ACE inhibitor
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[[Image:Captopril.png|thumb|Captopril, the first ACE inhibitor|200px|right]]
'''ACE inhibitors''', or inhibitors of [[angiotensin-converting enzyme|'''A'''ngiotensin-'''C'''onverting '''E'''nzyme]], are a group of [[pharmaceutical]]s that are used primarily in treatment of [[hypertension]] and [[congestive heart failure]], in some cases as the drugs of first choice.
==Clinical use==
Indications for ACE inhibitors include:
* Prevention of [[cardiovascular]] disorders
* [[Congestive heart failure]] (CHF)
* [[Hypertension]]
* Left [[ventricle (heart)|ventricular]] dysfunction
* Prevention of [[nephropathy]] in [[diabetes mellitus]]
In several of these indications, ACE inhibitors are used first-line as several agents in the class have been clinically shown to be superior to other classes of drugs in the reduction of [[morbidity]] and [[Mortality rate|mortality]].
ACE inhibitors are often combined with [[diuretic]]s in the control of hypertension (usually a [[thiazide]]), when an ACE inhibitor alone proves insufficient; and in chronic heart failure (usually [[furosemide]]) for improved symptomatic control. Thus there exists, on the market, combination products combining an ACE inhibitor with a thiazide (usually [[hydrochlorothiazide]]) in a single tablet to allow easy administration by patients.
==The renin-angiotensin-aldosterone system (RAAS)==
{{main|Renin-angiotensin system}}
This system is activated in response to hypotension, decreased sodium concentration in the distal tubule, decreased blood volume and renal sympathetic nerve stimulation. In such a situation, the kidneys release renin which cleaves the liver derived angiotensinogen into Angiotensin I. Angiotensin I is then converted to angiotensin II via the angiotensin-converting-enzyme (ACE) in the pulmonary circulation. The system in general aims to increase blood pressure.
Recently (2008), scientists have found that blocking this system increases the rate of metabolism. Current studies involve modifying the ACE inhibitor drugs and targeting the RAAS system, strictly for weight loss.
==Effects==
ACE inhibitors lower [[arteriole|arteriolar]] resistance and increase venous capacity; increase [[cardiac output]] and [[cardiac index]], stroke work and [[stroke volume|volume]], lower renovascular resistance, and lead to increased [[natriuresis]] (excretion of [[sodium]] in the [[urine]]).
Normally, angiotensin II will have the following effects:
*vasoconstriction (narrowing of blood vessels), which may lead to increased blood pressure and [[hypertension]]
*Specifically, angiotensin II constricts the [[efferent arteriole]]s of the [[kidney]], leading to increased perfusion pressure in the [[glomerulus|glomeruli]].
*[[Ventricular remodeling]] of the heart, which may lead to [[ventricular hypertrophy]] and CHF
*stimulate the adrenal cortex to release [[aldosterone]], a hormone that acts on kidney tubules to retain sodium and chloride ions and excrete potassium. Sodium is a "water-holding" molecule, so water is also retained, which leads to increased blood volume, hence an increase in blood pressure.
*stimulate the posterior pituitary into releasing [[vasopressin]] (also known as anti-diuretic hormone (ADH)) which also acts on the kidneys to increase water retention.
*decrease renal protein kinase C
With ACE inhibitor use, the effects of angiotensin II are prevented, leading to decreased blood pressure.
[[Epidemiology|Epidemiological]] and clinical studies have shown that ACE inhibitors reduce the progress of [[diabetic nephropathy]] independently from their blood pressure-lowering effect{{Fact|date=May 2008}} . This action of ACE inhibitors is utilised in the prevention of diabetic [[renal failure]].
ACE inhibitors have been shown to be effective for indications other than hypertension even in patients with normal blood pressure. The use of a maximum dose of ACE inhibitors in such patients (including for prevention of diabetic nephropathy, congestive heart failure, prophylaxis of cardiovascular events) is justified because it improves clinical outcomes, independent 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'').
==Adverse effects==
Common [[adverse drug reaction]]s (≥1% of patients) include: [[hypotension]], [[cough]], [[hyperkalemia]], [[headache]], [[Vertigo (medical)|dizziness]], [[Fatigue (physical)|fatigue]], [[nausea]], renal impairment.<ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3.</ref>
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 remains disputed by some authors.<ref name="Okumura2001">Okumura H, Nishimura E, Kariya S, et al. Angiotensin-converting enzyme (ACE) [http://www.jstage.jst.go.jp/article/yakushi/121/3/253/_pdf 阻害薬誘発性の咳嗽発現とACE遺伝子型,血漿中ブラジキニン,サブスタンスP及びACE阻害薬濃度との関連性] [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]. Yakugaku Zasshi 2001;121(3):253-7. Japanese. PMID 11265121</ref> Patients who experience this cough are often switched to [[angiotensin II receptor antagonist]]s.
Rash and taste disturbances, infrequent with most ACE inhibitors, are more prevalent in [[captopril]] and is attributed to its sulfhydryl moiety. This has led to decreased use of captopril in clinical setting, although it is still used in [[scintigraphy]] of the kidney.
