Quinapril pharmacokinetics and molecular data

Pharmacokinetics
Mechanism Mechanism in patients with low renin hypertension Absorption Metabolite absorption Metabolite elimination Metabolite elimination in patients with renal insufficiency Pharmacodynamics

Mechanism
Quinapril is deesterified to the principal metabolite, Quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. The effect of Quinapril in hypertension 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 caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone 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. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Return to top

Mechanism in patients with low renin hypertension
While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin aldosterone system, Quinapril exerts antihypertensive actions even in patients with low renin hypertension. Return to top

Absorption
Following oral administration, peak plasma Quinapril concentrations are observed within one hour. Based on recovery of Quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of Quinapril absorption are diminished moderately (approximately 25 to 30%) when Quinapril tablets are administered during a high-fat meal. Return to top

Metabolite absorption
Following absorption, Quinapril is deesterified to its major active metabolite, Quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of Quinapril hydrochloride, there is an effective accumulation half-life of Quinaprilat of approximately 3 hours, and peak plasma Quinaprilat concentrations are observed approximately 2 hours post-dose. Return to top

Metabolite elimination
Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of Quinapril and Quinaprilat are linear 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. Return to top

Metabolite elimination in patients with renal insufficiency
In patients with renal insufficiency, the elimination half-life of Quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma Quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory 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 heart failure; this reduction is attributable to decrease in renal function. Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of Quinapril. Studies in rats indicate that Quinapril and its metabolites do not cross the blood-brain barrier. Return to top

Pharmacodynamics
Single doses of 20 mg of Quinapril hydrochloride 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 to 80 mg. Return to top