When Is It Appropriate to Use Vasopressin Receptor Antagonists?
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JASN Express. Published on March 12, 2008 as doi: 10.1681/ASN.2008010089 CLINICAL COMMENTARY www.jasn.org When Is It Appropriate to Use Vasopressin Receptor Antagonists? Ruediger W. Lehrich and Arthur Greenberg Department of Medicine, Division of Nephrology, Duke University Medical Center, Durham, North Carolina ABSTRACT Hyponatremia is a common and challenging disorder. The mainstays of treatment serum sodium during correction is al- until recently were water restriction and hypertonic saline. The first nonpeptide ways required. VRA offer a new ap- vasopressin receptor antagonist (VRA) is now approved by the US Food and Drug proach to correct hyponatremia by re- Administration for use in patients with euvolemic and hypervolemic hyponatremia. versing the inability to excrete free water, VRA induce urinary dilution with an aquaresis that leads to an increase in serum thus remedying the fundamental patho- sodium concentration. In patients with heart failure, VRA modestly improve con- physiologic lesion. gestive symptoms but have no effect on short- or long-term mortality. Long-term effects have not been extensively studied, but serious adverse effects of VRA are rare, and the rate of rise in serum sodium that they produce seems unlikely to lead DEVELOPMENT OF VRA to osmotic demyelination. Beneficial effects beyond changing serum tonicity and alternative uses, such as in polycystic kidney disease, need further exploration. This Although peptide antagonists of vaso- commentary discusses the current and potential indications for use of VRA. pressin receptors showed promise in an- imal models in the 1970s, they had par- ●● J Am Soc Nephrol : –, 2008. doi: 10.1681/ASN.2008010089 tial agonist effect in humans and further development was abandoned. Subse- quently, nonpeptide receptor antago- Although patients with congestive heart duct cells. Because AQP3 and AQP4 are nists were identified and used success- failure (CHF), cirrhosis, or syndrome of constitutively expressed on the basolat- fully for the first time in humans in the inappropriate antidiuretic hormone se- eral membrane, insertion of AQP2 into early 1990s.6 In December 2005, the first cretion have disparate clinical features, the apical membrane is a critical limiting such compound, conivaptan, a com- they share common pathophysiologic step in urinary concentration. bined vasopressin 1a receptor (V1aR) mechanisms for developing hyponatre- Hypovolemic hyponatremia rapidly and V2R antagonist, was approved by the mia: Failed urinary dilution associated responds to correction of volume deple- Food and Drug Administration for use in with water retention. Lack of suppres- tion. For treating euvolemic or hypervo- euvolemic hyponatremia. An indication sion of arginine vasopressin (AVP) re- lemic hyponatremia, however, conven- for hypervolemic hyponatremia was lease despite hypo-osmolality plays the tional approaches have been electrolyte- granted more recently. Although effec- pivotal role; therefore, patients with any free water restriction, hypertonic saline tive in an oral formulation, conivaptan is of these disorders may respond to vaso- infusion, or demeclocycline, targeting an a potent CYP3A4 inhibitor. To protect pressin receptor antagonists (VRA).1–3 appropriately fast or slow correction, de- against the possibility of important drug The molecular target for AVP, the vaso- pending on the clinical situation. In interactions, its approval was limited to pressin 2 receptor (V2R), is one of three practice, of course, these therapies leave short-term, parenteral use. Three other vasopressin receptors. The intracellular much to be desired. Water restriction agents, tolvaptan, lixivaptan, and sat- effect of ligand binding depends on the can be difficult to implement. It is always localization of the receptor (Table 1). poorly tolerated and often of limited ef- Published online ahead of print. Publication date V2R located on the basolateral mem- ficacy. Hypertonic saline may lead to vol- available at www.jasn.org. brane of collecting duct cells are G-cou- ume overload or overly rapid correction Correspondence: Dr. Arthur Greenberg, Duke Uni- pled and activate the protein kinase A of chronic hyponatremia with osmotic versity Medical Center, Box 3014, Room 00554 signal cascade, leading to fusion of pre- demyelination. Formulas used to guide Duke Hospital South, Durham, NC 27710. Phone: 919-660-6860; Fax: 919-684-4476; E-mail: formed subapical vesicles containing dosage are complex and have been [email protected] membrane-bound aquaporin 2 (AQP2) shown to predict the rate of sodium rise Copyright © 2008 by the American Society of 4,5 into the apical membrane of collecting only variably. Frequent monitoring of