Hyponatremia
Table 1: Characteristics of Vasopressin Receptors Receptor
Old Nomenclature New Nomenclature V1a
V1 V1b V2 V3 V2 G-protein-coupled; phosphatidylinositol/calcium G-protein-coupled;
phosphatidylinositol/calcium Adenyl cyclase/cAMP
Signaling Pathway/Second Messenger Localization
Vascular smooth muscle, platelets, hepatocytes, myometrium
Anterior pituitary gland Nephron collecting duct, vascular Physiologic Effects Vasoconstriction and myocardial
hypertrophy, platelet aggregation, glycogenolysis, uterine contraction ACTH release
Insertion of AQP2 water channels into
endothelium, vascular smooth muscle apical membrane (increased water permeability), induction of AQP2 synthesis, vWF and factor 8 release, vasodilation
ACTH = adenocorticotropic hormone; AQP2 = aquaporin-2; cAMP = cyclic mononucleotide of adenosine; vWF = von Willebrand factor. Table 2: Large Studies in Patients with Hyponatremia Utilizing Conivaptan and Tolvaptan
Conivaptan Author/Journal/
Study Design Zelster et al., Am J Nephrol, 2007
Randomized, double blind,
placebo controlled
Patient Population Dose/Route n=84 Euvolemic/
hypervolemic hyponatremia
Conivaptan 40 mg/day versus 80 mg/day versus placebo plus conventional hyponatremia treatment (fluid restriction)
Results
• Conivaptan 40 mg/day: mean rise in the serum sodium concentration of 6.3 mmol/l
• Conivaptan 80 mg/day: mean rise in the serum sodium concentration of 9.4 mmol/l
• Fast onset of action: conivaptan increased serum sodium concentration within one to two hours after administration
• A 4-day intravenous infusion of conivaptan 40 mg/day is safe and effectively increases serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia
• Main side effect: few cases of infusion-site reactions, leading to the withdrawal of five patients
Ghali et al., J Clin
Randomized, double blind,
placebo controlled
Tolvaptan Schrier et al., N Engl J Med, 2006
Multicenter, randomized, double blind,
placebo controlled Berl et al.,
Multicenter, n=448
Euvolemic and hypervolemic hyponatremia
(sodium less than 135 mEq/l)
n=111
J Am Soc Nephrol, Patients with 2010
euvolemic/ hypervolemic
open label extension hyponatremia of SALT-1 and SALT-2
ADH-stimulated adenylate-cyclase activity. In 1985, Kinter et al. studied hydropenic and water-loaded rats and proved that the administration of the peptide SK&F 1019,26
a potent V1 and V2 antagonist in vitro, caused
increased urine volume and decreased urine osmolarity. Its effects were primarily mediated by blocking V2 receptors in the renal epithelia. Compared with lithium and demeclocycline, the onset was rapid and
102 Tolvaptan titrated regimen (15–60 mg/day orally)
Tolvaptan 15 mg/day orally, titrated up to 30–60 mg/day
• Serum sodium concentrations increased from 128.5 ± 4.5 mmol/l at baseline to 133.9 ± 4.8 mmol/l on day 4 and 135.7 ± 5.0 mmol/l on day 30 in the tolvaptan group
• Hyponatremia recurred within one week after discontinuation of the drug on day 30
• Long-term administration of tolvaptan maintained serum sodium levels at acceptable levels with a fair degree of safety • At 50 weeks of therapy 60 % of patients had a normalized serum sodium concentration.
• Tolvaptan is more efficacious in SIADH and CHF compared with patients with hyponatremia and cirrhosis
CHF = congestive heart failure; SALT = Study of ascending levels of tolvaptan in hyponatremia; SIADH = syndrome of inappropriate secretion of antidiuretic hormone.
the response was both predictable and dose dependent. The authors proposed the term aquaretic agents (water diuretic) to distinguish their pharmacological and therapeutic utility from conventional saluretic agents.25
n=74
Endocrinol Metab, Euvolemic and 2006
hypervolemic hyponatremia
Oral conivaptan 40 mg versus 80 mg versus placebo, given in two divided doses/day for five days
• Mean rise in the serum sodium concentration was 6.4 mmol/l and 8.2 mmol/l in the 40 mg/day conivaptan group and 80 mg/day conivaptan group
• Conivaptan was well tolerated and efficacious in correcting the serum sodium concentration
Although this and other ADH peptide analogs showed promising
results in vitro and in animal models, the outcomes were disappointing when tested in humans. Specifically, these peptides had a paradoxically
US NEPHROLOGY
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