Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Ramipril: Difference between pages

{{Short description|ACE inhibitor medication}}

{{Use dmy dates|date=April 2020}}

{{cs1 config|name-list-style=vanc|display-authors=6}}

| Watchedfields = changed

| verifiedrevid = 464379985

| image = Ramipril structure.svg

| alt =

| tradename = Altace, others

| DailyMedID = Ramipril

| pregnancy_category =

| routes_of_administration = [[By mouth]]

| legal_CA = Rx-only

| legal_CA_comment =

| protein_bound = 73% (ramipril)<br />56% (ramiprilat)

| metabolism = [[Liver]], to ramiprilat

| elimination_half-life = 13 to 17 hours

| excretion = [[Kidney]] (60%) and fecal (40%)

| IUPHAR_ligand = 6339

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| IUPAC_name = (2''S'',3a''S'',6a''S'')-1-[(2''S'')-2-[<nowiki />[(2''S'')-1-Ethoxy-1-oxo-4-phenylbutan-2-yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2''H''-cyclopenta[''b'']pyrrole-2-carboxylic acid

| C=23 | H=32 | N=2 | O=5

| melting_point = 109

<!-- Definition and medical uses -->

'''Ramipril''', sold under the brand name '''Altace''' among others, is an [[ACE inhibitor]] type medication used to treat [[hypertension|high blood pressure]], [[heart failure]], and [[diabetic kidney disease]].<ref name=AHFS2019/> It can also be used as a preventative medication in patients over 55 years old to reduce the risk of having a heart attack, stroke or cardiovascular death in patients shown to be at high risk, such as some diabetics and patients with vascular disease.<ref>{{cite journal | vauthors = Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G | title = Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients | journal = The New England Journal of Medicine | volume = 342 | issue = 3 | pages = 145–53 | date = January 2000 | pmid = 10639539 | doi = 10.1056/NEJM200001203420301 | doi-access = free }}</ref><ref>{{Cite journal|date=January 2000|title=Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy|author=HOPE study investigators|url=https://linkinghub.elsevier.com/retrieve/pii/S0140673699123237|journal=The Lancet|volume=355|issue=9200|pages=253–259|doi=10.1016/S0140-6736(99)12323-7|s2cid=1863533}}</ref><ref>{{cite journal | vauthors = Savarese G, Costanzo P, Cleland JG, Vassallo E, Ruggiero D, Rosano G, Perrone-Filardi P | title = A meta-analysis reporting effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure | journal = Journal of the American College of Cardiology | volume = 61 | issue = 2 | pages = 131–42 | date = January 2013 | pmid = 23219304 | doi = 10.1016/j.jacc.2012.10.011 | doi-access = free }}</ref> It is a reasonable initial treatment for high blood pressure.<ref name=AHFS2019/> It is taken by mouth.<ref name=AHFS2019/>

<!-- Side effects and mechanisms -->

Common side effects include headaches, dizziness, fatigue, and cough.<ref name=AHFS2019/> Serious side effects may include liver problems, [[angioedema]], [[kidney problems]], and [[high blood potassium]].<ref name=AHFS2019/> Use in [[pregnancy]] and [[breastfeeding]] is not recommended.<ref name=Preg2019>{{cite web |title=Ramipril Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/ramipril.html |website=Drugs.com |access-date=3 March 2019 }}</ref> It is an [[ACE inhibitor]] and works by decreasing [[Renin–angiotensin system|renin-angiotensin-aldosterone system]] activity.<ref name=AHFS2019>{{cite web |title=Ramipril Monograph for Professionals |url=https://www.drugs.com/monograph/ramipril.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=3 March 2019 }}</ref>

<!-- Society and culture -->

Ramipril was patented in 1981 and approved for medical use in 1989.<ref name=Fis2006>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=469 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA469 }}</ref> It is available as a [[generic medication]].<ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=172–173|edition=76}}</ref> In 2022, it was the 187th most commonly prescribed medication in the United States, with more than 2{{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 = Ramipril Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Ramipril | access-date = 30 August 2024 }}</ref>

== Activation and binding ==

Ramipril is a [[pro-drug]]. The molecule must be [[hydrolyzed]] by an [[esterase]] at the {{chem2|OCH2CH3}} and form a [[carboxylate]]. This carboxylate then interacts with the positive Zn²⁺ ion which is located at the active site of the ACE enzyme.<ref>{{cite journal | vauthors = Riordan JF | title = Angiotensin-I-converting enzyme and its relatives | journal = Genome Biology | volume = 4 | issue = 8 | pages = 225 | date = 2003 | pmid = 12914653 | pmc = 193637 | doi = 10.1186/gb-2003-4-8-225 | doi-access = free }}</ref> Ramipril is similar in structure to another ACE Inhibitor, [[trandolapril]], but it has a second [[cyclopentane]] ring instead of a [[cyclohexane]] ring.

