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The Role of V2 Receptor Antagonists in the Treatment of Hyponatremia

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The Role of V2 Receptor Antagonists in the Treatment of Hyponatremia ISSN 1738-5997 (Print) • ISSN 2092-9935 (Online) Review Electrolyte Blood Press 11:1-8, 2013 http://dx.doi.org/10.5049/EBP.2013.11.1.1 The Role of V2 Receptor Antagonists in the Treatment of Hyponatremia Biff F. Palmer, M.D. Department of Internal Medicine University of Texas Southwestern Medical Center Received: Feb 12, 2013 Accepted: Feb 18, 2013 Corresponding Author: Biff F. Palmer, M.D. Department of Internal Medicine University of Texas Southwestern Medical Center 5323 Harry Hines Blvd. Dallas, Texas 75390 Tel: +1-214-648-7848, FAX: +1-214-648-2071 E-mail: [email protected] This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License(http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction AVP in Regulation of Plasma Osmolality Under normal circumstances, there is a balance bet- AVP is synthesized in the supraoptic and paraventri- ween water intake and water excretion such that plasma cular nucleus of the hypothalamus and then stored in osmolality and the serum sodium (Na+) concentration the neurohypophysis. The release of AVP is exquisitely remain relatively constant. The principal mechanism sensitive to changes in plasma osmolality. AVP is not de- responsible for prevention of hyponatremia and hypo- tectable in the plasma at an osmolality below approx- smolality is renal water excretion. In all hyponatremic imately 280 mOsm/kg but increases in a nearly linear patients, water intake exceeds renal water excretion. fashion beginning with as little as a 2-3% increase in os- Excretion of water by the kidney is dependent on three molality above this value. The extreme sensitivity of this factors. First, there must be adequate delivery of filtrate system allows for plasma osmolality to be maintained to the tip of the loop of Henle. Second, solute absorption within a narrow range. in the ascending limb and the distal nephron must be A second major determinant of AVP release is the effec- preserved so that the tubular fluid will be diluted. Lastly, tive arterial blood volume. While AVP levels are very sen- arginine vasopressin (AVP) levels must be low in the plas- sitive to plasma osmolality, small changes of <10% in ma. Of these three requirements for water excretion, the blood pressure or blood volume have no effect on AVP one which is most important in the genesis of hypona- levels. However, once decreases in volume or pressure tremia is the failure to maximally suppress AVP levels. exceed this value, baroreceptor-mediated signals provide Given the central role of AVP in limiting renal water excre- persistent stimuli for AVP secretion. Baroreceptor-medi- tion, AVP receptor antagonists represent a physiologic ated AVP release will continue even when plasma osmo- and rational method to increase renal water excretion. lality falls below 280 mOsm/kg. Teleologically, this sys- Copyright © 2013 The Korean Society of Electrolyte Metabolisme 2 Biff F. Palmer • The Role of V2 Receptor Antagonists in the Treatment of Hyponatremia tem can be viewed as an emergency mechanism to defend increased intracellular levels of cAMP. In the kidney, gen- blood pressure. Thus, small decreases in blood volume eration of cAMP stimulates protein kinase A which then and blood pressure will cause the body to retain NaCl phosphorylates preformed aquaporin-2 water channels which will raise osmolality and lead to water retention. causing trafficking and insertion of the channels into the However, if NaCl is not available and if blood pressure luminal membrane of the tubular cells3). The insertion and volume are becoming dangerously low (down 10%), of the aquaporin-2 protein renders the collecting duct the body behaves as if defense of blood pressure is more selectively permeable to water, which is then reabsorbed important than defense of osmolality, and AVP is secre- from the tubular lumen into the blood driven by the osmo- ted. The specific compartment whose volume is sensed tic driving force of the hypertonic interstitium. In the in order to determine AVP secretion in this setting is the absence of AVP, aquaporin membrane insertion and apical effective arterial volume. This overriding effect of volume membrane water permeability are dramatically reduced. explains the persistence of high AVP levels in hypona- tremic patients with conditions such as heart failure and Physiologic Rationale for Use of AVP cirrhosis. Antagonists Other stimuli for the release of AVP include pain, nau- sea, and hypoxia. Inappropriate release of AVP can occur AVP antagonists block the V2 receptor located on the with a variety of central nervous system and pulmonary basolateral surface of the collecting duct thereby antago- diseases as well as with drugs, particularly those that act nizing the ability of AVP to cause insertion of the aqua- within the central nervous system2). Certain tumors can porin-2 water channels into the luminal membrane. The synthesize and release AVP. increase in urine output is similar in quantity to diuretics AVP exerts its effects on cells through three receptors. but differs in content. V2 receptor antagonists increase The V1A receptor is expressed in a variety of tissues but water excretion with little to no change in urinary elect- is primarily found on vascular smooth muscle cells. rolytes. As a result, lowering of the serum K+ level, meta- Stimulation of this receptor results in vasoconstriction, bolic alkalosis, and increases in the serum creatinine and platelet aggregation, inotropic stimulation and my- blood urea nitrogen concentration are avoided in contrast ocardial protein synthesis. The V1B receptor is expressed to diuretics such as furosemide and hydrochlorothiazide. in cells of the anterior pituitary and throughout the brain. In addition, orthostatic hypotension and activation of Stimulation of this receptor results in release of adreno- neurohumoral effectors such as angiotensin II, circulating corticotropin stimulating hormone (ACTH). Stimulation of catecholamines, and aldosterone are not features of V2 the V1A and V1B receptors activate phospholipase C lead- receptor blockade. These differences have lead to V2 ing to increases in inositol trisphosphate and diacylglycer- receptor antagonists being characterized as “aquaretic” ol with secondary increases in cell calcium and activation agents so as to distinguish them from diuretics. of protein kinase C. The physiologic rationale for use of V2 receptor antago- The V2 receptor is found on the basolateral surface of nists is best exemplified by considering the relationship the renal collecting duct and vascular endothelium where between the serum Na+ concentration and the total body it mediates the antidiuretic effects of AVP and stimulates content of Na+, K+, and water approximated by the equa- the release of von Willebrand factor respectively. Unlike tion: + + the V1A and V1B receptors, binding of AVP to the V2 recep- Plasma Na concentration ≈(Total body Na +Total + tor activates the GS-coupled adenyl cyclase system causing body K ) / Total body water Copyright © 2013 The Korean Society of Electrolyte Metabolism Electrolyte Blood Press 11:1-8, 2013 • http://dx.doi.org/10.5049/EBP.2013.11.1.1 3 + According to this equation, increasing the plasma Na Clinical Use of AVP Antagonists concentration can be achieved through the administra- tion of salt. This approach is clearly the treatment of choice Conivaptan (an intravenous V1a-V2 receptor antago- in patients who are total body salt depleted. By contrast, nist) is approved by the Food and Drug Administration in euvolemic and particularly in hypervolemic patients, for euvolemic and hypervolemic hyponatremia. The effe- such a strategy can cause potential worsening of the un- ctiveness of the drug was demonstrated in a randomized derlying disorder as in edematous patients with conge- placebo controlled trial of 84 hospitalized patients with stive heart failure or cirrhosis. In these patients selectively euvolemic or hypervolemic hyponatremia in which the reducing the denominator is the preferable strategy to raise serum Na+ ranged from 115 to <130 mEq/L5). The pa- the plasma Na+ concentration. The aquaretic properties tients were given a 20 mg loading dose followed by a of the V2 receptor antagonists are well suited for this continuous infusion of either 40 or 80 mg daily for 4 purpose. days. Conivaptan significantly raised the serum Na+ con- The first specific V2 receptor antagonists synthesized centration by 6.3 and 9.4 in the 40 and 80 mg/d arms were peptide analogues of AVP. This approach was later respectively as compared to 0.8 mEq/L in the placebo abandoned due to agonist effects noted upon chronic group. administration. Development of nonpeptide antagonists Conivaptan is also active as an oral formulation but capable of interacting with the receptor so as to prevent its distribution has been restricted to parenteral use for binding of native AVP without themselves stimulating the short-term (4 days maximum) in-hospital administration receptor are now in various stages of clinical develop- only. This restriction is due to potent inhibitory effects 4) ment . Tolvaptan, satavaptan and lixivaptan are selective of the drug on the hepatic cytochrome P450 3A4 enzyme for the V2 receptor and are administered orally. Conivap- system and the potential for untoward drug interactions. tan is an intravenous agent with blocking effects on both The inhibitory effects of other members of this class on the V2 and V1A receptor. These drugs (the vaptans) have the CYP3A4 system are more limited, allowing for oral been shown to be effective in increasing the serum Na+ formulations to be used in a clinical setting. concentration in patients with modest asymptomatic hypo- Tolvaptan is the only other AVP antagonist currently natremia. They can be considered in patients with euvole- approved by the Food and Drug Administration. Unlike mic and hypervolemic (dilutional) hyponatremia but sho- conivaptan, tolvaptan is an oral agent with effects con- uld not be used in patients with hypovolemic hypona- fined to the V2 receptor.
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