Vasopressin Antagonists in the Treatment of Water-Retaining Disorders
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Vasopressin Antagonists in the Treatment of Water-Retaining Disorders Sumit Kumar, MD, MPH,* and Tomas † Berl, MD Summary: 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. Semin Nephrol 28:279-288 © 2008 Elsevier Inc. All rights reserved. Keywords: Vasopressin, antagonists, hyponatremia, treatment yponatremia is perhaps the most com-VASOPRESSIN PHYSIOLOGY monly occurring electrolyte disorder in Hhospitalized patients.1 Although mild Vasopressin’s primary site of action is the hyponatremia (serum sodium level, 130-134principal cell of the renal collecting tubules, mEq/L) is very common, occurring in 15%where to the V2 receptors (V2R) predominantly 20% of hospitalized patients,2 it often is asymp-are expressed, although minor expression is tomatic. More severe hyponatremia (serum knownso- in the vascular endothelium where dium level,Ͻ 125 mEq/L) with possibly seriousthey stimulate the release of von Willebrand consequences occurs less commonly.3,4 The most factor and factor 8. The V2R is part of a common causes of hyponatremia are the broadersyn- family ofs -protein– G coupled recep- drome of inappropriate antidiuretic hormonetors that differ in localization and action. (SIADH) and hyponatremia associated with extra-These include the1a andV 1bV receptors. Upon cellular volume depletion.5 The pathophysiology sensing hyperosmolality, the osmoreceptors of hyponatremia directs the management, bringbut out the release of antidiuretic hormone central to most approaches is water restriction.(vasopressin) into the blood that then couples Most conventional approaches that include the with the V2R and activatesS-coupled the G ad- use of lithium, demeclocycline, urea, and saltenylyl tab- cyclase system, thereby increasing intra- lets are unsatisfactory, difficult to sustain, cellularand cyclic adenosine monophosphate. have serious side effects. Recently, exploitingProtein the kinase A gets stimulated by cyclic aden- known pathobiology of water transport and osineme- monophosphate, leading to the phos- tabolism, several agents have been developed that phorylation of preformed aquaporin-2, leading serve to fill this void and provide viable and sus- to cellular translocation of vesicular aqua- tainable water balance. porin-2 (AQP2) to the apical membrane of the principal cells, making the cells water perme- *Department of Nephrology, Presbyterian Hospital, Dallas, TX. able Fig.( ).16 The control of vasopressin is †Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado at Denver and Health Sciences Center, Denver, CO. governed by both osmotic and nonosmotic Address reprint requests to Tomas Berl, MD, Department of Medicine, Divi- stimuli, with changes in osmotic stimuli being sion of Renal Diseases and Hypertension, University of Colorado at Denver and Health Sciences Center, 4200 E. Ninth Ave, Box C281, Denver, CO the primary stimulus. The physiologic actions 80262. E-mail: [email protected] of the various vasopressin receptors are sum- 0270-9295/08/$ - see front matter 7 © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.semnephrol.2008.03.008 marized inTable .1 Seminars in Nephrology, Vol 28, No 3, May 2008, pp 279-288 279 280 S. Kumar and T. Berl Often patients may be volume depleted, but may have alterations in thirst perception. The mea- surement of urinary sodium can aid the diagnosis. A low urine Na (Ͻ20 mEq/L) may imply hypovo- lemia. Antidiuretic hormone (ADH) levels are in- creased to defend against volume contraction that leads to water retention and impaired water ex- cretion. On the other hand, hypervolemic pa- tients such as those with cirrhosis, congestive heart failure (CHF), and nephrotic syndrome have an excess of total body sodium, possibly even pulmonary vascular congestion, but have decreased effective arterial blood volume re- sulting in poor renal perfusion. These condi- tions are characterized inherently by avid so- dium and water retention caused by increased ADH levels. Patients with euvolemia present a different paradigm in the evaluation and man- agement of hyponatremia. Patients with the Figure 1. Cellular action of ADH. The binding of ADH with the basolateral V2 receptor in the principal cells of syndrome of inappropriate antidiuresis (SIAD) the renal collecting tubules affects all the events that have variable levels of measurable ADH and follow. The cytoplasmic vesicles carry