Drug Nomenclature

Pharmacopoeias. In US.

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Quinapril Hydrochloride). A white to off-white powder, with a pink cast at times. Freely soluble in aqueous solvents.

Suspension. Extemporaneous formulations of quinapril 1 mg/mL made by adding crushed Accupril tablets (Pfizer, US) to the following vehicles were found to be stable for 6 weeks when stored at 5°:

• Kphos 15% (Beach, US), Bicitra 15% (Draxis Pharma, US), OraSweet 70% (Paddock, US)

• Kphos 15%, Bicitra 15%, OraSweet SF 70%

• Kphos 15%, Bicitra 15%, simple syrup 70%

The suspension containing OraSweet SF was considered to be the formulation of choice.

Adverse Effects, Treatment, and Precautions

As for ACE inhibitors.

Breast feeding. After of a single dose of quinapril 20 mg in 6 women, quinapril was detected in the breast milk in a milk to plasma ratio of 0.12; no quinaprilat was detected. It was estimated that the dose received by the infant would only be about 1.6% of the maternal dose.

Interactions

As for ACE inhibitors.

Antibacterials. Quinapril has been reported to reduce the absorption of tetracyclines due to the presence of magnesium carbonate in the tablet formulation.

Pharmacokinetics

Quinapril acts as a prodrug of the diacid quinaprilat, its active metabolite. About 60% of an oral dose of quinapril is absorbed. Quinapril is metabolised mainly in the liver to quinaprilat and inactive metabolites. Peak plasma concentrations of quinaprilat are achieved within 2 hours of an oral dose of quinapril. Quinaprilat is about 97% bound to plasma proteins. After an oral dose, quinapril is excreted in the urine and faeces, as quinaprilat, other metabolites, and unchanged drug, with the urinary route predominating; up to 96% of an intravenous dose of quinaprilat is excreted in the urine.

The effective half-life for accumulation of quinaprilat is about 3 hours after multiple doses of quinapril; a long terminal phase half-life of 25 hours may represent strong binding of quinaprilat to angioten sinconverting enzyme.

The pharmacokinetics of both quinapril and quinaprilat are affected by renal and hepatic impairment. Dialysis has little effect on the excretion of quinapril or quinaprilat.

Small amounts of quinapril are distributed into breast milk.

Uses and Administration

Quinapril is an ACE inhibitor. It is used in the treatment of hypertension and heart failure.

Quinapril is converted in the body to its active metabolite quinaprilat. The haemodynamic effects are seen within 1 hour of a single oral dose and the maximum effect occurs after about 2 to 4 hours, although the full effect may not develop for 1 to 2 weeks during chronic use. The haemodynamic action persists for about 24 hours, allowing once-daily dosing. Quinapril is given orally as the hydrochloride, but doses are expressed in terms of the base. Quinapril hydrochloride 10.8 mg is equivalent to about 10.0 mg of quinapril. In the treatment of hypertension the initial dose is 10 mg of quinapril once daily. Since there may be a precipitous fall in blood pressure in some patients when starting therapy with an ACE inhibitor, the first dose should preferably be given at bedtime. An initial dose of 2.5 mg daily is recommended in the elderly, in patients with renal impairment, or in those taking a diuretic; if possible, the diuretic should be withdrawn 2 or 3 days before quinapril is started and resumed later if necessary.

The usual maintenance dose is 20 to 40 mg daily, as a single dose or divided into 2 doses, although up to 80 mg daily has been given.

In the management of heart failure, severe first-dose hypotension on introduction of an ACE inhibitor is common in patients on loop diuretics, but their temporary withdrawal may cause rebound pulmonary oedema. Thus treatment should begin with a low dose under close medical supervision. Quinapril is given in an initial dose of 2.5 mg daily. Usual maintenance doses range from 10 to 20 mg daily, as a single dose or divided into 2 doses; up to 40 mg daily has been given. Quinaprilat may be given intravenously in patients unable to take quinapril orally; doses range from 1.25 to 10 mg twice daily.

