View source for Biology:ACE inhibitor

{{short description|Class of medications used primarily to treat high blood pressure}}
{{Infobox drug class
| Name              = Angiotensin-converting-enzyme inhibitor
| Image             = Captopril skeletal.svg
| Alt               =
| Caption           = [[Chemistry:Captopril|Captopril]], the first synthetic ACE inhibitor
| Use               = [[Medicine:Hypertension|Hypertension]]
| Biological_target = [[Biology:Angiotensin-converting enzyme|Angiotensin-converting enzyme]]
| ATC_prefix        = C09A
| MeshID            = D000806
| Drugs.com         = {{Drugs.com|drug-class|angiotensin-converting-enzyme-inhibitors}}
| Consumer_Reports  = ace-inhibitors
| medicinenet       = ace_inhibitors
| rxlist            = 94663
}}
'''Angiotensin-converting-enzyme inhibitors''' ('''ACE inhibitors''') are a class of [[Chemistry:Medication|medication]] used primarily for the treatment of [[Medicine:Hypertension|high blood pressure]] and [[Medicine:Heart failure|heart failure]].<ref name="Kaplans Essentials of Cardiac Anesthesia 2018 p. ">{{cite book | title=Kaplan's Essentials of Cardiac Anesthesia | publisher=Elsevier | year=2018 | isbn=978-0-323-49798-5 | doi=10.1016/c2012-0-06151-0 | quote=Mechanisms of Action:ACE inhibitors act by inhibiting one of several proteases responsible for cleaving the decapeptide Ang I to form the octapeptide Ang II. Because ACE is also the enzyme that degrades bradykinin, ACE inhibitors increase circulating and tissue levels of bradykinin (Fig. 8.4). }}</ref><ref name="Aronow 2010 pp. 327–337">{{cite book | last=Aronow | first=Wilbert S. | title=Brocklehurst's Textbook of Geriatric Medicine and Gerontology | chapter=Cardiac Arrhythmias | publisher=Elsevier | year=2010 | isbn=978-1-4160-6231-8 | doi=10.1016/b978-1-4160-6231-8.10045-5 | pages=327–337 | quote=Angiotensin-converting enzyme inhibitors ACE inhibitors have been demonstrated to reduce sudden cardiac death in some studies of persons with CHF.24,56}}</ref> This class of medicine works by causing relaxation of blood vessels as well as a decrease in [[Medicine:Blood volume|blood volume]], which leads to lower [[Physics:Blood pressure|blood pressure]] and decreased [[Chemistry:Oxygen|oxygen]] demand from the [[Biology:Heart|heart]].

ACE inhibitors [[Biology:Enzyme inhibitor|inhibit]] the activity of [[Biology:Angiotensin-converting enzyme|angiotensin-converting enzyme]], an important component of the [[Medicine:Renin–angiotensin system|renin–angiotensin system]] which converts angiotensin I to angiotensin II,<ref name="Byrd Ram Lerma 2019 pp. 477–482">{{cite book | last1=Byrd | first1=James Brian | last2=Ram | first2=C. Venkata S. | last3=Lerma | first3=Edgar V. | title=Nephrology Secrets | chapter=Pharmacologic treatment of hypertension | publisher=Elsevier | year=2019 | isbn=978-0-323-47871-7 | doi=10.1016/b978-0-323-47871-7.00078-2 | pages=477–482 | quote=ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, thereby producing vasodilation and lowering BP. Because the hydrolysis of bradykinin is also inhibited by these drugs, cough (7% to 12%) can occur.}}</ref> and hydrolyses [[Chemistry:Bradykinin|bradykinin]].<ref name="Kaplans Essentials of Cardiac Anesthesia 2018 p. "/> Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of [[Chemistry:Bradykinin|bradykinin]], a [[Chemistry:Peptide|peptide]] vasodilator.<ref name="Kaplans Essentials of Cardiac Anesthesia 2018 p. "/><ref name="Byrd Ram Lerma 2019 pp. 477–482"/> This combination is synergistic in lowering blood pressure.<ref name="Kaplans Essentials of Cardiac Anesthesia 2018 p. "/><ref name="Byrd Ram Lerma 2019 pp. 477–482"/> As a result of inhibiting the ACE enzyme in the bradykinin system, the ACE inhibitor drugs allow for increased levels of bradykinin which would normally be degraded. Bradykinin produces prostaglandin. This mechanism can explain the two most common side effects seen with ACE Inhibitors: angioedema and cough.

Frequently prescribed ACE inhibitors include [[Chemistry:Benazepril|benazepril]], [[Chemistry:Zofenopril|zofenopril]], [[Chemistry:Perindopril|perindopril]], [[Biology:Trandolapril|trandolapril]], [[Chemistry:Captopril|captopril]], [[Biology:Enalapril|enalapril]], [[Biology:Lisinopril|lisinopril]], and [[Chemistry:Ramipril|ramipril]].{{TOC limit}}

==Medical use==
ACE inhibitors were initially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications.  Later, they were found useful for other cardiovascular and kidney diseases<ref name="Goodman-Gilman">{{cite book |author-first=Edwin K. |author-last=Jackson | chapter = Chapter 30. Renin and Angiotensin | title = Goodman & Gilman's The Pharmacological Basis of Therapeutics |editor1-first=Laurence L. |editor1-last=Brunton |editor2-first=John S. |editor2-last=Lazo |editor3-first=Keith |editor3-last=Parker  | publisher = McGraw-Hill | location = New York  | year = 2006 | isbn = 978-0-07-142280-2 | edition = 11th  |title-link=Goodman & Gilman's The Pharmacological Basis of Therapeutics }}</ref> including:
* Acute [[Medicine:Myocardial infarction|myocardial infarction]] (heart attack)<ref>{{cite web |url= https://www.lecturio.com/concepts/myocardial-infarction/| title= Myocardial Infarction
|website=The Lecturio Medical Concept Library |access-date= 27 August 2021}}</ref>
* [[Medicine:Heart failure|Heart failure]] (left ventricular systolic dysfunction)<ref>{{cite web |url= https://www.lecturio.com/concepts/congestive-heart-failure/| title= Congestive Heart Failure
|website=The Lecturio Medical Concept Library | date= 7 August 2020
|access-date= 27 August 2021}}</ref>
* Kidney complications of [[Medicine:Diabetes mellitus|diabetes mellitus]] ([[Medicine:Diabetic nephropathy|diabetic nephropathy]]) by means of decreasing the blood pressure and increasing perfusion in glomerular arterioles.<ref name="Kester Karpa Vrana 2012 pp. 125–151">{{cite book | last1=Kester | first1=Mark | last2=Karpa | first2=Kelly D. | last3=Vrana | first3=Kent E. | title=Elsevier's Integrated Review Pharmacology | chapter=Cardiovascular System | publisher=Elsevier | year=2012 | isbn=978-0-323-07445-2 | doi=10.1016/b978-0-323-07445-2.00008-2 | pages=125–151 | quote=ACE inhibitors also slow progression of kidney disease in patients with diabetic nephropathies. Renal benefits are probably a result of improved renal hemodynamics from decreased glomerular arteriolar resistance.}}</ref>

In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present,<ref>{{cite web|url=https://www.nice.org.uk/guidance/ng28/chapter/1-recommendations#blood-pressure-management-2|title=Type 2 diabetes in adults: management|date=May 2017|website=www.nice.org.uk|publisher=National Institute for Health and Care Excellence (NICE)|access-date=October 25, 2018}}</ref> but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dose combination drugs, such as [[Chemistry:ACE inhibitor and thiazide combination|ACE inhibitor and thiazide combination]]s. ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.<ref>{{cite journal|last1=Bangalore|first1=S|last2=Fakheri|first2=R|last3=Wandel|first3=S|last4=Toklu|first4=B|last5=Wandel|first5=J|last6=Messerli|first6=FH|title=Renin angiotensin system inhibitors for patients with stable coronary artery disease without heart failure: systematic review and meta-analysis of randomized trials|journal=BMJ (Clinical Research Ed.)|date=19 January 2017|volume=356|pages=j4|pmid=28104622|pmc=5244819|doi=10.1136/bmj.j4}}</ref>