==Medical uses==

Medical uses include:

* High blood pressure ([[Hypertension]])

* Congestive heart failure<ref>{{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 = 1303–11 | date = May 2008 | pmid = 18458262 | pmc = 2335176 | doi = 10.1503/cmaj.060068 }}</ref>

* Following [[myocardial infarction|heart attack]] in people with evidence of [[heart failure]]

* People over 55 years at high risk: prevention of heart attack, [[stroke]], cardiovascular death, or in need of [[revascularization]] procedures

* Prevent the onset and/or delay the progression of diabetic kidney disease, with or without proteinuria.<ref>{{cite journal | vauthors = Remuzzi G, Macia M, Ruggenenti P | title = Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study | journal = Journal of the American Society of Nephrology | volume = 17 | issue = 4 Suppl 2 | pages = S90-7 | date = April 2006 | pmid = 16565256 | doi = 10.1681/ASN.2005121324 | doi-access = free }} </ref> Randomized trial evidence suggests that a maximum tolerable dose prevents cardiovascular events and death in patients with diabetic kidney disease.

==Contraindications==

Contraindications to its use include [[volume depletion|volume-depleted]] patients, a history of [[angioedema]] while on an [[ACE inhibitor]], [[pregnancy]] and [[hypotension]].{{citation needed|date=August 2017}}

People should not take ramipril (or any ACE inhibitors) if they have [[hyperkalemia]]. It is also recommended to avoid using salt-substitutes as this can further increase potassium levels in the blood.<ref name="AHFS2019" />

Ramipril can be considered in patients with bilateral or unilateral significant [[renal artery stenosis]] (RAS).<ref name=":2">{{cite journal | vauthors = Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA | title = Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease | journal = Nephrology, Dialysis, Transplantation | volume = 27 | issue = 4 | pages = 1403–1409 | date = April 2012 | pmid = 21993376 | doi = 10.1093/ndt/gfr496 | doi-access = free }}</ref> An early rise in [[serum creatinine]] above baseline is expected after initiation of therapy with Ramipril, however, monitoring serum biochemistry and renal function after initiation is crucial.<ref name=":2" /><ref>{{cite journal | vauthors = Ahmed A | title = Use of angiotensin-converting enzyme inhibitors in patients with heart failure and renal insufficiency: how concerned should we be by the rise in serum creatinine? | journal = Journal of the American Geriatrics Society | volume = 50 | issue = 7 | pages = 1297–1300 | date = July 2002 | pmid = 12133029 | doi = 10.1046/j.1532-5415.2002.50321.x | s2cid = 31459410 }}</ref> Treatment with Ramipril in some patients with significant narrowing in both kidneys can increase serum creatinine concentration (measured in the blood test), which returns to baseline upon therapy cessation.<ref name=":0">{{cite journal | vauthors = Chrysochou C, Foley RN, Young JF, Khavandi K, Cheung CM, Kalra PA | title = Dispelling the myth: the use of renin-angiotensin blockade in atheromatous renovascular disease | journal = Nephrology, Dialysis, Transplantation | volume = 27 | issue = 4 | pages = 1403–1409 | date = April 2012 | pmid = 21993376 | doi = 10.1093/ndt/gfr496 | doi-access = free }}</ref>

==Adverse effects==

* Shakiness

* [[Dry cough]]

* Dizziness and lightheadedness due to low blood pressure

* Fatigue, especially in the early stages

* Mouth dryness in the early stages

* [[Nausea]]

* [[Fainting]]

* Signs of infection (e.g., fever, chills, persistent sore throat)

* Chest pain

* [[Neutropenia]] (low white blood cells)

* [[Erectile dysfunction|Impotence]] (erectile dysfunction)<ref>{{Cite web|url=http://heart-disease.emedtv.com/ramipril/ramipril-side-effects.html|title=Ramipril Side Effects|website=eMedTV: Health Information Brought To Life}}</ref>

* [[Hyperkalemia]]

Serious [[allergic reactions]] to this drug are unlikely, but immediate medical attention must be sought if they occur. Symptoms of a serious allergic reaction include, but are not limited to a [[rash]] or swelling of the face, mouth, tongue, or throat. In extreme cases, ramipril may lead to potentially fatal liver problems.

