Angiotensin-Converting Enzyme Inhibitors: A Comparative Review

Abstract

The chemistry, pharmacology, pharmacokinetics, adverse effects, and dosages of the three currently available angiotensin-converting enzyme (ACE) inhibitors are reviewed. This class of agents effectively inhibits the conversion of angiotensin I to the active vasoconstrictor angiotensin II, a hormone that also promotes, via aldosterone stimulation, increased sodium and water retention. The ACE inhibitors, therefore, are capable of lowering blood pressure primarily by promoting vasodilitation and reducing intravascular fluid volume. Captopril, the first orally active, commercially available ACE inhibitor, is a sulfhydryl-containing compound. Captopril was followed by the introduction of enalapril and lisinopril, two non-sulfhydryl ACE inhibitors. The pharmacokinetic profiles of these three ACE inhibitors differ. Captopril has rapid onset with relatively short duration of action, whereas enalapril and lisinopril have slower onset and relatively long duration of action. Captopril is an active ACE inhibitor in its orally absorbable parent form. In contrast, enalapril must be deesterified in the liver to the metabolite enalaprilat in order to inhibit the converting enzyme; this accounts for its delayed onset of action. Lisinopril does not require metabolic activation to be effective; however, a slow and incomplete absorption pattern explains the delay in onset of activity. Captopril and its disulfide metabolites are primarily excreted in the urine with minor elimination in the feces. Approximately two-thirds of an administered enalapril dose is excreted in the urine as both the parent drug and the metabolite enalaprilat; the remainder of these two substances are excreted in the feces. Lisinopril does not undergo measurable metabolism and approximately one-third is excreted unchanged in the urine with the remaining parent drug being excreted in the feces. The ACE inhibitors lower systemic vascular resistance with a resultant decrease in blood pressure. Their efficacy is comparable to diuretics and beta-blockers in treating patients with mild, moderate, or severe essential and renovascular hypertension. In those patients with severe congestive heart failure (CHF) the ACE inhibitors produce a reduction in systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure, and pulmonary artery pressure. These drugs may produce improvement in cardiac output and stroke volume and, with chronic administration, may promote regression of left ventricular hypertrophy. The antihypertensive effects of the ACE inhibitors are enhanced when these agents are combined with a diuretic. Captopril and enalapril have been shown to be of particular benefit as adjunctive therapy in patients with congestive heart failure, both in terms of subjective improvement of patient symptoms, and in improving overall hemodynamic status. Although only captopril and enalapril are currently approved by the Food and Drug Administration for the treatment of CHF, early data with lisinopril suggest beneficial effects comparable to those of captopril. Several unapproved, experimental uses for ACE inhibitors have recently been reported and include treatment of proteinuria, scleroderma renal crisis, idiopathic edema, Raynaud's syndrome, and hypertensive emergency. The ACE inhibitors as a group are generally effective and well tolerated in most patients, although the adverse effect profile may vary somewhat among individual agents.