There are three receptors for vasopressin (Antidiuretic
Hormone) - the V1a, V1b, and V2 receptors. The V2 receptors
primarily mediate the antidiuretic response, while V1a and V1b
receptors primarily cause vasoconstriction and
adrenocorticotropic hormone (ACTH) release, respectively.
V2 receptor antagonists, collectively known as Vaptans,
competitively block the binding of vasopressin to V2
receptors, which are located on renal collecting duct cells.
This prevents Vasopressin-mediated activation of these
receptors. These class of agents cause selective water
diuresis (aquaresis), and does not cause sodium
and potassium loss. These agents by causing aquaresis,
helps to raise serum sodium levels.
History of vasopressin receptor antagonists starts
by 1991, when a non peptide vasopressin receptor type 1
antagonist was developed [1]. Vaptans are non peptide
vasopressin receptor antagonists.
There are several trials addressing at the use of Vaptans in
euvolemic hyponatremia. All the available Vaptans have
been used in various trials and have shown increase in
serum sodium levels. Vaptans have been found useful in
pareneoplastic syndrome of inappropriate ant diuretic hormone
(SIADH) also.
In hypervolemic hyponatremia response to Vaptans are different
in different etiologies. Primarily it is used in two groups:
Hypervolemic due to congestive heart failure (CHF)
and Cirrhosis. Several trials addressed the
response to Vaptans in CHF, showed beneficial effect in
elevating serum sodium levels and decreasing
fluid overload.
In cirrhosis liver, non vasopressin mediated
mechanisms also lead to fluid retention,
hence the effectiveness of Vaptans are not
great. Nevertheless trials appeared to confer a slight
advantage in delaying ascites formation and increased serum
sodium in patients with hyponatremia more effectively than
placebo.
Vaptans treatment can be considered a valuable option in: 1)
hyponatremic patients with moderate symptoms (eg, confusion,
disorientation, nausea, unsteady gait), as an alternative to
hypertonic saline infusion; or 2) patients with mild symptoms
(eg, mild neurocognitive alterations, depression) or
asymptomatic, if fluid restriction fails or is not tolerated
[2].
Vaptans are available in oral and intravenous preparations.
Tolvaptan, Mozavaptan, Satavaptan, and Lixivaptan are
selective for the V2 receptor, while an intravenous agent,
Conivaptan, blocks both the V2 and V1a receptors.
Two approved and marketed Vaptans are Conivaptan
(intravenous) and tolvpatan.
Tolvaptan
Tolvaptan was approved by FDA in May 2009. Efficacy of
Tolvaptan was shown in 2 Randomized placebo
controlled, multicenter studies (SALT 1 & SALT
2 ). Together in these 2 studies, about 450
patients with hyponatremia (mean serum sodium 129 meq/L)
caused by the SIADH (190 patients), heart failure, or
cirrhosis were included. Compared with placebo,
tolvaptan significantly increased the serum sodium
concentration at day 4 (134 to 135 meq/L versus 130 meq/L) and
day 30 (136 versus 131 meq/L). In SALT
studies in patients with Serum Sodium Less
than 130 had statistically significant
improvement in mental scores, however clinical
improvement was minimal [3]. In SALTWATER an
open-label extension study, 111 patients were treated with
Tolvaptan for a mean follow-up of almost two years. The mean
serum sodium was maintained at more than 135 meq/L compared to
131 meq/L at baseline [4]. The major adverse effects were
symptoms related to volume depletion.
Another use of tolvaptan is to delay the progression of kidney
enlargement in autosomal dominant polycystic kidney disease
(ADPKD). Two major studies have shown that
patients with ADPKD and a total kidney volume 750
mL or above with relatively preserved renal function (eg,
estimated creatinine clearance 60 mL/minute or more) had
lower increase in kidney volume
and less annual decline of GFR [5,6]. In the
same study more than 2.5-fold increase in liver enzymes
was more common among patients who received Tolvaptan compared
with placebo. Based upon these data, the US FDA issued safety
warnings, recommended that liver function tests be promptly
performed among patients who report symptoms that suggest
liver injury (eg, fatigue, anorexia, right upper quadrant
discomfort, dark urine, jaundice); that Tolvaptan should not
be used in any patient for longer than 30 days; and that
Tolvaptan should not be used at all in patients with liver
disease (including cirrhosis) because it may potentially lead
to liver failure or death.
Another potential major complication of Tolvaptan is that
there may be overly rapid correction of the hyponatremia,
which can lead to irreversible neurologic injury.
Dosage: Initial, 15 mg once daily; after at
least 24 hours, may increase to 30 mg once daily to a maximum
of 60 mg once daily titrating at 24-hour intervals to desired
serum sodium concentration. No dosage adjustment
is required in patients with creatinine
clearance > 10ml/min, and not advised to
use if creatinine clearance < 10 ml/min.
Avoid use in patients with underlying liver disease. Dosage
reduction to be done with concomitant use with CYP3A
inhibitors
Conivaptan
Conivaptan was approved by FDA in December 2005. As Conivaptan
is available in intravenous preparation, it is only useful in
the treatment of SIADH in patients who are hospitalized.
Conivaptan is rapid in action (action
starts as early as one to two
hours) and help in rapid initial rise
in serum sodium [7]. However it is not shown that early
correction of serum sodium reduced hospital stay. Its
use is recommended in mild, moderate and severe hyponatremia
along with other modalities of treatment. As described in
Tolvaptan, it may also cause over correction of serum
sodium and permanent neurological damage
Dosage Intravenous: 20 mg infused over 30
minutes as a loading dose, followed by a continuous infusion
of 20 mg over 24 hours for 2-4 days; may increase to a
maximum dose of 40 mg over 24 hours if serum sodium not
rising sufficiently; total duration of therapy not to exceed 4
days. No dose reduction is needed if creatinine clearance >
30ml/min and not to use if it is < 30ml/min. No dose
modification is required in mild hepatic impairment and
requires dose reduction with moderate liver dysfunction. It is
not recommended to use in severe liver dysfunction. Dose
reduction to be done with concomitant use of with CYP3A
inhibitors.
Lixivaptan
Lixivaptan is an oral vaptan studied in two major
studies. In HARMONY study, 206 patients with or without
symptoms were randomly assigned to receive lixivaptan (25 to
100 mg/day) or placebo for 24 weeks. The serum sodium after
seven days of therapy (the primary endpoint) was significantly
higher with lixivaptan (135 versus 133 meq/L) and remained
significantly higher throughout the remainder of the study
[8].
In the inpatient trial (LIBRA study), 106 hyponatremic
patients (mean serum sodium 127 meq/L) with or without
symptoms were randomly assigned to lixivaptan (25 to 100
mg/day) or placebo and followed for 30 days ]. The serum
sodium at seven days (the primary outcome) was significantly
higher in the lixivaptan group (135 versus 131 meq/L). No
effect on cognitive function was observed [9].
Discontinuation rate in these studies were
high due to adverse reactions
Satavaptan
Satavpatan also has several trials done in euvolemic and
hypervolemic hyponatremia and has shown
improvement in serum sodium levels.
Conclusion
Vaptans are useful class of drugs in treating patients with
euvolemic and hypervolemic hyponatremia. It has to be used in
right indications and for required duration. Careful
monitoring is required to avoid rapid correction of serum
sodium and for adverse effects.
References
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effective, nonpeptide vasopressin V1 receptor antagonist.
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