| ACE inhibitor (angiotensin-converting enzyme inhibitor) |
|
|---|---|
| Drug class | |
Captopril, the first synthetic ACE inhibitor |
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| Use | Hypertension |
| ATC code | C09 |
| MeSH | D000806 |
| AHFS/Drugs.com | Drug Classes |
| Consumer Reports | best-buy-drugs |
| WebMD | medicinenet rxlist |
| Biological target | angiotensin-converting enzyme |
An ACE inhibitor (or angiotensin-converting-enzyme inhibitor) is a pharmaceutical drug used primarily for the treatment of hypertension (high blood pressure) and congestive heart failure.
Originally synthesized from compounds found in pit viper venom, ACE inhibitors inhibit angiotensin-converting enzyme (a component of the blood pressure-regulating renin-angiotensin system), thereby decreasing the tension of blood vessels and blood volume, thus lowering blood pressure.
Frequently-prescribed ACE inhibitors include captopril, enalapril, lisinopril, and ramipril.
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ACE inhibitors are used primarily to treat hypertension, although they may also be prescribed for cardiac failure, diabetic nephropathy,[1] renal disease, systemic sclerosis, left ventricular hypertrophy and other disorders.
Angiotensin-converting enzyme inhibitors reduce the activity of the renin-angiotensin-aldosterone system.
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), as well as 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 I is then converted to angiotensin II by angiotensin converting enzyme (ACE), which removes a further two residues, and is found in the pulmonary circulation, as well as in the endothelium of many blood vessels.[2] The system in general aims to increase 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.[3] They, therefore, lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac index, stroke work, and volume; lower renovascular resistance; and lead to increased natriuresis (excretion of sodium in the urine). Renin will increase in concentration in the blood due to negative feedback of conversion of AI to AII. Angiotensin I will increase for the same reason. AII will decrease. Aldosterone will decrease. Bradykinin will increase due to less inactivation that is done by ACE enzyme.
Under normal conditions, angiotensin II will have the following effects:
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.[4] 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, 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.).
ACE inhibitors have also been shown to cause a central enhancement of parasympathetic activity in healthy volunteers and patients with heart failure.[5][6] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.
The ACE inhibitor enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure.[7] Cachexia is a poor prognostic sign in patients with chronic heart failure.[8] ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.
Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal impairment.[9] Some evidence also suggests ACE inhibitors might increase inflammation-related pain.[10]
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.[11] 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, but the reason is still unknown. Some suggest 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. 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 very high risk of developing renal failure.[12]
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.[13]
A severe allergic reaction that rarely can affect the bowel wall and secondarily cause abdominal pain can occur. This "anaphylactic" reaction is very rare as well.
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.[14]
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.[15]
The ACE inhibitors are contraindicated in patients with:
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.[9] In the U.S., ACE inhibitors are required to 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.[16]
Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.
ACE inhibitors can be divided into three groups based on their molecular structure:
This is the largest group, including:
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.
Certain agents in the ACE inhibitor class have been proven, in large clinical studies, to reduce mortality in patients after myocardial infarction, and prevent development of heart failure. 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, some (mostly drug-company representatives) believe ramipril's benefits may extend beyond those of the general abilities it holds in common with other members of the ACE inhibitor class.
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[20][21][22]
| ACE inhibitors dosages for hypertension | |||||
|---|---|---|---|---|---|
| Dosage | |||||
| Note: bid = 2 times a day, tid = 3 times a day, d = daily Drug dosages from Drug Lookup, Epocrates Online. |
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| 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. |
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| ACE inhibitors dosages for hypertension | |||||
ACE inhibitors possess many common characteristics with another class of cardiovascular drugs, 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, so angiotensin II receptor antagonists may be useful because they act to prevent the action of angiotensin II at the AT1 receptor, leaving AT2 receptor unblocked; the latter may have consequences needing further study.
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 this combination of pharmacologic agents may be advantageous in the treatment of essential hypertension, chronic heart failure,[23] and nephropathy.[24][25] 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.[26]
Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.[27][28]
The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed the proteinuria and also exhibited a renoprotective effect in patients afflicted with diabetic nephropathy,[24] and pediatric IgA nephropathy.[29]
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.[30] Ferreira then went to John Vane's laboratory as a postdoctoral 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.[31]
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 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.[32] In 1970, Ng and Vane, using BPF provided by Sérgio Henrique Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[33]
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 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 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.[34] 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.[35] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[19]
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