1 / 28

Vasopressin Receptor Antagonists

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

Faraday
Download Presentation

Vasopressin Receptor Antagonists

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Vasopressin Receptor Antagonists Alicia Notkin July 17, 2007

  2. Outline • Introduction • Conivaptan • Tolvaptan • Lixivaptan • Satavaptan • Conclusion • References

  3. 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

  4. 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

  5. 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)

  6. 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

  7. Vasopressin Receptor Location & Functions (KI 2006)

  8. Structure of the Vasopressin V2 Receptor (Brenner & Rector 2004)

  9. Signal Transduction Via the V2 Receptor (Brenner & Rector 2004)

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Baseline Characteristics

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. The End

More Related