REVIEW New Horizons in the Pharmacologic Approach to Hyponatremia: The V2 Receptor Antagonists Biff F. Palmer, MD Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas. Disclosure: B.F. Palmer received an honorarium funded by an unrestricted educational grant from Otsuka America Pharmaceuticals, Inc., for time and expertise spent in the composition of this article. No editorial assistance was provided. He also receives speaker fees from Otsuka America Pharmaceuticals, Inc. 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. VC 2010 Society of Hospital Medicine. KEYWORDS: arginine vasopressin, AVP receptor antagonists, conivaptan, tolvaptan, hyponatremia. Under normal circumstances, there is a balance between pressure or blood volume have no effect on AVP levels. water intake and water excretion such that plasma osmolal- However, once decreases in volume or pressure exceed this ity and the serum sodium (Naþ) concentration remain rela- value, baroreceptor-mediated signals provide persistent tively constant. The principal mechanism responsible for stimuli for AVP secretion. Baroreceptor-mediated AVP prevention of hyponatremia and hyposmolality is renal release will continue even when plasma osmolality falls water excretion. In all hyponatremic patients, water intake below 280 mOsm/kg. Teleologically, this system can be exceeds renal water excretion. viewed as an emergency mechanism to defend blood pres- Excretion of water by the kidney is dependent on 3 fac- sure. Thus, small decreases in blood volume and blood tors. First, there must be adequate delivery of filtrate to the pressure will cause the body to retain NaCl which will raise tip of the loop of Henle. Second, solute absorption in the osmolality and lead to water retention. However, if NaCl is ascending limb and the distal nephron must be preserved not available and if blood pressure and volume are becom- so that the tubular fluid will be diluted. Lastly, arginine va- ing dangerously low (down 10%), the body behaves as if sopressin (AVP) levels must be low in the plasma. Of these 3 defense of blood pressure is more important than defense requirements for water excretion, the one which is most of osmolality, and AVP is secreted.1 The specific compart- important in the genesis of hyponatremia is the failure to ment whose volume is sensed in order to determine AVP maximally suppress AVP levels. Given the central role of secretion in this setting is the effective arterial volume. This AVP in limiting renal water excretion, AVP receptor antago- overriding effect of volume explains the persistence of high nists represent a physiologic and rational method to AVP levels in hyponatremic patients with conditions such as increase renal water excretion. heart failure and cirrhosis. Other stimuli for the release of AVP include pain, nausea, AVP in Regulation of Plasma Osmolality and hypoxia. Inappropriate release of AVP can occur with a AVP is synthesized in the supraoptic and paraventricular variety of central nervous system and pulmonary diseases nucleus of the hypothalamus and then stored in the neuro- as well as with drugs, particularly those that act within the hypophysis (reviewed in the article ‘‘Diagnostic Approach central nervous system.2 Certain tumors can synthesize and and Management of Inpatient Hyponatremia’’ in this sup- release AVP. plement). The release of AVP is exquisitely sensitive to AVP exerts its effects on cells through 3 receptors (Table changes in plasma osmolality. AVP is not detectable in the 1). The V1A receptor is expressed in a variety of tissues but plasma at an osmolality below approximately 280 mOsm/kg is primarily found on vascular smooth muscle cells. Stimula- but increases in a nearly linear fashion beginning with as tion of this receptor results in vasoconstriction, platelet little as a 2% to 3% increase in osmolality above this value. aggregation, inotropic stimulation and myocardial protein The extreme sensitivity of this system allows for plasma os- synthesis. The V1B receptor is expressed in cells of the ante- molality to be maintained within a narrow range. rior pituitary and throughout the brain. Stimulation of this A second major determinant of AVP release is the effec- receptor results in release of adrenocorticotropin stimulat- tive arterial blood volume. While AVP levels are very sensi- ing hormone (ACTH). Stimulation of the V1A and V1B recep- tive