New horizons in the pharmacologic approach to hyponatremia: The V2 receptor antagonists
Abstract
This article provides an overview of the developing niche for vasopressin 2 receptor antagonists (“vaptans”) in the management of hyponatremia in clinical practice. Specific areas of focus include the physiological and clinical rationale for use of this class of medications (including advantages over older and less specific therapeutic modalities), the practical limitations to the use of these new drugs (including issues of tolerability, toxicity, risk, and cost), and the unanswered question of the extent to which correcting hyponatremia will improve clinical outcomes. Journal of Hospital Medicine 2010;5:S27–S32. © 2010 Society of Hospital Medicine.
Under normal circumstances, there is a balance between water intake and water excretion such that plasma osmolality and the serum sodium (Na+) concentration remain relatively constant. The principal mechanism responsible for prevention of hyponatremia and hyposmolality is renal water excretion. In all hyponatremic patients, water intake exceeds renal water excretion. Excretion of water by the kidney is dependent on 3 factors. First, there must be adequate delivery of filtrate to the tip of the loop of Henle. Second, solute absorption in the ascending limb and the distal nephron must be preserved so that the tubular fluid will be diluted. Lastly, arginine vasopressin (AVP) levels must be low in the plasma. Of these 3 requirements for water excretion, the one which is most important in the genesis of hyponatremia is the failure to maximally suppress AVP levels. Given the central role of AVP in limiting renal water excretion, AVP receptor antagonists represent a physiologic and rational method to increase renal water excretion. AVP is synthesized in the supraoptic and paraventricular nucleus of the hypothalamus and then stored in the neurohypophysis (reviewed in the article Diagnostic Approach and Management of Inpatient Hyponatremia in this supplement). The release of AVP is exquisitely sensitive to changes in plasma osmolality. AVP is not detectable in the plasma at an osmolality below approximately 280 mOsm/kg but increases in a nearly linear fashion beginning with as little as a 2% to 3% increase in osmolality above this value. The extreme sensitivity of this system allows for plasma osmolality to be maintained within a narrow range.AVP in Regulation of Plasma Osmolality
A second major determinant of AVP release is the effective arterial blood volume. While AVP levels are very sensitive to plasma osmolality, small changes of 10% in blood pressure or blood volume have no effect on AVP levels. However, once decreases in volume or pressure exceed this value, baroreceptor‐mediated signals provide persistent stimuli for AVP secretion. Baroreceptor‐mediated AVP release will continue even when plasma osmolality falls below 280 mOsm/kg. Teleologically, this system can be viewed as an emergency mechanism to defend blood pressure. Thus, small decreases in blood volume and blood pressure will cause the body to retain NaCl which will raise osmolality and lead to water retention. However, if NaCl is not available and if blood pressure and volume are becoming dangerously low (down 10%), the body behaves as if defense of blood pressure is more important than defense of osmolality, and AVP is secreted.1 The specific compartment whose volume is sensed in order to determine AVP secretion in this setting is the effective arterial volume. This overriding effect of volume explains the persistence of high AVP levels in hyponatremic patients with conditions such as heart failure and cirrhosis.
Other stimuli for the release of AVP include pain, nausea, and hypoxia. Inappropriate release of AVP can occur with a variety of central nervous system and pulmonary diseases as well as with drugs, particularly those that act within the central nervous system.2 Certain tumors can synthesize and release AVP.
AVP exerts its effects on cells through 3 receptors (Table 1). The V1A receptor is expressed in a variety of tissues but is primarily found on vascular smooth muscle cells. Stimulation of this receptor results in vasoconstriction, platelet aggregation, inotropic stimulation and myocardial protein synthesis. The V1B receptor is expressed in cells of the anterior pituitary and throughout the brain. Stimulation of this receptor results in release of adrenocorticotropin stimulating hormone (ACTH). Stimulation of the V1A and V1B receptors activate phospholipase C leading to increases in inositol trisphosphate and diacylglycerol with secondary increases in cell calcium and activation of protein kinase C.
The V2 receptor is found on the basolateral surface of the renal collecting duct and vascular endothelium where it mediates the antidiuretic effects of AVP and stimulates the release of von Willebrand factor respectively. Unlike the V1A and V1B receptors, binding of AVP to the V2 receptor activates the GS‐coupled adenyl cyclase system causing increased intracellular levels of cyclic adenosine monophosphate (cAMP). In the kidney, generation of cAMP stimulates protein kinase A which then phosphorylates preformed aquaporin‐2 water channels causing trafficking and insertion of the channels into the luminal membrane of the tubular cells.3 The insertion of the aquaporin‐2 protein renders the collecting duct selectively permeable to water, which is then reabsorbed from the tubular lumen into the blood driven by the osmotic driving force of the hypertonic interstitium. In the absence of AVP, aquaporin membrane insertion and apical membrane water permeability are dramatically reduced.
Physiologic Rationale for Use of AVP Antagonists
AVP antagonists block the V2 receptor located on the basolateral surface of the collecting duct thereby antagonizing the ability of AVP to cause insertion of the aquaporin‐2 water channels into the luminal membrane. The increase in urine output is similar in quantity to diuretics but differs in content. V2 receptor antagonists increase water excretion with little to no change in urinary electrolytes. As a result, lowering of the serum K+ level, metabolic alkalosis, and increases in the serum creatinine and blood urea nitrogen concentration are avoided in contrast to diuretics such as furosemide and hydrochlorothiazide. In addition, orthostatic hypotension and activation of neurohumoral effectors such as angiotensin II, circulating catecholamines, and aldosterone are not features of V2 receptor blockade. These differences have lead to V2 receptor antagonists being characterized as aquaretic agents so as to distinguish them from diuretics.
The physiologic rationale for use of V2 receptor antagonists is best exemplified by considering the relationship between the serum Na+ concentration and the total body content of Na+, K+, and water approximated by the equation:
