Quinapril
QUINAPRIL- quinapril hydrochloride tablet
Dr.Reddy’s Laboratories Limited
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, quinapril tablets should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality
DESCRIPTION
Quinapril hydrochloride USP is the hydrochloride salt of quinapril, the ethyl ester of a non-sulfhydryl,angiotensin-converting enzyme (ACE) inhibitor, quinaprilat.
Quinapril hydrochloride USP is chemically described as [3S-[2[R*(R*)], 3R*]]-2-[2-[[1(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1 ,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, monohydrochloride. Its empirical formula is C2 SH30 N20 s -HCI and its structural formula is:
Quinapril hydrochloride USP is a white to off-white amorphous powder that is freely soluble inaqueous solvents.
Quinapril Tablets USP contain quinapril hydrochloride equivalent to 5 mg, 10 mg, 20 mg, or 40 mgof quinapril for oral administration.
Each tablet also contains lactose monohydrate, magnesium carbonate, magnesium stearate,crospovidone, povidone and opadry brown (hypromellose, titanium dioxide, ironoxide and macrogol).
CLINICAL PHARMACOLOGY
Mechanism of Action
Quinapril is deesterified to the principal metabolite, quinaprilat, which is aninhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzesthe conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril inhypertension 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 causedby intravenously administered angiotensin I, but has no effect on the pressor response toangiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion ofaldosterone 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. Incontrolled hypertension trials, treatment with quinapril hydrochloride alone resulted in meanincreases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negativefeedback on renin secretion leads to increased plasma renin activity (PRA).
While the principal mechanism of antihypertensive effect is thought to be through the reninangiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with lowrenin hypertension. Quinapril hydrochloride was an effective antihypertensive in all races studied,although it was somewhat less effective in blacks (usually a predominantly low renin group) than innonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptidevasodilator; whether increased levels of bradykinin playa role in the therapeutic effect of quinaprilremains to be elucidated.
Pharmacokinetics and Metabolism
Following oral administration, peak plasma quinaprilconcentrations are observed within one hour. Based on recovery of quinapril and its metabolites inurine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption arediminished moderately (approximately 25 to 30%) when quinapril hydrochloride tablets areadministered during a high-fat meal. Following absorption, quinapril is deesterified to its major activemetabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Followingmultiple oral dosing of quinapril hydrochloride, there is an effective accumulation half-life ofquinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observedapproximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% ofan IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolongedterminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and quinaprilat arelinear over a single-dose range of 5 to 80 mg doses and 40 to 160 mg in multiple daily doses.Approximately 97% 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 creatinineclearance decreases. There is a linear correlation between plasma quinaprilat clearance andcreatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuousambulatory 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 heartfailure; this reduction is attributable to decrease in renal function (see DOSAGE ANDADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis dueto impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites donot cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Hypertension
Single doses of 20 mg of quinapril hydrochloride provide over 80% inhibition ofplasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20%inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin IIlevels at 24 hours by doses of 20 to 80 mg.
Administration of 10 to 80 mg of quinapril hydrochloride to patients with mild to severe hypertensionresults in a reduction of sitting and standing blood pressure to about the same extent with minimaleffect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patientswho are salt-and/or volume-depleted (see WARNINGS). Antihypertensive activity commences within1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, mostof the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dosestudies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressurethroughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effectrepresents about 50% of the peak effect. While the dose-response relationship is relatively flat,doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice dailydosing tended to give a somewhat lower trough blood pressure than once daily dosing with the sametotal dose. The antihypertensive effect of quinapril hydrochloride continues during long-term therapy,with no evidence of loss of effectiveness.
Hemodynamic assessments in patients with hypertension indicate that blood pressure reductionproduced by quinapril is accompanied by a reduction in total peripheral resistance and renalvascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerularfiltration rate, or filtration fraction.
Use of quinapril hydrochloride with a thiazide diuretic gives a blood pressure lowering effect greaterthan that seen with either agent alone.
In patients with hypertension, quinapril hydrochloride 10 to 40 mg was similar in effectiveness tocaptopril, enalapril, propranolol, and thiazide diuretics.
Therapeutic effects appear to be the same for elderly (≥65 years of age) and younger adult patientsgiven the same daily dosages, with no increase in adverse events in elderly patients.
INDICATIONS AND USAGE
Hypertension
Quinapril hydrochloride is indicated for the treatment of hypertension. It may be used alone or incombination with thiazide diuretics.
In using quinapril hydrochloride, consideration should be given to the fact that another angiotensinconvertingenzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renalimpairment or collagen vascular disease. Available data are insufficient to show that quinaprilhydrochloride does not have a similar risk (see WARNINGS).
Angioedema in black patients
Black patients receiving ACE inhibitor monotherapy have beenreported to have a higher incidence of angioedema compared to non-blacks. It should also be notedthat in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in blackpatients than in non-blacks.
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