to plasma osmolality, small changes of <10% in blood tors activate phospholipase C leading to increases in inositol 2010 Society of Hospital Medicine DOI 10.1002/jhm.785 Published online in Wiley InterScience (www.interscience.wiley.com). Journal of Hospital Medicine Vol 5 No 6 Supplement 3 July/August 2010 S27 TABLE 1. Location and Function of TABLE 2. AVP Receptor Antagonists AVP Receptor Subtypes Currently Approved by FDA Subtype Location Function Parameter Tolvaptan Conivaptan V1A Vascular smooth muscle to Vasoconstriction Trade name Samsca Vaprisol include splanchnic bed Administration Oral Intravenous V1B Anterior pituitary Release of ACTH Dose 15–60 mg daily 20 mg loading dose followed by V2 Basolateral surface of renal Insertion of aquaporin channel 20–40 mg continuous infusion collecting duct, vascular into luminal membrane, Receptor V2 V1A and V2 endothelium, vascular smooth release of von Willebrand Protein binding (%) 99 98.5 muscle factor, vasodilation Half life 6–8 hours 3–8 hours Metabolism Hepatic (CYP3A4) Hepatic (CYP3A4) Abbreviations: ACTH, adrenocorticotropin stimulating hormone; AVP, arginine vasopressin. Elimination Feces Feces Abbreviations: AVP: arginine vasopressin; CYP3A4, cytochrome P450 3A4; FDA, Food and Drug Administration. 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 between the serum Naþ concentration and the total body mediates the antidiuretic effects of AVP and stimulates the content of Naþ,Kþ, and water approximated by the equation: release of von Willebrand factor respectively. Unlike the V1A þ and V1B receptors, binding of AVP to the V2 receptor acti- Plasma Na concentration þ þ vates the GS-coupled adenyl cyclase system causing ðTotal body Na þ Total body K Þ= Total body water increased intracellular levels of cyclic adenosine monophos- phate (cAMP). In the kidney, generation of cAMP stimulates According to this equation, increasing the plasma Naþ protein kinase A which then phosphorylates preformed concentration can be achieved through the administration aquaporin-2 water channels causing trafficking and inser- of salt. This approach is clearly the treatment of choice in tion of the channels into the luminal membrane of the tu- patients who are total body salt depleted. By contrast, in 3 bular cells. The insertion of the aquaporin-2 protein ren- euvolemic and particularly in hypervolemic patients, such a ders the collecting duct selectively permeable to water, strategy can cause potential worsening of the underlying which is then reabsorbed from the tubular lumen into the disorder as in edematous patients with congestive heart fail- blood driven by the osmotic driving force of the hypertonic ure or cirrhosis. In these patients selectively reducing the interstitium. In the absence of AVP, aquaporin membrane denominator is the preferable strategy to raise the plasma insertion and apical membrane water permeability are dra- þ Na concentration. The aquaretic properties of the V2 recep- matically reduced. tor antagonists are well suited for this purpose. The first specific V2 receptor antagonists synthesized Physiologic Rationale for Use of AVP Antagonists were peptide analogues of AVP. This approach was later AVP antagonists block the V2 receptor located on the baso- abandoned due to agonist effects noted upon chronic lateral surface of the collecting duct thereby antagonizing administration. Development of nonpeptide antagonists the ability of AVP to cause insertion of the aquaporin-2 capable of interacting with the receptor so as to prevent water channels into the luminal membrane. The increase in binding of native AVP without themselves stimulating the urine output is similar in quantity to diuretics but differs in receptor are now in various stages of clinical development.4 content. V receptor antagonists increase water excretion 2 Tolvaptan, satavaptan, and lixivaptan are selective for the V2 with little to no change in urinary electrolytes. As a result, receptor and are administered orally (Table 2). Conivaptan lowering of the serum Kþ level, metabolic alkalosis, and is an intravenous agent with blocking effects on both the V2 increases in the serum creatinine and blood urea nitrogen and V1A receptor. These drugs (the vaptans) have been concentration are avoided in contrast to diuretics such as shown to be effective in increasing the serum Naþ concen- furosemide and hydrochlorothiazide.