| Angiotensin-converting-enzyme inhibitor | |
|---|---|
| Drug class | |
 Captopril, the first synthetic ACE inhibitor | |
| Class identifiers | |
| Use | Hypertension |
| ATC code | C09A |
| Biological target | Angiotensin-converting enzyme |
| Clinical data | |
| Drugs.com | Drug Classes |
| Consumer Reports | Best Buy Drugs |
| WebMD | MedicineNet RxList |
| External links | |
| MeSH | D000806 |
| Legal status | |
| In Wikidata | |
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class ofmedication used primarily for the treatment ofhigh blood pressure andheart failure.[1][2] This class of medicine works by causing relaxation of blood vessels as well as a decrease inblood volume, which leads to lowerblood pressure and decreasedoxygen demand from theheart.
ACE inhibitorsinhibit the activity ofangiotensin-converting enzyme, an important component of therenin–angiotensin system which convertsangiotensin I toangiotensin II,[3] and hydrolysesbradykinin.[1] Therefore, ACE inhibitors decrease the formation of angiotensin II, avasoconstrictor, and increase the level ofbradykinin, apeptidevasodilator.[1][3] This combination is synergistic in lowering blood pressure.[1][3]
As a result of inhibiting the ACE enzyme in the bradykinin system, the ACE inhibitor drugs allow for increased levels of bradykinin which would normally be degraded. Bradykinin produces prostaglandin. This mechanism can explain the two most common side effects seen with ACE Inhibitors: angioedema and cough.
Frequently prescribed ACE inhibitors includebenazepril,zofenopril,perindopril,trandolapril,captopril,enalapril,lisinopril, andramipril.
ACE inhibitors wereinitially approved for the treatment of hypertension and can be used alone or in combination with other anti-hypertensive medications. Later, they were found useful for other cardiovascular and kidney diseases[4] including:
In treating high blood pressure, ACE inhibitors are often the first drug choice, particularly when diabetes is present,[8] but age can lead to different choices and it is common to need more than one drug to obtain the desired improvement. There are fixed-dosecombination drugs, such asACE inhibitor and thiazide combinations. ACE inhibitors have also been used inchronic kidney failure and kidney involvement insystemic sclerosis (hardening of tissues, as scleroderma renal crisis). In those with stable coronary artery disease, but no heart failure, benefits are similar to other usual treatments.[9]
In 2012, ameta-analysis published in theBMJ described the protective role of ACE inhibitors in reducing the risk ofpneumonia when compared toangiotensin II receptor blocker (ARBs).[10] The authors found a decreased risk in patients with previous stroke (54% risk reduction), with heart failure (37% risk reduction), and of Asian descent (43% risk reduction vs 54% risk reduction in non-Asian population). However, no reduced pneumonia-related mortality was observed.[11]
ACE inhibitors may also be used to help decrease excessive water consumption in people withschizophrenia resulting inpsychogenic polydipsia.[12][13] A double-blind, placebo-controlled trial showed that when used for this purpose,enalapril led to decreased consumption (determined by urine output and osmolality) in 60% of people;[14] the same effect has been demonstrated in other ACE inhibitors.[15]
Additionally ACE-I are commonly used after renal transplant to manage post-transplanterythrocytosis, a condition characterised by a persistently highhematocrit greater than 51% which often develops 8–24 months after successful transplantation,[16] as ACE-I have been shown to decreaseerythropoietin production.[17]
Common side effects include: low blood pressure,cough,hyperkalemia,headache,dizziness,fatigue,nausea, andkidney impairment.[18][19]
