280 likes | 375 Views
This outline provides insights into key vasopressin receptor antagonists - Conivaptan, Tolvaptan, Lixivaptan, and Satavaptan - offering a detailed review of their functions, structures, and clinical trials for managing hyponatremia related to various conditions. Understanding their mechanisms and efficacy can aid in selecting the most suitable treatment for patients.
E N D
Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007
Outline • Introduction • Conivaptan • Tolvaptan • Lixivaptan • Satavaptan • Conclusion • References
Introduction • SIADH – AVP release is not fully suppressed as it would normally be in a setting of hypotonicity • CHF – arterial under-distention & baroreceptor unloading inhibit vagal suppression of AVP (as well as renin & catecholamines) • Cirrhosis – splanchnic vasodilatation arterial underfilling w/ non-osmotic release of AVP
Introduction (cont.) • Even “asymptomatic” patients with chronic SIADH may have subtle psychomotor impairments • Association of hyponatremia w/ increased morbidity & mortality in patients w/ liver, heart, or neurologic disease
Introduction • Traditional SIADH treatments: water restriction, salt +/- a loop diuretic, increased osmole diet, demeclocycline, lithium • Difficult to treat when urine osmolality is particularly high • Treat based on severity of hyponatremia (how low & how symptomatic)
Introduction (cont.) • ADH receptor antagonists a selective water diuresis (Na/K excretion is not affected – Na & K loss are features of chronic SIADH) • Urine osmolality will then decrease • Serum Na will then increase
Structure of the Vasopressin V2 Receptor (Brenner & Rector 2004)
Signal Transduction Via the V2 Receptor (Brenner & Rector 2004)
Conivaptan • Only vasopressin receptor antagonist available in the U.S. • Non-selective (V2 & V1a): potential for splanchnic vasodilatation w/ subsequent hypotension or variceal bleeding b/c of V1a effects (so not tested in cirrhotics) • IV formulation only b/c of potent cyt P450 3A4 inhibition if given orally (so used only for inpatients) • Approved for euvolemic hyponatremia
Conivaptan – J Clin Endo Metab 2006 • 74 euvolemic (74%) or hypervolemic (26%) patients >/= 18 years w/ Na 115-130 mEq/l, FBG < 275mg/dl, serum osm < 290 mosm/kg H20, no volume depletion • Excluded patients w/ uncontrolled htn or arrhythmias, hypotension, untreated thyroid abnormalities or adrenal insufficiency, CrCl < 20 ml/min, LFTs > 5x normal, signs of liver disease, HIV, those requiring emergent treatment, those on meds that cause or treat SIADH • RCT giving oral conivaptan, 40 or 80mg/d, or placebo, given in 2 divided doses x 5 days
Conivaptan – J Clin Endo Metab 2006 • Fluid intake limited to 2L/24 hrs • 1* outcome: change from baseline in serum Na area under the curve • Statistically significant change from baseline in serum Na AUC w/ both doses (achieved in a statistically significant shorter amount of time) • AEs: HA, hypotension, nausea, constipation • Aquaretic effects persisted for at least 6hrs
Tolvaptan • Not yet available in the U.S. • V2 selective: blocks binding of arginine vasopressin to the V2 receptors of the distal nephron only • Oral
Tolvaptan – NEJM 2006 • Report of 2 RCT: SALT-1 & SALT-2 (Study of Ascending Levels of Tolvaptan in Hyponatremia) • Euvolemic or hypervolemic patients > 18 years w/ Na < 135 mmol/L & either chronic heart failure, cirrhosis, or SIADH; mostly outpatients • Excluded patients w/ psychogenic polydipsia, head trauma, postop conditions, uncontrolled hypothyroidism or adrenal insufficiency, or medication-induced hyponatremia
Tolvaptan – NEJM 2006 • Also excluded if: hypovolemic, recent MI, VT/VF, stroke, SBP < 90 mm Hg, Cr > 3.5 mg/dl, Child-Pugh score > 10 (unless exception), Na < 120 mmol/L w/ neurologic impairment, severe pulmonary HTN, uncontrolled DM, neurologic disease, little chance of short-term survival or unlikely to tolerate fluid volume shifts
Tolvaptan – NEJM 2006 • 223 given placebo, 225 given tolvaptan • Initial dose: 15mg qd, titrated to max of 60 based on serum Na • Primary endpoints: change in the average daily area under the curve for serum Na from baseline to day 4 & baseline to day 30
