VASOPRESSIN RECEPTOR ANTAGONISTS

TIM MẠCH

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

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. The End