Angiotensin-Converting Enzyme Inhibitors
Overview
ACEIs are a popular first-line therapy for hypertension. The major benefits of this drug class are its tolerability and lack of serious side effects. ACEIs can be used in patients with dyslipidemia because they do not seriously affect lipid profiles. Furthermore, inhibition of the renin-angiotensin-aldosterone system confers renoprotection independently of blood pressure lowering; in fact, the American Diabetes Association recommends that ACEIs be used as a first-line treatment in diabetics. A range of ACEIs is available, including enalapril (Merck’s Vasotec/Renitec, generics); lisinopril (Merck’s Prinivil, AstraZeneca’s Zestril, generics); ramipril (King Pharmaceuticals/Sanofi-Aventis’s Altace); captopril (Bristol-Myers Squibb’s Lopril, generics); quinipril hydrochloride (Pfizer’s Accupril, generics); trandolopril (Abbott’s Gopten); perindopril (Servier’s Conversyl); moexipril (Schwarz’s Moex); fosinopril sodium (Bristol-Myers Squibb’s Fosinorm, generics), and benazepril hydrochloride (Novartis’s Cibacan). Individual agents differ in chemistry, duration of action, and mode of excretion. The following sections discuss the three most popular ACEIs for the treatment of hypertension.
Mechanism Of Action
ACEIs lower blood pressure by inhibiting the vasoconstrictive action of the renin-angiotensin-aldosterone system. Pharmacologically, ACEIs prevent the conversion of angiotensin I (AI) into angiotensin II (All), a potent vasoconstrictive agent. Blocking the production of All — and subsequently, aldosterone — increases cardiac output and reduces sodium and water retention. All has several additional unwanted actions in the vasculature that ACEI therapy combats. The peptide causes the vascular smooth-muscle cells lining the vascular wall to contract, an action that ultimately leads to hypertrophy (an increase in cell size) and hyperplasia (an increase in cell number). This action manifests as a thickening of the arterial wall and a narrowing of the lumen, developments that increase the peripheral resistance of the vasculature. All also increases production of excess reactive oxygen species, which in turn increase vasoconstriction and damage the endothelial wall. Treatment with ACEIs also reduces the breakdown of the vasodilator bradykinin, an action that may enhance their efficacy. However, bradykinin accumulation can result in cough, a side effect of angiotensin-converting enzyme inhibition evident in 10-20% of patients.
Enalapril
One of the first ACEIs to market, still commonly used, is enalapril (Merck’s Vasotec/Renitec, generics), which was approved in the United States in December 1985 and is available in all of the major pharmaceutical markets. Enalapril has a moderate-range half-life of 11 hours and so requires less-frequent dosing than captopril. The agent is effective both alone and in combination with other antihypertensive therapies. Its effects can be observed one hour after treatment; peak blood pressure-lowering effects can be seen at four to six hours. Large-scale clinical trials of enalapril have focused on chronic heart failure, not hypertension. The Studies of Left-Ventricular Dysfunction (SOLVD) program examined enalapril‘ s efficacy in slowing the development of heart failure and lowering mortality in patients with left-ventricular dysfunction. In this trial, 2,569 patients with chronic heart failure and left-ventricular ejection fraction (LVEF) less than or equal to 35% were randomized to placebo (n = 1,284) or enalapril (20mg daily; n = 1,285) and followed for an average of 41.4 months. A 26% relative risk reduction for death or worsening chronic heart failure was identified in the enalapril arm (p < 0.0001). Therefore, it is not surprising that enalapril is a popular therapy for hypertensive patients with comorbid chronic heart failure.
Lisinopril
Lisinopril (Merck’s Prinivil, AstraZeneca’s Zestril) was launched in the United States as an antihypertensive in 1987 and is available in all of the major pharmaceutical markets.
Many studies have evaluated lisinopril‘s blood pressure-lowering actions. This agent has also been the subject of several long-term cardiovascular outcomes studies, the most controversial of which is the ALLHAT study. The ALLHAT study, which involved 33,357 patients at least 55 years old with one cardiovascular risk factor, determined that lisinopril was not superior to chlorthalidone in preventing CVD (ALLHAT Collaborative Research Group, 2000). Although most secondary outcomes were similar between lisinopril and chlorthalidone, the risk of CVD was significantly raised in the lisinopril-treated group.
Ramipril
Ramipril (King Pharmaceuticals/Sanofi-Aventis’s Altace/Delix/ Tritace) is available for the treatment of hypertension in all markets except Japan. It was first launched in France in 1989 and approved in the United States in 1991 but only as an FDA Class 1 C agent (i.e., little or no therapeutic advantage).
The placebo-controlled Heart Outcomes Prevention Evaluation (HOPE) trial involving 9,000 patients at high risk of a cardiovascular event demonstrated the benefits of ramipril treatment (2.5 or 10 mg per day) — independent of its blood pressure-lowering efficacy — in reducing cardiovascular mortality and morbidity. The trial did not target hypertensive patients exclusively, but 46% of the patients had elevated blood pressure and 80% had some form of CVD or diabetes. After a five-year follow-up, death rates from CVD, MI, or stroke were 8.1% in the placebo group and 6.1% in the ramipril group. Reductions in individual end points for MI and stroke were 12.3-9.9% in the ramipril group and 4.9-3.4% in the placebo group, respectively (Heart Outcomes Prevention Evaluation Study Investigators, 2000).
The African-American Study of Kidney Disease and Hypertension (AASK) demonstrated ramiprirs safety and efficacy in African-Americans, a demographic group typically considered resistant to treatments focusing on the renin-angiotensin-aldosterone system. In AASK, 1,094 African-Americans aged 18-70 with hypertensive renal disease were randomly assigned to one of three first-line treatments: metoprolol (50-200 mg per day), ramipril (2.5-10 mg per day), or amlodipine (5-10 mg per day). After three years, the primary trial outcome — rate of change of glomerular filtration rate — did not differ significantly between treatment groups. Treatment with ramipril, however, manifested risk reductions in the secondary (composite) trial outcome — a reduction in glomerular filtration rate by 50% or more and reductions in end-stage renal disease or death. Investigators concluded that in the treatment group, ramipril was more effective than metoprolol or amlodipine at slowing glomerular filtration rate decline.
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