Pfizer - Accupril (Quinapril) Tablets
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ACCUPRIL® is the hydrochloride salt of quinapril, the ethyl ester of a non-sulfhydryl, angiotensin-converting enzyme (ACE) inhibitor, quinaprilat. Quinapril hydrochloride is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid, monohydrochloride. Its empirical formula is C25H30N2O5 ∙HCl and its structural formula is:
Product Details
Quinapril hydrochloride is a white to off-white amorphous powder that is freely soluble in aqueous solvents.
ACCUPRIL tablets contain 5 mg (equivalent to 5.416 mg Quinapril Hydrochloride), 10 mg (equivalent to 10.832 mg Quinapril Hydrochloride), 20 mg (equivalent to 21.664 mg Quinapril Hydrochloride), or 40 mg (equivalent to 43.328 rag Quinapril Hydrochloride) of quinapril for oral administration. Each tablet also contains candelilla wax, crospovidone, gelatin, lactose, magnesium carbonate, magnesium stearate, synthetic red iron oxide, and titanium dioxide.
CLINICAL PHARMACOLOGY
Mechanism of Action
Quinapril is deesterified to the principal metabolite, quinapnlat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin 1 to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension and in congestive heart failure (CHF) appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmoI'L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. ACCUPRIL was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades biadykimn, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated
Pharmacokinetics and Metabolism
Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recover.' of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUFRIL tablets are administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an TV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 23 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5-80 mg doses and 40—160 mg in multiple dairy doses. Approximately 9 7% of either quinapril or quinaprilat circulating in plasma is bound to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulator.* peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat Elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deestenfication of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Pharmacokinetics and Metabolism
Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recover.' of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25-30%) when ACCUFRIL tablets are administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of ACCUPRIL, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an TV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 23 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5-80 mg doses and 40—160 mg in multiple dairy doses. Approximately 9 7% of either quinapril or quinaprilat circulating in plasma is bound to proteins.
In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulator.* peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat Elimination of quinaprilat may be reduced in elderly patients (>65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deestenfication of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
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