Renal impairment is a significant adverse effect of all ACE inhibitors. The reason for this is still unknown. Some suggest that it is associated with their effect on angiotensin II-mediated [[homeostasis|homeostatic]] functions such as renal blood flow. Renal blood flow may be affected by Angiotensin II because it vasoconstricts the [[efferent arteriole]]s of the [[glomerulus|glomeruli]] of the kidney, thereby increasing [[glomerular filtration rate]] (GFR). Hence, by reducing angiotensin II levels, ACE inhibitors may reduce GFR, a marker of [[renal function]]. However this is actually untrue as whilst the efferent arteriole is more relaxed, so too is the afferent arteriole which acts to increase GFR in a compensatory manner. Specifically, ACE inhibitors can induce or exacerbate renal impairment in patients with [[renal artery stenosis]]. This is especially a problem if the patient is also concomitantly taking an [[Non-steroidal anti-inflammatory drug|NSAID]] and a [[diuretic]] - the so-called "triple whammy" effect - such patients are at very high risk of developing renal failure.<ref name="Thomas2000">Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172(4):184–185. PMID 10772593</ref>
ACE inhibitors may cause [[hyperkalemia]], because angiotensin II increases aldosterone release. Since aldosterone is responsible for increasing the excretion of potassium, ACE inhibitors ultimately cause retention of potassium.
Some patients develop [[angioedema]] due to increased bradykinin levels. There appears to be a genetic predisposition towards this adverse effect in patients who degrade bradykinin slower than average.<ref name="Molinaro2002">Molinaro G, Cugno M, Perez M, et al. [http://jpet.aspetjournals.org/cgi/content/full/303/1/232 Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine(9)-bradykinin.] J Pharmacol Exp Ther 2002;303:232-7. PMID 12235256.</ref>
==Examples==
ACE inhibitors can be divided into three groups based on their molecular structure:
===Sulfhydryl-containing agents===
* [[Captopril]] (trade name Capoten), the first ACE inhibitor
* [[Zofenopril]]
===Dicarboxylate-containing agents===
This is the largest group, including:
* [[Enalapril]] (Vasotec/Renitec)
* [[Ramipril]] (Altace/Tritace/Ramace/Ramiwin)
* [[Quinapril]] (Accupril)
* [[Perindopril]] (Coversyl/Aceon)
* [[Lisinopril]] (Lisodur/Lopril/Novatec/Prinivil/Zestril)
* [[Benazepril]] (Lotensin)
===Phosphonate-containing agents===
* [[Fosinopril]] (Monopril), the only member
===Naturally occurring===
[[Casokinin]]s and [[lactokinin]]s are breakdown products of [[casein]] and [[whey]] that occur naturally after ingestion of [[milk]] products, especially [[cultured milk]]. Their role in blood pressure control is uncertain.<ref name="FitzGerald2004">FitzGerald RJ, Murray BA, Walsh DJ. [http://jn.nutrition.org/cgi/content/full/134/4/980S Hypotensive peptides from milk proteins.] J Nutr 2004;134:980S-8S. PMID 15051858.</ref> The [[tripeptide]]s Val-Pro-Pro and Ile-Pro-Pro produced by the [[probiotic]] [[Lactobacillus helveticus]] have been show to have ACE-inhibiting and antihypertensive functions.<ref>Aihara K, Kajimoto O, Hirata H, Takahashi R, Nakamura Y. [http://www.jacn.org/cgi/content/full/24/4/257 Effect of powdered fermented milk with Lactobacillus helveticus on subjects with high-normal blood pressure or mild hypertension.] J Am Coll Nutr. 2005 Aug;24(4):257-65 PMID 16093403.</ref>
==Comparative information==
Comparatively, all ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main point-of-difference lies with captopril, the first ACE inhibitor, which has a shorter duration of action and increased incidence of certain adverse effects (cf. [[captopril]]).
Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality post-[[myocardial infarction]], prevent development of heart failure, ''etc''. The ACE inhibitor most prominently recognized for these qualities is ramipril (Altace). Owing to the fact that ramipril has been shown to reduce mortality rates even among patient groups not suffering from hypertension, there is widespread belief that ramipril's benefits may extend beyond those of the general abilities it holds in common with other members of the ACE inhibitor class.
