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{{Short description|ACE inhibitor medication}}
{{distinguish|Allopurinol}}
{{Use dmy dates|date=January 2024}}
{{Drugbox
{{cs1 config |name-list-style=vanc |display-authors=6}}
| verifiedrevid = 443722649
{{Infobox drug
| IUPAC_name = (2''S'')-1-amino}propanoyl]pyrrolidine-2-carboxylic acid <BR><BR>(Diagrams above are enalapril and enalaprilat, respectively. Data below refers to enalapril unless indicated)
| Watchedfields = changed
| image = enalapril-structural.svg
| verifiedrevid = 458951007
| width = 200
| image2 = Enalapril VanDerVals transparent.png | image = Enalapril structure.svg
| width = 222
| alt =
| image2 = Enalapril ball-and-stick model.png
| width2 =
| alt2 =
| caption =


<!--Clinical data--> <!-- Clinical data -->
| tradename = Vasotec | pronounce =
| tradename = Vasotec, Renitec, Enacard, others
| Drugs.com = {{drugs.com|monograph|vasotec}}
| Drugs.com = {{drugs.com|monograph|enalaprilat-enalapril-maleate}}
| MedlinePlus = a686022 | MedlinePlus = a686022
| DailyMedID = Enalapril
| pregnancy_category = C,D
| pregnancy_AU = D
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Enalapril Use During Pregnancy | website=Drugs.com | date=28 February 2020 | url=https://www.drugs.com/pregnancy/enalapril.html | access-date=13 March 2020}}</ref>
| pregnancy_category = Contraindicated<ref name="Drugs.com pregnancy" />
| routes_of_administration = ]
| class = ]
| ATC_prefix = C09
| ATC_suffix = AA02
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Vasotec FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Aqumeldi EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only | legal_status = Rx-only
| routes_of_administration = I.V. and P.O.


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->
| bioavailability = 60% (oral) | bioavailability = 60% (by mouth)
| protein_bound = | protein_bound =
| metabolism = hepatic (to enalaprilat) | metabolism = ] (to enalaprilat)
| metabolites =
| onset =
| elimination_half-life = 11 hours (enalaprilat) | elimination_half-life = 11 hours (enalaprilat)
| duration_of_action =
| excretion = renal
| excretion = ]


<!--Identifiers--> <!-- Identifiers -->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 75847-73-3 | CAS_number = 75847-73-3
| ATC_prefix = C09 | CAS_supplemental =
| ATC_suffix = AA02
| ATC_supplemental =
| PubChem = 5388962 | PubChem = 5388962
| IUPHAR_ligand = 6322
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00584 | DrugBank = DB00584
Line 42: Line 77:
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 578 | ChEMBL = 578
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =


<!--Chemical data--> <!-- Chemical and physical data -->
| IUPAC_name = (2''S'')-1-amino}propanoyl]pyrrolidine-2-carboxylic acid
| C=20 | H=28 | N=2 | O=5
| C=20 | H=28 | N=2 | O=5
| molecular_weight = 376.447 g/mol
| smiles = O=C(O)2N(C(=O)(N(C(=O)OCC)CCc1ccccc1)C)CCC2 | SMILES = O=C(O)2N(C(=O)(N(C(=O)OCC)CCc1ccccc1)C)CCC2
| InChI = 1/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1
| InChIKey = GBXSMTUPTTWBMN-XIRDDKMYBI
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1 | StdInChI = 1S/C20H28N2O5/c1-3-27-20(26)16(12-11-15-8-5-4-6-9-15)21-14(2)18(23)22-13-7-10-17(22)19(24)25/h4-6,8-9,14,16-17,21H,3,7,10-13H2,1-2H3,(H,24,25)/t14-,16-,17-/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GBXSMTUPTTWBMN-XIRDDKMYSA-N | StdInChIKey = GBXSMTUPTTWBMN-XIRDDKMYSA-N
| density =
| density_notes =
| melting_point = 143
| melting_high = 144.5
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}
]
'''Enalapril''' (marketed as '''Renitec''' and '''Vasotec''') is an ] used in the treatment of ] and some types of chronic ]. ACE raises blood pressure by constricting blood vessels. ACE inhibitors like enalapril prevent this effect. Enalapril has been shown to lower the death rate in systolic heart failure.<ref>McMurray JJV, Systolic heart failure, N Engl J Med, 362:228, Jan. 21, 2010)</ref> Enalapril was the first member of the group of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors.


<!-- Definition and medical uses -->
==Development==
'''Enalapril''', sold under the brand name '''Vasotec''' among others, is an ] medication used to treat ], ], and ].<ref name=AHFS2016>{{cite web|title=Enalaprilat/Enalapril Maleate|url=https://www.drugs.com/monograph/enalaprilat-enalapril-maleate.html|publisher=The American Society of Health-System Pharmacists|access-date=8 December 2016|url-status=live|archive-url=https://web.archive.org/web/20161221010141/https://www.drugs.com/monograph/enalaprilat-enalapril-maleate.html|archive-date=21 December 2016}}</ref> For heart failure, it is generally used with a ], such as ].<ref name=WHO2008>{{cite book | title = WHO Model Formulary 2008 | year = 2009 | isbn = 9789241547659 | vauthors = ((World Health Organization)) | veditors = Stuart MC, Kouimtzi M, Hill SR | hdl = 10665/44053 | author-link = World Health Organization | publisher = World Health Organization | hdl-access=free | page=286 }}</ref> It is given by mouth or by ].<ref name=AHFS2016/> Onset of effects are typically within an hour when taken by mouth and last for up to a day.<ref name=AHFS2016/>
Enalapril is a treatment for high blood pressure that works by modulating the ] (RAS) system.


<!-- Side effect and mechanism -->
Squibb developed the first inhibitor, ], but it had adverse effects such as a metallic taste (which, as it turned out, was due to the ] group). ] developed enalapril as a competing product.
Common side effects include ], ], ], and cough.<ref name=AHFS2016/> Serious side effects include ] and ].<ref name=AHFS2016/> Use during ] is believed to result in harm to the baby.<ref name=AHFS2016/> It is in the ] family of medications.<ref name=AHFS2016/>


<!-- History and culture -->
==Enalaprilat==
Enalapril was patented in 1978, and came into medical use in 1984.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=467|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA467 |language=en |url-status=live |archive-url=https://web.archive.org/web/20161220130459/https://books.google.ca/books?id=FjKfqkaKkAAC&pg=PA467|archive-date=20 December 2016}}</ref> It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2022, it was the 141st most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Enalapril Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Enalapril | access-date = 30 August 2024 }}</ref> It is available as a ].<ref>{{cite web | title=Enalapril maleate: FDA-Approved Drugs | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212408 | access-date=24 September 2021}}</ref>
''']''', the first dicarboxylate-containing ACE inhibitor, was developed partly to overcome these limitations of captopril. The sulfhydryl-moiety was replaced by a carboxylate-moiety, but additional modifications were required in its structure-based design to achieve a similar potency to captopril.