In 2012, there was a [[Meta-analysis|meta-analysis]] published in the [[Medicine:The BMJ|BMJ]] that described the protective role of ACE inhibitors in reducing the risk of [[Medicine:Pneumonia|pneumonia]] when compared to [[Chemistry:Angiotensin II receptor blocker|angiotensin II receptor blocker]] (ARBs).<ref name="Caldeira Alarcao Vaz-Carneiro Costa pp. e4260–e4260">{{cite journal | last1=Caldeira | first1=D. | last2=Alarcao | first2=J. | last3=Vaz-Carneiro | first3=A. | last4=Costa | first4=J. | title=Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis | journal=The BMJ | publisher=BMJ | volume=345 | issue=jul11 1 | date=2012-07-11 | issn=1756-1833 | pmid=22786934 | pmc=3394697 | doi=10.1136/bmj.e4260 | pages=e4260}}</ref> The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37%  risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia related mortality was observed.<ref>{{Cite journal|last=Caldeira|first=Daniel|date=Summer 2012|title=Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis|journal=BMJ|volume=345|page=4260|doi=10.1136/bmj.e4260|pmid=22786934|pmc=3394697}}</ref>

===Other===
ACE inhibitors may also be used to help decrease excessive water consumption in people with [[Medicine:Schizophrenia|schizophrenia]] resulting in psychogenic polydipsia.<ref>{{cite web|url=http://bestpractice.bmj.com/best-practice/monograph/865/treatment/emerging.html|title=Psychogenic polydipsia – Management – Emerging treatments|date=May 5, 2016|publisher=British Medical Journal|access-date=October 28, 2016}}</ref><ref>{{Cite journal|last1=Dundas|first1=Brian|last2=Harris|first2=Melissa|last3=Narasimhan|first3=Meera|date=2007-07-03|title=Psychogenic polydipsia review: Etiology, differential, and treatment|journal=Current Psychiatry Reports|language=en|volume=9|issue=3|pages=236–241|doi=10.1007/s11920-007-0025-7|pmid=17521521|s2cid=27207760|issn=1523-3812}}</ref> A double-blind, placebo-controlled trial showed that when used for this purpose, [[Biology:Enalapril|enalapril]] led to decreased consumption (determined by urine output and osmolality) in 60% of people;<ref>{{Cite journal|last1=Greendyke|first1=R. M.|last2=Bernhardt|first2=A. J.|last3=Tasbas|first3=H. E.|last4=Lewandowski|first4=K. S.|date=1998-04-01|title=Polydipsia in chronic psychiatric patients: therapeutic trials of clonidine and enalapril|journal=Neuropsychopharmacology|volume=18|issue=4|pages=272–281|doi=10.1016/S0893-133X(97)00159-0|issn=0893-133X|pmid=9509495|doi-access=free}}</ref> the same effect has been demonstrated in other ACE inhibitors.<ref>{{Cite journal|last1=Sebastian|first1=C. S.|last2=Bernardin|first2=A. S.|date=1990-04-01|title=Comparison of enalapril and captopril in the management of self-induced water intoxication|journal=Biological Psychiatry|volume=27|issue=7|pages=787–790|issn=0006-3223|pmid=2183881|doi=10.1016/0006-3223(90)90594-r|s2cid=39998447}}</ref>

Additionally ACE-I are commonly used after renal transplant to manage post-transplant erythrocytosis, a condition characterised by a persistently high [[Medicine:Hematocrit|hematocrit]] greater than 51% which often develops 8–24 months after successful transplantation,<ref>{{Cite journal|last1=Vlahakos|first1=Demetrios V.|last2=Marathias|first2=Katerina P.|last3=Agroyannis|first3=Basil|last4=Madias|first4=Nicolaos E.|date=2003-04-01|title=Posttransplant erythrocytosis|url=https://www.kidney-international.org/article/S0085-2538(15)48996-3/abstract|journal=Kidney International|language=en|volume=63|issue=4|pages=1187–1194|doi=10.1046/j.1523-1755.2003.00850.x|pmid=12631334|issn=0085-2538|doi-access=free}}</ref> as ACE-I have been shown to decrease [[Biology:Erythropoietin|erythropoietin]] production.<ref>{{cite journal |last1=Cruzado |first1=Josep M. |last2=Rico |first2=Jorge |last3=Grinyó |first3=Josep M. |title=The renin angiotensin system blockade in kidney transplantation: pros and cons |journal=Transplant International |date=April 2008 |volume=21 |issue=4 |pages=304–313 |doi=10.1111/j.1432-2277.2008.00638.x|pmid=18266774 |s2cid=24893488 }}</ref>

==Adverse effects==
Common side effects include: low blood pressure, cough, [[Medicine:Hyperkalemia|hyperkalemia]], [[Medicine:Headache|headache]], dizziness, fatigue, nausea, and kidney impairment.<ref name="AMH2006">Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. {{ISBN|0-9757919-2-3}}.{{Page needed|date=September 2010}}</ref><ref name="Sidorenkov & Navis 2014">{{cite journal |vauthors=Sidorenkov G, Navis G | title = Safety of ACE inhibitor therapies in patients with chronic kidney disease | journal = Expert Opinion on Drug Safety | volume = 13 | issue = 10 | pages = 1383–1395 | year = 2014 | pmid = 25148900 | doi = 10.1517/14740338.2014.951328 | s2cid = 207488068 }}</ref>

The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effects on the fetus.<ref name="Sidorenkov & Navis 2014"/> Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction in [[Medicine:Glomerular filtration rate|glomerular filtration rate]] (GFR).<ref name="Tucker Perazella 2019 pp. 78–83">{{cite book | last1=Tucker | first1=Bryan M. | last2=Perazella | first2=Mark A. | title=Nephrology Secrets | chapter=Medications: 3. What are the major adverse effects on the kidney of ACE inhibitors and ARBs? | publisher=Elsevier | year=2019 | isbn=978-0-323-47871-7 | doi=10.1016/b978-0-323-47871-7.00019-8 | pages=78–83 | quote=due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs... results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries.}}</ref> However, the decrease may be significant in conditions of ''pre-existing'' decreased renal perfusions, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone.<ref name="Tucker Perazella 2019 pp. 78–83"/> Therefore, [[Medicine:Renal function|renal function]] should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion.<ref name="Sidorenkov & Navis 2014"/> A moderate reduction in renal function, no greater than 30% rise in serum [[Chemistry:Creatinine|creatinine]], that is stabilized after a week of treatment is deemed acceptable as part of the therapeutic effect, providing the residual renal function is sufficient.

Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a [[Chemistry:Diuretic|diuretic]].<ref name="Byrd Ram Lerma 2019 pp. 477–482 II"/> When the three drugs are taken together,  the risk of developing renal failure is significantly increased.<ref name="Thomas2000">{{cite journal | author = Thomas MC | title = Diuretics, ACE inhibitors and NSAIDs—the triple whammy | journal = The Medical Journal of Australia | volume = 172 | issue = 4 | pages = 184–5 | year = 2000 | pmid = 10772593 | doi = 10.5694/j.1326-5377.2000.tb125548.x | s2cid = 37558579 }}</ref>

[[Medicine:Hyperkalemia|High blood potassium]] is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. Suppression of angiotensin II leads to a decrease in aldosterone levels. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors can cause retention of potassium. Some people, however, can continue to lose potassium while on an ACE inhibitor.<ref name="Cohn2000">{{cite journal |vauthors=Cohn JN, Kowey PR, Whelton PK, Prisant LM | title = New guidelines for potassium replacement in clinical practice: a contemporary review by the National Council on Potassium in Clinical Practice | journal = Archives of Internal Medicine | volume = 160 | issue = 16 | pages = 2429–36 | year = 2000 | pmid = 10979053 | doi = 10.1001/archinte.160.16.2429 | doi-access = free }}</ref> Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.<ref name="Sidorenkov & Navis 2014"/>

Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in [[Chemistry:Bradykinin|bradykinin]] level.<ref name="Sidorenkov & Navis 2014"/>

A persistent dry cough is a relatively common adverse effect believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms has been disputed.<ref name="Okumura2001">{{cite journal|display-authors=3 |last1=Okumura |first1=Hiromi |last2=Nishimura |first2=Eriko |last3=Kariya |first3=Satoru |last4=OHTANI |first4=Michiteru |last5=UCHINO |first5=Katsuyoshi |last6=FUKATSU |first6=Tohru |last7=ODANAKA |first7=Jun |last8=TAKAHASHI |first8=Tsuyoshi |last9=WATANABE |first9=Kiyoshi |last10=ITOH |first10=Takashi |last11=HASHIGUCHI |first11=Masayuki |last12=ECHIZEN |first12=Hirotoshi |last13=RIKIHISA |first13=Tadaaki |title=No Relation between Angiotensin-Converting Enzyme (ACE) Inhibitor-Induced Cough and ACE Gene Polymorphism, Plasma Bradykinin, Substance P and ACE Inhibitor Concentration in Japanese Patients |journal=Yakugaku Zasshi |date=1 March 2001 |volume=121 |issue=3 |pages=253–257 |doi=10.1248/yakushi.121.253 |pmid=11265121 |doi-access=free }}</ref> Many cases of cough in people on ACE inhibitors may not be from the medication itself, however.<ref>{{cite journal |last1=Vukadinović |first1=D |last2=Vukadinović |first2=AN |last3=Lavall |first3=D |last4=Laufs |first4=U |last5=Wagenpfeil |first5=S |last6=Böhm |first6=M |title=Rate of Cough During Treatment With Angiotensin-Converting Enzyme Inhibitors: A Meta-Analysis of Randomized Placebo-Controlled Trials. |journal=Clinical Pharmacology and Therapeutics |date=March 2019 |volume=105 |issue=3 |pages=652–660 |doi=10.1002/cpt.1018 |pmid=29330882|s2cid=46779755 }}</ref> People who experience this cough are often switched to angiotensin II receptor antagonists.

Some (0.7%)<ref name="Byrd Ram Lerma 2019 pp. 477–482 II"/> develop [[Medicine:Angioedema|angioedema]] due to increased bradykinin levels.<ref>{{cite journal|last1=Bezalel|first1=S|last2=Mahlab-Guri|first2=K|last3=Asher|first3=I|last4=Werner|first4=B|last5=Sthoeger|first5=ZM|title=Angiotensin-converting enzyme inhibitor-induced angioedema.|journal=The American Journal of Medicine|date=February 2015|volume=128|issue=2|pages=120–5|doi=10.1016/j.amjmed.2014.07.011|pmid=25058867}}</ref> A genetic predisposition may exist.<ref name="Molinaro2002">{{cite journal | vauthors = Molinaro G, Cugno M, Perez M, Lepage Y, Gervais N, Agostoni A, Adam A | title = Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 303 | issue = 1 | pages = 232–7 | year = 2002 | pmid = 12235256 | doi = 10.1124/jpet.102.038067 | hdl = 2434/161106 | s2cid = 13866090 | url = https://air.unimi.it/bitstream/2434/161106/2/232.full.pdf }}</ref>

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.<ref>{{cite journal |last1=Augenstein |first1=VA |last2=Heniford |first2=BT |last3=Sing |first3=RF |title=Intestinal angioedema induced by angiotensin-converting enzyme inhibitors: an underrecognized cause of abdominal pain? |journal=The Journal of the American Osteopathic Association |date=March 2013 |volume=113 |issue=3 |pages=221–3 |pmid=23485983}}</ref>

===Blood===
Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.<ref>FDA Prescribing information, http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20A%29/ACE%20INHIBITORS.html</ref>

===Pregnancy===
In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause congenital malformations, [[Medicine:Stillbirth|stillbirth]]s, and neonatal deaths. Commonly reported fetal abnormalities include [[Medicine:Hypotension|hypotension]], renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, [[Medicine:Pulmonary hypoplasia|pulmonary hypoplasia]], patent ductus arteriosus, and incomplete ossification of the skull.<ref name="Sidorenkov & Navis 2014"/><ref name="pmid9520613">{{cite journal |vauthors=Sørensen AM, Christensen S, Jonassen TE, Andersen D, Petersen JS | title = [Teratogenic effects of ACE-inhibitors and angiotensin II receptor antagonists] | language = da | journal = Ugeskrift for Laeger | volume = 160 | issue = 10 | pages = 1460–4 | date = March 1998 | pmid = 9520613 }}</ref> Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to [[Medicine:Birth defect|birth defect]]s.<ref>{{cite journal |vauthors=Bullo M, Tschumi S, Bucher BS, Bianchetti MG, Simonetti GD | title = Pregnancy Outcome Following Exposure to Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Antagonists: A Systematic Review | journal = Hypertension | volume = 60 | issue = 2 | pages = 444–50 | year = 2012 | pmid = 22753220 | doi = 10.1161/HYPERTENSIONAHA.112.196352 | doi-access = free }}</ref><ref name="Byrd Ram Lerma 2019 pp. 477–482 II"/>

ACE inhibitors are ADEC [[Chemistry:Pregnancy category|pregnancy category]] D and should be avoided in women who are likely to become pregnant.<ref name="AMH2006" /> In the U.S., ACE inhibitors must be labeled with a [[Medicine:Boxed warning|boxed warning]] concerning the risk of birth defects when taken during the second and third trimester. Their use in the first trimester is also associated with a risk of major congenital malformations, particularly affecting the [[Biology:Circulatory system|cardiovascular]] and [[Biology:Central nervous system|central nervous system]]s.<ref name="Cooper2006">{{cite journal | vauthors = Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, Hall K, Ray WA | title = Major congenital malformations after first-trimester exposure to ACE inhibitors | journal = The New England Journal of Medicine | volume = 354 | issue = 23 | pages = 2443–2451 | year = 2006 | pmid = 16760444 | doi = 10.1056/NEJMoa055202 | doi-access = free }}</ref>

==Overdose==
Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe, [[Medicine:Hyperkalemia|hyperkalemia]], [[Medicine:Hyponatremia|hyponatremia]] and renal impairment with metabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable by [[Engineering:Hemodialysis|hemodialysis]].<ref>{{cite web|url=http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20A%29/ACE%20INHIBITORS.html |title=ACE Inhibitors |publisher=RxMed.com |access-date=2018-09-20}}</ref>

==Contraindications and precautions==
The ACE inhibitors are contraindicated in people with:
* Pregnancy or breastfeeding
* Previous [[Medicine:Angioedema|angioedema]] associated with ACE inhibitor therapy
* Bilateral renal artery stenosis<ref>{{cite web |title=ACE I |url=https://www.cvpharmacology.com/vasodilator/ACE |website=cvpharmacology}}</ref><ref name="ACEI contraindications">{{cite web |title=ACEI contraindications |url=https://www.openanesthesia.org/ace-i_contraindication/ |website=Open Anesthesia}}</ref>
* Hypersensitivity to ACE inhibitors<ref name="ACEI contraindications"/>

ACE inhibitors should be used with caution in people with:
* Impaired renal function
* Aortic valve stenosis or cardiac outflow obstruction
* [[Medicine:Hypovolemia|Hypovolemia]] or [[Medicine:Dehydration|dehydration]]
* [[Engineering:Hemodialysis|Hemodialysis]] with high-flux polyacrylonitrile membranes

A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects.<ref name="Sidorenkov & Navis 2014"/> The commonly reported adverse effects of drug combination with ACE inhibitor are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers, diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements.

Potassium supplementation should be used with caution and under medical supervision owing to the [[Medicine:Hyperkalemia|hyperkalemic]] effect of ACE inhibitors.<ref name="pmid11044229">{{cite journal |vauthors=Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, Hebert L, Agarwal R, Catanzaro D | title = ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group | journal = Kidney International | volume = 58 | issue = 5 | pages = 2084–92 | date = November 2000 | pmid = 11044229 | doi = 10.1111/j.1523-1755.2000.00381.x | doi-access = free }}</ref>

Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.<ref name="Sear 2019 pp. 535–555">{{cite book | last=Sear | first=John W. | title=Pharmacology and Physiology for Anesthesia | chapter=Antihypertensive Drugs and Vasodilators | publisher=Elsevier | year=2019 | isbn=978-0-323-48110-6 | doi=10.1016/b978-0-323-48110-6.00026-0 | pages=535–555| s2cid=220688413 |quote=Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs [cyclooxygenase inhibitors]) can reduce the hypotensive effects of ACE inhibitors. ACE inhibitors can inhibit the excretion of lithium and can result in lithium toxicity. Because these drugs do not affect the breakdown of kinins (as is seen with the ACE inhibitors), patients do not develop episodes of coughing and rarely develop angioneurotic edema.}}</ref><ref name="Byrd Ram Lerma 2019 pp. 477–482 II">{{cite book | last1=Byrd | first1=James Brian | last2=Ram | first2=C. Venkata S. | last3=Lerma | first3=Edgar V. | title=Nephrology Secrets | chapter=Pharmacologic treatment of hypertension | publisher=Elsevier | year=2019 | isbn=978-0-323-47871-7 | doi=10.1016/b978-0-323-47871-7.00078-2 | pages=477–482 | quote=Angioedema (0.7%) can also occur via pathobiology that remains obscure, and its occurrence can be life-threatening.  ...their efficacy is reduced by dietary or other sources of sodium, and renal function may be further threatened if given with NSAIDs.}}</ref>

==Mechanism of action==
ACE inhibitors reduce the activity of the [[Medicine:Renin–angiotensin system|renin–angiotensin–aldosterone system]] (RAAS) as the primary etiologic (causal) event in the development of hypertension in people with diabetes mellitus, as part of the insulin-resistance syndrome or as a manifestation of renal disease.<ref>{{cite journal | pmid = 16959581 | doi=10.1016/j.ecl.2006.06.007 | volume=35 | issue=3 | title=Hypertension and diabetes: role of the renin–angiotensin system. | date=Sep 2006 | journal=Endocrinol Metab Clin North Am | pages=469–90, vii | author=Jandeleit-Dahm K, Cooper ME}}</ref><ref>{{cite journal | vauthors = Wang W, McKinnie SM, Farhan M, Paul M, McDonald T, McLean B, Llorens-Cortes C, Hazra S, Murray AG, Vederas JC, Oudit GY | title = Angiotensin Converting Enzyme 2 Metabolizes and Partially Inactivates Pyrapelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System | journal = Hypertension | date = May 2016 | pmid = 27217402 | doi = 10.1161/HYPERTENSIONAHA.115.06892 | volume=68 | issue = 2 | pages=365–77| s2cid = 829514 | doi-access = free }}</ref>

===Renin–angiotensin–aldosterone system===
{{Main|Medicine:Renin–angiotensin system}}
[[Image:Renin-angiotensin-aldosterone system.svg|thumb|475px|[[Medicine:Renin–angiotensin system|Renin–angiotensin–aldosterone system]]]]
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such as [[Medicine:Hypotension|hypotension]], low distal tubule [[Biology:Sodium in biology|sodium]] concentration, decreased blood volume and high sympathetic tone trigger the release of the enzyme [[Biology:Renin|renin]] from the cells of juxtaglomerular apparatus in the kidney.

Renin activates a circulating liver derived prohormone [[Biology:Angiotensin|angiotensin]]ogen by proteolytic cleavage of all but its first ten [[Chemistry:Amino acid|amino acid]] residues known as angiotensin I. ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into angiotensin II. ACE is found in the [[Biology:Pulmonary circulation|pulmonary circulation]] and in the [[Biology:Endothelium|endothelium]] of many blood vessels.<ref>Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004){{Page needed|date=September 2010}}</ref> The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin is also very good at causing the blood vessels to tighten (a potent vasoconstrictor).

===Effects===
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).<ref name="Ogbru">{{cite web|url=http://www.medicinenet.com/ace_inhibitors/article.htm |title=ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors) |access-date=2010-03-20 |author =Ogbru O |work=MedicineNet.com |publisher=MedicineNet, Inc. | archive-url= https://web.archive.org/web/20100326095902/http://www.medicinenet.com/ace_inhibitors/article.htm| archive-date= 26 March 2010 | url-status= live}}</ref> They thereby lower [[Biology:Arteriole|arteriolar]] resistance and increase venous capacity; decrease [[Medicine:Cardiac output|cardiac output]], [[Medicine:Cardiac index|cardiac index]], stroke work, and [[Medicine:Stroke volume|volume]]; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease. [[Chemistry:Bradykinin|Bradykinin]] increases because of less inactivation by ACE.

Under normal conditions, angiotensin II has these effects:
* Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by ATII may lead to increased blood pressure and hypertension. Further, constriction of the efferent arterioles of the kidney leads to increased perfusion pressure in the glomeruli.
* It contributes to [[Medicine:Ventricular remodeling|ventricular remodeling]] and [[Medicine:Ventricular hypertrophy|ventricular hypertrophy]] of the heart through stimulation of the proto-oncogenes c-fos, c-jun, c-myc, transforming growth factor beta (TGF-B), through fibrogenesis and apoptosis (programmed cell death).
* Stimulation by ATII of the adrenal cortex to release [[Chemistry:Aldosterone|aldosterone]], a hormone that acts on kidney tubules, causes sodium and chloride ions retention and potassium excretion. Sodium is a "water-holding" ion, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
* Stimulation of the posterior pituitary to release [[Biology:Vasopressin|vasopressin]] (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na<sup>+</sup> level in the plasma may fall (hyponatremia), and this is a sign of increased risk of death in heart failure patients.
* A decrease renal protein kinase C

During the course of ACE inhibitor use, the production of ATII is decreased,{{noteTag|name=|1=ACE inhibitors don't appear to permanently reduce ATII plasma level after cessation of taking it. In short, ACE inhibitors don't cure high ATII plasma levels.<ref name="Gradman Traub 2007 pp. 985–1001"/> }}<ref name="Gradman Traub 2007 pp. 985–1001">{{cite book | last1=Gradman | first1=Alan H. | last2=Traub | first2=Darren | title=Comprehensive Hypertension | chapter=Angiotensin-Converting Enzyme Inhibitors | publisher=Elsevier | year=2007 | isbn=978-0-323-03961-1 | doi=10.1016/b978-0-323-03961-1.50083-0 | pages=985–1001 | quote=Despite the lack of long-term suppression in plasma angiotensin II levels, they maintain their BP-lowering effect without the development of tolerance. Importantly, ACE inhibitors do not interfere with cognitive function or cardiovascular reflexes.}}</ref> which prevents aldosterone release from the adrenal cortex.<ref name="Gradman Traub 2007 pp. 985–1001"/> This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.<ref name="Gradman Traub 2007 pp. 985–1001"/>

[[Social:Epidemiology|Epidemiological]] and clinical studies have shown ACE inhibitors reduce the progress of [[Medicine:Diabetic nephropathy|diabetic nephropathy]] independently from their blood pressure-lowering effect.<ref name="pmid10780101">{{cite journal | vauthors = Hoogwerf BJ, Young JB | title = The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not | journal = Cleveland Clinic Journal of Medicine | volume = 67 | issue = 4 | pages = 287–93 | year = 2000 | pmid = 10780101 | doi = 10.3949/ccjm.67.4.287 }}</ref> This action of ACE inhibitors is used in the prevention of diabetic renal failure.

