Valsartan

Structural formula
General
Non-proprietary name	Valsartan
other names	( S ) -3-Methyl-2- { N - [2 ′ - (2 H -tetrazol-5-yl) biphenyl-4-ylmethyl] pentanamido} -butanoic acid ( IUPAC ) ( S ) -3-Methyl-2- { N - [2 '- (2 H -tetrazol-5-yl) biphenyl-4-ylmethyl] pentanamido} -butyric acid
Molecular formula	C 24 H 29 N 5 O 3
Brief description	white hygroscopic solid
External identifiers / databases
CAS number 137862-53-4 EC number 604-045-2 ECHA InfoCard 100.113.097 PubChem 60846 ChemSpider 54833 DrugBank DB00177 Wikidata Q155472
Drug information
ATC code	C09 CA03 C09 DB01 C09 DA03
Drug class	Antihypertensive drug
Mechanism of action	AT 1 antagonist
properties
Molar mass	435.52 g · mol -1
Physical state	firmly
Melting point	116-117 ° C
solubility	practically insoluble in water, slightly soluble in ethanol , sparingly soluble in dichloromethane ≥20 mg ml −1 in DMSO
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances no GHS pictograms H and P phrases H: no H-phrases P: no P-phrases
Toxicological data	> 2000 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Valsartan is a drug from the AT ₁ antagonist group that is used in the treatment of high blood pressure and mild to moderate heart failure when ACE inhibitor therapy is unsuitable. Valsartan was patented in 1991 by Ciba-Geigy AG - now Novartis .

In July 2018, a suspected carcinogenic contamination of batches of a Chinese active ingredient manufacturer became known and affected finished medicinal products were withdrawn from the market in Europe and North America.

Clinical information

application areas

Valsartan is used to treat the following diseases:

Essential hypertension

• Treatment of mild and moderate degree essential hypertension.

Heart failure

• Valsartan is approved for the treatment of mild to moderate heart failure ( NYHA II and III), usually in co-medication with a diuretic and digitalis , if treatment with ACE inhibitors is unsuitable due to undesirable effects (dry cough). Side effects on the occasion of therapy with ACE inhibitors, which result from a general influence on the renin-angiotensin-aldosterone system (e.g. progressive renal insufficiency , hyperkalaemia (serum potassium value above 5.0 mmol / l)) do not constitute an indication for valsartan represent.

Acute myocardial infarction status

• Long-term prophylaxis in patients with a stable status after myocardial infarction associated with left ventricular dysfunction with an ejection fraction ≤ 40%.

Contraindications

Hypersensitivity to valsartan. Hereditary angioedema ; History of angioedema under therapy with an ACE inhibitor or angiotensin II receptor antagonist; Renal insufficiency (creatinine clearance <10 ml / min): no experience; There is no therapy experience with valsartan in children and adolescents (below 18 years of age).

Studies

The Val-HeFT study (Valsartan heart failure trial) published in 2001 with 5010 patients showed a reduced hospitalization rate in patients with heart failure with NYHA stages II to IV. There was no difference between valsartan plus standard therapy versus standard therapy plus placebo for the other endpoints of the study ( cardiopulmonary resuscitation , total mortality, etc.) . Patients without beta blockers and ACE inhibitors benefited from valsartan. The combination of ACE inhibitors, beta blockers and valsartan turned out to be rather unfavorable.

Use during pregnancy and breastfeeding

• pregnancy

There is no experience with valsartan in pregnant women. However, preclinical animal studies have shown valsartan to cause fetal and neonatal damage with fatalities attributed to the drug's effects in the renin-angiotensin-aldosterone system (RAAS). Drugs that act directly on the RAAS can cause damage to fetal development if used during the second and third trimester of pregnancy . Fetal kidney perfusion begins in humans, which is dependent on the development of the renin-angiotensin-aldosterone system, in the second trimester. Accordingly, the risk increases with therapy with valsartan-containing drugs in the second and third trimesters. The use of valsartan is not recommended in the first trimester, but switching to an agent therapy with a suitable safety profile is preferable. Valsartan is contraindicated in the second and third trimesters .

• Lactation

It is not known whether valsartan is excreted in breast milk. In contrast, significant levels of valsartan and its active metabolite were found in the milk of rats. Therefore, an alternative antihypertensive therapy with a better safety profile when used during breastfeeding is preferable, especially when breastfeeding newborns or premature babies.