Tolvaptan – NEJM 2006 • Increase in average daily AUC for serum Na was significantly greater in the tolvaptan group • Also seemed to be improvement in self-assessed mental component summary score • Dry mouth, thirst, as well as constipation, weakness, hyperglycemia, & urinary frequency were seen more in the tolvaptan group
Lixivaptan • Not yet available in the U.S. • V2 selective • Oral • Gastroenterology 2003 – RCT of 66 patients w/ cirrhosis & hyponatremia (no SIADH or CHF); assigned to 100 or 200mg/d of lixivaptan or placebo, plus 1L fluid restriction, until Na >/= 136 or 7 days
Lixivaptan (cont.) • Statistically significant difference in the # of patients achieving a normal serum Na compared to placebo • Significant reduction in Uosm & body weight • Significant increase in thirst in the high dose group
Lixivaptan (cont.) • Hepatology 2003 – 44 hospitalized patients w/ Na < 130 mmol/L (5 w/ SIADH, 33 w/ cirrhosis, 6 w/ CHF), given 25, 125, or 250mg 2x/d or placebo; doses held for excessive Na rise, dehydration, encephalopathy • Significant response (increased water clearance and serum Na) compared to placebo; significant dose related increase in Na • Higher doses significant dehydration
Satavaptan • Not yet available in the U.S. • V2 selective • Oral • CJASN 2006 – 34 patients treated w/ satavaptan 25mg, 50mg, or placebo x 5 days 23 days of open-label dosage-adjustment period • Statistically significant response in treatment group re. Na normalization or increase by >/= 5mmol/L
Conclusion • Vasopressin receptor antagonists can cause an electrolyte-free aquaresis, reduce urine osmolality, & raise serum Na • Risk of overly rapid correction of hyponatremia seems low • Main side effect is increased thirst • Tachyphylaxis does not seem to occur
Conclusion (cont.) • Possibility of hypotension & variceal bleeding in cirrhotics if given a V1aR blocker • ? Bleeding complications from V2R inhibition in vascular endothelium • ? Role in CHF mortality – data conflicting • $ v. benefit
Conclusion (cont.) • PCKD – polycystin defects may promote cyst development b/c they increases in intracellular cAMP (a second messenger for AVP acting at the V2R) – therefore, V2R antagonists may reduced cyst volume • Congenital NDI – type 2 V2R mutations cause misfolding & interfere w/ trafficking of the receptor from the ER to the cell membrane – VRA can bind to misfolded intracellular V2R & improve transport to the cell membrane
References • Abraham, WT et al. Aquaretic effect of lixivaptan, an oral, non-peptide, selective V2 receptor vasopressin antagonist, in New York Heart Association functional class II and III chronic heart failure patients. JACC 2006; 47(8):1615. • Gerbes, AL et al. Therapy of hyponatremia in cirrhosis with a vasopressin receptor antagonist: a randomized double- blind multicenter trial. Gastroenterology 2003; 124:933. • Ghali, JK et al. Efficacy and safety of oral conivaptan: a V1a/V2 vasopressin receptor antagonist, assessed in a randomized, placebo-controlled trial in patients with euvolemic or hypervolemic hyponatremia. J Clin Endo Metab 2006; 2145. • Gheorghiade, M et al. Effects of tolvaptan, a vasopressor antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 2004; 291:1963. • Gheorghiade, M et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation 2003; 107:2690. • Konstam, MA et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST outcome trial. JAMA 2007; 297:1319. • Renneboog, B et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006; 119:71. • Schrier, RW et al. Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia. NEJM 2006; 355:2099. • Soupart, A et al. Successful long-term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (ST121463B), an orally active nonpeptide vasopressin V2-receptor antagonist. Clin J Am Soc Nephrol 2006; 1:1154. • Udelson, JE et al. Acute hemodynamic effects of conivaptan, a dual V1a and V2 vasopressin receptor antagonist, in patients with advanced heart failure. Circulation 2001; 104:2417. • Verbalis, JG. Pathogenesis of hyponatremia in an experimental model of the syndrome of inappropriate antidiuresis. Am J Physiol 1994; 267:R1617. • Verbalis, JG et al. Vasopressin receptor antagonists. KI 2006; 69:2124. • Wong, F et al. A vasopressin receptor antagonist (VPA-985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo-controlled trial. Hepatology 2003; 37(1):182. • www.uptodate.com