Arginine vasopressin (AVP) is a

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1 Akash Parashar, MD; Patrick Martinucci, DO; Mandip Panesar, MD The authors are with the University at Buffalo, Erie County Medical Center, Buffalo, New York. Dr. Panesar is a member of D&T s Editorial Advisory Board. Arginine vasopressin (AVP) is a human peptide hormone released during states of hypovolemia that stimulates the kidneys to conserve water by concentrating urine and reducing urine volume. It is synthesized in the hypothalamus as a pre-prohormone precursor and stored in the posterior pituitary gland. It is now believed that the role of AVP is central to the pathogenesis of various diseases such as congestive heart failure (CHF), cirrhosis, and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). These clinical syndromes are characterized by elevated plasma levels of vasopressin and clinically manifest as a fluid retentive state. Therefore, patients become hyponatremic. There is a growing interest and effort to develop selective and long-lasting pharmaceutical agents that antagonize this effect. Over the past two decades, various vasopressin receptor antagonists (VRAs) have been developed and studied. The first nonpeptide vasopressin receptor antagonist was recently approved by the United States Food and Drug Administration (FDA), and other similar agents are presently in different stages of development. Clinically, these agents have the ability to reduce urine osmolality and increase free water excretion while preserving sodium and raising serum sodium concentration. This aquaretic effect is in contradistinction to that seen with traditional diuretics, which increase sodium excretion together with water excretion. artery, aortic arch, and left atrium and in response stimulate the release of vasopressin from the supraoptic and paraventricular nuclei. The body s protective mechanism to prevent the development of cardiovascular collapse when hypovolemia and hypotension are occurring is mediated by the vasoconstrictive properties of AVP. Vasopressin release is also regulated by osmoreceptors in the hypothalamus. The osmolality threshold for secretion is approximately 280 mosm/kg, after which a small increase in plasma osmolality leads to enhanced vasopressin secretion. It is also known that vasopressin secretion also may be stimulated by non-osmotic and nonhemodynamic factors including nausea, pain, hypoglycemia, exercise, and drugs. Once secreted into serum, vasopressin has a half-life of approximately 10 minutes and is degraded by a cysteine amino-terminal peptidase called vasopressinase. Vasopressin Receptors TABLE I: Vasopressin receptors ADH receptors are G-protein-coupled receptors. There are 3 subtypes that differ in their localization and signal transduction mechanisms (Table I). The vasopressin V1a receptor (V1aR) is a Gq-coupled receptor that activates phospholipase C and increases the concentration of intracellular free calcium. Vasopressin V2 receptors (V2Rs) are found in vascular endothelium and in principal cells of the renal collecting and connecting tubules. These receptors mediate release of von Willebrand factor and factor 8 and regulate the hydro-osmotic effect of vasopressin. The third subtype, V3 or V1b receptor, appears to mediate the paracrine effect of ADH on the pituitary gland and facilitates the release of ACTH. In the kidney, vasopressin acts on the V2 receptor and activates adenyl cyclase, and a protein kinase is activated that leads to insertion of preformed cytoplasmic vesicles into the apical membrane. These vesicles contain water channels called aquaporin-2 that allow water to be reabsorbed. Vasopressin Receptor The initial work done on vasopressin receptor antagonists (VRAs) focused on development of peptide analogs. 1 In the1980s a selective V2 receptor antagonist peptide, tested in animal studies, showed a weak V2 agonist effect in humans in a phase 1 trial. 2 The main hurdle in the development and therapeutic utility of a peptide vasopressin receptor antagonist was the lack of an oral bioavailable drug. 2 Consequently, attention was shifted toward developing a nonpeptide vasopressin receptor antagonist. Presently, 4 nonpeptide vasopressin receptor antagonists are in various stages of clinical trials (Table II). Vasopressin Physiology Arginine vasopressin, also known as antidiuretic hormone, is a 9-amino-acid peptide synthesized in the supraoptic and paraventricular nuclei of the hypothalamus. AVP is transported to the posterior lobe of the pituitary and stored in secretory granules. The two most important stimuli of AVP release are low blood volume and hypernatremia. Low blood volume is sensed by baroreceptors in the carotid Receptor Signaling Location Actions V1a V1b G-protein coupled; IP3 activation; increases intracellular Ca G-protein coupled; IP3 activation; increases intracellular Ca Blood vessels Myocardium Platelets Hepatocytes Anterior pituitary V2 Adenyl cyclase Basolateral membrane Collecting tubule Endothelium Vasoconstriction Myocardial hypertrophy Platelet aggregation Glycogenolysis ACTH release Water retention vwf and factor 8 release; vasodilatation May 2007 Dialysis & Transplantation 1

