Apo-Enalapril Mechanism of Action





Full Prescribing Info
Pharmacotherapeutic Group: Angiotensin Converting Enzyme Inhibitor.
Pharmacology: APO-ENALAPRIL (enalapril maleate) is an angiotensin converting enzyme (ACE) inhibitor which is used in the treatment of hypertension and heart failure.
ACE is a peptidyl dipeptidase which catalyzes the conversion of angiotensin I to the presser substance, angiotensin II. After absorption, enalapril, a prodrug is hydrolyzed to enalapril at, its active metabolite, which inhibits ACE. 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. Although the latter decrease is small, it results in a small increase in serum K+. In patients treated with enalapril and a thiazide diuretic there was essentially no change in serum potassium (see PRECAUTIONS).
ACE is identical to kininase II. Thus, enalapril may also block the degradation of bradykinin, a potent vasodepressor peptide. However, the role that this plays in the therapeutic effects of enalapril is unknown. While the mechanism through which enalapril lowers blood pressure is believed to be primarily the suppression of the renin-angiotensin aldosterone system, enalapril also lower blood pressure in patients with low-renin hypertension. However, black hypertensive patients (usually a low renin population) have a smaller average response to enalapril monotherapy that non-black patients.
Administration of enalapril to patients with hypertension results in a reduction of both supine and standing blood pressure. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In most patients studied, after oral administration of an individual dose of enalapril, the onset of antihypertensive activity is seen at one hour with peak reduction of blood pressure achieved by 4-6 hours. At recommended doses, the antihypertensive effect has been shown to the maintained for at least 24 hours. In some patients the effect may diminish towards the end of the dosing interval (see DOSAGE & ADMINISTRATION). On occasion, achievement of optimal blood pressure reduction may require several weeks of therapy.
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 enalapril, there was a increase in renal blood flow, glomerular filtration rate was usually unchanged.
When enalapril is given together with thiazide-type diuretics, its blood pressure lowering effect is approximately additive. Administration of enalapril to patients with congestive heart failure reduces afterload and preload of the heart, resulting in an increase in cardiac output, without reflex tachycardia.
A study in patients with severe congestive heart failure (New York Heart Association Class IV) has shown that enalapril when used as an adjunct to conventional therapy with digitalis and diuretics, reduced the mortality from progression of heart failure. No difference was seen in the incidence of sudden cardiac death.
Pharmacodynamics: The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min (0.5 mL/s) or less. With renal function <30 mL/min. (<0.50 mL/s), peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see Dosage & Administration). Enalaprilat is dialyzable at the rate of 62 mL/min (1.03 mL/s). Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain.
Comparative Bioavailability: A comparative bioavailability study was performed using normal human volunteers. The rate and extent of absorption of enalapril and its active metabolite enalaprilat were measured and compared after a single 20 mg dose of APO-ENALAPRIL (1x20 mg tablet or 4x55 mg tablets) and VASOTEC (1x20 mg tablet). The results are summarized as follows: (see Tables 1 and 2).

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Pharmacokinetics: Enalapril is rapidly absorbed after oral administration with peak serum concentrations occurring within one hour. Based on urinary recovery the extent of absorption of enalapril is approximately 60%.
Following absorption, enalapril is rapidly and extensively hydrolyzed to enalaprilat, a potent angiotensin converting enzyme inhibitor (which itself is poorly absorbed). Peak serum concentrations of enalaprilat occur 3 to 4 hours after an oral dose of enalapril maleate. Excretion of enalapril is primarily renal. Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril, 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 of significant metabolism of enalapril, the serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently associated with binding to ACE. The effective half life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The absorption of multiple doses of enalapril maleate is 11 hours. The absorption of enalapril is not influenced by the presence of food in the gastrointestinal tract.
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