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
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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
Vasopressin Receptor Location &
Functions (KI 2006)
Structure of the Vasopressin V2
Receptor (Brenner & Rector 2004)
Signal Transduction Via the V2
Receptor (Brenner & Rector 2004)
Conivaptan
• Only vasopressin receptor antagonist
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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%)
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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
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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
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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
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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
Baseline Characteristics
Tolvaptan – NEJM 2006
• Increase in average daily AUC for serum Na was
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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
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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/
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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
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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
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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
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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 doubleblind 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.
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