the water channels excessive water intake driven by nonosmotic to the apical membrane in response to the binding, stimuli that together result in hyponatremia. making it water permeable. ATP, adenosine triphos- The causes of SIAD can be divided broadly into phate; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A. Reprinted with permission from Kumar pulmonary, central nervous system, paraneo- and Berl.37 plastic (malignancy related), and drug induced (Table 2). The diagnostic criteria for SIAD are summarized in Table 3. APPROACH TO THE HYPONATREMIC PATIENT THERAPEUTIC The volume status of the patient allows classifica- APPROACH TO HYPONATREMIA tion of hyponatremia into hypovolemic, euv- There are no professional guidelines that out- olemic, and hypervolemic hyponatremia (Fig. 2).8 line the therapy for hyponatremia because Table 1. Physiologic Action of the Vasopressin Receptors Subtype Location Function V1a Vascular smooth muscle Vasoconstriction, myocardial hypertrophy Platelets Platelet aggregation Hepatocytes Glyogenolysis Myometrium Uterine contraction V1b Anterior pituitary gland Releases ACTH, prolactin, endorphins V2 Basolateral membrane of collecting Insertion of AQP2 water channels into apical tubule membrane, induction of AQP2 synthesis Vascular endothelium Releases von Willebrand factor and factor VIII Vascular smooth muscle Vasodilatation Abbreviation: ACTH, adrenocorticotropic hormone. Reprinted with permission from Chen et al.7 Vasopressin antagonists hyponatremia treatment 281 Figure 2. Classification of hyponatremia. Reprinted with permission from Kumar and Berl.37 there are no randomized controlled trials that VAPTANS: PHARMACOLOGY compare 2 or more therapeutic options. Stud- Conivaptan is the only combined V1a/V2 receptor ies, mainly retrospective in nature, have been whereas lixivaptan, satavaptan, and tolvaptan summarized recently.9 On the other hand, the are specific V2- receptor antagonists. All vaptans understanding of the pathophysiology, natural are orally active and all interact with the cyto- history, and end-organ complications has al- chrome P450 3A4 enzymes, however, conivaptan lowed acceptable standards of care to be devel- is the most potent inhibitor, limiting its use to oped over the past decades. The advent of new hospitalized patients only for short durations of agents that specifically inhibit the vasopressin 2 time. receptor in the kidney hold much promise for Structurally, the agents available and in cur- the future. Overall, the rapidity with which rent development (Table 4) are all benzazepine hyponatremia develops dictates the aggressive- or oxindole derivatives. The nonpeptide antag- ness of therapy. Most cases of hyponatremia, onists penetrate deeper into the transmem- especially mild, respond to a correction of the brane region of the V2R than does native argi- underlying pathophysiology and judicious wa- nine vasopressin (AVP), preventing binding of ter restriction. In patients with severe hypona- the native hormone without themselves inter- tremia (Ͻ125 mEq/L) and/or symptomatic pa- acting with the H1 helix site that is critical for 11 tients, the use of hypertonic saline has been V2R-mediated G-protein activation. There is popularized over the years.10 The pitfalls in- only a partial overlap in the binding sites for clude compliance with water restriction, the arginine vasopressin and the antagonists (Fig. risk for osmotic demyelination with overcorrec- 3). These agents displace radioactively labeled tion, and potential volume overload, among hormone from its receptor and thereby po- others, in patients treated with hypertonic sa- tently inhibit AVP stimulation of adenylate cy- line. clase.12 The development of orally active nonpeptide vasopressin antagonists has revolutionized the EUVOLEMIC HYPONATREMIA management of hyponatremia in various clini- cal settings. There is currently one agent, Hyponatremic Patients With SIADH conivaptan (a V1a/V2-receptor antagonist), avail- Early in the development, the first-generation able for intravenous use and 3 others in devel- oral vasopressin antagonist, OPC 31260, was opment for oral use (Table 4). used to treat patients with hyponatremia. In a 282 S. Kumar and T. Berl Table 2. Causes of SIADH Disorders of the Central Nervous Malignant Diseases Pulmonary Disorders System Carcinoma Infections Infection Lung Bacterial pneumonia Encephalitis Small-cell Viral pneumonia Meningitis Mesothelioma Pulmonary abscess Brain abscess Oropharynx