Hyponatremia
Vasopressin Receptor Antagonists for the Treatment of Hyponatremia David I Ortiz-Melo, MD,1
Arthur Greenberg, MD2 and Ruediger W Lehrich, MD3
1. Nephrology Fellow; 2. Professor of Medicine; 3. Assistant Professor of Medicine, Division of Nephrology, Department of Medicine, Duke University Medical Center
Abstract
Hyponatremia is the most frequent electrolyte disturbance in hospitalized patients, and a powerful predictor of poor outcome, especially in patients with chronic heart failure and cirrhosis. Hyponatremia is almost always the result of persistent antidiuretic hormone secretion in the absence of an osmotic stimulus. The resultant inability to excrete electrolyte-free water leads to water retention and subsequently to hyponatremia. Conventional treatment of euvolemic and hypervolemic hyponatremia consists mainly of electrolyte-free water restriction and hypertonic saline. More recently, vasopressin receptor antagonists, or vaptans, have been introduced for the treatment of hyponatremia. These agents have the unique characteristic of inducing electrolyte-free water clearance without a solute diuresis (aquaresis). In this article we discuss evidence for the use of vaptans in patients with hyponatremia. A brief history of the vaptans and their therapeutic indications and pharmacologic characteristics are also provided.
Keywords
Hyponatremia, vasopressin receptor antagonists, antidiuretic hormone, syndrome of inappropriate secretion of antidiuretic hormone, conivaptan, tolvaptan
Disclosure: David I Ortiz-Melo, MD, and Ruediger W Lehrich, MD, have no conflicts of interest to declare. Arthur Greenberg, MD, is a consultant for Astellas and serves on the advisory board, speakers bureau, and provides research support for Otsuka. Received: September 1, 2011 Accepted: October 14, 2011 Citation: US Nephrology, 2011;6(2):100–5 Correspondence: Ruediger W Lehrich, MD, Division of Nephrology, Department of Medicine, Duke University Medical Center, 2424 Erwin Road, Suite 605, Durham, NC 27705. E:
ruediger.lehrich@duke.edu
Hyponatremia is the most frequent electrolyte disturbance in hospitalized patients.1
Whether the cause of death in these patients is directly related to the electrolyte abnormality itself or a reflection of advanced underlying disease is still an area of debate.8,9
The severity of accompanying symptoms varies with the severity of the hyponatremia and the speed at which the serum sodium falls. Typically, patients with mild hyponatremia with serum sodium concentrations between 125 and 130 mmol/l have minimal or no symptoms. Patients with more severe hyponatremia with serum sodium concentrations below 125 mmol/l can present with ataxia, headaches, and lethargy. If hyponatremia worsens it can culminate in seizures, coma, cerebral edema, brainstem herniation, and death. Symptoms and outcome are worse if the hyponatremia has developed abruptly. Hyponatremia is a common finding in patients with advanced congestive heart failure (CHF), liver cirrhosis, severe volume depletion, and is the hallmark of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Hyponatremia is a powerful predictor of poor outcome in patients with CHF and liver cirrhosis. Moreover, low serum sodium has been associated with prolonged length of stay and increased mortality in hospitalized patients in general.2–7
60 mOsm/l can facilitate the clearance of 10–15 l of water intake per day. Together with changes in water ingestion promoted by changes in thirst, this wide range in urine concentration and water clearance maintains a stable serum osmolarity of 280–290 mOsm/l. Antidiuretic hormone (ADH) regulates urinary concentration and dilution. Circulating ADH causes the insertion of aquaporin-2 channels into the apical membrane of collecting duct epithelial cells, thereby increasing the permeability of the collecting duct to water and effecting water reabsorption. If serum osmolarity is high, ADH plasma levels increase to facilitate free water retention. This preserves serum osmolarity in a favorable range. As serum osmolarity falls, ADH plasma levels become undetectable and urinary electrolyte-free water clearance is maximal. Hyponatremia is almost always the result of persistent ADH secretion despite an absent osmotic stimulus. The inability to excrete electrolyte-free water leads to water retention and subsequently to hyponatremia.10–12
Urine osmolarity can vary remarkably to allow for variations in free water intake. If electrolyte-free water intake is minimal, a urine concentration of 1200 mOsm/l can be reached to maintain serum osmolarity within the normal range. If intake is excessive, a maximal urinary dilution of around
100
Conventional Treatment of Hyponatremia It is a useful approach to classify patients with hyponatremia according to their extracellular fluid volume. Patients with hyponatremia are hypovolemic, euvolemic, or hypervolemic. Treatment of hyponatremia is guided by the respective volume status.
Hypovolemic hyponatremia is characterized by hypotension and other hallmarks of decreased circulatory volume. In these patients,
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