Preparations

The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Quinapril Tablets.

Proprietary Preparations

Argentina: Accupril;

Australia: Accupril; Acquin; Asig; Filpril;

Austria: Accupro;

Belgium: Accupril;

Brazil: Accupril;

Canada: Accupril;

Chile: Accupril;

Czech Republic: Accupro;

Denmark: Accupro;

Finland: Accupro;

France: Acuitel; Korec;

Germany; Accupro; QuinaLich;

Greece: Accupron;

Hong Kong; Accupril;

Hungary: Accupro; Acumerck;

Indonesia: Accupril;

Italy: Accuprin; Acequin; Quinazil;

Japan: Conan;

Malaysia: Accupril †;

Mexico: Acupril;

The Netherlands: Acupril;

New Zealand: Accupril;

Philippines: Accupril;

Poland: Accupro; Acurenal; AprilGen;

Portugal; Acupril; Vasocon;

Russia: Accupro;

South Africa: Accupril; Quinaspen;

Singapore: Accupril †;

Spain: Acuprel; Acuretic; Ectren; Lidaltrin;

Sweden: Accupro;

Switzerland: Accupro;

Thailand: Accupril;

Turkey: Acuitel;

United Kingdom (UK): Accupro; Quinil;

United States of America (US and USA): Accupril;

Venezuela: Accupril; Quinalar; Solpres.

Multi-ingredient

Argentina: Accuretic;

Australia: Accuretic;

Austria; Accuzide;

Belgium: Accuretic; Co-Quinapril;

Canada: Accuretic;

Chile: Accuretic;

Czech Republic: Accuzide; Stadapress;

Finland: Accupro Comp;

France: Acuilix; Koretic;

Greece: Accuretic; Quimea;

Hungary: Accuzide;

Ireland: Accuretic;

Italy: Accuretic; Acequide; Quinazide;

The Netherlands: Acuzide;

New Zealand: Accuretic;

Philippines: Accuzide;

Poland: Accuzide;

Portugal: Acuretic;

South Africa: Accuretic;

Spain: Bicetil; Lidaltrin Diu;

Sweden: Accupro Comp;

Switzerland: Accuretic;

Turkey: Accuzide;

United Kingdom (UK): Accuretic;

United States of America (US and USA): Accuretic; Quinaretic;

Venezuela: Accuretic; Quinaretic.

ACE (angiotensin-converting enzyme) facilitates production of angiotensin II, which has a major role in regulating arterial blood pressure. ACE is distributed in many tissues and is present in several different cell types, but its principal location is in endothelial cells. Therefore, the major site for angiotensin II production is in the blood vessels, not the kidney. ACE inhibitors block the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor and stimulator of aldosterone secretion. ACE inhibitors also block the degradation of bradykinin and stimulate the synthesis of other vasodilating substances including prosta-glandin E₂ and prostacyclin. The fact that ACE inhibitors lower blood pressure in patients with normal plasma renin activity suggests that bradykinin and perhaps tissue production of ACE (angiotensin-converting enzyme) are important in hypertension.

Starting doses of ACE inhibitors should be low with slow dose titration. Acute hypotension may occur at the onset of ACE inhibitor therapy, especially in patients who are sodium- or volume-depleted, in heart failure exacerbation, very elderly, or on concurrent vasodilators or diuretics. Patients with these risk factors should start with half the normal dose followed by slow dose titration (e.g., 6-week intervals).

All 10 ACE inhibitors available in the United States can be dosed once daily for hypertension except captopril, which is usually dosed two or three times daily. The absorption of captopril (but not enalapril or lisinopril) is reduced by 30% to 40% when given with food.

ACE inhibitors decrease aldosterone and can increase serum potassium concentrations. Hyperkalemia occurs primarily in patients with chronic kidney disease or diabetes and in those also taking ARBs, NSAIDs, potassium supplements, or potassium-sparing diuretics.