ACE inhibitors have been shown to be effective for indications other than hypertension<ref>{{cite journal |last1=Bicket |first1=Daphne P. |title=Using ACE Inhibitors Appropriately |journal=American Family Physician |date=August 2002 |volume=66 |issue=3 |pages=461–469 |pmid=12182524 |url=https://www.aafp.org/afp/2002/0801/p461.html |access-date=20 February 2019}}</ref> even in patients with normal blood pressure.<ref>{{Cite journal |last1=Jerums |first1=G. |last2=Allen |first2=T. J. |last3=Campbell |first3=D. J. |last4=Cooper |first4=M. E. |last5=Gilbert |first5=R. E. |last6=Hammond |first6=J. J. |last7=O'Brien |first7=R. C. |last8=Raffaele |first8=J. |last9=Tsalamandris |first9=C. |last10=The Melbourne Diabetic Nephropathy Study Group |date=November 2004 |title=Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria |url=https://onlinelibrary.wiley.com/doi/10.1111/j.1464-5491.2004.01316.x |journal=Diabetic Medicine |language=en |volume=21 |issue=11 |pages=1192–1199 |doi=10.1111/j.1464-5491.2004.01316.x |issn=0742-3071}}</ref> The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, and prophylaxis of cardiovascular events) is justified,<ref>{{Cite journal |last1=Strippoli |first1=Giovanni F. M. |last2=Craig |first2=Maria |last3=Deeks |first3=Jonathan J. |last4=Schena |first4=Francesco Paolo |last5=Craig |first5=Jonathan C. |date=2004-10-07 |title=Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review |url=https://www.bmj.com/content/329/7470/828 |journal=BMJ |language=en |volume=329 |issue=7470 |pages=828 |doi=10.1136/bmj.38237.585000.7C |issn=0959-8138 |pmid=15459003|pmc=521570 }}</ref> because it improves clinical outcomes independently of the blood pressure-lowering effect of ACE inhibitors. Such therapy, of course, requires careful and gradual titration of the dose to prevent the effects of rapidly decreasing blood pressure (dizziness, fainting, etc.).

ACE inhibitors have also been shown to cause a central enhancement of parasympathetic nervous system activity in healthy volunteers and patients with heart failure.<ref>{{cite journal |vauthors=Ajayi AA, Campbell BC, Howie CA, Reid JL | title = Acute and Chronic Effects of the Converting Enzyme Inhibitors Enalapril and Lisinopril on Reflex Control of Heart Rate in Normotensive Man | journal = Journal of Hypertension | volume = 3 | issue = 1 | pages = 47–53 | year = 1985 | pmid = 2987341 | doi = 10.1097/00004872-198502000-00008 }}</ref><ref>{{cite journal |vauthors=Adigun AQ, Asiyanbola B, Ajayi AA | title = Cardiac autonomic function in Blacks with congestive heart failure: vagomimetic action, alteration in sympathovagal balance, and the effect of ACE inhibition on central and peripheral vagal tone | journal = Cell Mol Biol (Noisy le Grande) | volume = 47 | issue = 6 | pages = 1063–7 | year = 2001 | pmid = 11785658 }}{{Verify source|title?|date=October 2009}}</ref> This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.<ref>{{cite journal |vauthors=Binkley PF, Haas GJ, Starling RC, Nunziata E, Hatton PA, Leier CV, Cody RJ | title = Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure | journal = J Am Coll Cardiol | volume = 21 | issue = 3 | pages = 655–61 | date = 1 Mar 1993 | pmid = 8436747 | doi = 10.1016/0735-1097(93)90098-L | doi-access = free }}</ref>
ACE Inhibitors also reduce plasma [[Biology:Norepinephrine|norepinephrine]] levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of sympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure

The ACE inhibitor [[Biology:Enalapril|enalapril]] has also been shown to reduce cardiac [[Medicine:Cachexia|cachexia]] in patients with chronic heart failure.<ref>{{cite journal |vauthors=Adigun AQ, Ajayi AA | title = The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia | journal = European Journal of Heart Failure | volume = 3 | issue = 3 | pages = 359–63 | year = 2001 | pmid = 11378008 | doi = 10.1016/S1388-9842(00)00146-X | s2cid = 31118266 | doi-access = free }}</ref> Cachexia is a poor prognostic sign in patients with chronic heart failure.<ref>{{cite journal |vauthors=Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, Harrington D, Kox WJ, Poole-Wilson PA, Coats AJ | title = Wasting as independent risk factor for mortality in chronic heart failure | journal = The Lancet | volume = 349 | issue = 9058 | pages = 1050–3 | year = 1997 | pmid = 9107242 | doi = 10.1016/S0140-6736(96)07015-8 | s2cid = 27285694 }}</ref>
ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.<ref>{{cite journal |vauthors=von Haehling S, Morley JE, Anker SD | title = An overview of sarcopenia: facts and numbers on prevalence and clinical impact | journal = J Cachexia Sarcopenia Muscle | volume = 1 | issue = 2 | pages = 129–133 | date = December 2010 | pmid = 21475695 | pmc = 3060646 | doi = 10.1007/s13539-010-0014-2 }}</ref>

==Examples==
Currently, there are 10 ACE inhibitors approved for use in the {{wipe|United States}} by the [[Organization:Food and Drug Administration|FDA]]: [[Chemistry:Captopril|captopril]] (1981), [[Biology:Enalapril|enalapril]] (1985), [[Biology:Lisinopril|lisinopril]] (1987), [[Chemistry:Benazepril|benazepril]] (1991), [[Chemistry:Fosinopril|fosinopril]] (1991), [[Biology:Quinapril|quinapril]] (1991), [[Chemistry:Ramipril|ramipril]] (1991), [[Chemistry:Perindopril|perindopril]] (1993), [[Chemistry:Moexipril|moexipril]] (1995) and [[Biology:Trandolapril|trandolapril]] (1996).<ref>{{Cite web |title=Angiotensin-Converting Enzyme (ACE) Inhibitors |url=https://my.clevelandclinic.org/health/treatments/21934-ace-inhibitors |access-date=2022-11-05 |website=Cleveland Clinic}}</ref><ref>{{Cite web |title=Lisinopril |url=https://go.drugbank.com/drugs/DB00722 |access-date=2022-11-05 |website=go.drugbank.com}}</ref>

ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of the enzyme binding sites (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE:<ref name="Shibata Fujita 2018 pp. 230–241">{{cite book | last1=Shibata | first1=Shigeru | last2=Fujita | first2=Toshiro | title=Hypertension: A Companion to Braunwald's Heart Disease | chapter=Renin Angiotensin Aldosterone System Blockers | publisher=Elsevier | year=2018 | isbn=978-0-323-42973-3 | doi=10.1016/b978-0-323-42973-3.00024-x | pages=230–241 | quote=ACE inhibitors are classified according to the chemical structure of the site of binding (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE.}}</ref>

===Sulfhydryl-containing agents===
* [[Chemistry:Alacepril|Alacepril]]<ref name="Shibata Fujita 2018 pp. 230–241"/>
* [[Chemistry:Captopril|Captopril]] (trade name Capoten), the first ACE inhibitor.<ref name="Shibata Fujita 2018 pp. 230–241"/>
* [[Chemistry:Zofenopril|Zofenopril]]

These agents appear to show antioxidative properties but may be involved in adverse events such as skin eruptions.<ref name="Shibata Fujita 2018 pp. 230–241"/>