Valsartan for renal insufficiency

Since the Qo value of valsartan is high (Qo = 0.7), no dose adjustment is necessary in the case of impaired renal function. Many drugs with a high Qo value produce renally eliminated metabolites, the activity of which is not always known. Accordingly, caution should be exercised in the case of severe kidney function impairments.

Pharmacological properties

Mechanism of action

The valsartan acts as an AT ₁ antagonist directly on the angiotensin receptor. This means that bradykinin- induced dry coughs should occur less frequently than with ACE inhibitors .

Pharmacokinetics

According to current knowledge, no active metabolites of valsartan are formed, 30% of which is excreted via the kidneys. The remaining 70% is metabolized via the liver. In contrast to losartan, the bioavailability is lower and is around 23-25%. The bioavailability is reduced by food intake more strongly than with losartan and eprosartan , intake with simultaneous food intake lowers the plasma level by 48%. The maximum plasma level is reached after 2 hours. The biological half-life of valsartan is 6–9 hours.

Carcinogenic impurities

In July 2018, the contamination of certain batches of a Chinese active ingredient manufacturer with a substance considered to be carcinogenic was discovered. Affected finished medicinal products were withdrawn from the market in Europe and North America. As a result, impurities were found in valsartan from other active ingredient manufacturers as well as in other drugs from the sartan group ( irbesartan , losartan ).

→ Main article : Valsartan scandal

Trade names

Monopreparations

Angiosan (A), Cordinate (D), Diovan (protect / forte) (D, A, CH), Provas (D), Valsacor (D, A), Valsartan (A), numerous generics (D)

Combination preparations

• with hydrochlorothiazide : Co-Angiosan (A), CoDiovan (forte) (D, A, CH), Cordinate plus / -forte (D), Provas comp / -maxx (D), Cotareg (forte), numerous generics (D)
• with amlodipine : Copalia (A), Dafiro (A), Exforge (D, A, CH), Imprida (A)
• with amlodipine and hydrochlorothiazide: Dafiro HCT
• with sacubitril : Entresto

Web links

Wikibooks: Pharmacology and Toxicology: Cardiovascular  - Learning and Teaching Materials

Commons : Valsartan  - collection of images, videos and audio files

• What could be the implications of the valsartan recalls? DAZ online on July 5, 2018.
• Valsartan: batch-related recall of drugs containing valsartan, the active ingredient of which was produced by the Chinese manufacturer Zhejiang Huahai Pharmaceutical. Communication from the Federal Institute for Drugs and Medical Devices , as of July 11, 2018

Individual evidence

1. ↑ ^{a b} VALSARTAN FOR SYSTEM SUITABILITY CRS data sheet (PDF) at EDQM , accessed on July 26, 2009.
2. ↑ ^{a b c} Entry on valsartan. In: Römpp Online . Georg Thieme Verlag, accessed on November 12, 2014.
3. ↑ ^{a b c} Data sheet Valsartan ≥98% from Sigma-Aldrich , accessed on August 17, 2016 ( PDF ).
4. ↑ Specialist information Diovan ^® from Novartis-Pharma.
5. ↑ T. Stefenelli: AT1 receptor blocker according to Val-HeFT. In: Journal of Cardiology. 9 (7-8), 2002, pp. 332-334. (PDF file; 577 kB).
6. ↑ arznei telegram 2002: Heart failure: Valsartan can increase mortality .
7. ↑ ^{a b} Diovan specialist information, Novartis Pharma GmbH, as of March 2014.
8. ↑ dose adjustment in renal insufficiency in Dosing ( Memento of 27 September 2007 at the Internet Archive ).
9. ↑ G. Flesch, P. Muller, P. Lloyd: Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist. In: Eur J Clin Pharmacol . 52, 1997, pp. 115-120, doi: 10.1007 / s002280050259 .
10. ↑ Björn Lemmer , Kay Brune (Ed.): Pharmakotherapie . 14th edition. Springer, Heidelberg 2010, ISBN 978-3-642-10540-1 , pp. 232 f .
11. ↑ Hasso Scholz, Ulrich Schwabe (ed.): Pocket book of drug treatment: applied pharmacology . 13., revised. and updated edition. Springer, Berlin / Heidelberg 2005, ISBN 978-3-540-20821-1 , pp. 431; 878 .
12. ↑ Björn Lemmer, Kay Brune (Ed.): Pharmakotherapie . 14th edition. Springer, Heidelberg 2010, ISBN 978-3-642-10540-1 , pp. 207 .
13. ↑ Red List Online, as of August 2009.
14. ↑ Swiss Medicines Compendium , as of August 2009.
15. ↑ AGES-PharmMed, as of August 2009.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !