Renitec Mechanism of Action

RENITEC (enalapril maleate) is the maleate salt of enalapril, a derivative of two amino-acids, L-alanine and L-proline. Following oral administration, enalapril is rapidly absorbed and then hydrolyzed to enalaprilat, which is a highly specific, long-acting, non-sulphydryl angiotensin converting enzyme inhibitor.
RENITEC is indicated in the treatment of all grades of essential hypertension, and in renovascular hypertension. It may be used alone as initial therapy or concomitantly with other antihypertensive agents, especially diuretics.
RENITEC is also indicated in the treatment and prevention of heart failure.
A multicenter, placebo-controlled, double-blind study of left ventricular dysfunction (SOLVD) assessed the effects of RENITEC in 6,797 patients. 2,569 patients with all degrees of symptomatic heart failure (primarily mild to moderate New York Heart Association Class II and III) were randomized into the Treatment Arm, and 4,228 patients with asymptomatic left ventricular dysfunction were randomized into the Prevention Arm. The combined results demonstrated an overall reduced risk for the development of major ischemic events. RENITEC decreased the incidence of myocardial infarction and reduced the number of hospitalizations for unstable angina pectoris in patients with left ventricular dysfunction.
In addition, in the Prevention Arm, RENITEC significantly prevented the development of symptomatic heart failure and reduced the number of hospitalizations for heart failure. In the Treatment Arm, RENITEC, as an adjunct to conventional therapy, significantly reduced overall mortality and hospitalization for heart failure and improved NYHA functional class.
In a similar study involving 253 patients with severe heart failure (New York Heart Association Class IV), RENITEC was shown to improve symptoms and reduce mortality significantly.
The cardioprotective properties of RENITEC were demonstrated in these studies by the beneficial effects on survival and retardation of the progression of heart failure in patients with symptomatic heart failure; retardation of the development of symptomatic heart failure in asymptomatic patients with left ventricular dysfunction; and prevention of coronary ischemic events in patients with left ventricular dysfunction, specifically reduction in the incidence of myocardial infarction and reduction in hospitalization for unstable angina pectoris.
Pharmacology: Pharmacodynamics: Administration of RENITEC to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate.
Symptomatic postural hypotension is infrequent. In some patients the development of optimal blood pressure reduction may require several weeks of therapy. Abrupt withdrawal of RENITEC has not been associated with rapid increase in blood pressure.
Effective inhibition of ACE activity usually occurs 2 to 4 hours after oral administration of an individual dose of enalapril. Onset of antihypertensive activity was usually seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours after administration.
The duration of effect is dose-related. However, at recommended doses, antihypertensive and hemodynamic effects have been shown to be maintained for at least 24 hours.
The duration of hemodynamic effects appears to be dose-related.
Antihypertensive treatment with RENITEC leads to a significant regression of left ventricular hypertrophy with preservation of left ventricular systolic performance.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of RENITEC there was an increase in renal blood flow; glomerular filtration rate was unchanged. There was no evidence of sodium or water retention. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.
Chronic administration of RENITEC to patients with essential hypertension and renal insufficiency may be associated with improvements in renal function, evidenced by increased glomerular filtration rate.
In short term clinical studies in diabetic and nondiabetic patients with renal disease, decreases in albuminuria and urinary excretion of IgG and total urinary protein were seen after the administration of enalapril.
When given together with thiazide-type diuretics, the blood pressure-lowering effects of RENITEC are at least additive. RENITEC may reduce or prevent the development of thiazide-induced hypokalemia.
Treatment with RENITEC is not usually associated with adverse effects on plasma uric acid. Treatment with RENITEC has been associated with favorable effects on plasma lipoprotein fractions and favorable or no effect on total cholesterol levels.
In patients with heart failure on therapy with digitalis and diuretics, treatment with oral RENITEC was associated with decreases in peripheral resistance and blood pressure. Cardiac output increased, while heart rate (usually elevated in patients with heart failure) decreased. Pulmonary capillary wedge pressure was also reduced. Exercise tolerance and severity of heart failure, as measured by New York Heart Association criteria, improved. These actions continued during chronic therapy.
In patients with mild to moderate heart failure, enalapril retarded progressive cardiac dilatation/enlargement and failure, as evidenced by reduced left ventricular end diastolic and systolic volumes and improved ejection fraction.
Clinical data have shown that enalapril reduced the frequency of ventricular arrhythmias in patients with heart failure, although the underlying mechanisms and clinical significance are not known.
Pharmacokinetics: Metabolism: Oral enalapril is rapidly absorbed, with peak serum concentrations of enalapril occurring within one hour. Based on urinary recovery, the extent of absorption of enalapril from oral enalapril is approximately 60%.
Following absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Similar peak serum concentrations of enalaprilat occur about 4 hours after an oral dose of enalapril. Excretion of enalaprilat is primarily renal. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. Except for conversion to enalaprilat, there is no evidence for significant metabolism of enalapril. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of oral enalapril. The effective half-life for accumulation of enalaprilat following multiple doses of oral enalapril is 11 hours. The absorption of oral RENITEC is not influenced by the presence of food in the gastrointestinal tract. The extent of absorption and hydrolysis of enalapril are similar for the various doses in the recommended therapeutic range.
Studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of oral enalapril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of ¹⁴C enalapril maleate. Radioactivity was found to cross the placenta following administration of ¹⁴C enalapril maleate to pregnant hamsters.