ACE inhibitor

ACE inhibitors, or inhibitors of Angiotensin-Converting Enzyme, are a group of pharmaceuticals 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 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.

ACE inhibitors are often combined with diuretics 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)

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 as well as in the endothelium of blood vessels in many parts of the body. [Human Physiology, Silverthorn (Pearson Benjamin Cummings 2004)] 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 arteriolar resistance and increase venous capacity; increase cardiac output and cardiac index, stroke work and 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 arterioles of the kidney, leading to increased perfusion pressure in the 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.

Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effectFact|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 reactions (≥1% of patients) include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, renal impairment.Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3.]

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.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] Patients who experience this cough are often switched to angiotensin II receptor antagonists.

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 homeostatic functions such as renal blood flow. Renal blood flow may be affected by Angiotensin II because it vasoconstricts the efferent arterioles of the 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 NSAID and a diuretic - the so-called "triple whammy" effect - such patients are at very high risk of developing renal failure.Thomas MC. Diuretics, ACE inhibitors and NSAIDs - the triple whammy. Med J Aust 2000;172(4):184–185. PMID 10772593]

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.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.]

Examples

ACE inhibitors can be divided into three groups based on their molecular structure:

ulfhydryl-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

Casokinins and lactokinins 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.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.] The tripeptides Val-Pro-Pro and Ile-Pro-Pro produced by the probiotic Lactobacillus helveticus have been shown to have ACE-inhibiting and antihypertensive functions. [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.]

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). Because 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 ADEC Pregnancy category D, and should be avoided in women who are likely to become pregnant. In the U.S., ACE inhibitors are required to be labelled with a "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 malformations, particularly affecting the cardiovascular and central nervous systems.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]

Potassium supplementation should be used with caution and under medical supervision owing to the 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 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 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 AT₁ 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 AT₁ 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.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] 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] 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.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]

Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.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] 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]

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, and pediatric IgA nephropathy.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]

History

The first step in the development of (ACE) inhibitors was the discovery of angiotensin converting enzyme (ACE) in 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.K.K.F.Ng and J.R.Vane: Conversion of angiotensin I to angiotensin II. Nature 1967, 216, 762-766]

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.K.K.F.Ng and J.R.Vane: Fate of angiotensin I in the circulation. Nature 1968, 218, 144-150. ] 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.K.K.F.Ng and J.R.Vane: Some properties of angiotensin converting enzyme in the lung in vivo. Nature 1970, 225, 1142-1144.]

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