==Contraindications and precautions==
The ACE inhibitors are contraindicated in patients with:
* Previous [[angioedema]] associated with ACE inhibitor therapy
* [[Renal artery stenosis]] (bilateral, or unilateral with a solitary functioning kidney)
ACE inhibitors should be used with caution in patients with:
* Impaired renal function
* [[Aortic valve stenosis]] or cardiac outflow obstruction
* [[Hypovolaemia]] or [[dehydration]]
* [[Haemodialysis]] with high flux polyacrylonitrile membranes
ACE inhibitors are [[Australian Drug Evaluation Committee|ADEC]] [[Pregnancy category]] D, and should be avoided in women who are likely to become pregnant.<ref name="AMH2006" /> In the U.S., ACE inhibitors are required to be labelled with a "[[Black box warning|black box]]" warning concerning the risk of birth defects when taking during the second and third [[trimester]]. It has also been found that use of ACE inhibitors in the first trimester is also associated with a risk of major [[congenital malformation]]s, particularly affecting the [[Circulatory system|cardiovascular]] and [[central nervous system]]s.<ref name="Cooper2006">Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer S, Gideon PS, et al. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=16760444&dopt=ExternalLink Major congenital malformations after first-trimester exposure to ACE inhibitors.] N Engl J Med 2006;354(23):2443-51. PMID 16760444</ref>
Potassium supplementation should be used with caution and under medical supervision owing to the [[hyperkalemia|hyperkalaemic]] effect of ACE inhibitors.
==Angiotensin II receptor antagonists==
ACE inhibitors share many common characteristics with another class of cardiovascular drugs called [[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 there are other conversion pathways, and 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.
===Use in combination===
While counterintuitive at first glance, 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 that this combination of pharmacologic agents may be advantageous in the treatment of [[essential hypertension]], chronic [[heart failure]], and [[nephropathy]].<ref name="Luno2005">Luno J, Praga M, de Vinuesa SG. The reno-protective effect of the dual blockade of the renin angiotensin system (RAS). Curr Pharm Des 2005;11(10):1291-300. PMID 15853685</ref><ref name="vandeWal2005">van de Wal RM, van Veldhuisen DJ, van Gilst WH, Voors AA. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=16105846&dopt=ExternalLink Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?] Eur Heart J 2005;26(22):2361-7. PMID 16105846</ref> However, more studies are needed to confirm these highly preliminary results. While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.<ref name="Finnegan2003">Finnegan PM, Gleason BL. [http://www.theannals.com/cgi/content/full/37/6/886 Combination ACE inhibitors and angiotensin II receptor blockers for hypertension.] Ann Pharmacother 2003;37(6):886-9. PMID 12773079</ref>
Patients with heart failure may benefit from the combination in terms of reducing [[morbidity]] and [[ventricular remodeling]].<ref name="Krum2004">Krum H, Carson P, Farsang C, et al. Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT. Eur J Heart Fail 2004;6(7):937-45. PMID 15556056</ref><ref name="Solomon2005">Solomon SD, Skali H, Anavekar NS, et al. [http://circ.ahajournals.org/cgi/content/full/111/25/3411 Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction.] Circulation 2005;111(25):3411-9. PMID 15967846</ref>
The most compelling evidence has been found for the treatment of nephropathy: this combination therapy partially reversed the [[proteinuria]] and also exhibited a renoprotective effect in patients afflicted with [[diabetic nephropathy]],<ref name="Luno2005"/> and pediatric [[IgA nephropathy]].<ref name="Yang2005">Yang Y, Ohta K, Shimizu M, et al. Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy. Clin Nephrol 2005;64(1):35-40. PMID 16047643</ref>
==History==
{{Main|ACE inhibitors drug design}}
The first step in the development of (ACE) inhibitors was the discovery of angiotensin converting enzyme (ACE) in [[blood plasma|plasma]] by [[Leonard T. Skeggs]] and his colleagues in [[1956]]. 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 that the plasma (ACE) was too slow to account for the conversion of angiotensin I to angiotensin II ''in vivo''. Subsequent investigation showed that rapid conversion occurs during its passage through the pulmonary circulation.<ref name="Kevin">K.K.F.Ng and J.R.Vane: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766</ref>
[[Bradykinin]] is rapidly inactivated in the circulating blood and it disappears completely in a single passage through the pulmonary circulation. Angiotensin I also disappears in the pulmonary circulation due to 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">K.K.F.Ng and J.R.Vane: Fate of angiotensin I in the circulation. Nature 1968, 218, 144-150. </ref> In 1970, Ng and Vane using [[bradykinin potentiating factor]] (BPF) provided by [[Sérgio Henrique Ferreira]] showed that the conversion of angiotensin I to angiotensin II was inhibited during its passage through the pulmonary circulation.<ref name="Kevin3">K.K.F.Ng and J.R.Vane: Some properties of angiotensin converting enzyme in the lung in vivo. Nature 1970, 225, 1142-1144.</ref>
[[Bradykinin potentiating factor]] (BPF) is derived from the venom of the pit viper (''[[Bothrops jararaca]]''). It is a family of peptides and its potentiating action is linked to inhibition of bradykinin by ACE. Molecular analysis of BPF yielded a nonapeptide BPF [[teprotide]] (SQ 20,881) which showed the greatest (ACE) inhibition potency and hypotensive effect ''in vivo''. Teprotide had limited clinical value, due to 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.
Captopril was approved by the United States [[Food and Drug Administration]] in 1981. The first non-sulfhydryl-containing (ACE) inhibitor enalapril was marketed two years later. Since then, at least twelve other ACE inhibitors have been marketed.
==References==
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