==Mechanism of action==

{{see also|Renin–angiotensin system}}

[[File:Ramipril 1.25 MG Oral Capsule.jpg|thumb|Ramipril 1.25-mg oral capsule, <br />letter codes and icons may differ]]

[[ACE inhibitor]]s inhibit the actions of [[angiotensin converting enzyme]] (ACE), thereby lowering the production of [[angiotensin II]] and decreasing the breakdown of [[bradykinin]]. The decrease in angiotensin II results in relaxation of [[arteriole]] smooth muscle leading to a decrease in [[total peripheral resistance]], reducing blood pressure as the blood is pumped through widened vessels. Its effect on bradykinin is responsible for the dry cough [[side effect]].

Ramipril, a [[prodrug]] or precursor drug, is converted to the active [[metabolite]] ramiprilat by [[carboxylesterase 1]].<ref Name=Frampton>{{cite journal | vauthors = Frampton JE, Peters DH | title = Ramipril. An updated review of its therapeutic use in essential hypertension and heart failure | journal = Drugs | volume = 49 | issue = 3 | pages = 440–466 | date = March 1995 | pmid = 7774515 | doi = 10.2165/00003495-199549030-00008 | s2cid = 195691742 }}</ref><ref name="pmid24141856">{{cite journal | vauthors = Thomsen R, Rasmussen HB, Linnet K | title = In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors | journal = Drug Metabolism and Disposition | volume = 42 | issue = 1 | pages = 126–133 | date = January 2014 | pmid = 24141856 | doi = 10.1124/dmd.113.053512 | s2cid = 206496779 }}</ref> Ramiprilat is mostly [[excretion|excreted]] by the [[kidney]]s. Its [[half-life]] is variable (3–16 hours), and is prolonged by heart and [[liver failure]], as well as [[kidney failure]]. Peak effect occurs between 3 and 6 hours after dosing, with approximately 50% of this effect retained after 24 hours.<ref>{{cite journal | vauthors = McCarron D | title = 24-hour blood pressure profiles in hypertensive patients administered ramipril or placebo once daily: magnitude and duration of antihypertensive effects. | collaboration = Ramipril Multicenter Study Group | journal = Clinical Cardiology | volume = 14 | issue = 9 | pages = 737–742 | date = September 1991 | pmid = 1835914 | doi = 10.1002/clc.4960140908 | publisher = Wiley | doi-access = free }}</ref>

==Synthesis==

The penultimate step in the synthesis of ramipril combines an [[alanine]] derivative with a (''S,S,S'')-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid [[Protecting group|protected]] as its benzyl ester.<ref name=SC2008>{{cite journal |doi=10.1080/00397910801989238 |title=Expeditious Synthesis of Ramipril: An Angiotensin Converting Enzyme (ACE) Inhibitor |date=2008 | vauthors = Malakondaiah GC, Gurav VM, Reddy LA, Babu KS, Bhaskar BV, Reddy PP, Bhattacharya A, Anand RV |journal=Synthetic Communications |volume=38 |issue=11 |pages=1737–1744 }}</ref> In the original patented route, these components were obtained by a multi-step process.<ref name=US5061722>{{cite patent |country=US |number=5061722 |inventor=Volker Teetz, Rolf Geiger, Hansjorg Urbach, Reinhard Becker, Bernward Scholkens |status=patent |gdate=1991-10-29 |fdate=1989-01-12 |pridate=1989-01-12 |title=Cis, endo-2-azabicyclo-[3.3.0]-octane-3-carboxylic acids, a process for their preparation, agents containing these compounds and their use |assign1= Hoechst AG}}</ref>

:[[File:Ramipril synthesis.svg|upright=2]]

The [[acid chloride]] forms an [[amide]] bond with the amino group of the [[pyrrolidine]] ring in the presence of [[triethylamine]] and ramipril is the product after the benzyl ester has been removed by [[hydrogenation]].<ref name=SC2008/>

==Society and culture==

===US patent===

The compound was protected by a patent which was assigned to the German pharmaceutical company [[Hoechst AG]] (since merged into [[Aventis]]) on 29 October 1991.<ref name=US5061722/> The patent was scheduled to expire on 29 October 2008. On 11 September 2007, in an appeal by the Indian company [[Lupin Ltd.]], the United States [[Court of Appeals for the Federal Circuit]] reversed a district court trial verdict and found that Aventis's patent on ramipril was invalid for "obviousness", opening this drug to generic manufacturers.