Acute renal failure is a rare but serious side effect of ACE inhibitors; preexisting kidney disease increases the risk. Bilateral renal artery stenosis or unilateral stenosis of a solitary functioning kidney renders patients dependent on the vasoconstrictive effect of angiotensin II on efferent arterioles, making these patients particularly susceptible to acute renal failure.

The GFR decreases in patients receiving ACE inhibitors because of inhibition of angiotensin II vasoconstriction on efferent arterioles. Serum creatinine concentrations often increase, but modest elevations (e.g., absolute increases of less than 1 mg / dL) do not warrant changes. Therapy should be stopped or the dose reduced if larger increases occur.

Angioedema is a serious potential complication that occurs in less than 1% of patients. It may be manifested as lip and tongue swelling and possibly difficulty breathing. Drug withdrawal is necessary for all patients with angioedema, and some patients may also require drug treatment and / or emergent intubation. Cross-reactivity between ACE inhibitors and ARBs has been reported.

A persistent dry cough occurs in up to 20% of patients and is thought to be due to inhibition of bradykinin breakdown.

ACE inhibitors are absolutely contraindicated in pregnancy because of possible major congenital malformations associated with exposure in the first trimester and serious neonatal problems, including renal failure and death in the infant, from exposure during the second and third trimesters.

Managing Congestive Heart Failure

The management of patients with heart failure has improved substantially in recent years, primarily because of the addition of angiotensin-converting enzyme (ACE) inhibitors to the drug regimen. ACE inhibitors prevent the progressive deterioration of ventricular function, presumably through a combination of cardioprotective effects and the prevention of humoral activation. These agents are currently recommended for first-line therapy for CHF, with diuretics added as needed and digoxin reserved for patients unresponsive to or intolerant of ACE inhibitors.

Lifestyle modification – including sodium restriction, weight maintenance, avoidance of alcohol, and proper exercise – is also crucial for managing CHF. Sodium intake should be restricted to 3 g a day for mild to moderate disease and 2 g a day or less for severe or resistant disease. Alcohol should be restricted to 30 mL a day; better yet, patients should abstain completely. Exercise training is recommended, even for patients with considerable left ventricular impairment. It does not induce clinical deterioration, as previously supposed, but improves endurance and reduces exertional dyspnea and fatigue. It delays the onset of anaerobic metabolism in skeletal muscle, reversing the impairment of peripheral vasodilation and improving blood flow to exercising muscles. In one study, bicycle exercise 20 minutes a day 5 days a week improved oxygen consumption by about 20% and reduced the autonomic imbalance. However, patients who show no adaptation to low-intensity training within 6 weeks should not continue with the program.

On the basis of a physician’s analysis and recommendation, drugs that may worsen heart failure or make it more treatment resistant should be considered for discontinuation (e.g., nonsteroidal antiinflammatory drugs, beta-blockers, or first- generation calcium-channel blockers). Hypertension should be treated with direct vasodilators, alpha-1 adrenergic blockers, or centrally acting alpha-agonists. Angina may respond to revascularization; patients not fit for surgery may respond to long- acting nitrates and aspirin. When all else fails, heart transplantation may be indicated.

CHF is a serious disease, but compliance with the treatment plan and careful monitoring at each clinic visit will improve the prognosis and quality of life.

Pharmacotherapy of Heart Failure

In their comprehensive review of heart failure, Baker & Wright described a drug continuum ranging from an ACE inhibitor alone or with a diuretic for patients with mild heart failure to an ACE inhibitor plus digoxin, diuretics, and hydralazine or isosorbide dinitrate for patients with severe disease.

