AbstractAngiotensin-converting Enzyme Inhibitors Research Articles

The Place of Angiotensin-Converting Enzyme Inhibitors in Internal Medicine

Angiotensin-converting enzyme (ACE) inhibitors are of clinical value in chronic heart failure, essential hypertension, renovascular hypertension and diabetic nephropathy. In severe chronic heart failure, ACE inhibitors have been shown to prolong life. In essential hypertension, they are relatively free of adverse effects but are more expensive than diuretics or β-blockers. In renovascular hypertension, they help control blood pressure but renal function must be carefully monitored (especially in bilateral disease). In diabetic nephropathy, they slow the progression of the renal disease, probably by decreasing intraglomerular pressure.

Angiotensin-converting enzyme inhibitors. Emerging differences and new compounds.

Angiotensin-converting enzyme inhibitors (ACEIs), introduced in clinical practice in 1980, are a relatively new class of drugs. They have been useful in the treatment of hypertension, where they are effective monotherapy in 40% to 50% of the patients and in combination therapy in up to 90%. They are also useful in the symptomatic and hemodynamic improvement and in decreasing mortality of patients with congestive heart failure. In this respect, they appear to be superior to other vasodilators. The clinical success of the marketed compounds and the expected increase in market share of these drugs, estimated to approach one billion dollars in the next few years, has created great interest among clinicians and within the drug industry. The emerging differences among the three marketed ACEIs and promising new agents that are expected to be marketed in the next few years are the subject of this review.

Angiotensin Converting Enzyme Inhibitors Enhance the Antihypertensive Efficacy of Diuretics and Blunt or Prevent Adverse Metabolic Effects

Angiotensin converting enzyme (ACE) inhibition has provided a new approach to the treatment of hypertension. The broad efficacy of ACE inhibitors across the entire spectrum of hypertension exceeds original predictions. Diuretics have been shown to extend efficacy to over 85% of noncomplicated hypertensives. In addition to efficacy, combination of ACE inhibitors with diuretics permits prevention or attenuation of many undesirable side effects of diuretic therapy, including hypokalemia, hyperuricemia, hyperglycemia, and hypercholesterolemia. Thus, considerations of both efficacy and beneficial effects on cardiovascular disease risk factors make the combination of ACE inhibitors and diuretics an attractive one in the treatment of hypertension.

Cardiovascular drugs in children: angiotensin-converting enzyme inhibitors.

Angiotensin-converting enzyme inhibitors are potent vasodilators acting by inhibition of production of the vasoconstrictor angiotensin II. In adults, they are used for treatment of systemic hypertension and congestive heart failure and investigated for treatment of primary pulmonary hypertension. In infants and children, saralasin and captopril were found to be useful in treatment of systemic arterial hypertension, especially when associated with high plasma renin activity. Captopril has failed in the treatment of congestive heart failure associated with complex congenital heart diseases and in most cases of primary pulmonary hypertension. It has a clear beneficial effect in coarctation of the aorta and may have such an effect in endomyocardial diseases and ventricular septal defect. In adults, serious side effects have limited the use of captopril. New converting enzyme inhibitors, devoid of a sulfhydryl group, are expected to have a better safety profile.

When and how to use angiotensin-converting enzyme inhibition in congestive heart failure

Angiotensin-converting enzyme (ACE) inhibitors have been found effective in the treatment of congestive heart failure (CHF) and have been recommended as the first choice of vasodilator therapy by some observers. Favorable hemodynamic responses, apparent both at rest and during exercise, result from a considerable reduction in both systemic and pulmonary vascular resistance, apparently due to both the arterial and venodilating effects of these agents. In addition, the recently reported results of the Cooperative North Scandinavian Enalapril Survival Study demonstrate that ACE inhibitors reduce mortality rates in patients with CHF. The etiology of heart failure does not seem to predict clinical response to ACE inhibitors, nor do acute resting and exercise hemodynamic responses. A weak relation has been found between plasma renin activity and short-term hemodynamic and clinical responses, but this association is not evident over the long term. Therefore, a trial of therapy with ACE inhibitors is necessary to judge efficacy in an individual patient with advanced CHF symptoms. Two such agents--captopril and enalapril--are available. The former has a more rapid onset and shorter duration of action, whereas the latter may be given on a twice-daily basis, simplifying chronic therapy.

Angiotensin converting enzyme inhibition in plasma and tissues.

Angiotensin converting enzyme (ACE) and the ACE inhibitor lisinopril were measured in patients with renal impairment, by both radioinhibitor 125I MK351A binding studies, and by radioimmunoassay. Plasma concentration of lisinopril estimated by radioinhibitor binding displacement correlated closely with that measured by radioimmunoassay. Plateau lisinopril concentration in 8 patients with varying degrees of renal failure treated with 5 mg lisinopril per day for 1 week, was inversely related to renal function. Plasma lisinopril concentrations of 30-70 ng/ml were required for 50% inhibition of plasma ACE activity in vivo. Acute studies in the rat showed inhibition of ACE in different tissues had different time courses. These observations suggest that 125I MK351A binding studies in tissues will be useful in establishing the pharmacokinetic and pharmacodynamic profiles of newer ACE inhibitors, and may help delineate the contribution of ACE in different tissues to cardiovascular homeostasis.

Pharmacology of converting enzyme inhibitors.

Angiotensin converting enzyme inhibitors were developed to prevent the in vivo generation of angiotensin II and thereby to reduce peripheral vasoconstriction. However, these compounds exert some additional effects that may or may not be angiotensin dependent. These include potential sodium diuresis, bradykinin accumulation, prostaglandin release, blunting of sympathetic activity, parasympathomimetic actions, central effects, redistribution of blood flow toward some particularly important organs. Only the comprehensive assessment of the many complex interactions that exist between the renin-angiotensin and several other regulatory systems reveals the complete therapeutic profile of this class of pharmacologic agents.

Inhibition of the Renin-Angiotensin System in the Treatment of Heart Failure

Angiotensin converting enzyme inhibitors can be recommended in the treatment of severe cardiac failure (New York Heart Association Functional Class III or VI) where they are probably superior to other vasodilators. Their use should be considered when routine therapy with diuretics and digoxin has failed to ameliorate symptoms. Whether they can be recommended also for mild heart failure and whether the benefits outweigh any risks associated with long-term blockade of the renin-angiotensin system are questions that remain to be answered. Their use in hypertension and early in acute myocardial infarction might prevent the development of heart failure, but appropriate studies in man are awaited.