ACE Inhibitors
In less than 15 years, angiotensin converting enzyme (ACE) inhibitors have become one of the most important classes of drugs for treating hypertension and chronic heart failure. Because of their safety, efficacy, and ability to reverse some of the structural changes associated with high blood pressure, ACE inhibitors are now recommended as first-line therapy for hypertension, and they are the cornerstone in managing chronic heart failure. Currently there are seven ACE inhibitors marketed in the United States – captopril (Capoten / Squibb), benazepril (Lotensin / Ciba), enalapril (Vasotec / Merck), fosinopril (Monopril / Mead Johnson), lisinopril (Prinivil / Merck, Zestril / Zeneca), quinapril (Accupril / Warner- Lambert), and ramipril (Altace / Hoechst) – and several others are in various stages of development. These drugs all have a similar mechanism of action: the inhibition of converting enzyme, a crucial component of the renin-angiotensin system (RAS) that is involved in the regulation of arterial blood pressure, renal hemodynamics, and fluid and electrolyte balance.
The first step in the RAS cascade is the secretion of the enzyme renin by renal juxtaglomerular cells in response to low blood pressure, sympathetic activation, hypovolemia, and low sodium flux. Renin acts on angiotensinogen to produce angiotensin I, a biologically inactive prohormone. Angiotensin I is then cleaved to form active angiotensin II by ACE, a zinc-containing enzyme located in the endothelial lining of the vasculature of the lungs. Angiotensin II is one of the most potent vasocon-strictors known. It is also active in the central nervous system and adrenal glands and stimulates aldosterone secretion, resulting in salt retention. In addition to systemic blood pressure control, angiotensin converting enzyme is involved in microvascular regulation. ACE is also known as kininase II, part of the kallikrein-kinin- prostaglandin system. As kininase II, this enzyme is involved in the breakdown of kinins, which are potent vasodilators. Thus converting enzyme/kininase II is part of an elaborate homeostatic mechanism that elevates blood pressure through vasoconstriction, inhibition of vasodilation, and blood volume expansion.
The earliest ACE inhibitors were derived from natural peptides extracted from a Brazilian snake. Eventually, researchers learned how to synthesize an agent with more favorable pharmacokinetics – and captopril was born. Captopril and other ACE inhibitors act by binding the zinc ion on ACE. Captopril contains a sulfhydryl group that binds zinc but is thought to contribute to certain side effects (taste disturbances and skin rashes). Subsequent ACE inhibitors were designed with a carboxyl zinc ligand (enalapril, lisinopril, quinapril, ramipril, cilazapril, perindopril) or a phosphinic acid zinc ligand (fosinopril). Some angiotensin converting enzyme inhibitors (enalapril, fosinopril, quinapril, ramipril, cilazapril, and perindopril) are prodrugs that require hydrolysis before they can inhibit ACE . This improves absorption and usually delays the onset and prolongs the duration of action.
ACE inhibitors have proved to be useful for a number of conditions associated with RAS activation, such as essential hypertension, renovascular hypertension, intractable hypertension, and chronic heart failure. They reduce blood pressure through vasodilation and reduction of blood volume. Total peripheral resistance is lowered without altering heart rate, cardiac output, or pulmonary wedge pressure (unless heart failure is present). Left ventricular mass is reduced in hypertensive patients. ACE inhibitors also increase renal blood flow, usually without altering the glomerular filtration rate. Because the renin-angiotensin system is involved in local regulation of glomerular and tubular function, ACE inhibitors have been used successfully in patients with progressive renal failure (e.g., patients with diabetes or scleroderma). Common side effects are cough and taste disturbances (particularly in renal failure). Less common side effects include rash, hypotension, renal hemodynamic dysfunction and, rarely, angioedema. These drugs should be used cautiously in the elderly, in patients with renal impairment or renovascular disease, and in patients using nonsteroidal antiinflammatory drugs.
