ACE+INHIBITORS


 * Angiotensin-converting enzyme inhibitors (ACE inhibitors)**
 * History:** The history of angiotensin-converting enzyme (ACE) inhibitors began in 1954, when the importance of this enzyme was initially recognized. In 1968, the first compound capable of inhibiting the conversion of angiotensin I to angiotensin II was isolated from snake venom. The first clinically useful ACE inhibitor was never commercially marketed, however, because it was not bioavailable after oral administration. In 1980, captopril became the first angiotensin-converting enzyme inhibitor approved for clinical use. Since then, at least 40 ACE-inhibitor compounds have been identified and either are still under investigation or have been approved.

Because of severe, though infrequent, adverse effects, captopril initially was regarded as a second-line agent in the treatment of hypertension. Many of these adverse reactions were blamed on the presence of a sulfhydryl group in the captopril molecule because similar reactions (neutropenia, proteinuria, rash, dysgeusia) had occurred during therapy with other sulfhydryl-containing compounds (e.g., penicillamine). In addition, switching patients from captopril to enalapril, which does not possess a sulfhydryl group, alleviated these reactions in some patients. However, reducing the maximum daily dose of captopril from 450 mg/day to 150 mg/day also reduced the incidence of these reactions.

Since the incidence of captopril-induced adverse reactions has decreased and because additional ACE inhibitors are now available, these agents have become important drugs in the treatment of hypertension. Quality-of-life studies proclaimed them superior to other, older antihypertensive agents. In addition, these drugs display favorable effects on elevated serum lipids and left ventricular hypertrophy, conditions that often coexist in patients receiving treatment for hypertension. Finally, there are now several once daily ACE inhibitors, which facilitates compliance in the treatment of chronic disease states such as hypertension.

Equally important is the use of ACE inhibitors in treating congestive heart failure. As early as 1979, captopril was shown to be beneficial; however, enalapril has received more attention and was approved by the FDA for use in this condition. As a result of several major trials published in 1991—1992 that demonstrated a favorable effect on mortality, enalapril is now recognized as a first-line agent for congestive heart failure.

ACE inhibitors are being investigated for use during the acute and recovery phases of a myocardial infarction. In 1992, the results of several studies evaluating the use of ACE inhibitor therapy in this setting were published. The SAVE investigators reported that ACE inhibitor therapy (i.e., captopril) was associated with an improvement in survival and reduction in mortality and morbidity due to major cardiovascular events.[593] However, ACE inhibitor therapy (i.e., enalapril) was not found more effective at improving survival than placebo at 180 days post infarction in the CONSENSUS II trial.[594]

Several explanations for the discrepancy in these results are possible. Normally, within 72 hours after acute coronary occlusion the cardiac muscle undergoes an adaptive process to establish a new pressure-volume relation; stroke volume is preserved despite a decreased ejection fraction. Therapy was initiated earlier in the CONSENSUS study (i.e., within 24 hours after the onset of chest pain) compared to the SAVE study (i.e., therapy was initiated 3—16 days after myocardial infarction). Delayed administration of ACE inhibitors may avoid attenuating the normal adaptive process. Also, early hypotensive reactions in the elderly were observed in the CONSENSUS study, another reason why the normal adaptive process could be disrupted. Finally, captopril (SAVE study) possesses a sulfhydryl group while enalapril (CONSENSUS study) does not. Could it be possible that the free-radical-scavenging ability of captopril offered protection, as some have suggested,[595] that enalapril does not? Following coronary reperfusion in dogs, only captopril improved postischemic derangements in contractility, a mechanism thought to be due to the free-radical-scavenging ability of captopril.[596] In late 1993, captopril received an expanded indication to improve survival in patients with left ventricular dysfunction following myocardial infarction.

Conclusive evidence of the benefits of ACE inhibitors in treatment and prevention of heart failure was established by the SOLVD investigators in two landmark clinical trials in patients with left ventricular dysfunction. In an investigation of chronic heart failure patients (NYHA I—III) with reduced ejection fraction, the addition of enalapril to conventional therapy (e.g., digoxin and diuretics) significantly reduced mortality and hospitalizations.[2778] In an evaluation of patients with asymptomatic left ventricular dysfunction, enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations compared to placebo.[2779]

The market introduction of angiotensin II antagonists (such as losartan, irbesartan, valsartan, candesartan, eprosartan, and telmisartan) has led to the recent completion of two large comparative trials of ACE inhibitors versus losartan in the treatment of heart failure. ACE inhibitors remain the first-line treatment of heart failure; however, angiotensin II antagonists may be considered as alternative agents in patients with ACE-induced cough. The first trial, ELITE I, demonstrated a lower all-cause mortality and hospitalization rate for losartan compared to the captopril group. The dose of losartan in this study was initially 12.5 mg PO once daily which was titrated to 50 mg PO once daily.[1479] In a followup study (ELITE II), elderly patients >= 60 years, NYHA II—IV heart failure and ejection fraction <= 0.4 (stratified for beta-blocker use) were randomly assigned to receive either losartan titrated to 50 mg once daily or captopril titrated to 50 mg three times daily. In this trial, there were no significant differences in all-cause mortality, sudden death rate, or resuscitated arrests. In addition, significantly fewer patients in the losartan group (excluding those who died) discontinued study treatment because of adverse effects (9.7% vs. 14.7%), including cough (0.3% vs. 2.7%).[2780]

