Fosinopril
{{Short description|Antihypertensive drug of the ACE inhibitor class}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461113624
| IUPAC_name = (2S,4S)-4-cyclohexyl-1-[2-[hydroxy(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid
| image = Fosinopril structure.svg
| width = 240
| tradename = Monopril
| Drugs.com = {{drugs.com|monograph|monopril}}
| MedlinePlus = a692020
| pregnancy_AU = D
| pregnancy_category =
| legal_status = Rx-only
| routes_of_administration = By mouth
| bioavailability = ~36%
| protein_bound = 87% (fosinoprilat)
| metabolism = liver, GIT mucosa (to fosinoprilat)
| elimination_half-life = 12 hours (fosinoprilat)
| excretion = kidney
| IUPHAR_ligand = 6456
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 98048-97-6
| ATC_prefix = C09
| ATC_suffix = AA09
| ATC_supplemental =
| PubChem = 55891
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00492
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10482016
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = R43D2573WO
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07992
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 3039598
| C=30 | H=46 | N=1 | O=7 | P=1
| smiles = O=C(CP(=O)(CCCCc1ccccc1)OC(OC(=O)CC)C(C)C)N2C[C@@H](C[C@H]2C(O)=O)C3CCCCC3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C30H46NO7P/c1-4-28(33)37-30(22(2)3)38-39(36,18-12-11-15-23-13-7-5-8-14-23)21-27(32)31-20-25(19-26(31)29(34)35)24-16-9-6-10-17-24/h5,7-8,13-14,22,24-26,30H,4,6,9-12,15-21H2,1-3H3,(H,34,35)/t25-,26+,30?,39-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BIDNLKIUORFRQP-YYTCENNOSA-N
}}
Fosinopril is an angiotensin converting enzyme (ACE) inhibitor{{cite journal | vauthors = Pilote L, Abrahamowicz M, Eisenberg M, Humphries K, Behlouli H, Tu JV | title = Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure | journal = CMAJ | volume = 178 | issue = 10 | pages = 1303–1311 | date = May 2008 | pmid = 18458262 | pmc = 2335176 | doi = 10.1503/cmaj.060068 }} used for the treatment of hypertension and some types of chronic heart failure. Fosinopril is the only phosphonate-containing ACE inhibitor marketed, by Bristol-Myers Squibb under the trade name Monopril. Fosinopril is a cascading pro-drug. The special niche for the medication that differentiates it from the other members of the ACE Inhibitor drug class is that was specifically developed for the use for patients with renal impairment. This was through manipulation of the metabolism and excretion, and is seen that fifty percent of the drug is hepatobiliary cleared, which can compensate for diminished renal clearance. The remaining fifty percent is excreted in urine. It does not need dose adjustment.
It was patented in 1980 and approved for medical use in 1991.{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=468 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA468 |language=en}}
Medical uses
In congestive heart failure, the ability of the heart to pump enough blood to satisfy the physiological needs of the body is reduced.{{cite book | vauthors = Guyton AC, Hall JE |title=Textbook of medical physiology: online access + interactive extras: studentconsult.com |date=2006 |publisher=Elsevier, Saunders |location=Philadelphia, Pa |isbn=978-0-7216-0240-0 |edition=11th}} This condition has a variety of causes, including damaged heart valves, myocardial infarction, hypertension, vitamin B1 deficiency, and genetic mutations. When subsequent blood flow to the kidneys is reduced, the kidneys respond by increasing the secretion of renin from the juxtaglomerular apparatus. Renin converts the inactive angiotensinogen into angiotensin I, which is converted to angiotensin II (AII) by angiotensin converting enzyme (ACE). AII can have negative effects on the cardiovascular system after events such as heart failure and myocardial infarction. AII causes arterial vasoconstriction and hypertension, resulting in an increase in afterload, increasing the resistance against which the heart works.{{cite book | vauthors = Katzung BG, Masters SB, Trevor AJ | date = 2009 | title = Basic and Clinical Pharmacology | edition = 11th | location = New York | publisher = McGraw-Hill | isbn = 978-0-07-160405-5}} Additionally, chronic increase in production of AII is associated with structural changes to the myocardium{{cite journal | vauthors = Yamagishi H, Kim S, Nishikimi T, Takeuchi K, Takeda T | title = Contribution of cardiac renin-angiotensin system to ventricular remodelling in myocardial-infarcted rats | journal = Journal of Molecular and Cellular Cardiology | volume = 25 | issue = 11 | pages = 1369–1380 | date = November 1993 | pmid = 8301670 | doi = 10.1006/jmcc.1993.1149 }} which reduces the functionality of the heart.
In heart failure patients, fosinopril increases exercise tolerance and lowers the frequency of events associated with worsening heart failure, such as dyspnea, the need for supplemental diuretics, fatigue, and hospitalizations.{{cite journal | vauthors = Erhardt L, MacLean A, Ilgenfritz J, Gelperin K, Blumenthal M | title = Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Fosinopril Efficacy/Safety Trial (FEST) Study Group | journal = European Heart Journal | volume = 16 | issue = 12 | pages = 1892–1899 | date = December 1995 | pmid = 8682023 | doi = 10.1093/oxfordjournals.eurheartj.a060844 }}
Chemistry
Unlike other ACE inhibitors that are primarily excreted by the kidneys, fosinopril is eliminated from the body by both renal and hepatic pathways.{{cite journal | vauthors = Zannad F, Chati Z, Guest M, Plat F | title = Differential effects of fosinopril and enalapril in patients with mild to moderate chronic heart failure. Fosinopril in Heart Failure Study Investigators | journal = American Heart Journal | volume = 136 | issue = 4 Pt 1 | pages = 672–680 | date = October 1998 | pmid = 9778071 | doi = 10.1016/s0002-8703(98)70015-8 }} This characteristic of fosinopril makes the drug a safer choice than other ACE inhibitors for heart failure patients with impaired kidney function resulting from poor perfusion{{cite journal | vauthors = Greenbaum R, Zucchelli P, Caspi A, Nouriel H, Paz R, Sclarovsky S, O'Grady P, Yee KF, Liao WC, Mangold B | display-authors = 6 | title = Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency | journal = British Journal of Clinical Pharmacology | volume = 49 | issue = 1 | pages = 23–31 | date = January 2000 | pmid = 10606834 | pmc = 2014892 | doi = 10.1046/j.1365-2125.2000.00103.x }} as fosinopril can still be eliminated by the liver, preventing accumulation of the drug in the body.
Fosinopril is de-esterified by the liver or gastrointestinal mucosa and is converted to its active form, fosinoprilat.{{cite journal | vauthors = Duchin KL, Waclawski AP, Tu JI, Manning J, Frantz M, Willard DA | title = Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects | journal = Journal of Clinical Pharmacology | volume = 31 | issue = 1 | pages = 58–64 | date = January 1991 | pmid = 1646240 | doi = 10.1002/j.1552-4604.1991.tb01887.x | s2cid = 24683211 }} Fosinoprilat competitively binds to ACE, preventing ACE from binding to and converting angiotensin I to angiotensin II. Inhibiting the production of AII lowers peripheral vascular resistance, decreases afterload, and decreases blood pressure, thus helping to alleviate the negative effects of AII on cardiac performance.
References
{{reflist}}
{{ACE inhibitors}}
{{Angiotensin receptor modulators}}