Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of cardiovascular and kidney diseases. This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart.
ACE inhibitors inhibit the activity of angiotensin-converting enzyme, an important component of the renin–angiotensin system which converts angiotensin I to angiotensin II, and hydrolyzes bradykinin. Therefore, ACE inhibitors decrease the formation of angiotensin II, a vasoconstrictor, and increase the level of bradykinin, a peptide vasodilator. This combination is synergistic in lowering blood pressure.
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 include benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.
Medical uses ACE inhibitors were initially 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 including: Acute myocardial infarction (heart attack) Heart failure (left ventricular systolic dysfunction) Kidney complications of diabetes mellitus (diabetic nephropathy) by means of decreasing the blood pressure and preventing glomerular hyperfiltration injury
In treating high blood pressure, ACE inhibitors are a first-line initial drug choice. Age, frailty, and race can influence treatment choices and it is common to need more than one drug to obtain the desired improvement.
All ACE inhibitors but enalapril, which can be given intravenously, are administered orally. Each one has different strengths with different starting dosages. Dosage should be adjusted according to the clinical response.Common Medication Conversions (Equivalents): Ace Inhibitors . GlobalRPh.com. Accessed 2009-11-22.Treating High Blood Pressure and Heart Disease: the ACE Inhibitors. Consumer Reports Health Best Buy Drugs. June 2009. Most ACE inhibitors can be dosed once daily with the exception of captopril. 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. There are fixed-dose combination drugs, such as ACE inhibitor and thiazide combinations.
ACE inhibitors have also been used in chronic kidney failure and kidney involvement in systemic 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.
In 2012, a meta-analysis published in the BMJ described the protective role of ACE inhibitors in reducing the risk of pneumonia when compared to angiotensin II receptor blocker (ARBs). 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.
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, 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 may also be used to help decrease excessive water consumption in people with schizophrenia resulting in psychogenic polydipsia. 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; the same effect has been demonstrated in other ACE inhibitors.
Use of ACE inhibitors in kidney transplant patients may have little to no benefits.
Specific populations
Pregnancy In pregnant women, ACE inhibitors taken during all the trimesters have been reported to cause 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. Overall, about half of newborns exposed to ACE inhibitors are adversely affected, leading to birth defects.
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 must be labeled with a boxed 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.
Breastfeeding ACE inhibitors may be used with caution during breastfeeding due to evidence showing small amounts being present in breastmilk. Enalapril is most commonly prescribed and has the most data published. The medications are considered safe for the mother.
In children Common ACE inhibitors used in pediatrics for hypertension include captopril, enalapril, and lisinopril and are used in patients older than six years old.
In the elderly ACE inhibitors are strongly advised not to be started in elderly patients presenting with dehydration. Potassium and creatinine must be monitored during course of treatment.
Contraindications The ACE inhibitors are contraindicated in people with: Pregnancy Previous angioedema associated with ACE inhibitor therapy Bilateral renal artery stenosis Hypersensitivity to ACE inhibitors Impaired renal function Aortic valve stenosis or cardiac outflow obstruction Dehydration (hypovalemia)
ACE inhibitors should be used with caution in people with hemodialysis with high-flux polyacrylonitrile membranes.
Interactions A combination of ACE inhibitor with other drugs may increase effects of these drugs, but also the risk of adverse effects. Commonly reported adverse effects of drug combination with ACE inhibitor are acute renal failure, hypotension, and hyperkalemia. Drugs interacting with ACE inhibitor should be prescribed with caution. Special attention should be given to combinations of ACE inhibitor with diuretics (especially potassium-sparing diuretics), NSAIDs, anticoagulants, cyclosporine, DPP-4 inhibitors, and potassium supplements
Angiotensin II receptor antagonists (ARBs) should not be used with ACE inhibitors. Dual RAAS inhibitor therapy (ACE inhbitors, ARBs, direct renin inhibitors, or mineralocorticoid receptor antagonists) has been found to significantly increase the risk of developing kidney damage and hyperkalemia.
Potassium supplementation should be used with caution and under medical supervision owing to the hyperkalemic effect of ACE inhibitors.
Concomitant use with cyclooxygenase inhibitors tends to decrease ACE inhibitor's hypotensive effect.
Adverse effects Common side effects include low blood pressure, cough, hyperkalemia, headache, dizziness, fatigue, nausea, and kidney impairment.
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. Kidney problems may occur with all ACE inhibitors that directly follows from their mechanism of action. However, the decrease may be significant in conditions of pre-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. 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. Generally, a moderate reduction in renal function (no greater than 30% rise in serum creatinine which stabilizes within 2–4 weeks) is considered acceptable as part of the therapeutic effect.
Reduced GFR is especially a problem if the patient is concomitantly taking an NSAID and a diuretic. When the three drugs are taken together, the risk of developing renal failure is significantly increased.
Hyperkalemia, or high blood potassium, is a common adverse effect of treatment in 2% to 6% of patients. 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. 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.
Another possible adverse effect specific for ACE inhibitors, but not for other RAAS blockers, is an increase in bradykinin level. Additional research on this topic is required.
A persistent dry cough is a common adverse effect produced by ACE inhibitors in 10% to 20% of patients. People who experience coughing are often switched to angiotensin II receptor antagonists.
Between 0.1% and 0.7% of patients develop angioedema or swelling. A genetic predisposition may exist.
Blood Hematologic effects, such as neutropenia, agranulocytosis and other blood dyscrasias, have occurred during therapy with ACE inhibitors, especially in people with additional risk factors.FDA Prescribing information, http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20A%29/ACE%20INHIBITORS.html
Overdose There are few reports of ACE inhibitor overdose, toxicity is more likely with the addition of other hypertensive drugs or higher than recommended doses. The most likely manifestations are hypotension, which may be severe, hyperkalemia, hyponatremia and renal impairment with metabolic acidosis. Related symptoms of hypotension are treated with naloxone. 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 by hemodialysis.
Pharmacology
Mechanism of action ACE 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 of renal disease.