As investigation of ACE inhibitors continues, more clinical applications arise. The use of ACE inhibitors has been investigated in the treatment of progressive renal diseases. ACE inhibitors have reduced proteinuria, slowed the decline of renal plasma flow and glomerular filtration rate in patients with diabetic nephropathy. ACE inhibitors have been studied in patients with systemic lupus and study results demonstrated prevention of continued decline of renal function. ACE inhibitors have been found useful in scleroderma renal crisis, reducing decline in renal function in non-diabetics, diagnosis of renal artery stenosis, Bartter syndrome, and Raynaud's disease, among others. Except for diabetic proteinuria, these are not FDA-approved uses at this time.


 * Mechanism of Action:** It is well known that ACE inhibitors, by serving as a substrate for angiotensin-converting enzyme, interfere with the conversion of angiotensin I to angiotensin II. This, in turn, reduces aldosterone output and also causes a reflex increase in renin secretion. Interestingly, it appears that tissue-specific renin-angiotensin systems also might exist. The actions of ACE inhibitors on these "local" systems could be more responsible for their clinical effects than are their actions on circulating (i.e., generalized) systems. These local systems function in an autocrine, paracrine, or intracrine fashion, and many tissues, including the heart, the adrenals, the kidneys, and others, are believed to contain their own renin-aldosterone system. Actions on local systems could explain why the clinical effects of ACE inhibition persist longer than drug serum concentrations can be detected. It also might explain differences in clinical actions among these agents on a specific organ (e.g., heart, kidney) and/or certain adverse effects.

ACE inhibitors reduce the production of angiotensin II, lowering intraglomerular hypertension and reducing alterations in renal hemodynamics. This action reduces proteinuria, slows the decline of renal plasma flow and glomerular filtration rate in patients with diabetic nephropathy. Patients with systemic sclerosis have elevated peripheral renin levels and may develop scleroderma renal crisis (SRC). SRC is associated with a sudden onset of malignant hypertension and a subsequent rapid decline in renal function. ACE inhibitors have been shown to be effective in some SRC patients by decreasing renin-induced angiotensin II activity, reducing blood pressure, and preserving renal function. The beneficial effects in systemic lupus patients are attributed mainly to hypertension control.[597]

Much interest surrounds the ability of ACE inhibitors to impact on morbidity and mortality associated with ischemic heart disease and heart failure. A review of these studies concluded that ACE inhibitors reduce death and the risk of hospitalization associated with heart failure.[1041] Favorable trends in myocardial infarction, sudden or presumed arrhythmic death, and stroke and pulmonary emboli suggest that ACE inhibitors may possess other beneficial mechanisms. Some that have been proposed include an antiischemia mechanism, prevention of ventricular remodeling, or blunting of neurohormonal activation.[1041] The presence of a sulfhydryl group by captopril has been identified as a potential free radical scavenger.


 * Distinguishing Features:** Agents in this category include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril. Distinguishing features for captopril include a rapid onset and the shortest duration of action, as well as inclusion of a sulfhydryl group in the molecular structure. Benazepril, fosinopril, lisinopril, moexipril, quinapril, ramipril, and trandolapril all possess a slower onset and a longer duration of action relative to captopril and are all acceptable for once-a-day therapy for hypertension. None of these compounds contains a sulfhydryl group, and all except lisinopril and captopril are prodrugs that require bioactivation. Finally, enalapril is the only agent available in both oral and parenteral forms and is intermediate between captopril and the others in duration of action. It does not contain a sulfhydryl group.

Some head-to-head comparisons are beginning to appear in the literature. In the treatment of heart failure, symptomatic hypotension and a decline in creatinine clearance occurred more often with enalapril than captopril.[82] In the treatment of hypertension, captopril displayed greater beneficial effects on quality-of-life parameters than did enalapril.[83] Although these studies fuel controversy, it is likely that controversies will continue to appear due to the number of ACE inhibitors and their significance in clinical medicine.


 * Adverse Reactions:** Aside from the reactions mentioned above, ACE inhibitors have infrequent and mild side effects. Patients with renal artery stenosis should not receive ACE inhibitors because renal insufficiency can result. ACE inhibitors also can decrease renal function in patients with heart failure, hyponatremia, or hypovolemic states. Angioedema occurs rarely, but is more frequent in black patients receiving ACE inhibitors. Pregnancy is also a relative contraindication, and ACE inhibitors are labeled by the FDA as category D during the second and third trimester and C during the first trimester. ACE inhibitors can cause a dry cough due to their ability to affect prostaglandin synthesis in the lung. This can complicate accurate monitoring of ACE inhibitor therapy for heart failure.

In summary, ACE inhibitors are an important therapeutic group. In June 1994, an agency of Health and Human Services recommended that ACE inhibitors be prescribed for all patients with left ventricular systolic dysfunction unless specific contraindications exist. Thus, the use of ACE inhibitors is likely to grow. More than 40 ACE-inhibitor compounds are being investigated, and many of these will be brought to market. It also is expected that these drugs will be approved for use in many other renal and cardiovascular syndromes. .