ACE inhibitor

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ACE inhibitor
(angiotensin-converting enzyme inhibitor)
Drug class
Captopril skeletal.svg
Captopril, the first synthetic ACE inhibitor
Use Hypertension
Biological target angiotensin-converting enzyme
ATC code C09
External links
MeSH D000806
AHFS/ Drug Classes
Consumer Reports Best Buy Drugs
WebMD medicinenet  rxlist

An ACE inhibitor (or angiotensin-converting-enzyme inhibitor) is a pharmaceutical drug used primarily for the treatment of hypertension (elevated blood pressure) and congestive heart failure (CHF).

This group of drugs causes dilatation (relaxation) of blood vessels, which results in lower blood pressure. In treating heart disease ACE inhibitors are usually used with other medications. A typical treatment plan will often include an ACE inhibitor, a beta blocker, a long-acting nitrate and a calcium channel blocker in combinations that are adjusted to the individual patient's needs.

ACE inhibitors inhibit the angiotensin-converting enzyme (a component of the blood pressure-regulating renin-angiotensin system), thereby decreasing the tension of blood vessels and the blood volume, thus lowering blood pressure.

Frequently prescribed ACE inhibitors include perindopril, captopril, enalapril, lisinopril, and ramipril.

Medical use[edit]

ACE inhibitors were initially approved for the treatment of hypertension (high blood pressure), and can be used alone or in combination with other anti-hypertensive medications.

Later, they were found useful in other cardiovascular and renal (kidney) diseases[1] including:

ACE inhibitors have also been used in Chronic renal failure and renal involvement in systemic sclerosis (hardening of tissues, as scleroderma renal crisis)



ACE inhibitors are approved for the treatment of hypertension (high blood pressure), and can be used alone or in combination with other anti-hypertensive medications. Efficiency is better with association of diuretics. There is no clinically meaningful BP lowering difference between different ACE inhibitors. The BP lowering effect of ACE inhibitors is modest; the magnitude of trough BP lowering at one-half the manufacturers' maximum recommended dose and above is -8/-5 mm Hg. Furthermore, 60 to 70% of this trough BP lowering effect occurs with recommended starting doses.[2] In people with hypertension ACE inhibitors lower risk of death and risk of stroke, coronary heart disease and cardiovascular events. ACE inhibitors and calcium channel blockers may be similarly effective as low dose diuretics, but the evidence is less robust. So low-dose thiazides should be the first choice drug in most patients with elevated blood pressure.[3] In hypertension there was mortality reduction with ACE inhibitor treatment, contrary to ARBs.[4]

Acute myocardial infarction[edit]

In Acute myocardial infarction (AMI, heart attack) treatment with ace inhibitor is started within 24 hours in prevention of remodelling of left ventricle.[1] The ACE-inhibitors class decrease mortality when continued for 10 days (3 to 5 deaths prevented per 1000). No other class of drug, apart from nitrates showed a reduction in mortality.[5]

Heart failure[edit]

In cardiac failure or (left ventricular systolic dysfunction) ACE inhibitors, associated with diuretics lower risk of death and cardiovascular events.[6] They are used together with diuretics, beta blocking agents and sometimes aldosterone antagonists.

Diabetic nephropathy[edit]

In diabetics with proteinuria ACE inhibitors prevent progression of renal impairment. The effects of ACE inhibitors on renal outcomes (end-stage kidney disease, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial for ACE inhibitors and for angiotensin 2 receptor antagonists. In placebo controlled studies, only ACE inhibitors at the maximum tolerable dose, (but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality.[7]


ACE inhibitors have also been used in chronic renal failure and renal involvement in other diseases. ACE inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage non-diabetic renal disease.[8] But there is currently insufficient evidence to determine the effectiveness of ACEi or ARB in patients with stage 1 to 3 chronic kidney disease who do not have diabetes mellitus.[9]

Dual blockade[edit]

Dual blockade of the renin-angiotensin system include the combination of an ACE inhibitor and an angiotensin-receptor blocker (ARBs), or a direct renin inhibitor (aliskiren Tekturna, Novartis). A meta analysis of 33 randomised controlled trials on dual blockade of the renin-angiotensin system found although it might have seemingly beneficial effects on certain surrogate endpoints as albuminuria and proteinuria, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia (increased potassium in the blood), hypotension, and renal failure compared with monotherapy. The risk to benefit ratio argues against the use of dual therapy.[10] In 2009 Lancet retracted the 2003 COOPERATE trial of dual renin-angiotensin system inhibition which concluded that combination therapy of an ACE inhibitor and an ARB was superior to an ACE inhibitor alone, and spanked the lead author for serious misconduct.[11][12] By 2008, about 140,000 patients in the U.S. took combined therapy.[13]

