Vasopressin_Receptor_Antagonists - Vasopressin Receptor...

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Unformatted text preview: Vasopressin Receptor Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007 Outline Outline • • • • • • • Introduction Conivaptan Tolvaptan Lixivaptan Satavaptan Conclusion References Introduction Introduction • SIADH – AVP release is not fully suppressed as • • it would normally be in a setting of hypotonicity CHF – arterial under­distention & baroreceptor unloading inhibit vagal suppression of AVP (as well as renin & catecholamines) Cirrhosis – splanchnic vasodilatation arterial underfilling w/ non­osmotic release of AVP Introduction (cont.) 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 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.) 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 Vasopressin Receptor Location & Vasopressin Receptor Location & Functions (KI 2006) Structure of the Vasopressin V2 Structure of the Vasopressin V2 Receptor (Brenner & Rector 2004) Signal Transduction Via the V2 Signal Transduction Via the V2 Receptor (Brenner & Rector 2004) Conivaptan Conivaptan • Only vasopressin receptor antagonist • • • available in the U.S. Non­selective (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 Conivaptan – J Clin Endo Metab 2006 • 74 euvolemic (74%) or hypervolemic (26%) • • patients >/= 18 years w/ Na 115­130 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 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 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 Tolvaptan – NEJM 2006 • Report of 2 RCT: SALT­1 & SALT­2 (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 medication­induced hyponatremia Tolvaptan – NEJM 2006 Tolvaptan – NEJM 2006 • Also excluded if: hypovolemic, recent MI, VT/VF, stroke, SBP < 90 mm Hg, Cr > 3.5 mg/dl, Child­Pugh score > 10 (unless exception), Na < 120 mmol/L w/ neurologic impairment, severe pulmonary HTN, uncontrolled DM, neurologic disease, little chance of short­term survival or unlikely to tolerate fluid volume shifts Tolvaptan – NEJM 2006 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 Baseline Characteristics Baseline Characteristics Tolvaptan – NEJM 2006 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 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.) 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.) 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 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 open­label dosage­adjustment period Statistically significant response in treatment group re. Na normalization or increase by >/= 5mmol/L Conclusion Conclusion • Vasopressin receptor antagonists can cause an electrolyte­free 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.) 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.) 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 References • • • • • • • • • • • • • Abraham, WT et al. Aquaretic effect of lixivaptan, an oral, non­peptide, 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, placebo­controlled 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 V2­receptor blockade with tolvaptan in patients with chronic heart failure: results from a double­blind, 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 V2­receptor antagonist, for hyponatremia. NEJM 2006; 355:2099. Soupart, A et al. Successful long­term treatment of hyponatremia in syndrome of inappropriate antidiuretic hormone secretion with satavaptan (ST121463B), an orally active nonpeptide vasopressin V2­receptor 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 (VPA­985) improves serum sodium concentration in patients with hyponatremia: a multicenter, randomized, placebo­controlled trial. Hepatology 2003; 37(1):182. The End The End ...
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This note was uploaded on 12/24/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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