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Enalapril

Enalapril is an angiotensin converting enzyme (ACE) inhibitor used in the treatment of hypertension and some types of chronic heart failure. Enalapril was the first member of the group of ACE inhibitors known as the dicarboxylate-containing ACE inhibitors. It is marketed by Merck & Co. (Merck, Sharp & Dohme) under the trade names, Renitec® and Vasotec®. more...

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Development

Enalapril was developed by researchers at Merck & Co. as part of their efforts to develop novel treatments for hypertension by modulating the renin-angiotensin-aldosterone (RAS) system.

The success of Squibb in developing the first inhibitor, captopril, provided a major impetus for Merck's research laboratories to develop a competing product. Captopril was not without its problems, however, as it was believed (and shown to be true) that the sulfhydryl-moeity of captoril was responsible for such adverse effects as metallic taste.

Enalaprilat

Enalaprilat, the first dicarboxylate-containing ACE inhibitor, was developed partly to overcome these limitations of captopril. The sulfhydryl-moeity was replaced by a carboxylate-moeity, but additional modifications were required in its structure-based design to achieve a similar potency to captopril.

Enalaprilat itself, however, was not without its problems. The consequence of the structural modifications was that it proved to be have unfavourable ionisation characteristics to allow sufficient potency for oral administration (in tablets). Thus enalaprilat was only suitable for intravenous administration. This was overcome by the researchers at Merck by the esterification of enalaprilat with ethanol to produce enalapril. As a prodrug, enalapril is metabolised in vivo to the active form enalaprilat by various esterases.

A prototype for others

Most importantly, perhaps, the QSAR-based modifications in structure serendipitously led to an improved understanding of the structure of ACE which aided in the development of subsequent carboxylate-containing ACE inhibitors.

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Enalapril for Attenuating Renal Function Decline in Diabetes
From American Family Physician, 11/15/98 by Richard Sadovsky

Albuminuria in persons with diabetes mellitus is a risk factor for the development of nephropathy and for cardiovascular morbidity. Angiotensin converting enzyme (ACE) inhibitors have been shown in previous studies to attenuate progression of nephropathy in both types of diabetes in hypertensive and normotensive patients with microalbuminuria. ACE inhibitors also lower urinary albumin excretion in normotensive and normoal-buminuric patients with type 1 diabetes, although the relationship between albuminuria and later nephropathy in these patients has not been established. Ravid and associates evaluated the effects of early introduction of the ACE inhibitor enalapril in the management of normotensive, normoalbuminuric patients with type 2 diabetes.

The randomized, double-blind, placebo-controlled study included 156 patients younger than 60 years of age who were diagnosed with type 2 diabetes when they were 40 years of age or older. All of the patients had a baseline mean blood pressure of less than 107 mm Hg and albuminuria (albumin excretion: 30 mg per 24 hours or less [30 mg per day]). Patients were randomly assigned to receive either 10 mg of enalapril daily or a placebo and remained in the study for six years.

At semiannual visits, hemoglobin [A.sib.1c], serum creatinine, serum electrolyte and urinary creatinine levels, and 24-hour albumin excretion were measured. Blood pressure was also monitored; if the systolic pressure dropped below 100 mm Hg, the enalapril dosage was reduced by one half. Evidence of retinopathy was evaluated by an ophthalmologist.

Transition to microalbuminuria after six years differed significantly in the treatment and placebo groups. Microalbuminuria was found in five (6.5 percent) of the 77 patients in the enalapril group compared with 15 (19.0 percent) of the 79 patients in the placebo group. The absolute risk reduction with enalapril was 12.5 percent. The placebo group also had a greater decrease in creatinine clearance by the fifth and sixth years.

Annual funduscopic examinations revealed 15 new cases of retinopathy in the placebo group (19 percent) and six new cases in the enalapril group (7.8 percent). Enalapril was associated with an absolute risk reduction of 11.2 percentage points for the development of retinopathy during the course of six years.

The mean blood pressure of the enalapril group was significantly lower than the placebo group only during the fifth year of the study.

The authors conclude that enalapril appears to offer a modest renal protective effect in normotensive, normoalbuminuric patients with type 2 diabetes. The population in this study was at low risk for development of diabetic nephropathy, making the recommendation of universal use of ACE inhibitors in all normotensive, normoalbuminuric patients with well-controlled diabetes inappropriate at this time. Further studies are needed to identify which low-risk patients are likely to benefit from such therapy and to establish if the onset of overt diabetic nephropathy will be delayed with such therapy.

RICHARD SADOVSKY, M.D.

Ravid M, et al. Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial Ann Intern Med June 15, 1998;128:982-8.

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