On April 4, 2014 EMA recommends against combined use of medicines affecting the renin-angiotensin (RAS) system, and in particular that patients with diabetes-related kidney problems (diabetic nephropathy) should not be given an ARB with an ACE-inhibitor. .[14]

With regard to blood pressure, a small additional fall with dual RAS blockade was observed when compared with that seen in monotherapy. However the 2008 ONTARGET study showed no benefit of combining the agents and more adverse events as hypotension, hyperkalaemia and renal impairment.[15]

Earlier studies have found that people with heart failure might benefit from the combination in terms of reducing morbidity and ventricular remodeling.[16][17] But a 2013 meta analysis found combination therapy with ARBs and ACE inhibitors reduced admissions for heart failure in patients with congestive heart failure when compared to ACE inhibitor therapy alone, but didn't reduce overall mortality or all-cause hospitalization and was associated with more adverse events. The combination therapy had a higher risk of worsening renal function, worsening symptomatic hypotension, a higher rate of permanent discontinuation of trial medications,[18] and a higher risk of hyperkalaemia.[10]

In the treatment of nephropathy early surrogate evidence found the combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy,[19] and pediatric IgA nephropathy.[20] A 2011 systematic review of 58 trials in patients with micro- and macroalbuminuria found there was no significant reduction in the risk of all-cause mortality or cardiac–cerebrovascular mortality with combined therapy with ACEI + ARB versus monotherapy. The risk of non fatal cardiovascular events was lower with combined therapy with ACEI + ARB versus monotherapy. Development of end-stage kidney disease and progression of microalbuminuria to macroalbuminuria were not reduced with combined therapy with ACEI + ARB versus monotherapy.[21]

Mechanism of action[edit]

Angiotensin-converting enzyme inhibitors reduce the activity of the 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 (outward indication) of renal disease.[22]

Renin-angiotensin-aldosterone system[edit]

One mechanism for maintaining the blood pressure is the release of a protein called renin from cells in the kidney (to be specific, the juxtaglomerular apparatus). This produces another protein, angiotensin, which signals the adrenal gland to produce a hormone called aldosterone. This system is activated in response to a fall in blood pressure (hypotension) and markers of problems with the salt-water balance of the body, such as decreased sodium concentration in the distal tubule of the kidney, decreased blood volume, and stimulation of the kidney by the sympathetic nervous system. In such situations, the kidneys release renin, which acts as an enzyme and cuts off all but the first 10 amino acid residues of angiotensinogen (a protein made in the liver, and which circulates in the blood). These 10 residues are then known as angiotensin I. Angiotensin converting enzyme (ACE) then removes a further two residues, converting angiotensin I into angiotensin II. Angiotensin II is found in the pulmonary circulation and in the endothelium of many blood vessels.[23] 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).


ACE inhibitors block the conversion of angiotensin I to angiotensin II.[24] They thereby: lower arteriolar resistance and increase venous capacity; decrease cardiac output, cardiac index, stroke work, and volume; lower resistance in blood vessels in the kidneys; and lead to increased natriuresis (excretion of sodium in the urine). Renin will increase in concentration in the blood as a result of negative feedback of conversion of AI to AII. Angiotensin I will increase for the same reason. Angiotensin II and Aldosterone will decrease. Bradykinin will increase because of less inactivation that is done by ACE.

Under normal conditions, angiotensin II will have the following effects:

  • Vasoconstriction (narrowing of blood vessels) and vascular smooth muscle hypertrophy (enlargement) induced by AII 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 ventricular remodeling and 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 AII of the adrenal cortex to release 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 vasopressin (antidiuretic hormone, ADH) also acts on the kidneys to increase water retention. If ADH production is excessive in heart failure, Na+ 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.

With ACE inhibitor use, the production of angiotensin II is decreased, leading to decreased blood pressure.