Nephrology J Am Soc Nephrol ●●: –, 2008 ISSN : 1046-6673/●●00- 1 CLINICAL COMMENTARY www.jasn.org Table 1. Vasopressin receptors, localization, and effectsa Receptor Localization Effect V1a Vascular smooth muscle Vasoconstriction, myocardial hypertrophy Platelets Platelet aggregation Hepatocytes Glycogenolysis Myometrium Uterine contraction V1b (V3) Anterior pituitary ACTH release V2 Basolateral membrane, collecting tubule Insertion of AQP2 water channels into apical membrane Induction of AQP2 synthesis Vascular endothelium vWF and factor 8 release Vascular smooth muscle Vasodilation aAQP2, aquaporin 2; vWF, von Willebrand factor. avaptan, each a selective V2R antagonist intravenously to patients with hypervo- mmol/L on day 4 and 135.7 Ϯ 5.0 (V2RA), are in various stages of develop- lemic or euvolemic hyponatremia, so- mmol/L on day 30 in patients who re- ment for commercial use. Tolvaptan is dium rose approximately 8 mEq/L dur- ceived active drug but only from 128.7 Ϯ the furthest along, and the highest qual- ing the first 24 h in the group that 4.1 to 129.7 Ϯ 4.9 and 131.0 Ϯ 6.2 ity data are available for this congener. received active drug versus 0.5 mEq/L in mmol/L, respectively, in the placebo Characteristics of these agents are sum- the group that was treated with fluid re- group. The rise in sodium exceeded 12 marized in Table 2. striction alone. Electrolyte-free water ex- mmol/L per 24 h in only four of the 225 cretion was higher and minimum uri- patients who received tolvaptan. Dry nary osmolality lower in the active drug mouth and increased thirst and urina- USE OF VRA IN HYPONATREMIA group.8 tion were more frequent in the treatment Schrier et al.9 conducted two identical group, and the remainder of adverse ef- Decaux7 demonstrated in 2001 that oral trials to test the efficacy of oral tolvaptan fects was similar in both groups. Serious administration of conivaptan in two pa- in patients with euvolemic and hypervo- adverse effects potentially a result of tients with well-established, longstand- lemic hyponatremia. Suitably named tolvaptan treatment occurred in eight ing syndrome of inappropriate antidi- SALT-1 and SALT-2 for Study of As- patients: Hypotension, dizziness, syn- uretic hormone secretion led to a rise in cending Levels of Tolvaptan in Hypona- cope, acute renal failure, and hypernatre- sodium with a concomitant decrease in tremia, an American and international mia. This study clearly demonstrated body weight. This effect was sustained, cohort of 448 patients was randomly as- that orally administered tolvaptan effec- reversing only after discontinuation of signed to tolvaptan or placebo. In tively and safely treats euvolemic and hy- conivaptan (Figure 1). In a placebo-con- SALT-1, sodium rose from 128.5 Ϯ 4.5 pervolemic hyponatremia. trolled trial of conivaptan administered mmol/L at baseline to 133.9 Ϯ 4.8 In smaller studies, the selective V2RA Table 2. Characteristics and clinical indications for the combined V1a/V2 receptor blocker conivaptan and the selective V2 receptor blockers tolvaptan, lixivaptan, and satavaptana Parameter Conivaptan Tolvaptanb Characteristics receptor antagonism V1a and V2 V2 route of administration Intravenousc Oral urine osmolarity Decreased Decreased free water clearance Increased Increased ϩ Na excretion/24 h Unchanged Unchanged Recommendations for use euvolemic hyponatremia (SIADH)d Yese Yes, once available hypervolemic hyponatremia (CHF)d Yese Yes, once available hypervolemic hyponatremia (cirrhosis)d No, safety data lacking Yes, once available hypervolemic hyponatremiad Never Never acute symptomatic hyponatremia Not yet, insufficient data Not yet, insufficient data ADPKD No data Phase III trial ongoing CHF No, no data Selected patients with severe congestive symptoms aADPKD, autosomal dominant polycystic kidney disease; CHF, congestive heart failure; SIADH, syndrome of inappropriate antidiuretic hormone secretion. bLike tolvaptan, lixivaptan and satavaptan are selective V2RA with similar characteristics and anticipated indications. cConivaptan is effective when administered orally, but only the parenteral formulation is approved by the Food and Drug Administration. dRefers to chronic and non–life-threatening hyponatremia. eFood and Drug Administration–approved indication. 2 Journal of the American Society of Nephrology J Am Soc Nephrol ●●: –, 2008 www.jasn.org CLINICAL COMMENTARY 142 64 63 138 62 132 61 60 126 59 Body weight (kg) Body Serum Na (mEq/L) 120 58 0 28 56 84 91 98 105 119 Days Conivaptan (20 mg BID) Water restriction Urea (30 g/day) Figure 1. Patient who had chronic hyponatremia secondary to syndrome of inappropriate antidiuretic hormone secretion and underwent treatment with oral conivaptan, water restriction, and urea. Changes in body weight (F) and changes in serum sodium (᭜) are depicted. BID, twice