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Vasopressin is synthesized in the hypothalamus and secreted from the pituitary gland

Vasopressin Synthesis - Hypothalamus and Vasopressin Secretion - Posterior Pituitary

Vasopressin, also known as antidiuretic hormone, is a 9-amino-acid peptide that is synthesized in the nerve bodies in the supraoptic and paraventricular nuclei of the hypothalamus and is secreted from the posterior pituitary gland.1

Vasopressin is released in response to decreased plasma volume and increased serum osmolality2

Vasopressin Secretion - Pituitary Gland

Secretion of vasopressin is normally stimulated by increased plasma osmolality via activation of osmoreceptors in the anterior hypothalamus and by decreased blood volume or pressure via activation of baroreceptors in the carotid sinus, aortic arch, cardiac atria, and pulmonary venous system.1,3

The primary role of vasopressin is to control water balance, electrolyte balance, and blood pressure

Effects Of Vasopressin On The Kidneys

Vasopressin controls the body’s water and electrolyte balance, and blood pressure through its antidiuretic effects on the kidney, resulting in decreased plasma osmolality, and/or increased arterial circulating volume.3,4

The antidiuretic effects of vasopressin occur when it binds to the V2-receptors

Vasopressin -Antidiuretic Effects

Vasopressin contributes to water homeostasis by promoting the reabsorption of fluid through the V2-receptors by binding to these receptors, causing the translocation of aquaporin-2 water channels to the apical membrane in the collecting duct of the kidney.3,4

The diagram below illustrates the mechanism of antidiuresis by vasopressin.

Adapted from Finley, Circulation, 2008.

Vasopressin V2-receptor activation: The binding of vasopressin to the V2-receptor stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A. This pathway increases the exocytosis of aquaporin water channel–containing vesicles and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin-2 channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct.5

Relationship of vasopressin to hyponatremia

Inappropriately elevated plasma levels of vasopressin in conditions such as SIADH and heart failure increase water reabsorption and retention, which will disproportionately expand the plasma volume, thus resulting in dilutional hyponatremia. In patients with syndrome of inappropriate antidiuretic hormone (SIADH), vasopressin release is not fully suppressed, despite hypo-osmolality, owing to other causes, including ectopic production of vasopressin by some tumors. The persistence of vasopressin release due to nonosmotic hemodynamic stimuli is also predominantly responsible for water retention and hyponatremia with hypervolemia and edema-forming disorders, such as heart failure.3

INDICATION and IMPORTANT SAFETY INFORMATION for SAMSCA® (tolvaptan)

INDICATION:

SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH).

Important Limitations:

  • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA
  • It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

IMPORTANT SAFETY INFORMATION:

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM

  • SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely.
  • Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable

WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)

  • Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS.

SAMSCA is contraindicated in the following conditions:

  • — Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA-approved REMS
  • — Urgent need to raise serum sodium acutely
  • — Inability of the patient to sense or appropriately respond to thirst
  • — Hypovolemic hyponatremia
  • — Concomitant use of strong CYP 3A inhibitors
  • — Anuric patients
  • — Hypersensitivity (e.g. anaphylactic shock, rash generalized) to tolvaptan or its components
  • Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae: During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided. Co-administration of diuretics also increases the risk of too rapid correction of serum sodium and such patients should undergo close monitoring of serum sodium.
  • Liver Injury: Tolvaptan can cause serious and potentially fatal liver injury. In clinical trials, cases of serious liver injury have been attributed to chronically administered tolvaptan in patients with ADPKD. Liver failure requiring transplantation has been reported in postmarketing experience with tolvaptan in ADPKD. Limit duration of therapy with SAMSCA to 30 days. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired.
  • Dehydration and Hypovolemia: In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted
  • Co-administration with Hypertonic Saline: Not recommended
  • Other Drugs Affecting Exposure to SAMSCA:
  • CYP 3A Inhibitors: Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors
  • CYP 3A Inducers: Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased
  • P-gp Inhibitors: The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors
  • Hyperkalemia or Drugs that Increase Serum Potassium: Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels

Adverse Reactions: The most common adverse reactions (SAMSCA incidence  ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%)

Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo

Pregnancy and Nursing Mothers: SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.

 

 

References:

1
Verbalis JG. Disorders of body water homeostasis. Best Pract Res Clin Endocrinol Metab. 2003;17(4):471-503.
2
Douglas I. Hyponatremia: why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006;73(suppl 3):S4-S12.
3
Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med. 2013;126(10 suppl 1):S1-S4.
4
Knoers NVAM. Hyperactive vasopressin receptors and disturbed water homeostasis. N Engl J Med. 2005;352(18):1847-1850.
5
Finley JJ, Konstam MA, Udelson JE. Arginine vasopressin antagonists for the treatment of heart failure and hyponatremia. Circulation. 2008;118(4):410-421.