Quality of Life – Captopril Versus Enalapril
There do not seem to be many practical differences between the various angiotensin converting enzyme inhibitors. Some are cheaper (ramipril) and some more expensive (fosinopril); some are direct acting (captopril, lisinopril) and some require prodrug activation (all others); some are given twice daily (captopril) and some once daily; and at least one has a dual renal/hepatic route of excretion (fosinopril) – but these particular benefits have yet to translate into meaningful differences in clinical practice. They all appear safe and effective. But how do patients rank them? Testa et al. asked the patients themselves. They studied two ACE inhibitors – captopril and enalapril – with similar mechanisms of action, similar side effect profiles, and similar laboratory results. Subjects were 379 hypertensive male volunteers. Captopril was given 25-50 mg twice daily and enalapril 5-20 mg/day for 24 weeks, with the addition of hydrochlorothiazide if needed. The investigators used an extensive quality-of-life questionnaire that required 30-40 minutes to complete and was sensitive enough to measure a meaningful difference.
Throughout the trial, no differences were observed in blood pressure control, frequency of withdrawal from the study, or major side effects. However, patients receiving captopril reported more favorable changes in overall quality of life, general perceived health, health status, vitality, sleep, and emotional control. The difference was primarily in patients entering the study with a generally good quality of life. Both agents improved quality of life when baseline quality was low, but enalapril reduced the quality of life in the men with good quality at baseline. This difference between captopril and enalapril may be due to differences in central nervous system distribution. Recent evidence suggests that ACE inhibitors and angiotensin II antagonists reduce anxiety and improve cognitive function, possibly by cholinergic mechanisms. “The most striking finding in this study,” concluded the investigators, “was that two ACE inhibitors that acted identically with regard to efficacy, adverse events, and laboratory outcomes acted quite differently with regard to quality of life.”
Comparative Efficacy of Antihypertensive Agents
Sixty-eight antihypertensive drugs in eight therapeutic classes are available. How do the angiotensin converting enzyme inhibitors compare with drugs in other classes? A number of comparative trials have sought to answer this question. The most recent was a double-blind, placebo-controlled, multicenter study by Materson et al. comparing the efficacy of six antihypertensive agents in six classes: the ACE inhibitor captopril, the calcium channel blocker diltiazem (Cardizem / Marion Merrell Dow), the thiazide diuretic hydrochlorothiazide (Hydrodiuril / Merck), the central adrenergic blocker clonidine (Catapres / Boehringer Ingelheim), the alpha1- adrenergic blocker prazosin (Minipress / Pfizer), and the beta-blocker atenolol (Tenormin / Zeneca). Subjects were 1300 male volunteers – middle-aged and elderly, black and white (about half of each) – randomized to receive one of the six drugs (single-drug therapy) or placebo. The study was strictly concerned with drug efficacy; life-style modification was not used, and quality of life was not assessed. Only 41% of those enrolled completed the study.
The investigators reported that captopril was the most effective antihypertensive agent in younger white patients, atenolol was the most effective in older white patients, and sustained-release diltiazem was the most effective in black patients regardless of age. Overall, diltiazem was slightly, although statistically significantly, more effective in achieving blood pressure control than the other antihypertensive agents studied. Study results are similar to those reported by Saunders et al., who found the calcium channel blocker verapamil (Calan / Searle) more effective than captopril and atenolol in black patients. However, other investigators have reported no differences in efficacy between antihypertensive agents in the various classes.
In the Treatment of Mild Hypertension Study (TMHS), interim results have not demonstrated a difference in efficacy between five different types of antihypertensive agents: the diuretic chlorthalidone, the beta-blocker acebutolol (Sectra / Wyeth- Ayerst), the alpha1- adrenergic blocker doxazosin (Cardura / Roerig), the calcium channel blocker amlodipine (Norvasc / Pfizer), and the ACE inhibitor enalapril (Vasotec / Merck). This study involved 900 patients – men and women, black and white – and 94% finished the first year of the study. Patients were successful in life-style modification – weight loss, reduction in sodium and alcohol intake, and increase in physical activity. Life-style modification alone significantly reduced blood pressure. The addition of an antihypertensive agent further reduced blood pressure, but there were no significant differences among the groups.