ACE inhibitors

ACE inhibitors have been shown to prevent or slow the progression of heart failure in patients with symptomatic and asymptomatic left ventricular dysfunction. Currently, four agents are approved by the FDA for treating CHF: captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil), and quinapril (Accupril). Clinical studies have shown that these agents reduce mortality, enhance functional status, and reduce hospitalization for cardiac reasons. Yet despite overwhelming evidence of efficacy, note the authors, these agents are used in too few patients or at suboptimal dosages. Clinicians continue to use older drugs, some inappropriately, and avoid ACE inhibitors because they are unfamiliar with this class of drugs or are overly concerned with side effects.

According to Baker & Wright, “The important benefits and the relatively low risks suggest that a trial of ACE inhibitors is warranted in all patients with heart failure due to left ventricular systolic dysfunction, unless specific contraindications exist.” Even patients with mild disease but no volume overload show improvement in fatigue and exertional dyspnea, so it is reasonable to begin therapy with an ACE inhibitor and then add a diuretic when needed. Contraindications include significant renal insufficiency, hyperkalemia (serum potassium concentration 5.5 mmol/L or greater), and angioedema. Angioedema is a life-threatening side effect, said the authors, and an absolute contraindication to further use of any ACE inhibitor.

Other side effects include orthostatic hypotension (necessitating dose reduction or drug discontinuation), dizziness (often responsive to dose reduction), and cough. ACE inhibitor cough may respond to inhaled cromolyn sodium or dose reduction, but most patients will tolerate cough in exchange for the possibility of prolonging life. It is important to note that heart failure itself is associated with a cough.

ACE inhibitor therapy should be initiated at a low dose for patients without volume depletion (orthostatic hypotension, prerenal azotemia, or metabolic alkalosis). Volume-depleted patients should discontinue diuretic therapy for 24 to 48 hours before initiation until volume depletion resolves. Therapy should not be initiated when serum potassium is 5.5 mmol/L or greater, and potassium-sparing diuretics and oral potassium supplements should be stopped before ACE inhibitor therapy regardless of serum potassium. These agents may be restarted if the patient remains hypokalemic on full therapeutic doses of ACE inhibitors, although serum potassium should be monitored. If hyperkalemia develops, ACE inhibitors should be discontinued permanently.

Dosage should be reduced in patients with renal impairment and adjusted slowly upwards, with careful monitoring.

For patients at risk of first-dose hypotension (severe heart failure, age over 75 years, initial systolic blood pressure less than 100 mm Hg, or serum sodium less than 135 mmol/L), a small dose of a short-acting agent (captopril 6.25 mg) and close monitoring is recommended. If the test dose is tolerated, doses can be increased slowly. Patients should be monitored after 1 week, volume status reassessed, and treatment modified if renal impairment, hyperkalemia, or hypotension develops. When overdiuresis occurs, the diuretic dose should be reduced and the ACE inhibitor tried again.

Doses of ACE inhibitors should be adjusted upwards for 2 to 3 weeks to reach target levels (e.g., 50 mg three times daily for captopril, 10 mg twice daily for enalapril). Creatinine and volume status should be monitored as the dose increases; volume depletion should be managed by reducing the ACE inhibitor to the highest tolerated dose, reducing the diuretic dose, and then increasing the ACE inhibitor again. It may take several months for the full effect of ACE inhibitor therapy on functional status to appear.

Diuretics

Sodium and water overload, seen in nearly all patients with heart failure, are treated with diuretics and sodium restriction. Thiazide diuretics (hydrochlorothiazide (Hydrodiuril), chlorthalidone (Thalitone)) are usually adequate for mild heart failure, with loop diuretics (furosemide (Lasix), bumetanide (Bumex), ethacrynic acid (Edecrin)) reserved for severe volume overload or thiazide-resistant edema. According to Baker and Wright, it is generally better to give the thiazide or furosemide once daily; doubling the dose is preferable to giving the same dose twice daily (except for furosemide greater than 160 mg/day). Excessive diuresis should be avoided; volume depletion can cause hypotension or renal insufficiency when ACE inhibitors are added. Weighing the patient each morning is important to monitor diuresis. Nonsteroidal antiinflammatory drugs may decrease diuretic efficacy.

