information for 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 information for 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 information for accupril.

ACCUPRIL tablets contain 5 mg, 10 mg, 20 mg, or 40 mg of quinapril for oraladministration information for accupril. Each tablet also contains candelilla wax, crospovidone, gelatin,lactose, magnesium carbonate, magnesium stearate, synthetic red iron oxide,and titanium dioxide information for 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 information for accupril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin Ito the vasoconstrictor, angiotensin II information for 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 information for 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 information for accupril. Angiotensin II also stimulates the secretionof aldosterone from the adrenal cortex, thereby facilitating renal sodium andfluid reabsorption information for accupril. Reduced aldosterone secretion by quinapril may result ina small increase in serum potassium information for accupril. In controlled hypertension trials, treatmentwith ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (seePRECAUTIONS ) information for accupril. Removal of angiotensin II negative feedback on renin secretionleads to increased plasma renin activity (PRA) information for 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 information for 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 information for 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 information for accupril.

Pharmacokinetics and Metabolism: Following oral administration, peak plasmaquinapril concentrations are observed within one hour information for accupril. Based on recovery ofquinapril and its metabolites in urine, the extent of absorption is at least60% information for accupril. The rate and extent of quinapril absorption are diminished moderately (approximately25-30%) when ACCUPRIL tablets are administered during a high-fat meal information for accupril. Followingabsorption, quinapril is deesterified to its major active metabolite, quinaprilat(about 38% of oral dose), and to other minor inactive metabolites information for 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 information for 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 information for 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 information for accupril. Approximately 97% of either quinapril or quinaprilat circulating in plasma isbound to proteins information for accupril.

In patients with renal insufficiency, the elimination half-life of quinaprilatincreases as creatinine clearance decreases information for accupril. There is a linear correlation betweenplasma quinaprilat clearance and creatinine clearance information for accupril. In patients with end-stagerenal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysishas little effect on the elimination of quinapril and quinaprilat information for 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 ) information for accupril. Quinaprilat concentrations are reduced inpatients with alcoholic cirrhosis due to impaired deesterification of quinapril information for accupril. Studies in rats indicate that quinapril and its metabolites do not cross theblood-brain barrier information for accupril.

Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibitionof plasma ACE for 24 hours information for 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 information for accupril. With chronicdosing, however, there is substantial inhibition of angiotensin II levels at24 hours by doses of 20-80 mg information for 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 information for accupril. Symptomatic postural hypotension isinfrequent although it can occur in patients who are salt- and/or volume-depleted(see WARNINGS ) information for accupril. Antihypertensive activity commences within 1 hour with peakeffects usually achieved by 2 to 4 hours after dosing information for accupril. During chronic therapy,most of the blood pressure lowering effect of a given dose is obtained in 1-2weeks information for 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 information for accupril. The trough effect represents about50% of the peak effect information for 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 information for accupril. The antihypertensive effect of ACCUPRILcontinues during long-term therapy, with no evidence of loss of effectiveness information for 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 information for accupril.

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

In patients with hypertension, ACCUPRIL 10-40 mg was similar in effectivenessto captopril, enalapril, propranolol, and thiazide diuretics information for 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 information for 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 information for accupril. Similarfavorable hemodynamic effects were seen with oral quinapril in baseline-controlledtrials, and such effects appeared to be maintained during chronic oral quinapriltherapy information for accupril. Quinapril reduced renal hepatic vascular resistance and increased renaland hepatic blood flow with glomerular filtration rate remaining unchanged information for accupril.

A significant dose response relationship for improvement in maximal exercisetolerance has been observed with ACCUPRIL therapy information for 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 information for accupril. Favorable effectswere maintained for up to two years of open label therapy information for accupril. The effects of quinaprilon long-term mortality in heart failure have not been evaluated information for accupril.

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

Heart Failure
ACCUPRIL is indicated in the management of heart failure as adjunctive therapywhen added to conventional therapy including diuretics and/or digitalis information for 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 information for accupril. Available data are insufficientto show that ACCUPRIL does not have a similar risk (see WARNINGS ) information for accupril.

Angioedema in black patients: Black patients receiving ACE inhibitor monotherapyhave been reported to have a higher incidence of angioedema compared to non-blacks information for 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 information for 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 information for accupril.

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