Ramipril

RAMIPRIL- ramipril capsule
Golden State Medical Supply, Inc.

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ramipril should be discontinued as soon as possible. See WARNINGS: Fetal/neonatal morbidity and mortality.

DESCRIPTION

Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C and 112°C.

Ramipril’s chemical name is (2S ,3aS ,6aS)-1[(S)-N-[(S) -1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b ] pyrrole-2-carboxylic acid, 1-ethyl ester; its structural formula is:

Chemical Structure -- Ramipril
(click image for full-size original)

Its empiric formula is C23 H32 N2 O5 , and its molecular weight is 416.5.

Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl angiotensin converting enzyme inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.

Ramipril is supplied as hard shell capsules for oral administration containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril. The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains D&C Yellow # 10 and FD&C Yellow # 6 the 2.5 mg capsule shell contains D&C Red # 28, D&C Yellow # 10 and FD&C Red #40, the 5 mg capsule shell contains D&C Red # 28, D&C Red # 33, D&C Yellow # 10 and FD&C Blue #1, and the 10 mg capsule shell contains D&C Red # 28, and FD&C Blue #1. Capsule shells are imprinted with ink containing Shellac and Black iron oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Ramipril and ramiprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ramipril alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ramipril and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater, and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater. (See PRECAUTIONS.) Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ramipril remains to be elucidated.

While the mechanism through which ramipril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, ramipril has an antihypertensive effect even in patients with low-renin hypertension. Although ramipril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-black patients.

Pharmacokinetics and Metabolism

Following oral administration of ramipril, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50 to 60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced.

In a trial in which subjects received ramipril capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in apple sauce, serum ramiprilat levels were essentially unrelated to the use or nonuse of the concomitant liquid or food.

Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2 to 4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro , these percentages are independent of concentration over the range of 0.01 to 10 mcg/mL.

Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril.

Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 to 20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.

Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2 to 4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9 to 18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5 to 10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13 to 17 hours.

After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ramipril, especially at low doses (2.5 mg), but the difference is clinically insignificant.

In patients with creatinine clearance less than 40 mL/min/1.73m2 , peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3 to 4 times as large as it is in patients with normal renal function who receive similar doses.

The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 mL/min/1.73m2 had higher peak and trough ramiprilat levels and slightly longer times to peak concentrations. (See DOSAGE AND ADMINISTRATION.)

In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose of plasma ACE activity does not vary with hepatic function.

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