===Brand names===

Ramipril is marketed as Prilace by [[Arrow Pharmaceuticals]] in Australia, Ramipro by [[Westfield Pharma]] in the Philippines, Triatec by [[Sanofi-Aventis]] in Italy and United States and Altace by [[King Pharmaceuticals]] in the United States, Novapril by Pharmanova in Ghana, Ramitens by PharmaSwiss, Ampril by Krka in Slovenia, Corpril by Cemelog-BRS in Hungary, Piramil and Prilinda by Hemofarm in Serbia, by Lek in Poland and by Novartis and Opsonin Pharma Limited as Ramace in Bangladesh, and in Canada as Altace (Sanofi-Aventis) and Ramipril (Pharmascience).

Ramipril is marketed in India under the brand names Cardace, Zigpril, Ramistar, Odipril and Zorem . Ramipril is marketed in Myanmar under brand name Endpril .

==Research==

The 2001 Heart Outcomes and Prevention Evaluation trial seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive.<ref>{{cite web | url = http://www.hypertensiononline.org/slides2/slide01.cfm?q=ramipril&dpg=10 |publisher= Hypertension Online|title=HOPE Trial: Main Outcomes and Serum Creatinine|date=13 August 2001| archive-url = https://archive.today/20120802091011/http://www.hypertensiononline.org/slides2/slide01.cfm?q=ramipril&dpg=10 | archive-date=2 August 2012|quote=Ramipril significantly reduced the high cardiovascular risk associated with renal insufficiency}}</ref><ref>{{Cite journal | vauthors = Malmberg K, Rydén L |title=Ramipril reduced mortality and cardiovascular morbidity in high risk adults| publisher = BMJ Publishing Group Ltd |date=March 2000|journal=BMJ Evidence-Based Medicine|volume=5|issue=2|pages=47 |doi=10.1136/ebm.5.2.47 |doi-access=free}}</ref> However, the trial and the interpretation of its results have been criticised.<ref>{{cite web | vauthors = Jafary F, Yusuf S, Nissen S | series = Controversies in Cardiology II | work = MedScape | url = http://www.medscape.com/viewarticle/430926 | title = Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?|year=2002}}</ref>

The Acute Infarction Ramipril Efficacy (AIRE) trial<ref name=Frampton/><ref>{{cite journal | vauthors = | title = Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators | journal = Lancet | volume = 342 | issue = 8875 | pages = 821–8 | date = October 1993 | pmid = 8104270 | doi = 10.1016/0140-6736(93)92693-N | s2cid = 5770772 }}</ref> showed a 27% reduction in mortality for patients receiving ramipril for chronic heart failure following a [[myocardial infarction]].

Ramipril was found to have similar results as [[telmisartan]], an [[angiotensin II receptor antagonist|angiotensin II receptor blocker]].<ref>{{cite journal | vauthors = Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C | title = Telmisartan, ramipril, or both in patients at high risk for vascular events | journal = The New England Journal of Medicine | volume = 358 | issue = 15 | pages = 1547–59 | date = April 2008 | pmid = 18378520 | doi = 10.1056/NEJMoa0801317 | hdl-access = free | hdl = 2437/81925 }}</ref>

== References ==

{{Reflist}}

{{ACE inhibitors}}

{{Angiotensin receptor modulators}}

{{Authority control}}

{{Portal bar | Medicine}}

[[Category:ACE inhibitors]]

[[Category:Carboxamides]]

[[Category:Carboxylic acids]]

[[Category:Enantiopure drugs]]

[[Category:Ethyl esters]]

[[Category:Prodrugs]]

[[Category:Sanofi]]

[[Category:Drugs developed by Pfizer]]

[[Category:Drugs developed by AstraZeneca]]

[[Category:Wikipedia medicine articles ready to translate]]