What is the role of vasopressin receptor antagonists in the treatment of acute syndrome of inappropriate antidiuretic hormone secretion (SIADH)?

Updated: Aug 16, 2019
  • Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Inhibition of the AVP V2 receptor reduces the number of aquaporin-2 water channels in the renal collecting duct and decreases the water permeability of the collecting duct. Collectively, agents that competitively block ADH action and increase water excretion are called aquaretics, and they are useful in the treatment of the hyponatremia in SIADH. The term "vaptan" has been coined to officially name all the members of this new class of drugs. [5]

Two aquaretics are currently approved by the US Food and Drug Administration (FDA). Conivaptan is a parenteral nonpeptide dual AVP V1a- and V2-receptor antagonist, which is approved for use in hospitalized patients with euvolemic (dilutional) and hypervolemic hyponatremia. The drug is given as a 20-mg loading dose followed by a continuous infusion or as intermittent boluses, but it should not be used for more than 4 days. The pivotal studies in euvolemic hyponatremia showed that compared with fluid restriction alone, conivaptan together with a 2 L fluid restriction over 4 days increased serum Na by 6 mEq/L, with a median increase of 4 mEq/L by 23 hours. [34]

Tolvaptan is a selective oral V2 receptor antagonist also approved for use in hospitalized patients for hypervolemia and euvolemic hyponatremia. [35] The drug is started at 15 mg once daily and titrated up to 60 mg daily as required, and it is best to avoid fluid restriction during the dose-finding phase. In the pivotal studies, which included patients with heart failure, cirrhosis, and SIADH, tolvaptan compared with fluid restriction alone increased serum Na by 8 mEq/L over 30 days, although with withdrawal of the drug, serum Na+ falls back to that seen in the placebo group. [36]

This is a useful drug to consider in a patient in whom serum Na+ does not rise by 2 mEq in the first 24 hrs after a 1000-mL fluid restriction. Once the drug is initiated, the patient can be discharged in 24-48 hours if neurological symptoms have resolved or the patient was asymptomatic at presentation. If the underlying cause of SIADH has resolved, the drug can be withdrawn after 2-4 weeks, while carefully monitoring serum Na+ daily for the next 5 days. If the serum Na+ falls again and if is less than 125 for more than 48 hours, the patient may need to be admitted again before reinitiating tolvaptan. Tolvaptan can also be considered for long-term therapy of chronic hyponatremia. [37]

Results of a study by Morris et al suggest that low baseline serum Na+ and serum urea nitrogen (SUN) values can identify patients with SIADH who are likely to experience rapid correction of hyponatremia with tolvaptan, and who are thus at risk of overcorrection. In their study, which included 28 patients with SIADH treated with tolvaptan, the rate of increase in serum Na+ concentration was significantly greater (mean 24-hour increase of 15.4 mEq/L) in patients with baseline serum Na+ of 121 mEq/L or less and baseline SUN of 10 mg/dL or less, than it was in patients with higher baseline Na and SUN concentrations.

The vaptans can have a profound effect on serum Na and they should be used by physicians experienced in the management of hyponatremia. These drugs should be avoided in hypovolemic hyponatremia. The vaptans are more likely to be effective compared with fluid restriction alone in patients in whom the sum of urinary potassium and Na+ concentration is greater than the plasma concentration. They offer the benefit of prompt correction of serum Na+, producing water excretion without electrolyte excretion and eliminating the need for fluid restriction. The primary risk of using these drugs is an excessively rapid rate of correction of the serum sodium concentration.

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