==Medical uses==
], however, had a problem of its own. The consequence of the structural modifications was that it proved to have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus enalaprilat was only suitable for ] administration. This was overcome by the researchers at Merck by the ] of enalaprilat with ethanol to produce '''enalapril'''.
]
Enalapril is used to treat hypertension, symptomatic heart failure, and asymptomatic left ventricular dysfunction.<ref name=MedlinePlus>{{cite web | publisher = U.S. National Library of Medicine | date = October 2010 | url = https://www.nlm.nih.gov/medlineplus/druginfo/meds/a686022.html | work = MedlinePlus | title = Enalapril | archive-url = https://web.archive.org/web/20150208220907/http://www.nlm.nih.gov/medlineplus/druginfo/meds/a686022.html | archive-date = 8 February 2015 }}</ref> ACE-inhibitors (including enalapril) have demonstrated ability to reduce the progression and worsening of existing chronic kidney disease in the presence of proteinuria/microalbuminuria (protein in the urine, a biomarker for chronic kidney disease).<ref name="pmid26597926">{{cite journal | vauthors = Xie X, Liu Y, Perkovic V, Li X, Ninomiya T, Hou W, Zhao N, Liu L, Lv J, Zhang H, Wang H | display-authors = 6 | title = Renin-Angiotensin System Inhibitors and Kidney and Cardiovascular Outcomes in Patients With CKD: A Bayesian Network Meta-analysis of Randomized Clinical Trials | journal = American Journal of Kidney Diseases | volume = 67 | issue = 5 | pages = 728–741 | date = May 2016 | pmid = 26597926 | doi = 10.1053/j.ajkd.2015.10.011 | doi-access = free }}</ref> This renal protective effect is not seen in the absence of proteinuria/microalbuminuria, including in diabetic populations.<ref name="pmid26868137">{{cite journal | vauthors = Bangalore S, Fakheri R, Toklu B, Messerli FH | title = Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials | journal = BMJ (Clinical Research Ed.) | volume = 352 | issue = | pages = i438 | date = February 2016 | pmid = 26868137 | pmc = 4772784 | doi = 10.1136/bmj.i438 }}</ref> The benefit has been particularly demonstrated in patients with hypertension and/or diabetes, and is likely to be seen in other populations (although further studies and subgroup analyses of existing studies are needed)<ref name="pmid30948820">{{cite journal | vauthors = Mishima E, Haruna Y, Arima H | title = Renin-angiotensin system inhibitors in hypertensive adults with non-diabetic CKD with or without proteinuria: a systematic review and meta-analysis of randomized trials | journal = Hypertension Research | volume = 42 | issue = 4 | pages = 469–482 | date = April 2019 | pmid = 30948820 | doi = 10.1038/s41440-018-0116-3 | s2cid = 96434746 }}</ref><ref name="pmid26597926"/><ref name="McMurray">{{cite journal | vauthors = McMurray JJ | title = Clinical practice. Systolic heart failure | journal = The New England Journal of Medicine | volume = 362 | issue = 3 | pages = 228–238 | date = January 2010 | pmid = 20089973 | doi = 10.1056/NEJMcp0909392 | quote = Two large trials showed that when patients with NYHA class II, III, or IV heart failure were treated with enalapril, as compared with placebo, in addition to diuretics and digoxin, the rates of admission to the hospital were reduced, and the relative risk reduction for death was 16 to 40%. }}</ref> It is widely used in ].<ref name="pmid23869492">{{cite journal | vauthors = He YM, Feng L, Huo DM, Yang ZH, Liao YH | title = Enalapril versus losartan for adults with chronic kidney disease: a systematic review and meta-analysis | journal = Nephrology | volume = 18 | issue = 9 | pages = 605–614 | date = September 2013 | pmid = 23869492 | doi = 10.1111/nep.12134 | s2cid = 31791094 }}</ref> Furthermore, enalapril is an emerging treatment for ]. A double-blind, placebo-controlled trial showed that when used for this purpose, enalapril led to decreased water consumption (determined by urine output and osmolality) in 60% of patients.<ref>{{cite journal | vauthors = Greendyke RM, Bernhardt AJ, Tasbas HE, Lewandowski KS | title = Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril | journal = Neuropsychopharmacology | volume = 18 | issue = 4 | pages = 272–281 | date = April 1998 | pmid = 9509495 | doi = 10.1016/S0893-133X(97)00159-0 | doi-access = free }}</ref>