2 TABLE II: Vasopressin receptor antagonists undergoing commercial development. Compound Receptor Route Manufacturer Conivaptan (YM-087) V1a/V2 Intravenous Astellas (Tokyo, Japan) Lixivaptan (VPA-985) V2 Oral CardioKine (Philadelphia, PA) Tolvaptan (OPC-41061) V2 Oral Otsuka (Tokyo, Japan) Satavaptan (SR ) V2 Oral Sanofi-Aventis (Paris, France) Conivaptan (YM-087) The FDA approved conivaptan, a combined V1a/V2 receptor antagonist, in December 2005 with indications for the treatment of euvolemic hyponatremia (e.g., the syndrome of inappropriate secretion of antidiuretic hormone or in the setting of hypothyroidism, adrenal insufficiency, and pulmonary disorders) in hospitalized patients. Conivaptan has an oral bioavailability of 44% and a very short half-life. 3 Clinical trials (Table III) have shown that both oral and intravenous administration of conivaptan resulted in a seven-fold increase in urine flow rate and a fall in urinary osmolarity (from 600 to 100 mosm/l). These findings were in accordance with those of the previous studies done in laboratory animals. 4,5 The peak effect was observed 2 hours after drug intake, and the aquaretic effect lasted for at least 6 hours. In a phase 3 randomized, double-blind, placebo-controlled study, the results of which were presented at the Scientific Meeting of the American Heart Association in 2004, patients with hyponatremia (Na 115 to 130 meq/l) were randomized to receive a 20-mg bolus injection of conivaptan followed by conivaptan infusion of 40 or 80 mg/day for 4 days. The study group consisted of a mixed population of euvolemic and hypervolemic patients, and it was found that heart failure was the cause of hyponatremia in approximately 30% of patients. At both doses, conivaptan was significantly better than placebo in increasing the serum sodium level. The increase in serum sodium seen with conivaptan 40 and 80 mg/day was dose related and gradual over the 4-day period. Conivaptan was well tolerated in all patients. 7 To date, the most common adverse events associated with conivaptan include vomiting, hypokalemia, and infusion site reactions. Most reactions have been reported as being mild and have not led to discontinuation of therapy. Conivaptan therapy is initiated with a 20-mg intravenous loading dose, followed by 20 mg administered as a continuous infusion for 24 hours, and may be given for an additional 1 3 days as a continuous infusion of 20 mg/day for a maximum of 5 days. 7 Because conivaptan has an aquaretic effect, a rapid rise in serum sodium levels ( 12 meq/l in 24 hours) can result. Therefore, frequent monitoring of serum sodium level and volume status is advised as a preventive measure. In patients who develop high levels of sodium, conivaptan should be immediately discontinued, and the sodium level and neurological status be checked frequently. Lixivaptan (VPA 985) In 1998 Chan et al. reported an orally active V-2 receptor antagonist named VPA-985, or lixivaptan. 9 A randomized, placebo-controlled, double-blind trial of 60 patients with cirrhosis and dilutional hyponatremia showed normalization of serum sodium in 27% and 50% patients receiving 100 and 200 mg of lixivaptan daily, respectively. 10 Furthermore, a decrease in body weight, a dose-dependant reduction in urine osmolarity, and increase in urine volume were also reported (Table IV). This has also been seen in patients with cirrhosis 11,12 and in patients with hyponatremia secondary to SIADH. 13,14 In a study by Wong et al., 44 hospitalized patients (33 patients with cirrhosis, 6 with CHF, and 5 with SIADH) were studied on a constant sodium intake, with lixivaptan doses of 25, 125, and 250 mg twice daily or placebo. Lixivaptan produced a significant overall aquaretic response when compared to placebo, with significant dose-related increases in free water clearance and serum sodium and without significant changes in orthostatic blood pressure or serum creatinine levels. 15 From the results of these studies, it has been concluded that lixivaptan is safe and effective at various doses at correcting abnormal renal water handling and hyponatremia in patients who are in a water-retentive state. Tolvaptan (OPC-41061) Tolvaptan is an oral, nonpeptide, selective V2 receptor antagonist that has been studied primarily in patients with congestive heart failure (Table V). It is administered once per day and has been shown to generate dose-dependant production of dilute urine without altering serum electrolytes. 