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 most cases as the drugs of first choice.
Indications for ACE inhibitors include:
* Prevention of
cardiovascular disorders
*
Congestive heart failure*
Hypertension* Left
ventricular dysfunction
* Prevention of
nephropathy in
diabetes mellitusIn 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.
ACE inhibitors lower
arteriolar resistance and increase venous capacitance; increase
cardiac output and
cardiac index, stroke work and
volume, lower renovascular resistance, and lead to increased
natriuresis (excretion of
sodium in the
urine).
Epidemiological and clinical studies have shown that ACE inhibitors reduce the progress of
diabetic nephropathy independently from their blood pressure-lowering effect. 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 patient suffering from the effects of rapidly decreasing their blood pressure (dizziness, fainting,
etc).
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) 阻害薬誘発性の'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, and is associated with their effect on angiotensin II-mediated
homeostatic functions such as renal bloodflow. 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]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. 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.]ACE inhibitors can be divided into three groups based on their molecular structure:
Sulfhydryl-containing ACE inhibitors
*
Captopril (Capoten®), the first ACE inhibitor
Dicarboxylate-containing ACE inhibitors
This is the largest group, including:
*
Enalapril (Vasotec®/Renitec®)
*
Ramipril (Altace®/Tritace®/Ramace®)
*
Quinapril (Accupril®)
*
Perindopril (Coversyl®)
*
Lisinopril (Lisodur®/Lopril®/Prinivil®/Zestril®)
*
BenazeprilPhosphonate-containing ACE inhibitors
*
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
sour milk. Their role in blood pressure control is uncertain.
[FitzGerald RJ, Murray BA, Walsh DJ. Hypotensive peptides from milk proteins. J Nutr 2004;134:980S-8S. PMID 15051858.]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. While these effects are likely to be class-effects, good
evidence-based medicine practice would direct the use of those agents with established clinical efficacy.
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. 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.
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 AT
1 receptor.
Use in combination with ACE inhibitors
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
1 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. 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. 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. 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, (Luno et al., 2005) 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]The first step in the development of ACE inhibitors was the discovery of angiotensin converting enzyme (ACE) in
1956 by
Leonard T. Skeggs. The importance of this enzyme in blood pressure regulation was initially underestimated. Fourteen years later, the pharmacologist
Sérgio Henrique Ferreira discovered that the venom of the pit viper (
Bothrops jararaca) was able to potentiate the action of
bradykinin. A family of peptides, designated
bradykinin potentiating factors (BPFs) was isolated from the venom and their action was linked to inhibition of bradykinin degradation by ACE.
The nonapeptide BPF
teprotide (SQ 20,881) was found to have the greatest ACE inhibition potency and hypotensive effect
in vivo. Teprotide had limited clinical value, however, 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 nine other ACE inhibitors have been marketed.
