Vasopressin Excess and Hyponatremia

Nature Clinical Practice Nephrology, 2007

The American Journal of the Medical Sciences, 2007

Hyponatremia, the most common electrolyte disorder in hospitalized patients, has been associated with high rate of mortality among both this population and nonhospitalized patients. This review describes briefly the classification and pathogenesis of hyponatremia, and, in greater detail, the management of hyponatremia with a particular emphasis on the clinical pharmacology of arginine vasopressin (AVP) antagonists. This review includes more in-depth discussion on the pharmacology of conivaptan, an AVP antagonist recently approved by the United States Food and Drug Administration. KEY INDEXING TERMS: Hyponatremia; Management of hyponatremia; AVP-receptor antagonists. [Am J Med Sci 2007;333(2):101-105.]

Hepatology, 2003

for The North American VPA-985 Study Group Hyponatremia in advanced cirrhosis and ascites or congestive heart failure (CHF) is the result of an inappropriate increase in vasopressin secretion, which acts through activation of specific V 2 receptors in the distal renal nephron to increase water reabsorption. This study investigates the efficacy and safety of 3 different doses of the V 2 receptor antagonist, VPA-985, in correcting hyponatremia over a 7-day inpatient study period. Forty-four hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with syndrome of inappropriate antidiuretic hormone (SIADH) were studied on a constant sodium intake, with VPA doses of 25, 125, and 250 mg twice daily or placebo. Serum sodium measurements were repeated after every daily dose, and the next dose withheld for excessive serum sodium rises. Fluid intake was adjusted according to previous 24-hour urinary outputs. Adverse events were based on clinical signs of dehydration or encephalopathy. VPA-985 produced a significant overall aquaretic response compared with placebo, with significant dose related increases in free water clearance (P < .05) and serum sodium (P < .05), without significant changes in orthostatic blood pressure or serum creatinine levels. Five patients (50%) on 250 mg twice daily had to have medication withheld on multiple occasions. End-of-study plasma vasopressin levels increased significantly in the 2 larger dose groups. In conclusion, VPA-985 appears effective and safe in appropriate doses in correcting abnormal renal water handling and hyponatremia in conditions associated with water retention. Higher doses of VPA-985 may produce significant dehydration and will require close monitoring with their use.

International journal of applied & basic medical research, 2012

Arginine vasopressin (AVP) plays an important role in water and sodium homeostasis. It acts via three receptor subtypes-V1a, V1b, and V2-distributed widely throughout the body. Vaptans are nonpeptide vasopressin receptor antagonists (VRA). By property of aquaresis, VRAs offer a novel therapy of water retention. Conivaptan is a V1a/V2 nonselective VRA approved for euvolemic and hypervolemic hyponatremia. Tolvaptan is the first oral VRA. Other potential uses of this new class of drugs include congestive heart failure (CHF), cirrhosis of liver, syndrome of inappropriate secretion of antidiuretic hormone, polycystic kidney disease, and so on. These novel drugs score over diuretics as they are not associated with electrolyte abnormalities. Though much remains to be elucidated before the VRAs are applied clinically, the future holds much promise.

The American Journal of Medicine, 2007

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.

Seminars in nephrology, 2008

The tools available to physicians for the treatment of hyponatremia, the most common of electrolyte disorders, are limited by lack of effectiveness, compliance difficulties, and toxicity problems. For this reason the development of novel oral antagonists of vasopressin provide a new approach to the management of these disorders. Since vasopressin plays a central role in the pathogenesis of most hyponatremic disorders, the inhibition of binding of the hormone to its receptors is likely to provide a most reliable and reproducible response leading to increases in free water excretion. This article reviews many of the studies that have been undertaken with this new class of agents, both in hypovolemic and hypervolemic settings.

Annals of neurology, 2006

Hyponatremia is frequently associated with neurological disease, neurosurgical procedures, and use of psychoactive drugs. Arginine vasopressin (AVP), or antidiuretic hormone, is the principal physiological regulator of water and electrolyte balance, and disruption of the normal AVP response to osmotic stimuli is a common cause of dilutional hyponatremia in neurological disorders. The hyponatremia-induced shift in water from the extracellular to the intracellular compartment can lead to cerebral edema and serious neurological complications, especially if the decrease in serum sodium concentration ([Na ؉ ]) is large or rapid. Overly rapid correction of the serum [Na ؉ ] may lead to osmotic demyelination and irreversible brain injury. Fluid restriction is considered first-line treatment and pharmacological agents currently used in the treatment of hyponatremia are limited by inconsistent response and adverse side effects. AVP receptor antagonists represent a new approach to the treatment of hyponatremia by blocking tubular reabsorption of water by binding to V 2 receptors in the renal collecting ducts, resulting in aquaresis. Initial clinical experience with AVP receptor antagonists for hyponatremia has shown that these agents augment free water clearance, decrease urine osmolality, and correct serum [Na ؉ ] and serum osmolality. Controlled clinical trials now underway will help elucidate the role of AVP receptor antagonism in the treatment of hyponatremia.

The American Journal of Cardiology, 2006

Hyponatremia is common and is associated with a poor prognosis. Traditional management with fluid restriction is difficult to maintain, and it is often ineffective. The objective of this study was to determine the effect of tolvaptan versus fluid restriction on serum sodium concentration. The study was a prospective, multicenter, randomized, active-controlled, open-label trial. Twenty-eight hospitalized subjects with serum sodium <135 mmol/L were enrolled in the study. After a 2-day run-in period, subjects were randomized 2:1 to tolvaptan alone (n ‫؍‬ 17) or fluid restriction (1,200 ml/day) plus placebo (n ‫؍‬ 11). Oral tolvaptan was started at 10 mg/day and increased to 60 mg/day as needed. Treatment was continued for up to 27 days, and follow-up continued for up to 65 days. The primary end point was the normalization of serum sodium, defined as >135 mmol/L or a >10% increase from baseline. At the last inpatient visit, serum sodium had increased by 5.7 ؎ 3.2 mmol/L in the tolvaptan group and 1.0 ؎ 4.7 mmol/L in the fluid restriction group (p ‫؍‬ 0.0065). No differences in adverse events were observed between the groups. In conclusion, tolvaptan appears to be more effective than fluid restriction at correcting hyponatremia in hospitalized subjects, without an increase in adverse events.

2007

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists. © 2007 Elsevier Inc. All rights reserved.

Although hyponatremia is a common, usually mild, and relatively asymptomatic disorder of electrolytes, acute severe hyponatremia can cause substantial morbidity and mortality, particularly in patients with concomitant disease. In addition, overly rapid correction of chronic hyponatremia can cause severe neurologic deficits and death, and optimal treatment strategies for such cases are not established. An expert panel assessed the potential contributions of aquaretic nonpeptide small-molecule arginine vasopressin receptor (AVPR) antagonists to hyponatremia therapies. This review presents their conclusions, including identification of appropriate treatment populations and possible future indications for aquaretic AVPR antagonists.