Fosinopril

Structural formula
	Mixture of diastereomers . There is an additional stereocenter on the phosphorus atom.
General
Non-proprietary name	Fosinopril
other names	(2 S , 4 S ) -4-Cyclohexyl-1- {2 '- [(( R , S ) -2-methyl-1-propionyloxypropoxy) - (4-phenylbutyl) phosphinoyl] acetyl} pyrrolidine-2-carboxylic acid
Molecular formula	C 30 H 46 NO 7 P (fosinopril) ; C 30 H 46 NNaO 7 P (fosinopril sodium salt) ;
External identifiers / databases
PubChem	55891
ChemSpider	50469
DrugBank	DB00492
Wikidata	Q425293
Drug information
ATC code	C09 AA09
Drug class	ACE inhibitors
Mechanism of action	Inhibition of the angiotensin converting enzyme
properties
Molar mass	563.66 g · mol -1 (fosinopril) ; 585.64 g · mol -1 (· fosinopril sodium salt) ;
safety instructions
	Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS hazard labeling ; no classification available
	As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Fosinopril is a drug from the group of ACE inhibitors that is used to treat arterial hypertension (high blood pressure) and heart failure . Fosinopril itself is an inactive prodrug . After activation to fosinoprilat, its principle of action is based on the inhibition of the angiotensin converting enzyme (ACE).

pharmacology

application areas

Fosinopril is used as monotherapy and in combination with other antihypertensive agents, preferably diuretics, for the therapy of high blood pressure and for the treatment of heart failure, with synergistic effects and thus an increased blood pressure lowering. In severe forms of heart failure, a combination with digitalis is possible and indicated.

Mechanism of action

Fosinopril leads as inhibitor of angiotensin converting enzyme in a decreased formation of angiotensin II from angiotensin I . This reduced formation of angiotensin II causes a decrease in the tone of the blood vessels and thus a decrease in blood pressure. The decrease in the angiotensin II level also leads to a reduction in the release of aldosterone from the adrenal cortex and thus to an influence on the water balance (see also renin-angiotensin-aldosterone system ).

Side effects

Most of the side effects of fosinopril are associated with slower breakdown and accumulation of bradykinin due to ACE inhibitors . These include skin reactions such as B. exanthema and hives , also angioedema . Serious allergic skin reactions, however, are only very rarely observed.

Respiratory side effects include dry cough, hoarseness, and sore throat. Asthma attacks and shortness of breath can also occur, albeit rarely.

An excessive decrease in blood pressure may occur as a result of the main action of fosinopril. As a result, dizziness, headache, and drowsiness may occasionally be observed. Serious cardiovascular events such as angina pectoris , myocardial infarction and syncope have only been reported in isolated cases.

Functional kidney dysfunctions can occasionally be observed through interference with the water and electrolyte balance. A proteinuria (excretion of protein in the urine), however, was rarely observed.

Since fosinopril in pregnancy u. a. Can cause growth and bone formation disorders in the child combined with increased mortality, fosinopril must not be taken during this time and should be replaced by other suitable therapeutic measures.

Interactions

Fosinopril increases the blood sugar lowering effect of insulin and oral antidiabetic drugs, as well as the blood count-altering effects of immunosuppressants .

By interfering with the water and electrolyte balance, the elimination of electrolytes can be slowed down, which should be taken into account in particular when treating with lithium and potassium-sparing diuretics.

When combined with other antihypertensive drugs, increased blood pressure lowering should be taken into account.

Potency

Fosinopril is available in strengths of 5, 10 and 20 mg and combined with the diuretic hydrochlorothiazide (HCT) in 20 / 12.5 mg.

A dose adjustment is not necessary in the case of liver or kidney dysfunction, as elimination (excretion) takes place in the same way and so there are sufficient possibilities for compensation.

chemistry

Fosinopril is a second generation ACE inhibitor that is only remotely similar to other drugs of the otherwise largely monoform group of ACE inhibitors. The synthesis starts from the amino acid (2 S , 4 R ) -4- hydroxyproline , which is converted into fosinopril in a multi-step reaction sequence . Fosinopril is currently the only ACE inhibitor with a phosphinate structure .

The substance is an inactive prodrug, which is achieved through esterification and acetal formation . The terminal acetyl group is split off in the organism in the liver by esterases . The hemiacetal formed in this way slowly disintegrates, creating the active fosinoprilat.

Stereoisomerism

Fosinopril contains four stereocenters , three of which are on carbon atoms and one on the phosphorus atom. So theoretically there are 16 stereoisomers . The stereocenters on the pyrrolidine ring are clearly defined [(2 S , 4 R )]. However, the absolute configuration of the stereocenter on the carbon atom in the side chain and on the phosphorus atom is not uniform. The drug fosinopril is thus a mixture of diastereomers . Stereoisomers generally have different pharmacological effects.

Trade names

Monopreparations

Dynacil (D), Fositen (CH), Fositens (A), various generics (A)

Combination preparations

In combination with hydrochlorothiazide : Dynacil comp (D), Fosicomp (A, CH), generics (D, A, CH)

Individual evidence

↑ This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.
↑ ABDA database (as of July 16, 2008) of DIMDI .
↑ Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances , 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, pp. 937–938, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.
↑ European Patent No. 1383779 by Jupin Laboratories Ltd., Bombay (India), filing date: August 17, 2001.
↑ EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology , European Journal of Clinical Pharmacology 26 (1984) 663-668. doi : 10.1007 / BF00541922 .
↑ Red List online, as of October 2014.
↑ AM comp. d. Switzerland, as of October 2009.
↑ AGES-PharmMed, as of October 2009.

[NV-1] This substance has either not yet been classified with regard to its hazardousness or a reliable and citable source has not yet been found.

[2] ABDA database (as of July 16, 2008) of DIMDI .

[A._Kleemann-3] Axel Kleemann , Jürgen Engel, Bernd Kutscher and Dietmar Reichert: Pharmaceutical Substances , 4th edition (2000), 2 volumes published by Thieme-Verlag Stuttgart, pp. 937–938, ISBN 978-1-58890-031-9 ; online since 2003 with biannual additions and updates.

[Europapatent-4] European Patent No. 1383779 by Jupin Laboratories Ltd., Bombay (India), filing date: August 17, 2001.

[Ariëns-5] EJ Ariëns: Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology , European Journal of Clinical Pharmacology 26 (1984) 663-668. doi : 10.1007 / BF00541922 .

[6] Red List online, as of October 2014.

[7] AM comp. d. Switzerland, as of October 2009.

[8] AGES-PharmMed, as of October 2009.