===Dicarboxylate-containing agents===
This is the largest group, including:
* [[Biology:Enalapril|Enalapril]] (Vasotec/Renitec/Berlipril/Enap/Enalapril Profarma)
* [[Chemistry:Ramipril|Ramipril]] (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace/Ramitac)
* [[Biology:Quinapril|Quinapril]] (Accupril)
* [[Chemistry:Perindopril|Perindopril]] (Coversyl/Aceon/Perindo)
* [[Biology:Lisinopril|Lisinopril]] (Listril/Lopril/Novatec/Prinivil/Zestril, Lisidigal)
* [[Chemistry:Benazepril|Benazepril]] (Lotensin)
* [[Biology:Imidapril|Imidapril]] (Tanatril)
* [[Biology:Trandolapril|Trandolapril]] (Mavik/Odrik/Gopten)
* [[Chemistry:Cilazapril|Cilazapril]] (Inhibace)

===Phosphonate-containing agents===
* [[Chemistry:Ceronapril|Ceronapril]] (never marketed)
* [[Chemistry:Fosinopril|Fosinopril]] (Fositen/Monopril)

===Naturally occurring===
* A comprehensive resource on anti-hypertensive peptides is available in form of a database. It contains around 1700 unique antihypertensive peptides<ref name="pmid25392419">{{cite journal |vauthors=Kumar R, Chaudhary K, Sharma M, Nagpal G, Chauhan JS, Singh S, Gautam A, Raghava GP | title = AHTPDB: a comprehensive platform for analysis and presentation of antihypertensive peptides | journal = Nucleic Acids Res. | volume = 43 | issue = Database issue| pages = D956–62 | year = 2015 | pmid = 25392419 | doi = 10.1093/nar/gku1141 | pmc=4383949}}</ref>
* Arfalasin (HOE 409) is angiotensin antagonist.<ref name="Google Patents 1975">{{cite web | title=US4013791A - Peptides having an antihypertensive effect | website=Google Patents | date=1975-12-03 | url=https://patents.google.com/patent/US4013791 | access-date=2020-03-21}}</ref>

====Dairy products====
* Caso[[Biology:Kinin|kinin]]s and lactokinins, breakdown products of casein and whey, occur naturally after ingestion of milk products, especially cultured milk. Their role in blood pressure control is uncertain.<ref name="FitzGerald2004">{{cite journal | vauthors = FitzGerald RJ, Murray BA, Walsh DJ | title = Hypotensive peptides from milk proteins | journal = The Journal of Nutrition | volume = 134 | issue = 4 | pages = 980S–8S | year = 2004 | pmid = 15051858 | doi = 10.1093/jn/134.4.980S | doi-access = free }}</ref>
* The [[Chemistry:Lactotripeptides|lactotripeptides]] Val-Pro-Pro and Ile-Pro-Pro produced by the [[Biology:Probiotic|probiotic]] ''[[Biology:Lactobacillus helveticus|Lactobacillus helveticus]]'' or derived from casein have been shown to have ACE-inhibiting and antihypertensive functions.<ref name="pmid16093403">{{cite journal |vauthors=Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y | title = Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension | journal = Journal of the American College of Nutrition | volume = 24 | issue = 4 | pages = 257–65 | year = 2005 | pmid = 16093403 | doi = 10.1080/07315724.2005.10719473 | s2cid = 18513821 }}</ref><ref name="pmid19061526"/> In one study, ''L. helveticus'' PR4 was isolated from Italian cheeses.<ref name="Minervini 2003">{{cite journal |title=Angiotensin I-Converting-Enzyme-Inhibitory and Antibacterial Peptides from Lactobacillus helveticus PR4 Proteinase-Hydrolyzed Caseins of Milk from Six Species |journal=Applied and Environmental Microbiology |date=2003 |last1=Minervini |first1=F. |last2=Algaron |first2=F. |last3=Rizzello |first3=C. G. |last4=Fox |first4=P. F. |last5=Monnet |first5=V. |volume=69 |issue=9 |pages=5297–5305 |pmid=12957917 |doi=10.1128/AEM.69.9.5297-5305.2003 |pmc=194939 |bibcode=2003ApEnM..69.5297M }}</ref>

==Comparative information==
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with [[Chemistry:Captopril|captopril]], the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also the only ACE inhibitor capable of passing through the [[Biology:Blood–brain barrier|blood–brain barrier]], although the significance of this characteristic has not been shown to have any positive clinical effects.

In a large clinical study, one of the agents in the ACE inhibitor class, [[Chemistry:Ramipril|ramipril]] (Altace), demonstrated an ability to reduce the mortality rates of patients with a [[Medicine:Myocardial infarction|myocardial infarction]] and to slow the subsequent development of heart failure. This finding was made after it was discovered that regular use of ramipril reduced mortality rates even in test subjects who did not have hypertension.<ref>[http://www.medscape.com/viewarticle/430926 "Debate: Do ACE Inhibitors Have Unique Properties, Beyond Their Antihypertensive Effect?"]</ref>

Some believe ramipril's additional benefits may be shared by some or all drugs in the ACE-inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.<ref>{{Cite journal |author=The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators |date=October 1993 |title=Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure|journal=Lancet |volume=342 |issue=8875 |pages=821–8 |doi=10.1016/0140-6736(93)92693-N |pmid=8104270|s2cid=5770772 }}</ref>

A meta-analysis confirmed that ACE inhibitors are effective and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158,998 patients, of whom 91% were hypertensive. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383).
ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84–0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94–1.04; P=0.683). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are associated with a statistically significant 13% all-cause mortality reduction.
Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with [[Chemistry:Perindopril|perindopril]], would result in an important gain of lives saved.<ref>{{cite journal | pmid = 22511654 | doi=10.1093/eurheartj/ehs075 | volume=33 | issue=16 | title=Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin–angiotensin–aldosterone system inhibitors involving 158,998 patients | pmc=3418510 |vauthors=van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, Boersma E | journal=Eur Heart J | pages=2088–97| year=2012 }}</ref>

===Equivalent doses in hypertension===
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.<ref>[http://www.tripanswers.org/answer.aspx?criteria=&tagtrail=%2fACE+Inhibitors%2fdose+equivalence%2fCardiovascular+disease%2f&qid=3447&src=0 What are the dose comparisons of all ACE inhibitors used in hypertension?] {{Webarchive|url=https://web.archive.org/web/20150402093937/http://www.tripanswers.org/answer.aspx?criteria=&tagtrail=%2fACE+Inhibitors%2fdose+equivalence%2fCardiovascular+disease%2f&qid=3447&src=0 |date=2015-04-02 }} TripAnswers, [[Medicine:Trip (search engine)|Trip]], May 25, 2007. Accessed 2009-11-21</ref><ref>Common Medication Conversions (Equivalents): [https://globalrph.com/medcalcs/drug-comparisons-ace-inhibitors-medication-equivalents/ Ace Inhibitors] {{Webarchive|url=https://web.archive.org/web/20150317170410/http://www.globalrph.com/aceinh.cgi |date=2015-03-17 }}. GlobalRPh.com. Accessed 2009-11-22.</ref><ref>[http://www.consumerreports.org/health/best-buy-drugs/ace-inhibitors.htm Treating High Blood Pressure and Heart Disease: the ACE Inhibitors]. Consumer Reports Health Best Buy Drugs. June 2009.</ref>
{| class=wikitable
|-
!colspan=6 | ACE inhibitors dosages for hypertension
|-
!colspan=2| ||| ||colspan=3 |Dosage
|-
|colspan=6 | Note: bid = two times a day, tid = three times a day, d = daily <br>Drug dosages from Drug Lookup, [https://online.epocrates.com/ Epocrates Online].
|-
! Name || Equivalent daily dose ||| || Start || Usual || Maximum
|-
| Benazepril || 10&nbsp;mg||| || 10&nbsp;mg || 20–40&nbsp;mg || 80&nbsp;mg
|-
| Captopril || 50&nbsp;mg (25&nbsp;mg bid) ||| || 12.5–25&nbsp;mg bid-tid || 25–50&nbsp;mg bid-tid || 150&nbsp;mg/d
|-
| Enalapril || 5&nbsp;mg ||| || 5&nbsp;mg || 10–40&nbsp;mg || 40&nbsp;mg
|-
| Fosinopril || 10&nbsp;mg || ||| 10&nbsp;mg || 20–40&nbsp;mg || 80&nbsp;mg
|-
| Lisinopril || 10&nbsp;mg || ||| 10&nbsp;mg || 10–40&nbsp;mg || 80&nbsp;mg
|-
| Moexipril || 7.5&nbsp;mg || ||| 7.5&nbsp;mg || 7.5–30&nbsp;mg || 30&nbsp;mg
|-
| Perindopril || 4&nbsp;mg ||| || 4&nbsp;mg || 4–8&nbsp;mg || 16&nbsp;mg
|-
| Quinapril || 10&nbsp;mg || ||| 10&nbsp;mg || 20–80&nbsp;mg || 80&nbsp;mg
|-
| Ramipril || 2.5&nbsp;mg || ||| 2.5&nbsp;mg || 2.5–20&nbsp;mg || 20&nbsp;mg
|-
| Trandolapril || 2&nbsp;mg || ||| 1&nbsp;mg || 2–4&nbsp;mg || 8&nbsp;mg
|- Imidapril || 5&nbsp;mg || ||| 5&nbsp;mg || 10&nbsp;mg ||20&nbsp;mg
|}

