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ACCUPRIL (QUINAPRIL HYDROCHLORIDE): PHARMACODYNAMICS

Hypertension

Single doses of 20 mg of Accupril (Quinapril Hydrochloride) tablets provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I 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. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20.80 mg.

Administration of 10 to 80 mg of Quinapril (Accupril) to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and/or volume-depleted. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1.2 weeks. In multiple-dose studies, 10.80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5.11/3.7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40.80 mg were somewhat more effective at trough than 10.20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of Quinapril (Accupril) tablets continues during long-term therapy, with no evidence of loss of effectiveness.

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

Use of Quinapril HCl (Accupril) with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone.

In patients with hypertension, Quinapril HCl (Accupril) tablets 10-40 mg was similar in effectiveness to enalapril, captopril, propranolol, and thiazide diuretics.

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 in adverse events in elderly patients.

Heart Failure

In a placebo-controlled trial involving patients with congestive heart failure treated with digitalis and diuretics, parenteral quinaprilat, the active metabolite of quinapril, reduced pulmonary capillary wedge pressure and systemic vascular resistance and increased cardiac output/index. Similar favorable hemodynamic effects were seen with oral quinapril in baseline-controlled trials, and such effects appeared to be maintained during chronic oral quinapril therapy. Quinapril reduced renal hepatic vascular resistance and increased renal and hepatic blood flow with glomerular filtration rate remaining unchanged.
A significant dose response relationship for improvement in maximal exercise tolerance has been observed with Quinapril Hydrochloride (Accupril) therapy. Beneficial effects on the severity of heart failure as measured by New York Heart Association (NYHA) classification and Quality of Life and on symptoms of dyspnea, fatigue, and edema were evident after 6 months in a double-blind, placebo-controlled study. Favorable effects were maintained for up to two years of open label therapy. The effects of quinapril on long-term mortality in heart failure have not been evaluated.

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