Epidemiological and clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure-lowering effect.[25] 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 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, and prophylaxis of cardiovascular events) is justified,[by whom?] 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.[26][27] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.[28] ACE Inhibitors also reduce plasma 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 enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure.[29] Cachexia is a poor prognostic sign in patients with chronic heart failure.[30]

Adverse effects[edit]

Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal impairment.[31] Fein also suggests ACE inhibitors might increase inflammation-related pain, perhaps mediated by the buildup of bradykinin that accompanies ACE inhibition.[32]

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.[33] 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 this 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 potential adverse effect of all ACE inhibitors, but the reason is still unknown. It may be associated with their effect on angiotensin II-mediated homeostatic functions, such as renal blood flow.[citation needed] 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. To be specific, they can induce or exacerbate renal impairment in patients with renal artery stenosis. This is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, there is a significantly increased risk of developing renal failure.[34]

ACE inhibitors may cause hyperkalemia. 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.[35]

A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.[citation needed]

Some patients develop angioedema due to increased bradykinin levels. There appears to be a genetic predisposition toward this adverse effect in patients who degrade bradykinin more slowly than average.[36]

In pregnant women, ACE inhibitors taken during the first trimester have been reported to cause major congenital malformations, stillbirths, and neonatal deaths. Commonly reported fetal abnormalities include hypotension, renal dysplasia, anuria/oliguria, oligohydramnios, intrauterine growth retardation, pulmonary hypoplasia, patent ductus arteriosus, and incomplete ossification of the skull.[37] Overall, about half of newborns exposed to ACE inhibitors are adversely affected.[38]

Contraindications and precautions[edit]

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)[39]
  • Hypersensitivity to ACE inhibitors

ACE inhibitors should be used with caution in patients with:

ACE inhibitors are ADEC pregnancy category D, and should be avoided in women who are likely to become pregnant.[31] In the U.S., ACE inhibitors must be labeled with a "black box" 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 cardiovascular and central nervous systems.[40]

Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.[41]


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

Sulfhydryl-containing agents[edit]

Dicarboxylate-containing agents[edit]

This is the largest group, including:

Phosphonate-containing agents[edit]

  • Fosinopril (Fositen/Monopril) is the only member of this group

Naturally occurring[edit]

Comparative information[edit]

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. Captopril is also the only ACE inhibitor that is capable of passing through the 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, ramipril (Altace), demonstrated an ability to reduce the mortality rates of patients suffering from 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 not having suffered from hypertension.[45]

ACE Inhibitor equivalent doses in hypertension[edit]

The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[46][47][48]

ACE inhibitors dosages for hypertension
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
Name Equivalent daily dose Start Usual Maximum
Benazepril 10 mg 10 mg 20–40 mg 80 mg
Captopril 50 mg (25 mg bid) 12.5–25 mg bid-tid 25–50 mg bid-tid 450 mg/d
Enalapril 5 mg 5 mg 10–40 mg 40 mg
Fosinopril 10 mg 10 mg 20–40 mg 80 mg
Lisinopril 10 mg 10 mg 10–40 mg 80 mg
Moexipril 7.5 mg 7.5 mg 7.5–30 mg 30 mg
Perindopril 4 mg 4 mg 4–8 mg 16 mg
Quinapril 10 mg 10 mg 20–80 mg 80 mg
Ramipril 2.5 mg 2.5 mg 2.5–20 mg 20 mg
Trandolapril 2 mg 1 mg 2–4 mg 8 mg
Name Equivalent daily dose Start Usual Maximum
Note: bid = 2 times a day, tid = 3 times a day, d = daily
Drug dosages from Drug Lookup, Epocrates Online.
ACE inhibitors dosages for hypertension


ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.[49]


The first step in the development of ACE inhibitors was the discovery of ACE in plasma by Leonard T. Skeggs and his colleagues in 1956. Brazilian scientist Sergio Ferreira reported a bradykinin-potentiating factor (BPF) present in the venom of Bothrops jararaca, a South American pit viper, in 1965.[50] Ferreira then went to 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.[51]

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.[52] In 1970, Ng and Vane, using BPF provided by Sérgio Henrique Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[53]

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 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.

Captopril was approved by the United States Food and Drug Administration in 1981. The first nonsulfhydryl-containing ACE inhibitor, enalapril, was marketed two years later. At least twelve other ACE inhibitors have since been marketed.

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 tripeptide isoleucine-proline-proline (IPP) from the dairy protein. 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 lactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.[54] 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.[55] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[44]

See also[edit]


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