16 The ACTIV in the CHF study demonstrated that initiating tolvaptan for decompensated heart failure can produce less fluid retention and decreased body weight and at the same time normalize the serum sodium level in patients with hyponatremia. This study also demonstrated that tolvaptan did not have any effects on heart rate, blood pressure, serum potassium level, or renal function. 17 In a recent phase 3 trial with tolvaptan, SALT2 (sodium assessment with increasing levels of tolvaptan in hyponatremia), approximately 200 patients with hyponatremia received mg of tolvaptan in a stepwise fashion for 30 days. The results showed that patients treated with tolvaptan had significant improvement in sodium levels compared with patients who received the placebo (presented at the American Society of Nephrology Annual Meeting, Philadelphia, Pa., November 2005). Satavaptan (SR ) Satavaptan is a potent and highly selective non-peptide AVP-V2 receptor antagonist. 18 This has been shown in both rat and human kidney preparations. It has been shown to produce a strong and pure aquaretic response when given orally or intravenously to rats 19 and this response was maintained during chronic treatments in normally 2 Dialysis & Transplantation May 2007

3 TABLE III: Published clinical studies on conivaptan. Burnier et al. 3 Udelson et al. 6 Verbalis 7 Jalal K. Ghali Single oral dose of 60 mg and single IV dose of 50 mg in a crossover study Single intravenous dose (10, 20, or 40 mg) 20-mg bolus injection of conivaptan followed by conivaptan infusion of 40 mg/day (n 29) or 80 mg/day (n 26) for 4 days; a third group received placebo (n 29) 40 and 80 mg/day orally for 5 days Healthy CHF (NYHA class III and IV Hyponatremia (Na 115 to 130 meq/l) Euvolemic or hypervolemic hyponatremia Seven-fold increase in urine volume, fall in urine osmolality, increase in plasma osmolality 20- and 40-mg doses significantly reduced pulmonary capillary wedge pressure, right atrial pressure, and increased urine output Dose-related gradual correction of hyponatremia in both treatment groups. Prompt increase in serum sodium, no increased incidence of hypotension or tachycardia, no significant elevation of BUN and serum creatinine. hydrated conscious rats. 20 Although satavaptan is proving to have potential, more studies are needed to show its efficacy for edematous states associated with hyponatremia and hypoosmolality. Potential Clinical Indications for Vasopressin Receptor V2R antagonists are likely to become a key player in the management of euvolemic (SIADH) and hypervolemic (CHF and cirrhosis) hyponatremia because hyponatremia remains the most common electrolyte abnormality encountered in hospitalized patients. Of the various V2R antagonists to date, tolvaptan is the best studied for use in heart failure and has been shown to produce a rapid and sustained decrease in body weight of patients with congestive heart failure and to correct hyponatremia. Compared with loop diuretics, AVP receptor antagonists have many favorable properties. Loop diuretics can decrease serum sodium/potassium levels, plasma osmolality, renal blood flow, and hence, the glomerular filtration rate. Furthermore, orthostatic hypotension can occur. In contrast, the V2 receptor antagonist tolvaptan normalizes or improves serum sodium levels and has no effect on serum potassium levels, blood pressure, BUN/creatinine levels and does not influence the body s neurohormonal activity. It may have the added beneficial effects of increasing plasma osmolality and renal blood flow along with the glomerular filtration rate. This may partially explain the enhanced diuresis seen with tolvaptan when compared with loop diuretics. There is an ongoing multicenter, double-blind, placebo-controlled clinical trial involving hospitalized patients with congestive heart failure that is investigating these potential effects on clinical outcomes. 18 Precautions for the Use of Vasopressin Receptor Vasopressin receptor antagonists have not been shown to significantly increase the incidence of hypotension, tachycardia, or renal impairment. 10 However, there is a theoretical risk of variceal bleeding in patients with cirrhosis and portal hypertension secondary to V1a receptor blockade. Therefore, only selective V2 receptor blockers should be used in such patients until further data are available. Potential Use in Polycystic Kidney Disease An exciting area of current research focuses on the effect of vasopressin receptor antagonists on the prevention and treatment of polycystic kidney disease. Laboratory studies suggest that camp stimulates both cyst formation and fluid secretion into the pathologic cysts that are characteristic of this disease. In animal models V2 receptor antagonists have been shown to inhibit the development of and progression to polycystic kidney disease (PKD) Wang et al. showed that the administration of a V2 antagonist, OPC-41061, at 3-10 weeks of age lowered camp levels in the kidney, protecting against the development of PKD in rats. 23 Results showed a significantly lower kidney weight and cyst volume. Of note, the renoprotective effect of OPC was achieved using low doses, limiting the potential adverse effect of water depletion. May 2007 Dialysis & Transplantation 3

