Losartan

from Wikipedia, the free encyclopedia
Structural formula
Structural formula of losartan
General
Non-proprietary name Losartan
other names
  • 2-butyl-4-chloro-1- {4- [2- (2 H -tetrazol-5-yl) phenyl] benzyl} imidazole-5-methanol ( IUPAC )
  • Losartanum ( Latin )
Molecular formula C 22 H 23 ClN 6 O
External identifiers / databases
CAS number
  • 114798-26-4
  • 124750-99-8 (potassium salt)
EC number 601-329-8
ECHA InfoCard 100.110.555
PubChem 3961
ChemSpider 3824
DrugBank DB00678
Wikidata Q410074
Drug information
ATC code

C09 CA01

Drug class

Antihypertensive drugs

Mechanism of action

AT 1 antagonist

properties
Molar mass 422.91 g · mol -1
Physical state

Solid

Melting point

183.5-184.5 ° C

pK s value

5-6

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances

Potassium salt

no GHS pictograms
H and P phrases H: no H-phrases
P: no P-phrases
Toxicological data

1000 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 .

Losartan is a drug from the group of AT 1 antagonists (syn .: sartans) and is used, among other things, to treat high blood pressure .

Clinical information

Application areas (indications)

Use during pregnancy and breastfeeding

  • pregnancy

There is no experience with losartan in pregnant women. However, preclinical animal studies have shown 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 in the second and third trimesters 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 losartan-containing drugs in the second and third trimesters, which is why it must not be used during this period.

  • Lactation

It is not known whether losartan is excreted in breast milk . Significant levels of losartan and its active metabolite were found in milk in the rat. Use during breastfeeding is not recommended.

Special patient groups (diabetics, kidney patients)

Since the Qo value of losartan is high (Qo = 0.95), 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-toxicological properties

The drug losartan (angiotensin II receptor subtype 1 antagonist, AT 1 receptor antagonist, angiotensin receptor blocker, sartan ) has a high affinity for subtype 1 of the angiotensin II receptor and blocks the contractility of smooth muscle cells , reducing the Increase in blood pressure as a result of exogenously supplied angiotensin II and lowers the blood pressure in angiotensin II-dependent hypertension by competitive blockade of the receptors. Losartan is metabolized to its carboxylated active metabolite E 3174 after oral administration , whereby losartan by no means only acts as a prodrug , but also has a high level of activity itself. In contrast to losartan, its metabolite E 3174 shows a non-competitive form of receptor inhibition, which also lasts much longer in its effect and thus leads to an effective increase in angiotensin II inhibition. Due to the long half-life , the single daily administration of losartan is sufficient to achieve an effective reduction in blood pressure over 24 hours.

The LD 50 in rats is 1000 mg kg −1 after oral administration. There is limited information on overdose in humans. The most likely signs of overdose should be hypotension (drop in blood pressure) and tachycardia (rapid pulse). Bradycardia can occur as a result of parasympathetic ( vagal stimulation ). In the event of a symptomatic drop in blood pressure, the vital functions should be closely monitored, and circulatory support should be given. Losartan and its active metabolite cannot be eliminated by hemodialysis .

Others

Chemical information

The monopotassium salt with the empirical formula C 22 H 22 ClKN 6 O, molar mass 461.00 g · mol −1 , and the CAS number 124750-99-8 is used for all pharmaceutical dosage forms .

Development and marketing

Losartan was developed in 1986 by DuPont and launched in 1995 by the pharmaceutical company MSD Sharp & Dohme as the first AT 1 antagonist. In 1997 Losartan was awarded the Galenus von Pergamon Prize , a science award for pharmaceutical research in Germany. Losartan generics have been available since early 2010.

Contamination with nitrosamines

Like the structurally related active ingredient valsartan, losartan is also affected by the occurrence of nitrosamine impurities. As a result, from December 2018 there were recalls of losartan-containing medicines.

Trade names

Monopreparations

  • Cosaar (A, CH), Lanosar (A), Lorzaar (D), Losindia (A), Malokartan (A), Renosaar (A), Tamasol (A), numerous generics (D, A, CH)

Combination preparations

  • Cosaar plus (A, CH), Fortzaar (D, A), Lanosar comp. (A), Lorzaar plus (D), Losathia (A), Losadinol (A), Losivik (A), Vilbitan (A), numerous generics (D, A)

Web links

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

literature

  • W. Forth, D. Henschler, W. Rummel: General and special pharmacology and toxicology . 9th edition. Urban & Fischer, Munich 2005, ISBN 3-437-42521-8 .
  • Patent US5138069 . ‌
  • Inga Voges: Study to determine angiotensin II receptor mRNA levels on the hypothalamus-pituitary-adrenal axis under the influence of antihypertensive drugs . 2005 ( d-nb.info - Inaugural dissertation; University of Lübeck; Medical Faculty).
  • LX Wang, M. Ideishi, E. Yahiro, H. Urata, K. Arakawa, K. Saku: Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia / reperfusion-induced myocardial injury. In: Hypertension research: official journal of the Japanese Society of Hypertension . tape 24 , no. 2 , 2001, p. 179-187 , PMID 11325078 .
  • YH Liu, XP Yang, VG Sharov, O. Nass, HN Sabbah, E. Peterson, OA Carretero: Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. In: Journal of Clinical Investigation . tape 99 , no. 8 , March 15, 1997, p. 1926-1935 , doi : 10.1172 / JCI119360 .

Individual evidence

  1. ↑ a b Entry on Losartan. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.
  2. ↑ a b Datasheet Losartan potassium, analytical standard from Sigma-Aldrich , accessed on May 14, 2017 ( PDF ).
  3. ↑ a b Entry on Losartan in the DrugBank of the University of Alberta .
  4. ↑ Richard B. Devereux, Björn Dahlöf, Eva Gerdts, Kurt Boman, Markku S. Nieminen, Vasilios Papademetriou, Jens Rokkedal, Katherine E. Harris, Jonathan M. Edelman, Kristian Wachtell: Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol . The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial . In: Circulation . tape 110 , no. 11 , September 14, 2004, p. 1456–1462 , doi : 10.1161 / 01.CIR.0000141573.44737.5A , PMID 15326072 ( full text (HTML) full text (PDF; 363 kB) ).
  5. ^ A b MSD Sharp & Dohme: Fachinformation Lorzaar. As of January 2019.
  6. ↑ Dose adjustment in case of renal insufficiency ( Memento of September 27, 2007 in the Internet Archive ) for dosing
  7. ↑ Gaurab Bhardwaj: How the Anti-Hypertensive Losartan was Discovered. ( Memento of December 22, 2014 in the Internet Archive ) (PDF; 101 kB) 2006.