Valsartan

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Valsartan
Valsartan.svg
Valsartan ball-and-stick.png
Systematic (IUPAC) name
(S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
Clinical data
Trade namesDiovan
AHFS/Drugs.commonograph
MedlinePlusa697015
Licence dataUS FDA:link
Pregnancy cat.
Legal status
Routesoral
Pharmacokinetic data
Bioavailability25%
Protein binding95%
Half-life6 hours
ExcretionRenal 30%, biliary 70%
Identifiers
CAS number137862-53-4 YesY
ATC codeC09CA03
PubChemCID 60846
IUPHAR ligand3937
DrugBankDB00177
ChemSpider54833 YesY
UNII80M03YXJ7I YesY
KEGGD00400 YesY
ChEBICHEBI:9927 YesY
ChEMBLCHEMBL1069 YesY
Chemical data
FormulaC24H29N5O3 
Mol. mass435.519 g/mol
 YesY (what is this?)  (verify)
 
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Valsartan
Valsartan.svg
Valsartan ball-and-stick.png
Systematic (IUPAC) name
(S)-3-methyl-2-(N-{[2'-(2H-1,2,3,4-tetrazol-5-yl)biphenyl-4-yl]methyl}pentanamido)butanoic acid
Clinical data
Trade namesDiovan
AHFS/Drugs.commonograph
MedlinePlusa697015
Licence dataUS FDA:link
Pregnancy cat.
Legal status
Routesoral
Pharmacokinetic data
Bioavailability25%
Protein binding95%
Half-life6 hours
ExcretionRenal 30%, biliary 70%
Identifiers
CAS number137862-53-4 YesY
ATC codeC09CA03
PubChemCID 60846
IUPHAR ligand3937
DrugBankDB00177
ChemSpider54833 YesY
UNII80M03YXJ7I YesY
KEGGD00400 YesY
ChEBICHEBI:9927 YesY
ChEMBLCHEMBL1069 YesY
Chemical data
FormulaC24H29N5O3 
Mol. mass435.519 g/mol
 YesY (what is this?)  (verify)

Valsartan (trade name Diovan) is an angiotensin II receptor antagonist (more commonly called an ARB, or angiotensin receptor blocker), with particularly high affinity for the type I (AT1) angiotensin receptor. It blocks the actions of angiotensin II, which include constricting blood vessels and activating aldosterone, to reduce blood pressure. [1] In the U.S., valsartan is indicated for treatment of high blood pressure, congestive heart failure (CHF), or post-myocardial infarction (MI).[2] In 2005, Valsartan was prescribed more than 12 million times in the United States[citation needed] and global sales were approximately $6.1 billion in 2010.[3] The patents for valsartan and valsartan/hydrochlorothiazide expired in September 2012.[4][5]

Contraindications[edit]

Valsartan should not be given with aliskiren to people with diabetes.[2]

Valsartan falls in FDA Pregnancy Category D with a black box warning for fetal toxicity.[2] Discontinuation of these agents is recommended immediately after detection of pregnancy and an alternative medication should be started.[2] The US labeling makes no recommendation regarding continuation or discontinuation of valsartan for breast-feeding mothers.[2] The Canadian labeling does not recommend use by nursing women.[6]

Side effects[edit]

Interactions[edit]

The US prescribing information list the following drug interactions for valsartan:

Myocardial infarction controversy[edit]

In 2003, the CHARM-alternative trial found a significant +52% (p=0.025) increase in myocardial infarction with candesartan (versus placebo) despite a reduction in blood pressure.[8] Then, in 2004, the VALUE trial found that valsartan produced a statistically significant 19% (p=0.02) relative increase in the prespecified secondary end point of myocardial infarction (fatal and non-fatal) when compared to amlodipine.[9] Whether angiotensin receptor blockers may or may not increase the risk of myocardial infarction (heart attack) was announced in BMJ[10] and was debated in 2006 in the medical journal of the American Heart Association.[11][12] To date[when?], there is no consensus on whether ARBs have a tendency to increase MI, but there is also no substantive evidence to indicate that ARBs are able to reduce MI.

Indeed, as a consequence of AT1 blockade, ARBs increase Angiotensin II levels several-fold above baseline by uncoupling a negative-feedback loop. Increased levels of circulating Angiotensin II result in unopposed stimulation of the AT2 receptors, which are, in addition upregulated. Unfortunately, recent data suggest that AT2 receptor stimulation may be less beneficial than previously proposed and may even be harmful under certain circumstances through mediation of growth promotion, fibrosis, and hypertrophy, as well as proatherogenic and proinflammatory effects.[13][14][15]

Research[edit]

In patients with impaired glucose tolerance, valsartan may decrease the incidence of developing diabetes mellitus type 2. However, the absolute risk reduction is small (less than 1 percent per year) and diet, exercise or other drugs, may be more protective. In the same study, no reduction in the rate of cardiovascular events (including death) was shown.[16]

A prospective study released in 2010, based on 819,491 cases in U.S. Department of Veterans Affairs database from 2002 to 2006, demonstrated a significant reduction in the incidence and progression of Alzheimer's disease and dementia.[17] An earlier study released by the Journal of Clinical Investigation in 2007 found some efficacy in the use of valsartan in the treatment and prevention of Alzheimer's disease (in a mouse model).[18]

A dose-dependent Coxsackie virus and adenovirus receptor mRNA and protein downregulation upon Valsartan and Bosentan treatment was reported in 2010. So Bosentan maybe protect the myocardium and other tissues from coxsackie- and adenoviral infection.[19]


See also[edit]

References[edit]

  1. ^ Marks JW (2007-02-15). "Valsartan, Diovan". MedicineNet. Retrieved 2010-03-04. 
  2. ^ a b c d e f "Diovan prescribing information". Novartis. 
  3. ^ "Novartis Annual Report". Novartis. 2010. Retrieved June 15, 2011.
  4. ^ Philip Moeller (April 29, 2011). "Blockbuster Drugs That Will Go Generic Soon". U.S.News & World Report. 
  5. ^ Eva Von Schaper (August 5, 2011). "Novartis's Jimenez Has Blockbuster Plans For Diovan After Patent Expires". Bloomberg. 
  6. ^ Lexi-Drugs Online. "Valsartan". Lexi-Comp. 
  7. ^ Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X. 
  8. ^ Granger CB, McMurray JJ, Yusuf S, et al. (September 2003). "Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial". The Lancet 362 (9386): 772–6. doi:10.1016/S0140-6736(03)14284-5. PMID 13678870. 
  9. ^ Julius S, Kjeldsen SE, Weber M, et al. (June 2004). "Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial". The Lancet 363 (9426): 2022–31. doi:10.1016/S0140-6736(04)16451-9. PMID 15207952. 
  10. ^ Verma S, Strauss M (November 2004). "Angiotensin receptor blockers and myocardial infarction: These drugs may increase myocardial infarction—and patients may need to be told". BMJ 329 (7477): 1248–9. doi:10.1136/bmj.329.7477.1248. PMC 534428. PMID 15564232. 
  11. ^ Strauss MH, Hall AS (August 2006). "Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox". Circulation 114 (8): 838–54. doi:10.1161/CIRCULATIONAHA.105.594986. PMID 16923768. 
  12. ^ Tsuyuki RT, McDonald MA (August 2006). "Angiotensin receptor blockers do not increase risk of myocardial infarction". Circulation 114 (8): 855–60. doi:10.1161/CIRCULATIONAHA.105.594978. PMID 16923769. 
  13. ^ Levy BI (September 2005). "How to explain the differences between renin angiotensin system modulators". Am. J. Hypertens. 18 (9 Pt 2): 134S–141S. doi:10.1016/j.amjhyper.2005.05.005. PMID 16125050. 
  14. ^ Levy BI (January 2004). "Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system". Circulation 109 (1): 8–13. doi:10.1161/01.CIR.0000096609.73772.C5. PMID 14707017. 
  15. ^ Reudelhuber TL (December 2005). "The continuing saga of the AT2 receptor: a case of the good, the bad, and the innocuous". Hypertension 46 (6): 1261–2. doi:10.1161/01.HYP.0000193498.07087.83. PMID 16286568. 
  16. ^ McMurray JJ, Holman RR, Haffner SM, et al. (April 2010). "Effect of valsartan on the incidence of diabetes and cardiovascular events" (PDF). The New England Journal of Medicine 362 (16): 1477–90. doi:10.1056/NEJMoa1001121. PMID 20228403. 
  17. ^ Li NC, Lee A, Whitmer RA, et al. (January 2010). "Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis". BMJ 340: b5465. doi:10.1136/bmj.b5465. PMC 2806632. PMID 20068258. 
  18. ^ Wang J, Ho L, Chen L, et al. (November 2007). "Valsartan lowers brain β-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease" (PDF). J. Clin. Invest. 117 (11): 3393–402. doi:10.1172/JCI31547. PMC 2040315. PMID 17965777. Retrieved 2009-11-11. 
  19. ^ Funke C, Farr M, Werner B, Dittmann S, Uberla K, Piper C, Niehaus K, Horstkotte D (Apr 2010). "Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells.". Journal of General Virology 91 (8): 1959–1570. doi:10.1099/vir.0.020065-0. PMID 20392896. 

External links[edit]