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.
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.[citation needed]
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 converting enzyme (ACE) then removes a further two residues which converts angiotensin I into angiotensin II. Angiotensin II 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.
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-oncogens 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 is caused.
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,[by whom?] 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.[7] Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure. ACE Inhibitors also reduce plasma norepinephrine levels and NE -induced vasoconstriction, only 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.[8] Cachexia is a poor prognostic sign in patients with chronic heart failure.[9] ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.[10]
Common adverse drug reactions include: hypotension, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and renal impairment.[11] Some evidence also suggests ACE inhibitors might increase inflammation-related pain, perhaps mediated by the buildup of bradykinin that accompanies ACE inhibition.[12]
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.[13] 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.[14]
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.[15]
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.[16]
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.[17]
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)
- 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.[11] 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.[18]
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:
- Fosinopril (Fositen/Monopril) is the only member of this group
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 which 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 who suffered 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 who did not suffer from hypertension.[22]
Some believe that ramipril's additional benefits may be shared by some or all drugs in the ACE inhibitor class. However, ramipril currently remains the only ACE inhibitor for which such effects are actually evidence-based.[23]
A meta-analysis confirmed that ACE inhibitors are pivotal and certainly the first-line choice in hypertension treatment. This meta-analysis was based on 20 trials and a cohort of 158 998 patients, of whom 91% were hypertensive. Angiotensin-converting enzyme (ACE) inhibitors were used as the active treatment in 7 trials (n=76 615) and angiotensin receptor blocker (ARB) in 13 trials (n=82 383). Results showed that ACE inhibitors were associated with a statistically significant 10% mortality reduction: (HR 0.90; 95% CI, 0.84-0.97; P=0.004). In contrast, no significant mortality reduction was observed with ARB treatment (HR 0.99; 95% CI, 0.94-1.04; P=0.683). Interestingly, analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens were associated with a statistically significant 13% all-cause mortality reduction. Taking into account the broad spectrum of the hypertensive population, one might expect that an effective treatment with ACE inhibitors, in particular with perindopril, would result in an important gain of lives saved.
Van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158 998 patients. Eur Heart J. 2012 Apr 17. [Epub ahead of print]</ref>
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[24][25][26]
| 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. |
| 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 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 blockage is dose-dependent, 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,[27] and nephropathy.[28][29] However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events.[30] While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.[31]
Patients with heart failure may benefit from the combination in terms of reducing morbidity and ventricular remodeling.[32][33]
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,[28] and pediatric IgA nephropathy.[34]
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.[35] 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.[36]
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.[37] In 1970, Ng and Vane, using BPF provided by Sérgio Henrique Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[38]
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.[39] 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.[40] Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[21]
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