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Vasopressin receptor antagonist

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A vasopressin receptor antagonist (VRA) is an agent that interferes with action at the vasopressin receptors. Most commonly VRAs are used in the treatment of hyponatremia, especially in patients with congestive heart failure, liver cirrhosis or SIADH.[1]

Types

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Vaptans

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The "vaptan" drugs act by directly blocking the action of vasopressin at its receptors (V1A, V1B and V2). These receptors have a variety of functions, with the V1A and V2 receptors are expressed peripherally and involved in the modulation of blood pressure and kidney function respectively, while the V1A and V1B receptors are expressed in the central nervous system. V1A is expressed in many regions of the brain, and has been linked to a variety of social behaviors in humans and animals.

The vaptan class of drugs contains a number of compounds with varying selectivity, several of which are either already in clinical use or in clinical trials as of 2009.[2][3][4]

Unselective (mixed V1A/V2)
V1A selective (V1RA)
V1B selective (V3RA)
V2 selective (V2RA)

Somatostatin

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Somatostatin is a competitive inhibitor. [5]

Demeclocycline and lithium

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Demeclocycline, a tetracycline antibiotic, is sometimes used to block the action of vasopressin in the kidney in hyponatremia due to inappropriately high secretion of vasopressin (SIADH), when fluid restriction has failed.[6] Demeclocycline is not a direct antagonist of the vasopressin receptors however, but rather inhibits activation of the intracellular second messenger cascade of this receptor in the kidney by an unknown mechanism.[7][8]

Lithium, as lithium carbonate, possesses similar properties to those of demeclocycline on the action of vasopressin in the kidney, and was used clinically before demeclocycline, which largely superseded it for this indication.[7][8]

Medical use

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Hyponatremia

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V2R antagonists have become a mainstay of treatment for euvolemic (i.e., SIADH, postoperative hyponatremia) and hypervolemic hyponatremia (i.e., CHF and cirrhosis).[9] V2RAs predictably cause aquaresis leading to increased [Na+] in majority of patients with hyponatremia due to SIADH, CHF, and cirrhosis. The optimum use of VRAs has not yet been determined, but some predictions can be made with reasonable certainty. For hyponatremia in hospitalized patients, who are unable to take medication orally or for those in whom a more rapid correction of hyponatremia is desired, conivaptan (V1/V2R antagonist) will likely be the preferred agent. Selective V2R antagonists such as tolvaptan, lixivaptan etc. will likely be useful in patients for whom oral therapy is suitable and for more chronic forms of hyponatremia.[9]

Congestive heart failure

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Neurohormonal activation characteristic of CHF, including increased renin, angiotensin, aldosterone, and catecholamines, contributes to progression of CHF. It has been suggested that cardiovascular mortality may be reduced by selective V2RA such as tolvaptan in the higher risk group with kidney function impairment or severe congestive findings.[9] But until FDA indication is granted for use in CHF with or without accompanying hyponatremia, VRAs are not recommended in patients with CHF.[9]

Cirrhosis

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V2RA may be particularly beneficial in the treatment of patients with advanced liver cirrhosis and ascites.[10] Blockade of V2R will induce an effective aquaresis and inhibition of V2-mediated vasodilation. This aquaresis, in combination with a diuresis, may provide a potential therapy for patients with resistant ascites. V2 receptor antagonism increases plasma vasopressin concentration, which may cause unopposed hyperstimulation of the vasoconstrictor V1 receptor. Given the potential hyperstimulation of V1R, V2RA may have additional secondary preventative benefits in patients with cirrhosis through a reduction in portal pressure and a decreased risk of variceal bleeding.[10]

Polycystic kidney disease

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Polycystin defects increase intracellular cAMP, secondary messenger for vasopressin acting at V2R, leading to cyst development.[9] cAMP-dependent genes promote fluid secretion into developing renal cysts and increase cell proliferation. Studies in several animal models of polycystic kidney disease have shown a reduction in kidney size and cyst volume after treatment with specific V2 receptor antagonist.[9] Full scale therapeutic trials of V2RAs in patients with autosomal dominant polycystic kidney disease are currently ongoing.[9]

Nephrogenic diabetes insipidus

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Congenital nephrogenic diabetes insipidus (NDI) may result from V2R or aquaporin-2 (AQP2) mutations. Exogenously administered V2R antagonists can bind to misfolded intracellular V2R, and improve transport of V2R to the cell membrane.[9] Clinical studies in patients with X-linked NDI showed that the selective V1R antagonist relcovaptan (SR49059, Sanofi-Aventis) significantly increased urine osmolality and decreased 24-hour urine flow.[9] Thus V1R and/or V2R antagonists may serve as molecular chaperones to mitigate misfolding defects in selected patients with type 2 NDI.[9]

References

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  1. ^ Palm C, Pistrosch F, Herbrig K, Gross P (July 2006). "Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia". Am. J. Med. 119 (7 Suppl 1): S87–92. doi:10.1016/j.amjmed.2006.05.014. PMID 16843091.
  2. ^ Serradeil-Le Gal C, Wagnon J, Valette G, Garcia G, Pascal M, Maffrand JP, Le Fur G (2002). "Chapter 15 Nonpeptide vasopressin receptor antagonists: Development of selective and orally active V1a, V2 and V1b receptor ligands". Vasopressin and Oxytocin: From Genes to Clinical Applications. Progress in Brain Research. Vol. 139. pp. 197–210. doi:10.1016/S0079-6123(02)39017-4. ISBN 978-0-444-50982-6. PMID 12436936.
  3. ^ Lemmens-Gruber R, Kamyar M (2006). "Vasopressin antagonists". Cellular and Molecular Life Sciences. 63 (15): 1766–79. doi:10.1007/s00018-006-6054-2. PMC 11136164. PMID 16794787. S2CID 30709102.
  4. ^ Decaux G, Soupart A, Vassart G (2008). "Non-peptide arginine-vasopressin antagonists: the vaptans". Lancet. 371 (9624): 1624–32. doi:10.1016/S0140-6736(08)60695-9. PMID 18468546. S2CID 1245079.
  5. ^ Inhibition by somatostatin of the vasopressin-stimulated adenylate cyclase in a kidney-derived line of cells grown in defined medium. FEBS Letters. https://doi.org/10.1016/0014-5793(84)80304-X
  6. ^ Padfield PL, Hodsman GP, Morton JJ (September 1978). "Demeclocycline in the treatment of the syndrome of inappropriate antidiuretic hormone release: with measurement of plasma ADH". Postgrad Med J. 54 (635): 623–7. doi:10.1136/pgmj.54.635.623. PMC 2425217. PMID 103083.
  7. ^ a b Ajay K. Singh, Gordon H. Williams (12 January 2009). Textbook of Nephro-Endocrinology. Academic Press. pp. 250–251. ISBN 978-0-08-092046-7.
  8. ^ a b L. Kovács, B. Lichardus (6 December 2012). Vasopressin: Disturbed Secretion and Its Effects. Springer Science & Business Media. pp. 179–180. ISBN 978-94-009-0449-1.
  9. ^ a b c d e f g h i j Greenberg A, Verbalis JG (2006). "Vasopressin receptor antagonists". Kidney Int. 69 (12): 2124–30. doi:10.1038/sj.ki.5000432. PMID 16672911.
  10. ^ a b Ferguson JW, Therapondos G, Newby DE, Hayes PC (2003). "Therapeutic role of vasopressin receptor antagonism in patients with liver cirrhosis". Clin Sci (Lond). 105 (1): 1–8. doi:10.1042/CS20030062. PMID 12639215.
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