==Combination with angiotensin II receptor antagonists==
ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, angiotensin II receptor antagonists, which are often used when patients are intolerant of the adverse effects produced by ACE inhibitors. ACE inhibitors do not completely prevent the formation of angiotensin II, as blockage is dose-dependent, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT<sub>1</sub> receptor, leaving AT<sub>2</sub> receptor unblocked; the latter may have consequences needing further study.

The combination therapy of angiotensin II receptor antagonists with ACE inhibitors may be superior to either agent alone. This combination may increase levels of bradykinin while blocking the generation of angiotensin II and its activity at the AT<sub>1</sub> receptor. This 'dual blockade' may be more effective than using an ACE inhibitor alone, because angiotensin II can be generated via non-ACE-dependent pathways. Preliminary studies suggest this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic [[Medicine:Heart failure|heart failure]],<ref name="dimopoulos">{{cite journal |vauthors=Dimopoulos NA, Salukhe TV, Coats AJ, Mayet J, Piepoli M, Francis DP | title = Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker) | journal = Int J Cardiol | volume =  93| issue = 2 | pages = 105–111 | year = 2004 | pmid = 14975535 | doi = 10.1016/j.ijcard.2003.10.001 }}</ref> and nephropathy.<ref name="Luno2005">{{cite journal | vauthors = Luno J, Praga M, de Vinuesa SG | title = The reno-protective effect of the dual blockade of the renin angiotensin system (RAS) | journal = Current Pharmaceutical Design | volume = 11 | issue = 10 | pages = 1291–300 | year = 2005 | pmid = 15853685 | doi = 10.2174/1381612053507413 }}</ref><ref name="vandeWal2005">{{cite journal | vauthors = van de Wal RM, van Veldhuisen DJ, van Gilst WH, Voors AA | title = Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense? | journal = European Heart Journal | volume = 26 | issue = 22 | pages = 2361–7 | year = 2005 | pmid = 16105846 | doi = 10.1093/eurheartj/ehi454 | doi-access = free }}</ref> However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events.<ref>{{cite journal |author1=ONTARGET Investigators |last2=Yusuf |first2=S |last3=Teo |first3=KK |last4=Pogue |first4=J |last5=Dyal |first5=L |last6=Copland |first6=I |last7=Schumacher |first7=H |last8=Dagenais |first8=G |last9=Sleight |first9=P |last10=Anderson |first10=C |title=Telmisartan, ramipril, or both in patients at high risk for vascular events |journal=The New England Journal of Medicine |date=10 April 2008 |volume=358 |issue=15 |pages=1547–59 |doi=10.1056/NEJMoa0801317 |pmid=18378520|hdl=2437/81925 |hdl-access=free |url=https://dea.lib.unideb.hu/dea/bitstream/2437/81925/1/ris_file_up_22_Telmisartan%20ramipril%20or%20both%20in%20patients%20at%20high%20risk%20for%20vascular%20events.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://dea.lib.unideb.hu/dea/bitstream/2437/81925/1/ris_file_up_22_Telmisartan%20ramipril%20or%20both%20in%20patients%20at%20high%20risk%20for%20vascular%20events.pdf |archive-date=2022-10-09 |url-status=live }}</ref> While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.<ref name="Finnegan2003">{{cite journal | vauthors = Finnegan PM, Gleason BL | title = Combination ACE inhibitors and angiotensin II receptor blockers for hypertension | journal = Annals of Pharmacotherapy | volume = 37 | issue = 6 | pages = 886–9 | year = 2003 | pmid = 12773079 | doi = 10.1345/aph.1C393 | s2cid = 25509704 }}</ref> There are warnings about the combination of ACE inhibitors with ARBs.<ref>{{cite web|url=http://www.medscape.com/viewarticle/823514|title=EMA: Don't Combine ARBs, ACE Inhibitors, and Direct Renin Inhibitors|author=Shelley Wood|date=11 April 2014|website=www.medscape.com}}</ref>

Patients with heart failure may benefit from the combination in terms of reducing morbidity and [[Medicine:Ventricular remodeling|ventricular remodeling]].<ref name="Krum2004">{{cite journal | vauthors = Krum H, Carson P, Farsang C, Maggioni AP, Glazer RD, Aknay N, Chiang YT, Cohn JN | title = Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT | journal = European Journal of Heart Failure | volume = 6 | issue = 7 | pages = 937–45 | year = 2004 | pmid = 15556056 | doi = 10.1016/j.ejheart.2004.09.005 | s2cid = 40739892 | doi-access = free }}</ref><ref name="Solomon2005">{{cite journal |vauthors=Solomon SD, Skali H, Anavekar NS, Bourgoun M, Barvik S, Ghali JK, Warnica JW, Khrakovskaya M, Arnold JM, Schwartz Y, Velazquez EJ, Califf RM, McMurray JV, Pfeffer MA | title = Changes in Ventricular Size and Function in Patients Treated with Valsartan, Captopril, or Both After Myocardial Infarction | journal = Circulation | volume = 111 | issue = 25 | pages = 3411–3419 | year = 2005 | pmid = 15967846 | doi = 10.1161/CIRCULATIONAHA.104.508093 | doi-access = free }}</ref>

The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients with [[Medicine:Diabetic nephropathy|diabetic nephropathy]],<ref name="Luno2005"/> and pediatric [[Medicine:IgA nephropathy|IgA nephropathy]].<ref name="Yang2005">{{cite journal |vauthors=Yang Y, Ohta K, Shimizu M, Nakai A, Kasahara Y, Yachie A, Koizumi S | title = Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy | journal = Clinical Nephrology | volume = 64 | issue = 1 | pages = 35–40 | date = Jul 2005 | pmid = 16047643 | doi = 10.5414/CNP64035 }}</ref>