==Side effects==
As a ], enalapril is metabolised ''in vivo'' to the active form enalaprilat by various ]s. Peak plasma enalaprilat concentrations occur 2 to 4 hours after oral enalapril administration. Elimination thereafter is biphasic, with an initial phase which reflects renal filtration (elimination half-life 2 to 6 hours) and a subsequent prolonged phase (elimination half-life 36 hours), the latter representing equilibration of drug from tissue distribution sites.
The most common side effects of enalapril include increased ] (20%), dizziness (2–8%), low blood pressure (1–7%), syncope (2%), and dry cough (1–2%). The most serious common adverse event is ] (swelling) (0.68%) which often affects the face and lips, endangering the patient's airway. Angioedema can occur at any point during treatment with enalapril, but is most common after the first few doses.<ref name="Vasotec FDA label"/> Angioedema and fatality therefrom are reportedly higher among black people.<ref name="Vasotec FDA label"/> Agranulocytosis has been observed with Enalapril.<ref>{{cite journal | vauthors = Todd PA, Goa KL | title = Enalapril. A reappraisal of its pharmacology and therapeutic use in hypertension | journal = Drugs | volume = 43 | issue = 3 | pages = 346–381 | date = March 1992 | pmid = 1374319 | doi = 10.2165/00003495-199243030-00005 | s2cid = 262278681 }}</ref>


Some evidence suggests enalapril will cause injury and death to a developing fetus. In pregnancy, enalapril may result in damage to the fetus's kidneys and resulting ] (not enough amniotic fluid). Enalapril is secreted in breast milk and is not recommended for use while breastfeeding.<ref name="Vasotec FDA label">{{cite web | title=Vasotec- enalapril maleate tablet | website=DailyMed | date=12 November 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=39631f1f-5d19-43c1-b504-bf56d991ed97 | access-date=26 April 2020}}</ref>
The prolonged phase does not contribute to drug accumulation on repeated administration but is thought to be of pharmacological significance in mediating drug effects. Renal impairment results in significant accumulation of enalaprilat and necessitates dosage reduction. Accumulation is probably the cause of reduced elimination in healthy elderly individuals and in patients with concomitant diabetes, hypertension and heart failure.


==Mechanism of action==
==A prototype for others==
{{see also|Renin–angiotensin system}}
Most importantly, perhaps, the ]-based modifications in structure serendipitously led to an improved understanding of the structure of ACE which aided in the development of subsequent ]-containing ACE inhibitors.
Normally, ] is converted to ] by an ] (ACE). Angiotensin II constricts blood vessels, increasing blood pressure. ], the active metabolite of enalapril, inhibits ACE. Inhibition of ACE decreases levels of angiotensin II, leading to less vasoconstriction and decreased blood pressure.<ref name="Vasotec FDA label"/>


==Pharmacokinetics==
Enalapril is a prodrug that is converted by deesterification to converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies.
] data of enalapril:<ref name="Vasotec FDA label"/>
* Onset of action: about 1 hour
* Peak effect: 4–6 hours
* Duration: 12–24 hours
* Absorption: ~60%
* Metabolism: prodrug, undergoes biotransformation to ]<ref>Menard J and Patchett A. Angiotensin-Converting Enzyme Inhibitors. Pp 14-76 in Drug Discovery and Design. Volume 56 of Advances in Protein Chemistry. Eds Richards FM, Eisenberg DS, and Kim PS. Series Ed. Scolnick EM. Academic Press, 2001. {{ISBN|9780080493381}}. {{webarchive|url=https://web.archive.org/web/20170910175508/https://books.google.com/books?id=aH6vjC-tXV8C&pg=PA30 |date=10 September 2017 }}</ref>


