Content deleted Content added
Ozzie10aaaa (talk | contribs) |
→Renin–angiotensin–aldosterone system: Adding class=skin-invert-image to drawings for readability in dark mode |
||
| (8 intermediate revisions by 3 users not shown) | |||
Line 6:
| Name = Angiotensin-converting-enzyme inhibitor
| Image = Captopril skeletal.svg
| ImageClass = skin-invert-image
| Alt =
| Caption = [[Captopril]], the first synthetic ACE inhibitor
Line 46 ⟶ 47:
Common side effects include: low blood pressure, [[cough]], [[hyperkalemia]], [[headache]], [[Vertigo (medical)|dizziness]], [[Fatigue (physical)|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 [[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 | s2cid=239423283 | 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, [[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 [[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.{{cn|date=August 2024}}
Reduced GFR is especially a problem if the patient is concomitantly taking an [[Non-steroidal anti-inflammatory drug|NSAID]] and a [[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>
Line 54 ⟶ 55:
Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in [[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|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 antagonist]]s.{{cn|date=August 2024}}
Some (0.7%)<ref name="Byrd Ram Lerma 2019 pp. 477–482 II"/> develop [[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>
Line 72 ⟶ 73:
==Contraindications and precautions==
The ACE inhibitors are contraindicated in people with:{{cn|date=August 2024}}
* Pregnancy or breastfeeding
* Previous [[angioedema]] associated with ACE inhibitor therapy
Line 78 ⟶ 79:
* Hypersensitivity to ACE inhibitors<ref name="ACEI contraindications"/>
ACE inhibitors should be used with caution in people with:{{cn|date=August 2024}}
* Impaired renal function
* [[Aortic valve stenosis]] or cardiac outflow obstruction
Line 95 ⟶ 96:
===Renin–angiotensin–aldosterone system===
{{Main|Renin–angiotensin system}}
[[Image:Renin-angiotensin-aldosterone system.svg|thumb|475px|class=skin-invert-image|[[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 [[hypotension]], low [[Distal convoluted tubule|distal tubule]] [[Sodium in biology|sodium]] concentration, decreased blood volume and high [[sympathetic nervous system|sympathetic]] tone trigger the release of the enzyme [[renin]] from the cells of [[juxtaglomerular apparatus]] in the kidney.{{cn|date=August 2024}}
Renin activates a circulating liver derived [[prohormone]] [[angiotensin]]ogen by proteolytic cleavage of all but its first ten [[amino acid]] residues known as [[angiotensin I]]. [[Angiotensin converting enzyme|ACE]] (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I into [[angiotensin II]]. ACE is found in the [[pulmonary circulation]] and in the [[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 II is also a potent [[vasoconstrictor]].<ref name="Weir 1999 pp. 205–213">{{cite journal | last=Weir | first=M | title=The renin-angiotensin-aldosterone system: a specific target for hypertension management | journal=American Journal of Hypertension | publisher=Oxford University Press (OUP) | volume=12 | issue=4 | year=1999 | issn=0895-7061 | doi=10.1016/s0895-7061(99)00103-x | pages=205–213| pmid=10619573 }}</ref>
===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 [[arteriole|arteriolar]] resistance and increase venous capacity; decrease [[cardiac output]], [[cardiac index]], stroke work, and [[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. [[Bradykinin]] increases because of less inactivation by ACE.{{cn|date=August 2024}}
Under normal conditions, angiotensin II has these effects:
Line 112 ⟶ 113:
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"/>
[[Epidemiology|Epidemiological]] and clinical studies have shown ACE inhibitors reduce the progress of [[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]].{{cn|date=August 2024}}
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 |pmid=15498085 |s2cid=12855742 |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.).{{cn|date=August 2024}}
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 [[norepinephrine]] levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles of [[sympathetic nervous system|sympathetic]] and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure{{cn|date=August 2024}}
The ACE inhibitor [[enalapril]] has also been shown to reduce cardiac [[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>
Line 135 ⟶ 136:
===Dicarboxylate-containing agents===
This is the largest group, including:{{cn|date=August 2024}}
* [[Enalapril]] (Vasotec/Renitec/Berlipril/Enap/Enalapril Profarma)
* [[Ramipril]] (Altace/Prilace/Ramace/Ramiwin/Triatec/Tritace/Ramitac)
Line 159 ⟶ 160:
==Comparative information==
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie with [[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 [[blood–brain barrier]], although the significance of this characteristic has not been shown to have any positive clinical effects.{{cn|date=August 2024}}
In a large clinical study, one of the agents in the ACE inhibitor class, [[ramipril]] (Altace), demonstrated an ability to reduce the mortality rates of patients with a [[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>
Line 204 ⟶ 205:
==Combination with angiotensin II receptor antagonists==
ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, [[angiotensin II receptor antagonist]]s, 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.{{cn|date=August 2024}}
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 [[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>
| |||