe the vasopressin receptors, and the mechanism of action of vasopressin antagonists.

The V1A receptor is found in liver, smooth muscle, myocardium, brain, and platelets; the V1B receptor is involved in the secretion of corticotropin in the anterior pituitary. The V2 receptor is located primarily in the basolateral membrane of collecting-duct cells. The binding of the hormone to the V2 receptor on the basolateral membrane of the principal cell of the collecting duct activates adenylyl cyclase and generates cyclic AMP (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates protein kinase A, which phosphorylates aquaporin water channels (AQP2) and induces them to relocate to the luminal membrane. This promotes the reabsorption of water from tubular fluid to blood, rendering the tubular fluid more concentrated (increased osmolality). In the presence of a vasopressin antagonist, the signaling pathway is not activated. As a consequence, the water permeability of the cell remains high and water is not reabsorbed, causing the excretion of dilute urine (decreased osmolality) and thereby increasing the level of sodium in the blood compartment.

Figure 1. Binding of Vasopressin to Its Receptor and Location of Antagonist.

Figure 2. Cellular Effects of Vasopressin and Consequences of Vasopressin Antagonism.

What vasopressin antagonists are approved for use in the United States?

Tolvaptan and conivaptan (with the latter blocking both the V1A and V2 receptors) have garnered approval for the treatment of euvolemic and hypervolemic hyponatremia in the United States. Conivaptan and tolvaptan have differing affinities for the vasopressin receptor. The relative inhibition of the two receptors (V2:V1 selectivity ratio) is much greater with tolvaptan (by a factor of 29) than with conivaptan (by a factor of 5.7). Thus, conivaptan is a nonselective vasopressin inhibitor, whereas tolvaptan is a more selective V2 inhibitor. Each of the drugs has a half-life that ranges from 6 to 10 hours and has activity that peaks several hours after administration. Both increase urine flow and the excretion of electrolyte-free water, without substantial changes in sodium or potassium excretion, leading to their designation as aquaretic agents.

Table 2. Inhibitory Constants and Pharmacokinetics of Two Vasopressin Antagonists.

Morning Report Questions

Q: When should vasopressin antagonists be avoided?

A: Dependence on the excretion of free water makes the response to vasopressin antagonists too slow to benefit patients with hyponatremia who have severe cerebral symptoms. Such patients require a prompt decrease in the volume of brain water, which is best achieved with hypertonic saline. Similarly, patients with hypovolemic hyponatremia require volume repletion to halt nonosmotic release of vasopressin. Furthermore, V1A-receptor antagonists can cause hypotension in such patients. Neither drug is effective in patients with advanced chronic kidney disease (stage 4 or 5).

Q: Is there consensus regarding the use of vasopressin antagonists?

A: Despite the paucity of data, panels have put forth recommendations for the treatment of hyponatremia. Of the available guidelines, two have garnered the most attention. The first set of guidelines was prepared by an expert panel that was supported by the manufacturer of tolvaptan; the second set, the European Clinical Practice Guideline, was developed by members of three medical societies with an interest in hyponatremia without support from the pharmaceutical industry. The two panels have divergent recommendations regarding the use of vasopressin antagonists. The European guidelines do not recommend the use of vasopressin antagonists in patients with euvolemia who have SIADH [syndrome of inappropriate secretion of antidiuretic hormone] and recommend against their use in patients with heart failure, in whom the need for water restriction and the wider use of urea are recommended. In contrast, the expert panel recommends that vasopressin antagonists be used in patients with SIADH when water restriction fails and states that vasopressin antagonists are “a viable option along with loop diuretics” in patients with heart failure. The European panelists express concern regarding the neurologic consequences of overcorrection, the risk of hepatotoxicity, and the lack of data supporting a survival benefit. The recommendations of the expert panel also have merit, particularly since none of the alternative approaches have been subjected to the rigors of a regulatory process requiring randomized, controlled trials nor have they received the approval of any regulatory agency.

Table 3. Recommendations for the Use of Vaptans in the Treatment of Hyponatremia.

Comments are closed.