Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2021 Publisher: Organon Pharma Pty Ltd, Building A, 26 Talavera Road, Macquarie Park NSW 2113
Enalapril maleate is a pro-drug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. The liver appears to be the main site for this conversion.
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 haemodynamic effects have been shown to be maintained for at least 24 hours.
In haemodynamic 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 or no change in renal blood flow; glomerular filtration rate was unchanged. However, in patients with low pretreatment glomerular filtration rates, the rates were usually increased.
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 thiazideinduced hypokalaemia.
In patients with heart failure on therapy with digitalis and diuretics, treatment with oral or parenteral 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.
How enalapril, or converting enzyme inhibitors in general, lower blood pressure is not entirely clear. The mechanism most favoured is inhibition of the angiotensin converting enzyme (ACE), a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. Inhibition of ACE results in decreased plasma angiotensin II, which leads to increased plasma renin activity (due to removal of negative feedback of renin release), and decreased aldosterone secretion.
While the mechanism through which RENITEC lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, which plays a major role in the regulation of blood pressure, RENITEC is antihypertensive even in patients with lowrenin hypertension. RENITEC may also block the degradation of bradykinin, a potent vasodepressor peptide; however, the role that this plays in the therapeutic effect of RENITEC remains to be elucidated.
In a multicentre, placebo-controlled clinical trial (SOLVD), 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤35% were randomised to placebo or enalapril and followed for up to 55 months (SOLVD-Treatment).
A second multicentre trial used the SOLVD protocol for a study of patients with minimal or no symptoms of heart failure. SOLVD-Prevention patients, who had left ventricular ejection fraction ≤35% and no history of symptomatic heart failure were randomised to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. These patients had little or no limitation of exercise tolerance due to dyspnoea or fatigue at randomisation and did not require treatment with digitalis, diuretics or vasodilators for heart failure at entry into the trial. The majority of patients in the trial had a history of ischaemic heart disease. A history of myocardial infarction was present in 80% of patients, current angina pectoris in 34% and a history of hypertension in 37%. Patients who had a recent myocardial infarction (i.e. within the preceding 30 days) were not included in the SOLVD trials.
In patients with left ventricular ejection fractions of less than 35%, RENITEC has been shown to retard the progression of heart failure, reduce hospitalisations for heart failure and reduce the risk of myocardial infarction. In addition, in patients who have significant symptoms of heart failure (New York Heart Association Classes 2-4) and also left ventricular ejection fractions of less than 35%, RENITEC has been shown to improve survival and reduce hospitalisations for unstable angina pectoris.
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 RENITEC is approximately 60%. The oral bioavailability of enalaprilat is approximately 40%. Protein binding is approximately 50%.
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.
Following absorption, oral enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor. Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of RENITEC.
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 RENITEC. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to angiotensin converting enzyme (ACE).
In subjects with normal renal function, steady state serum concentrations of enalaprilat were achieved by the fourth day of administration of RENITEC. The plasma concentration time profile of enalaprilat was complex with several exponentials including a very prolonged terminal phase (t1/2>30 hr). The effective half-life for accumulation of enalaprilat following multiple doses of oral RENITEC is 11 hours.
Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli, sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
There was no evidence of a carcinogenic effect when enalapril was administered for 106 weeks to rats at doses up to 90 mg/kg/day. Enalapril has also been administered for 94 weeks to male and female mice at doses up to 90 mg and 180 mg/kg/day, respectively, and showed no evidence of carcinogenicity.
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