4 TABLE IV: Published clinical studies on lixivaptan (VPA 985). Grebes et al mg PO bid 7 days Cirrhosis with hyponatremia 60 At 100 mg dose: lowered urine 100 mg PO bid 7 days ( 132 mmol/l) osmolality, increased serum Placebo 7 days sodium, decreased body weight Decaux et al. 13 Guyader et al. 11 Wong et al ,100 mg bid 25, 50, 100, 200, 300 mg 25, 125, and 250 mg PO bid 7 days Placebo 7 days Patients with hyponatremic cirrhosis with ascites and SIADH patients Cirrhosis with ascites TABLE V: Published clinical studies on tolvaptan (VPA 985). Hyponatremia with cirrhosis, CHF, or SIADH Lowered urine osmolality, increased serum sodium, increased urine volume Increased free water clearance, increased serum sodium Increased free water clearance, increased serum sodium Gheorghiade et al , 45, and 60 mg daily CHF (NYHA II and III); 254 Decreased edema and body weight; PO 25 days 28% had baseline normalized serum sodium; no adverse Placebo 25 days hyponatremia changes in HR, BP, renal function, or serum potassium Gheorghiade et al. 17 Gheorghiade et al , 60, 90 mg PO qd days 30 mg/day CHF (EF 40%); 21.3% had baseline hyponatremia CHF (EF 40%) NYHA Class III or IV (Expected) Decreased edema and body weight; normalized serum sodium; no adverse changes in HR, BP, renal function, or serum potassium; lowered 60-day mortality rate in patients with renal dysfunction or severe congestion; no difference in rehospitalization rate Ongoing phase 3 trial Otsuka Pharmaceuticals is enrolling patients with PKD in a phase 3 trial of tolvaptan. This study, which recently designated fast track by the FDA because of its promise as a treatment for PKD, is looking at the effectiveness of a tolvaptan to slow or stop cyst growth and prevent the secondary complications of the disease including hypertension, proteinuria, and kidney pain. Conclusion Vasopressin receptor antagonists have a potential for use in various clinical settings. Conivaptan is approved for the treatment of euvolemic hyponatremia, and more trials are needed to investigate its role in the management of acutely decompensated and chronic CHF. Tolvaptan may benefit patients with PKD. Although these agents 4 Dialysis & Transplantation May 2007 are proving to be of some clinical benefit, further studies are required to assess the safety profile of the long-term use of vasopressin receptor antagonists. D&T References 1. Manning M, Sawyer WH. Synthesis and receptor specificities of vasopressin antagonists. Cardiovasc Pharmacol. 1986;J8(suppl 7):S29-S Kinter LB, Ilson BE, Caltabianol S, et al. Antidiuretic hormone antagonism in humans: are there predictors? In: Jard S, Jamison R, eds. Vasopressin. Third International Vasopressin Conference. Paris: John Libbey Eurotext: Paris; 1991: Burnier M, Fricker AF, Hayoz D, et al. Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects. Eur J Clin Pharmacol. 1999;55: Yatsu T, Tomura Y, Tahara A, et al. Pharmacological profile of YM087, a novel nonpeptide dual vasopressin V 1A and V 2 receptor antagonist, in dogs. Eur J Pharmacol. 1997;321: Tahara A, Tomura Y, Wada K, Kusayama T, et al. Pharmacological profile of YM087,a novel potent nonpeptide vasopressin V1a and V2 receptor antagonist, in vitro and in vivo. J Pharmacol Exp Ther. 1997;282: Udelson JE, Smith WB, Hendrix GH, et al. Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure. Circulation. 2001;104: Verbalis J. Novel vasopressin V1a and V2 antagonist (conivaptan) increased serum sodium concentration and effective water clearance in hyponatremia clinical trials. Abstract presented at American Heart Association Scientific Conference, November 10, 2004, New Orleans, LA. 8. Ghali JK, Koren MJ, Taylor JR, et al. Efficacy and safety of oral conivaptan: A V 1A /V 2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endocrinol Metab. 2006;91: Chan PS, Coupet J, Park HC, Lai F,et al. VPA-985, a nonpeptide orally active and selective vasopressin V2 receptor antagonist. Adv Exp Med Biol. 1998;449: Gerbes AL, Gulberg V, Gines P, et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double-blind multicenter trial. Gastroenterology. 2003;124:

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