Diuretics deplete potassium, but ACE inhibitors decrease potassium losses, so using both types of drug may avoid hypokalemia. Serum potassium should be checked every 3 days or so during initiation, adjustment, or modification of diuretic or ACE inhibitor therapy, note Baker & Wright; then every few months thereafter. Serum potassium concentration measurements may overestimate total body potassium stores; therefore, a value less than 4.0 mmol/L indicates the need for potassium supplementation or a potassium-sparing diuretic. (The diuretic may be more effective than the supplement but will increase the risk of hyperkalemia when used with an ACE inhibitor.) High- dose diuretic therapy also depletes magnesium, so concentrations should be checked and oral supplementation given when necessary. For severe and persistent fluid overload, hospitalization and intravenous diuretic therapy may be necessary. Intestinal edema may impair the absorption of oral diuretics.

Digoxin: Cardiac glycosides have been used against CHF for more than 200 years. Digoxin, the glycoside of choice, improves physical function and decreases symptoms in the majority of patients with left ventricular dysfunction, although it has a variable effect on exercise tolerance, dyspnea, fatigue, and diuretic use, and there is no evidence that it reduces mortality. Patients with the most severe disease are most likely to benefit. Digoxin can also be added to the drug regimen in patients who remain symptomatic despite optimal treatment with ACE inhibitor and diuretic.

The initial dose is 0.25 mg/day (0.125 mg/day for patients who are small or elderly or who have renal insufficiency or baseline conduction abnormality). Steady state will be reached in 1 week (2-3 weeks in patients with renal impairment); patients should then be checked for toxicity (electrocardiogram, serum digoxin level, serum electrolytes, blood urea nitrogen, creatinine). Subsequently, serum digoxin concentrations should be checked annually, or more often if heart failure worsens, renal function deteriorates, toxicity develops (confusion, nausea, anorexia, or visual disturbances), or medications are added that may alter digoxin levels.

Hydralazine and isosorbide dinitrate

Studies have shown that these agents in combination increase maximum oxygen consumption and reduce mortality for up to 3 years in patients with heart failure (beyond 3 years, no mortality difference has been seen). They are used in patients who cannot tolerate ACE inhibitors, and they are particularly useful when the systolic blood pressure remains greater than 120 mm Hg or there is severe mitral regurgitation. However, they are not approved by the FDA for heart failure. Side effects are considerable (18%-33% of patients in clinical trials discontinued one or both drugs). Another nitrate – nitroglycerin – is useful in patients with severe heart failure and pulmonary symptoms unresponsive to aggressive treatment. Tablets or spray may alleviate transient symptoms of pulmonary congestion, and topical nitroglycerin ointment used at bedtime may be particularly effective for paroxysmal nocturnal dyspnea.

Anticoagulants

There are no controlled trials analyzing the efficacy of anticoagulation therapy for CHF patients with sinus rhythm. Yet long-term anticoagulant therapy is often prescribed for heart failure, presumably to prevent arterial thromboemboli that may result from low cardiac output, aberrant cardiac blood flow, and poor contractility. In two large trials, 16% and 20% of patients enrolled were taking anticoagulants for unspecified reasons. Yet a meta-analysis of 11 studies involving patients not receiving anticoagulants showed that arterial thromboembolism is rare in CHF (incidence generally less than 3%). According to Baker & Wright, until the risks and benefits of anticoagulation are evaluated in a clinical trial, anticoagulants should be discouraged for patients with heart failure in sinus rhythm, unless they have a history of ventricular thrombus, stroke, or arterial emboli.

