diabetic nephropathy treatments accupril ramipril

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 diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril.

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

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 diabetic nephropathy treatments accupril ramipril. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin Ito the vasoconstrictor, angiotensin II diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril. Angiotensin II also stimulates the secretionof aldosterone from the adrenal cortex, thereby facilitating renal sodium andfluid reabsorption diabetic nephropathy treatments accupril ramipril. Reduced aldosterone secretion by quinapril may result ina small increase in serum potassium diabetic nephropathy treatments accupril ramipril. In controlled hypertension trials, treatmentwith ACCUPRIL alone resulted in mean increases in potassium of 0.07 mmol/L (seePRECAUTIONS ) diabetic nephropathy treatments accupril ramipril. Removal of angiotensin II negative feedback on renin secretionleads to increased plasma renin activity (PRA) diabetic nephropathy treatments accupril ramipril.

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 diabetic nephropathy treatments accupril ramipril. ACCUPRIL was an effectiveantihypertensive in all races studied, although it was somewhat less effectivein blacks (usually a predominantly low renin group) than in nonblacks diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril.

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

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

Pharmacodynamics and Clinical Effects
Hypertension: Single doses of 20 mg of ACCUPRIL provide over 80% inhibitionof plasma ACE for 24 hours diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril. With chronicdosing, however, there is substantial inhibition of angiotensin II levels at24 hours by doses of 20-80 mg diabetic nephropathy treatments accupril ramipril.

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 diabetic nephropathy treatments accupril ramipril. Symptomatic postural hypotension isinfrequent although it can occur in patients who are salt- and/or volume-depleted(see WARNINGS ) diabetic nephropathy treatments accupril ramipril. Antihypertensive activity commences within 1 hour with peakeffects usually achieved by 2 to 4 hours after dosing diabetic nephropathy treatments accupril ramipril. During chronic therapy,most of the blood pressure lowering effect of a given dose is obtained in 1-2weeks diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril. The trough effect represents about50% of the peak effect diabetic nephropathy treatments accupril ramipril. 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 diabetic nephropathy treatments accupril ramipril. The antihypertensive effect of ACCUPRILcontinues during long-term therapy, with no evidence of loss of effectiveness diabetic nephropathy treatments accupril ramipril.

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 diabetic nephropathy treatments accupril ramipril.

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

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

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 diabetic nephropathy treatments accupril ramipril.

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 diabetic nephropathy treatments accupril ramipril. Similarfavorable hemodynamic effects were seen with oral quinapril in baseline-controlledtrials, and such effects appeared to be maintained during chronic oral quinapriltherapy diabetic nephropathy treatments accupril ramipril. Quinapril reduced renal hepatic vascular resistance and increased renaland hepatic blood flow with glomerular filtration rate remaining unchanged diabetic nephropathy treatments accupril ramipril.

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

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

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

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 diabetic nephropathy treatments accupril ramipril. Available data are insufficientto show that ACCUPRIL does not have a similar risk (see WARNINGS ) diabetic nephropathy treatments accupril ramipril.

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

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 diabetic nephropathy treatments accupril ramipril.

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