The main adverse effects of ACE inhibition can be understood from their pharmacological action. The other reported adverse effects are liver problems and effects on the fetus.[19] Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. Patients starting on an ACE inhibitor usually have a modest reduction inglomerular filtration rate (GFR).[20] However, the decrease may be significant in conditions ofpre-existing decreased renal perfusions, such as renal artery stenosis, heart failure, polycystic kidney disease, or volume depletion. In these patients, the maintenance of GFR depends on angiotensin-II-dependent efferent vasomotor tone.[20] Therefore,renal function should be closely monitored over the first few days after initiation of treatment with ACE inhibitor in patients with decreased renal perfusion.[19] Generally, a moderate reduction in renal function (no greater than 30% rise in serumcreatinine which stabilizes within 2-4 weeks) is considered acceptable as part of the therapeutic effect.[21][22]
Reduced GFR is especially a problem if the patient is concomitantly taking anNSAID and adiuretic.[23] When the three drugs are taken together, the risk of developing renal failure is significantly increased.[24]
High blood potassium is another possible complication of treatment with an ACE inhibitor due to its effect on aldosterone. 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.[25] Hyperkalemia may decrease the velocity of impulse conduction in the nerves and muscles, including cardiac tissues. This leads to cardiac dysfunction and neuromuscular consequences, such as muscle weakness, paresthesia, nausea, diarrhea, and others. Close monitoring of potassium levels is required in patients receiving treatment with ACE inhibitors who are at risk of hyperkalemia.[19]
Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase inbradykinin level.[19]
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.[26] Many cases of cough in people on ACE inhibitors may not be from the medication itself, however.[27] People who experience this cough are often switched toangiotensin II receptor antagonists.[citation needed]
Some (0.7%)[23] developangioedema due to increased bradykinin levels.[28] A genetic predisposition may exist.[29]
A severe rare allergic reaction can affect the bowel wall and secondarily cause abdominal pain.[30]
Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.[31]
In pregnant women, ACE inhibitors taken during all the trimesters have been reported to causecongenital malformations,stillbirths, andneonatal deaths. Commonly reported fetal abnormalities includehypotension,renal dysplasia, anuria/oliguria,oligohydramnios,intrauterine growth retardation,pulmonary hypoplasia,patent ductus arteriosus, and incomplete ossification of the skull.[19][32] Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading tobirth defects.[33][23]
ACE inhibitors areADECpregnancy category D and should be avoided in women who are likely to become pregnant.[18] In the U.S., ACE inhibitors must be labeled with aboxed 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 majorcongenital malformations, particularly affecting thecardiovascular andcentral nervous systems.[34]
Symptoms and Treatment: There are few reports of ACE inhibitor overdose in the literature. The most likely manifestations are hypotension, which may be severe,hyperkalemia,hyponatremia andrenal impairment withmetabolic acidosis. Treatment should be mainly symptomatic and supportive, with volume expansion using normal saline to correct hypotension and improve renal function, and gastric lavage followed by activated charcoal and a cathartic to prevent further absorption of the drug. Captopril, enalapril, lisinopril and perindopril are known to be removable byhemodialysis.[35]
The ACE inhibitors are contraindicated in people with:[citation needed]
ACE inhibitors should be used with caution in people with:[citation needed]
A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects.[19] The commonly reported adverse effects of drug combination with ACE inhibitor are acute renal failure, hypotension, and hyperkalemia. The drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with other RAAS blockers,diuretics (especially potassium-sparing diuretics), NSAIDs,anticoagulants,cyclosporine,DPP-4 inhibitors, andpotassium supplements.
Potassium supplementation should be used with caution and under medical supervision owing to thehyperkalemic effect of ACE inhibitors.[38]
Concomitant use withcyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.[39][23]
ACE inhibitors reduce the activity of therenin–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 of renal disease.[40][41]
The renin–angiotensin–aldosterone system is a major blood pressure regulating mechanism. Markers of electrolyte and water imbalance in the body such ashypotension, lowdistal tubulesodium concentration, decreased blood volume and highsympathetic tone trigger the release of the enzymerenin from the cells ofjuxtaglomerular apparatus in the kidney.[citation needed]
Renin activates a circulating liver derivedprohormoneangiotensinogen by proteolytic cleavage of all but its first tenamino acid residues known asangiotensin I.ACE (angiotensin converting enzyme) then removes a further two residues, converting angiotensin I intoangiotensin II. ACE is found in thepulmonary circulation and in theendothelium of many blood vessels.[42] The system increases blood pressure by increasing the amount of salt and water the body retains, although angiotensin II is also a potentvasoconstrictor.[43]
ACE inhibitors block the conversion of angiotensin I (ATI) to angiotensin II (ATII).[44] They thereby lowerarteriolar resistance and increase venous capacity; decreasecardiac output,cardiac index, stroke work, andvolume; lower resistance in blood vessels in the kidneys; and lead to increasednatriuresis (excretion of sodium in the urine). Renin increases in concentration in the blood as a result of negative feedback of conversion of ATI to ATII. ATI increases for the same reason; ATII and aldosterone decrease.Bradykinin increases because of less inactivation by ACE.[citation needed]
Under normal conditions, angiotensin II has these effects:[citation needed]
During the course of ACE inhibitor use, the production of ATII is decreased,[note 1][45] which prevents aldosterone release from the adrenal cortex.[45] This allows the kidney to excrete sodium ions along with obligate water, and retain potassium ions. This decreases blood volume, leading to decreased blood pressure.[45]
Epidemiological and clinical studies have shown ACE inhibitors reduce the progress ofdiabetic nephropathy independently from their blood pressure-lowering effect.[46] This action of ACE inhibitors is used in the prevention of diabeticrenal failure.[citation needed]
ACE inhibitors have been shown to be effective for indications other than hypertension[47] even in patients with normal blood pressure.[48] 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,[49] 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.).[citation needed]
ACE inhibitors have also been shown to cause a central enhancement ofparasympathetic nervous system activity in healthy volunteers and patients with heart failure.[50][51] This action may reduce the prevalence of malignant cardiac arrhythmias, and the reduction in sudden death reported in large clinical trials.[52]ACE Inhibitors also reduce plasmanorepinephrine levels, and its resulting vasoconstriction effects, in heart failure patients, thus breaking the vicious circles ofsympathetic and renin angiotensin system activation, which sustains the downward spiral in cardiac function in congestive heart failure[citation needed]
The ACE inhibitorenalapril has also been shown to reduce cardiaccachexia in patients with chronic heart failure.[53] Cachexia is a poor prognostic sign in patients with chronic heart failure.[54]ACE inhibitors are under early investigation for the treatment of frailty and muscle wasting (sarcopenia) in elderly patients without heart failure.[55]
Currently, there are 10 ACE inhibitors approved for use in theUnited States by theFDA:captopril (1981),enalapril (1985),lisinopril (1987),benazepril (1991),fosinopril (1991),quinapril (1991),ramipril (1991),perindopril (1993),moexipril (1995) andtrandolapril (1996).[56][57]
ACE inhibitors are easily identifiable by their common suffix, '-pril'. ACE inhibitors can be divided into three groups based on their molecular structure of theenzyme binding sites (sulfhydryl,phosphinyl,carboxyl) to the active center of ACE:[58]
These agents appear to showantioxidative properties but may be involved in adverse events such asskin eruptions.[58]
This is the largest group, including:[citation needed]
All ACE inhibitors have similar antihypertensive efficacy when equivalent doses are administered. The main differences lie withcaptopril, the first ACE inhibitor. Captopril has a shorter duration of action and an increased incidence of adverse effects. It is also capable of passing through theblood–brain barrier.[65][66]
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 with amyocardial 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 have hypertension.[67]
Some believe 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.[68]
A meta-analysis confirmed that ACE inhibitors are effective 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. ACE inhibitors were used as the active treatment in seven trials (n=76,615) and angiotensin receptor blocker (ARB) in 13 trials (n=82,383).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). Analysis of mortality reduction by different ACE inhibitors showed that perindopril-based regimens are 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 withperindopril, would result in an important gain of lives saved.[69]
The ACE inhibitors have different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.[70][71][72]
| ACE inhibitors dosages for hypertension | |||||
|---|---|---|---|---|---|
| Dosage | |||||
| Note:bid = two times a day,tid = three 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 | 150 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 | |
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.[citation needed]
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 ofessential hypertension, chronicheart failure,[73] andnephropathy.[74][75] However, the more recent ONTARGET study showed no benefit of combining the agents and more adverse events.[76] While statistically significant results have been obtained for its role in treating hypertension, clinical significance may be lacking.[77] There are warnings about the combination of ACE inhibitors with ARBs.[78]
Patients with heart failure may benefit from the combination in terms of reducingmorbidity andventricular remodeling.[79][80]
The most compelling evidence for the treatment of nephropathy has been found: This combination therapy partially reversed theproteinuria and also exhibited a renoprotective effect in patients withdiabetic nephropathy,[74] and pediatricIgA nephropathy.[81]
Leonard T. Skeggs and his colleagues (includingNorman Shumway) discovered ACE inplasma in 1956.[82] It was also noted that those who worked in banana plantations in South-western Brazil collapsed after being bitten by apit viper, leading to a search for a blood pressure lowering component in its venom.[83] Brazilian scientistSérgio Henrique Ferreira reported abradykinin-potentiating factor (BPF) present in the venom ofBothrops jararaca, a South American pit viper, in 1965.[84] Ferreira then went toJohn 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 andJohn R. Vane showed plasma ACE is too slow to account for the conversion of angiotensin I to angiotensin IIin vivo. Subsequent investigation showed rapid conversion occurs during its passage through the pulmonary circulation.[85]
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.[86] In 1970, Ng and Vane, using BPF provided by Ferreira, showed the conversion is inhibited during its passage through the pulmonary circulation.[87]
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 BPFteprotide (SQ 20,881), which showed the greatest ACE inhibition potency and hypotensive effectin 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.[88]
Captopril was approved by the United StatesFood and Drug Administration in 1981.[89] The first nonsulfhydryl-containing ACE inhibitor, enalapril, was approved four years later.[90] At least 8 other ACE inhibitors have since been marketed.[91]
In 1991, Japanese scientists created the first milk-based ACE inhibitor, in the form of a fermented milk drink, using specific cultures to liberate thetripeptideisoleucine-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 aslactotripeptides. In 1996, the first human study confirmed the blood pressure-lowering effect of IPP in fermented milk.[92] 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.[93]Since the first lactotripeptides discovery, more than 20 human clinical trials have been conducted in many different countries.[63]
Mechanisms of Action:ACE inhibitors act by inhibiting one of several proteases responsible for cleaving the decapeptide Ang I to form the octapeptide Ang II. Because ACE is also the enzyme that degrades bradykinin, ACE inhibitors increase circulating and tissue levels of bradykinin (Fig. 8.4).
Angiotensin-converting enzyme inhibitors ACE inhibitors have been demonstrated to reduce sudden cardiac death in some studies of persons with CHF.24,56
ACE inhibitors inhibit the conversion of angiotensin I to angiotensin II, thereby producing vasodilation and lowering BP. Because the hydrolysis of bradykinin is also inhibited by these drugs, cough (7% to 12%) can occur.
ACE inhibitors also slow progression of kidney disease in patients with diabetic nephropathies. Renal benefits are probably a result of improved renal hemodynamics from decreased glomerular arteriolar resistance.
due to inhibition of angiotensin II production by ACE inhibitors or competitive antagonism of the angiotensin II receptor by ARBs... results in loss of angiotensin II–induced efferent arteriolar tone, leading to a drop in glomerular filtration fraction and GFR. The efferent arteriolal vasodilation reduces intraglomerular hypertension (and pressure-related injury) and maintains perfusion (and oxygenation) of the peritubular capillaries.
Angioedema (0.7%) can also occur via pathobiology that remains obscure, and its occurrence can be life-threatening. ...their efficacy is reduced by dietary or other sources of sodium, and renal function may be further threatened if given with NSAIDs.
Coadministration of nonsteroidal anti-inflammatory drugs (NSAIDs [cyclooxygenase inhibitors]) can reduce the hypotensive effects of ACE inhibitors. ACE inhibitors can inhibit the excretion of lithium and can result in lithium toxicity. Because these drugs do not affect the breakdown of kinins (as is seen with the ACE inhibitors), patients do not develop episodes of coughing and rarely develop angioneurotic edema.
Despite the lack of long-term suppression in plasma angiotensin II levels, they maintain their BP-lowering effect without the development of tolerance. Importantly, ACE inhibitors do not interfere with cognitive function or cardiovascular reflexes.
ACE inhibitors are classified according to the chemical structure of the site of binding (sulfhydryl, phosphinyl, carboxyl) to the active center of ACE.