Preventing Heart Failure Following Acute Myocardial Infarction

Left ventricular dilatation and neuroendocrine activation are common after acute anterior myocardial infarction (MI). A decade ago it was suggested that ACE inhibitors may attenuate vascular remodeling after acute MI, and soon thereafter several clinical trials were launched to determine the efficacy of ACE inhibitors in prolonging survival and reducing the risk of CHF after MI. Results from clinical trials involving about 100,000 patients have since demonstrated that ACE inhibitors do indeed improve the outcome for patients with acute MI. Three long-term studies involving selected high-risk patients demonstrated that ACE inhibitor therapy reduced overall mortality about 20% (40-70 lives saved per 1000 patients, depending on the mortality in the placebo group). Short-term studies involving a broad cross-section of patients with acute MI also showed a reduction in mortality (about 5 lives saved per 1000 patients). The greatest benefits were seen in higher-risk patients: those with anterior- wall infarction, asymptomatic ventricular dysfunction, CHF, or a prior infarction.

The results of two of these trials – the Chinese Cardiac Study (CCS-1) and the fourth International Study of Infarct Survival (ISIS-4) – were reported recently in The Lancet. In the Chinese study, 13,634 patients hospitalized within 36 hours after onset of suspected acute MI were randomized to either captopril or placebo. Captopril (6.25 mg initially, 12.5 mg 2 hours later, then 12.5 mg three times daily) was well tolerated and modestly effective for reducing 4-week mortality, compared with placebo.

In the ISIS-4 study, captopril was compared with oral mononitrate, intravenous magnesium sulfate, and placebo in 58,050 patients hospitalized within 24 hours of the onset of suspected acute MI. Compared with placebo, captopril significantly reduced 5- week mortality (7%, corresponding to about 5 fewer deaths per 1000 patients, or 10 fewer deaths per 1000 patients with heart failure or a history of MI). The survival advantage appeared to be maintained for 12 months. Side effects included hypotension, cardiogenic shock, and some renal dysfunction. In both the mononitrate and the magnesium sulfate groups, there were no significant reductions in 5-week mortality, nor did follow-up demonstrate any later survival advantage.

In a similar study, zofenopril (Bristol-Myers Squibb) significantly reduced mortality (25%) and the risk of severe heart failure (34%) in 1556 patients enrolled within 24 hours after onset of suspected acute anterior MI. Even though therapy was limited to 6 weeks, after 1 year the mortality rate was significantly lower in the zofenopril group than the placebo group (10% versus 14.1%).

Which patients should be treated, and when? According to New England Journal of Medicine editorialist Marc Pfeffer, ACE inhibitor therapy should be considered for a broad range of patients who have acute MI and a systolic blood pressure greater than 100 mm Hg. Treatment should be initiated in a monitored setting because of the risk of hypotension, and it should be initiated as soon as possible during the acute phase of the MI. Patients with left ventricular dysfunction, who stand to benefit the most, should receive long-term therapy. Whether long-term therapy will benefit patients with good ventricular function remains to be seen, said Pfeffer. The National Institutes of Health have begun two major trials to evaluate long-term therapy in patients with coronary artery disease and preserved left ventricular function or a population at high risk for coronary artery disease. “At present, the message is that the addition of an ACE inhibitor to the therapeutic regimen in the early phase of an acute MI can be safe and effective,” said Pfeffer. He favors a “loose fit” approach: ACE inhibitor therapy for patients who have or are likely to have ventricular dysfunction, even before an objective assessment of cardiac function has been carried out.

Dear Richard:

Doxazosin (Cardura) is an alpha adrenergic receptor blocker similar to prazosin (Minipress) and terazosin (Hytrin). In a large placebo controlled trial of 665 patients taking Cardura for an average of 85 days, 0.8% reported a decrease in libido with the drug versus 0.3% taking placebo, a difference that is not statistically significant. We are not aware of any reports of ACE inhibitors (such as Accupril) causing decreased libido. I would consider consulting an urologist, an endocrinologist. or impotence specialist if your libido does not return to normal after changing from Cardura to another blood pressure medication, as there may be another reason for the decrease in libido.

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.