==History==
Leonard T. Skeggs and his colleagues (including Norman Shumway) discovered ACE in [[Biology:Blood plasma|plasma]] in 1956.<ref name=Bernstein>{{Cite journal|last1=Bernstein|first1=Kenneth E.|last2=Ong|first2=Frank S.|last3=Blackwell|first3=Wendell-Lamar B.|last4=Shah|first4=Kandarp H.|last5=Giani|first5=Jorge F.|last6=Gonzalez-Villalobos|first6=Romer A.|last7=Shen|first7=Xiao Z.|last8=Fuchs|first8=Sebastien|date=January 2013|title=A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme|journal=Pharmacological Reviews|volume=65|issue=1|pages=1–46|doi=10.1124/pr.112.006809|issn=0031-6997|pmc=3565918|pmid=23257181}}</ref> It was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by a [[Biology:Pit viper|pit viper]], leading to a search for a blood pressure lowering component in its venom.<ref name="Aung2012">{{Cite book|last1=Myat|first1=Aung|chapter-url=https://books.google.com/books?id=DDmYywOVlToC&pg=PA286|title=Landmark Papers in Cardiovascular Medicine|last2=Gershlick|first2=A. H.|last3=Gershlick|first3=Tony|date=2012|publisher=[[Organization:Oxford University Press|Oxford University Press]]|isbn=978-0-19-959476-4|location=Oxford|pages=2286–287|language=en|chapter=17. Systemic arterial hypertension|lccn=2012940771}}</ref> Brazilian scientist Sérgio Henrique Ferreira reported a [[Chemistry:Teprotide|bradykinin-potentiating factor]] (BPF) present in the venom of ''[[Biology:Bothrops jararaca|Bothrops jararaca]]'', a South American pit viper, in 1965.<ref name="pmid14302350">{{cite journal | author = Ferreira SH | title = A bradykinin-potentiating factor (bpf) present in the venom of bothrops jararaca | journal = Br J Pharmacol Chemother | volume = 24 | issue = 1 | pages = 163–9 | date = February 1965 | pmid = 14302350 | pmc = 1704050 | doi = 10.1111/j.1476-5381.1965.tb02091.x }}</ref> Ferreira then went to [[Biography:John Vane|John Vane]]'s laboratory as a postdoctoral fellow with his already-isolated BPF. The conversion of the inactive angiotensin I to the potent angiotensin II was thought to take place in the plasma. However, in 1967, Kevin K. F. Ng and John R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin II ''in vivo''. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.<ref name="Kevin">{{cite journal |vauthors=Ng KK, Vane JR | title = Conversion of Angiotensin I to Angiotensin II | journal = Nature | volume = 216 | issue = 5117 | pages = 762–6 | year = 1967 | pmid = 4294626 | doi = 10.1038/216762a0 | bibcode = 1967Natur.216..762N | s2cid = 4289093 }}</ref>

Bradykinin is rapidly inactivated in the circulating blood, and it disappears completely in a single pass through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation because of its conversion to angiotensin II. Furthermore, angiotensin II passes through the lungs without any loss. The inactivation of bradykinin and the conversion of angiotensin I to angiotensin II in the lungs was thought to be caused by the same enzyme.<ref name="Kevin2">{{cite journal |vauthors=Ng KK, Vane JR | title = Fate of Angiotensin I in the Circulation | journal = Nature | volume = 218 | issue = 5137 | pages = 144–50 | year = 1968 | pmid = 4296306 | doi = 10.1038/218144a0 | bibcode = 1968Natur.218..144N | s2cid = 4174541 }}</ref> In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.<ref name="Kevin3">{{cite journal |vauthors=Ng KK, Vane JR | title = Some Properties of Angiotensin Converting Enzyme in the Lung in vivo | journal = Nature | volume = 225 | issue = 5238 | pages = 1142–4 | year = 1970 | pmid = 4313869 | doi = 10.1038/2251142b0 | bibcode = 1970Natur.225.1142N | s2cid = 4200012 }}</ref>

BPFs are members of a family of peptides whose potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF [[Chemistry:Teprotide|teprotide]] (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effect ''in vivo''. Teprotide had limited clinical value as a result of its peptide nature and lack of activity when given orally. In the early 1970s, knowledge of the structure-activity relationship required for inhibition of ACE was growing. David Cushman, Miguel Ondetti and colleagues used peptide analogues to study the structure of ACE, using carboxypeptidase A as a model. Their discoveries led to the development of captopril, the first orally-active ACE inhibitor, in 1975.<ref>{{Cite journal|title=History of the design of captopril and related inhibitors of angiotensin converting enzyme.|journal=Hypertension|year=1991|doi=10.1161/01.HYP.17.4.589|last1=Cushman|first1=D. W.|last2=Ondetti|first2=M. A.|volume=17|issue=4|pages=589–592|pmid=2013486|s2cid=30766421|doi-access=free}}</ref>

Captopril was approved by the United States [[Organization:Food and Drug Administration|Food and Drug Administration]] in 1981.<ref>{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018343 |access-date=2023-09-29 |website=www.accessdata.fda.gov |language=en}}</ref> The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later.<ref>{{Cite web |title=Drugs@FDA: FDA-Approved Drugs |url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=018998 |access-date=2023-09-29 |website=www.accessdata.fda.gov |language=en}}</ref> At least 8 other ACE inhibitors have since been marketed.<ref>{{Cite journal |last=Bicket |first=Daphne P. |date=2002-08-01 |title=Using ACE Inhibitors Appropriately |url=https://www.aafp.org/pubs/afp/issues/2002/0801/p461.html |journal=American Family Physician |language=en-US |volume=66 |issue=3 |pages=461–469}}</ref>

In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate the [[Chemistry:Tripeptide|tripeptide]] [[Chemistry:Isoleucine|isoleucine]]-[[Chemistry:Proline|proline]]-proline (IPP) from the dairy protein. [[Chemistry:Valine|Valine]]-proline-proline (VPP) is also liberated in this process—another milk tripeptide with a very similar chemical structure to IPP. Together, these peptides are now often referred to as [[Chemistry:Lactotripeptides|lactotripeptides]]. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.<ref>{{cite journal | vauthors = Hata Y, Yamamoto M, Ohni M, Nakajima K, Nakamura Y, Takano T | title = A placebo-controlled study of the effect of sour milk on blood pressure in hypertensive subjects | journal = The American Journal of Clinical Nutrition | volume = 64 | issue = 5 | pages = 767–71 | year = 1996 | pmid = 8901799 | doi = 10.1093/ajcn/64.5.767 | doi-access = free }}</ref> Although twice the amount of VPP is needed to achieve the same ACE-inhibiting activity as the originally discovered IPP, VPP also is assumed to add to the total blood pressure lowering effect.<ref name="pmid7673515">{{cite journal | vauthors = Nakamura Y, Yamamoto N, Sakai K, Takano T | title = Antihypertensive effect of sour milk and peptides isolated from it that are inhibitors to angiotensin I-converting enzyme | journal = Journal of Dairy Science | volume = 78 | issue = 6 | pages = 1253–7 | year = 1995 | pmid = 7673515 | doi = 10.3168/jds.S0022-0302(95)76745-5 | doi-access = free }}</ref>
Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.<ref name="pmid19061526">{{cite journal | vauthors = Boelsma E, Kloek J | title = Lactotripeptides and antihypertensive effects: a critical review | journal = The British Journal of Nutrition | volume = 101 | issue = 6 | pages = 776–86 | year = 2009 | pmid = 19061526 | doi = 10.1017/S0007114508137722 | doi-access = free }}</ref>

==Note==
{{notefoot}}

==See also==
* [[Chemistry:Angiotensin II receptor blocker|Angiotensin II receptor blocker]]
** [[Chemistry:Discovery and development of angiotensin receptor blockers|Discovery and development of angiotensin receptor blockers]]
* Loop diuretic, also used to treat CHF
* [[Biology:Renin inhibitor|Renin inhibitor]]

==References==
{{reflist}}

==External links==
* [https://pharmaceutical-journal.com/article/news/from-snake-venom-to-ace-inhibitor-the-discovery-and-rise-of-captopril From snake venom to ACE inhibitor — the discovery and rise of captopril]

{{ACE inhibitors}}
{{Major Drug Groups}}
{{Enzyme inhibition}}
{{Angiotensin receptor modulators}}

{{DEFAULTSORT:Ace Inhibitor}}
[[Category:ACE inhibitors]]

{{Sourceattribution|ACE inhibitor}}