accupril

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-isoquinolinecarboxylicacid, monohydrochloride accupril. Its empirical formula is C 25 H 30 N 2 O 5 ·HCland its structural formula is:

Quinapril hydrochloride is a white to off-white amorphous powder that is freelysoluble in aqueous solvents accupril.

ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oraladministration accupril. Each tablet also contains candelilla wax, crospovidone, gelatin,lactose, magnesium carbonate, magnesium stearate, synthetic red iron oxide,and titanium dioxide accupril.

CLINICAL PHARMACOLOGY
Mechanism of Action: Quinapril is deesterified to the principal metabolite,quinaprilat, which is an inhibitor of ACE activity in human subjects and animals accupril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin Ito the vasoconstrictor, angiotensin II accupril. The effect of quinapril in hypertensionand in congestive heart failure (CHF) appears to result primarily from the inhibitionof circulating and tissue ACE activity, thereby reducing angiotensin II formation accupril. Quinapril inhibits the elevation in blood pressure caused by intravenously administeredangiotensin I, but has no effect on the pressor response to angiotensin II,norepinephrine or epinephrine accupril. Angiotensin II also stimulates the secretionof aldosterone from the adrenal cortex, thereby facilitating renal sodium andfluid reabsorption accupril. Reduced aldosterone secretion by quinapril may result ina small increase in serum potassium accupril. In controlled hypertension trials, treatmentwith ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (seePRECAUTIONS ) accupril. Removal of angiotensin II negative feedback on renin secretionleads to increased plasma renin activity (PRA) accupril.

While the principal mechanism of antihypertensive effect is thought to be throughthe renin-angiotensin-aldosterone system, quinapril exerts antihypertensiveactions even in patients with low renin hypertension accupril. ACCUPRIL was an effectiveantihypertensive in all races studied, although it was somewhat less effectivein blacks (usually a predominantly low renin group) than in nonblacks accupril. ACE isidentical to kininase II, an enzyme that degrades bradykinin, a potent peptidevasodilator; whether increased levels of bradykinin play a role in the therapeuticeffect of quinapril remains to be elucidated accupril.

Pharmacokinetics and Metabolism: Following oral administration, peak plasmaquinapril concentrations are observed within one hour accupril. Based on recovery ofquinapril and its metabolites in urine, the extent of absorption is at least60% accupril. The rate and extent of quinapril absorption are diminished moderately (approximately25-30%) when ACCUPRIL tablets are administered during a high-fat meal accupril. Followingabsorption, quinapril is deesterified to its major active metabolite, quinaprilat(about 38% of oral dose), and to other minor inactive metabolites accupril. Followingmultiple oral dosing of ACCUPRIL, there is an effective accumulation half-lifeof quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrationsare observed approximately 2 hours post-dose accupril. Quinaprilat is eliminated primarilyby renal excretion, up to 96% of an IV dose, and has an elimination half-lifein plasma of approximately 2 hours and a prolonged terminal phase with a half-lifeof 25 hours accupril. The pharmacokinetics of quinapril and quinaprilat are linear overa single-dose range of 5-80 mg doses and 40-160 mg in multiple daily doses accupril. Approximately 97% of either quinapril or quinaprilat circulating in plasma isbound to proteins accupril.

In patients with renal insufficiency, the elimination half-life of quinaprilatincreases as creatinine clearance decreases accupril. There is a linear correlation betweenplasma quinaprilat clearance and creatinine clearance accupril. In patients with end-stagerenal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysishas little effect on the elimination of quinapril and quinaprilat accupril. Eliminationof quinaprilat may be reduced in elderly patients (>/=65 years) and in thosewith heart failure; this reduction is attributable to decrease in renal function(see DOSAGE AND ADMINISTRATION ) accupril. Quinaprilat concentrations are reduced inpatients with alcoholic cirrhosis due to impaired deesterification of quinapril accupril. Studies in rats indicate that quinapril and its metabolites do not cross theblood-brain barrier accupril.

Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibitionof plasma ACE for 24 hours accupril. Inhibition of the pressor response to angiotensinI is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours,50% inhibition for about 8 hours, and 20% inhibition at 24 hours accupril. With chronicdosing, however, there is substantial inhibition of angiotensin II levels at24 hours by doses of 20-80 mg accupril.

Administration of 10 to 80 mg of ACCUPRIL to patients with mild to severe hypertensionresults in a reduction of sitting and standing blood pressure to about the sameextent with minimal effect on heart rate accupril. Symptomatic postural hypotension isinfrequent although it can occur in patients who are salt- and/or volume-depleted(see WARNINGS ) accupril. Antihypertensive activity commences within 1 hour with peakeffects usually achieved by 2 to 4 hours after dosing accupril. During chronic therapy,most of the blood pressure lowering effect of a given dose is obtained in 1-2weeks accupril. In multiple-dose studies, 10-80 mg per day in single or divided doseslowered systolic and diastolic blood pressure throughout the dosing interval,with a trough effect of about 5-11/3-7 mm Hg accupril. The trough effect represents about50% of the peak effect accupril. While the dose-response relationship is relatively flat,doses of 40-80 mg were somewhat more effective at trough than 10-20 mg, andtwice daily dosing tended to give a somewhat lower trough blood pressure thanonce daily dosing with the same total dose accupril. The antihypertensive effect of ACCUPRILcontinues during long-term therapy, with no evidence of loss of effectiveness accupril.

Hemodynamic assessments in patients with hypertension indicate that blood pressurereduction produced by quinapril is accompanied by a reduction in total peripheralresistance and renal vascular resistance with little or no change in heart rate,cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction accupril.

Use of ACCUPRIL with a thiazide diuretic gives a blood-pressure lowering effectgreater than that seen with either agent alone accupril.

In patients with hypertension, ACCUPRIL 10-40 mg was similar in effectivenessto captopril, enalapril, propranolol, and thiazide diuretics accupril.

Therapeutic effects appear to be the same for elderly (>/=65 years of age)and younger adult patients given the same daily dosages, with no increase inadverse events in elderly patients accupril.

Heart Failure: In a placebo-controlled trial involving patients with congestiveheart failure treated with digitalis and diuretics, parenteral quinaprilat,the active metabolite of quinapril, reduced pulmonary capillary wedge pressureand systemic vascular resistance and increased cardiac output/index accupril. Similarfavorable hemodynamic effects were seen with oral quinapril in baseline-controlledtrials, and such effects appeared to be maintained during chronic oral quinapriltherapy accupril. Quinapril reduced renal hepatic vascular resistance and increased renaland hepatic blood flow with glomerular filtration rate remaining unchanged accupril.

A significant dose response relationship for improvement in maximal exercisetolerance has been observed with ACCUPRIL therapy accupril. Beneficial effects on theseverity of heart failure as measured by New York Heart Association (NYHA) classificationand Quality of Life and on symptoms of dyspnea, fatigue, and edema were evidentafter 6 months in a double-blind, placebo-controlled study accupril. Favorable effectswere maintained for up to two years of open label therapy accupril. The effects of quinaprilon long-term mortality in heart failure have not been evaluated accupril.

INDICATIONS AND USAGE
Hypertension
ACCUPRIL is indicated for the treatment of hypertension accupril. It may be used aloneor in combination with thiazide diuretics accupril.

Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapywhen added to conventional therapy including diuretics and/or digitalis accupril.

In using ACCUPRIL, consideration should be given to the fact that another angiotensin-convertingenzyme inhibitor, captopril, has caused agranulocytosis, particularly in patientswith renal impairment or collagen vascular disease accupril. Available data are insufficientto show that ACCUPRIL does not have a similar risk (see WARNINGS ) accupril.

Angioedema in black patients: Black patients receiving ACE inhibitor monotherapyhave been reported to have a higher incidence of angioedema compared to non-blacks accupril. It should also be noted that in controlled clinical trials ACE inhibitors havean effect on blood pressure that is less in black patients than in non-blacks accupril.

CONTRAINDICATIONS
ACCUPRIL is contraindicated in patients who are hypersensitive to this productand in patients with a history of angioedema related to previous treatment withan ACE inhibitor accupril.

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