== Structure activity relationship ==
==Side Effects==
Enalapril has an L-proline moiety as a part of the molecule which is responsible for the oral ] of the drug. It is a pro-drug, which means that it exerts its function after being metabolized. The "-OCH2CH3" part of the molecule will split during the metabolism and at the carbon will be a carboxylate, which then interacts with the Zn+2 site of the ACE enzyme. This structural feature and mechanism of metabolism that must occur before the drug can inhibit the enzyme explains why it has a greater duration of action than another similar drug used for the same indication, Captopril. Duration of effect is dose-related; at recommended doses, antihypertensive and haemodynamic effects have been shown to be maintained for at least 24 hours.<ref>{{cite web| title=Enalapril 10mg Tablets - Summary of Product Characteristics. Section 5.1 Pharmacodynamic properties|publisher=emc (electronic medicines compendium)| date=21 February 2023 | url=https://www.medicines.org.uk/emc/product/561/smpc}}</ref><ref>{{cite journal | vauthors = Given BD, Taylor T, Hollenberg NK, Williams GH | title = Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects | journal = Journal of Cardiovascular Pharmacology | volume = 6 | issue = 3 | pages = 436–441 | year = 1984 | pmid = 6202969 | doi = 10.1097/00005344-198405000-00010 | doi-access = free }}</ref> Enalapril has a slower onset of action than Captopril but a greater duration of action. However, unlike Captopril, Enalapril does not have a thiol moiety.
Most common side effects include hypotension, dizziness when standing up, and dry cough.<ref></ref>


==Synthesis== ==History==
Squibb developed the first ACE inhibitor, ], but it had adverse effects such as a metallic taste (which, as it turned out, was due to the ] group). ] developed enalapril as a competing product.<ref>{{cite journal | vauthors = Bryan J | title = From snake venom to ACE inhibitor--The discovery and rise of captopril. | journal = Pharmaceutical Journal | date = April 2009 | volume = 282 | issue = 7548 | pages = 455 | url = http://www.pharmaceutical-journal.com/news-and-analysis/news/from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril/10884359.article }}</ref><ref name=HistDD>{{cite book | vauthors = Li JJ | veditors = Li JJ, Corey EJ | chapter = Chapter 1: History of Drug Discovery | title = Drug Discovery: Practices, Processes, and Perspectives | publisher = John Wiley & Sons | date = April 2013 | isbn = 9781118354469 }}</ref>{{rp|12–13}}
]


] was developed first, partly to overcome these limitations of captopril. The ] moiety was replaced by a ] moiety, but additional modifications were required in its structure-based design to achieve a potency similar to captopril. Enalaprilat, however, had a problem of its own in that it had poor oral availability. This was overcome by the Merck researchers through the ] of enalaprilat with ] to produce enalapril.<ref name=HistDD/>
Patchett, A. A.; in Chronicles of Drug Discovery, Vol. 3; Lednicer, D., ed., ACS Books,
Washington, DC, 1993, 125.


Merck introduced enalapril to market in 1981; it became Merck's first billion dollar-selling drug in 1988.<ref name=HistDD/> The patent expired in 2000, opening the way for generics.<ref>Staff, Drug Discovery Online.
==References==
{{webarchive|url=https://web.archive.org/web/20160512204725/http://www.drugdiscoveryonline.com/doc/patent-expiry-looms-18-blockbusters-expose-37-0003 |date=12 May 2016 }} Page accessed 23 April 2016</ref>
{{reflist}}


== Society and culture ==
==External links==
=== Legal status ===
{{commons}}
In September 2023, the ] (CHMP) of the ] adopted a positive opinion, recommending the granting of a pediatric use marketing authorization for the medicinal product Aqumeldi, intended for the treatment of heart failure in children from birth to less than 18 years of age.<ref name="Aqumeldi: Pending EC decision" /> The applicant for this medicinal product is Proveca Pharma Limited.<ref name="Aqumeldi: Pending EC decision">{{cite web | title=Aqumeldi: Pending EC decision | website=European Medicines Agency | date=15 September 2023 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/aqumeldi | access-date=21 September 2023}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Aqumeldi was approved for medical use in the European Union in November 2023.<ref name="Aqumeldi EPAR">{{cite web | title=Aqumeldi EPAR | website=European Medicines Agency | date=15 November 2023 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/aqumeldi | access-date=20 January 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>
*

== References ==
{{Reflist}}


{{ACE inhibitors}} {{ACE inhibitors}}
{{Angiotensin receptor modulators}}
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