What about the quality of life? As editorialist Suzanne Oparil noted, in the TMHS study, measures of life quality were high at entry and improved during follow-up in all groups, but particularly in the acebutolol and chlorthalidone groups. “These findings suggest,” wrote Oparil, “that in well-motivated patients with mild-to- moderate hypertension, life-style modification is effective in lowering blood pressure and maintaining quality of life, and may be more important than the initial choice of antihypertensive agent.” In a study by Jachuck et al. comparing diuretics, propranolol, and methyldopa, the investigators reported that physicians almost universally thought patients were better off after beginning therapy, whereas about half the patients felt better and half felt the same or worse, and family members overwhelmingly thought the patient’s condition was worse with therapy. Energy level, ambition, and sexual activity declined; irritability and forgetfulness increased; and social, marital, and occupational functioning deteriorated. Furthermore, Croog et al. demonstrated that captopril improved quality of life, while methyldopa and propranolol worsened it.
Twenty years ago, only half the patients with hypertension were aware of any blood pressure elevation, and only a third or so were taking medication. Today, around 85% of hypertensive patients are aware of their condition and about 75% are taking medication. However, with the stricter definition of hypertension advocated by the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure – namely, blood pressure below 140/90 mm Hg – only about 21% of hypertensive patients are adequately controlled. Understanding which drug will be the most effective for an individual patient will certainly improve blood pressure control, and understanding which drug will be the most acceptable to the patient will also improve blood pressure control by improving compliance.
ACE Inhibitors in Congestive Heart Failure
Congestive heart failure (CHF) is characterized by left ventricular dysfunction, reduced exercise tolerance, and shorted life expectancy. Only a few years ago, patients with CHF had a poor prognosis, with more than 50% dying within 5 years. The angiotensin converting enzyme inhibitors have changed that. Several large-scale, multicenter trials have demonstrated that ACE inhibitors markedly reduce morbidity and mortality in patients with CHF, and administration is associated with a low incidence of side effects. Enalapril has been shown to reduce mortality by 27%-31% in severe heart failure and by 23% in mild to moderate heart failure, to significantly reduce the incidence of myocardial infarction (MI), and to substantially reduce hospitalizations. Captopril has been shown to slow the progression of CHF in patients with mild to moderate heart failure, and to reduce postinfarction mortality by 17% and the development of severe heart failure by 37%.
In his minireview of ACE inhibitors in congestive heart failure, Graham Jackson wrote that ACE inhibitors should be used as soon as possible in symptomatic heart failure, whether or not symptoms are controlled with diuretics. Where ACE inhibitors are not tolerated, hydralazine/isosorbide dinitrate (ISDN) should be considered. Combining an ACE inhibitor with isosorbide mononitrate may also be beneficial. In asymptomatic left ventricular dysfunction, postinfarction ACE inhibition is indicated. Patients included in trials are carefully selected and closely observed and the dosages of ACE inhibitors are generally higher than currently used in clinical practice. “We almost certainly underdose these agents in general,” wrote Jackson, “but in the elderly we do need to be cautious… As the ACE inhibitors become more widely used, adverse effects may increase, and so these initially encouraging figures must not lead to complacent monitoring.”
Expanded Indications for Lisinopril, Quinapril, Enalapril, and Captopril
Four ACE inhibitors have received expanded indications from the FDA’s Cardiovascular and Renal Drugs Advisory Committee. Two agents currently approved for hypertension – lisinopril (Prinivil / Merck; Zestril / Zeneca) and quinapril (Accupril / Warner-Lambert) – were recommended for approval for the treatment of congestive heart failure (CHF). Enalapril (Vasotec / Merck), which is approved for the treatment of symptomatic CHF as well as hypertension, was recommended for the prevention of CHF in asymptomatic patients with left ventricular dysfunction. The panel specified that this new indication is for patients with an ejection fraction less than 35%; enalapril should delay the clinical manifestations of heart failure and decrease the need for hospitalization. Captopril (Capoten / Squibb), currently marketed for congestive heart failure and hypertension, was recommended for approval for reducing mortality in stable MI survivors with left ventricular dysfunction.
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