Pharmacologic Category: Antihypertensive.
Pharmacology: Pharmacodynamics: Quinapril hydrochloride is the salt of quinapril, the ethyl ester of a nonsulfhydryl, ACE inhibitor, quinaprilat.
Administration of 10 mg to 40 mg of quinapril to patients with mild to moderate hypertension results in a reduction of both sitting and standing blood pressure with minimal effect on heart rate. Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. Achievement of maximum blood pressure-lowering effects may require 2 weeks of therapy in some patients. At the recommended doses, antihypertensive effects are maintained in most patients throughout the 24-hour dosing interval and continued during long-term therapy.
Hemodynamic assessments in patients with hypertension have indicated 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, GFR or filtration fraction.
Concomitant therapy with thiazide-type diuretics and/or the addition of beta-blocker therapy enhances the antihypertensive effects of quinapril, giving a blood pressure-lowering effect greater than that seen with either agent alone.
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 the incidence of adverse events in elderly patients.
Quinapril administration to patients with congestive heart failure reduces peripheral vascular resistance, mean arterial pressure, systolic and diastolic blood pressure, and pulmonary capillary wedge pressure, and increases cardiac output.
In 149 patients undergoing elective coronary bypass surgery, treatment with quinapril 40 mg reduced the incidence of post-operative ischemic events compared to placebo during a 1-year follow-up.
In patients with documented coronary artery disease (CAD) but without manifest hypertension or heart failure, quinapril improves abnormal endothelial function measured in coronary and brachial arteries.
Quinapril enhances endothelial function by mechanisms leading to increased availability of nitric oxide. Endothelial dysfunction is considered an important underlying pathophysiological mechanism in CAD. The clinical significance of improving endothelial function has not been established.
Mechanism of Action: Quinapril is rapidly deesterified to quinaprilat (quinapril diacid, the principal metabolite), which, in human studies, is a potent ACE inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor angiotensin II, which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion by the adrenal cortex. The mode of action of quinapril in humans and animals is to inhibit circulating and tissue ACE activity, thereby decreasing vasopressor activity and aldosterone secretion. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA).
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. Quinapril monotherapy was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in non-blacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.
In animal studies, the antihypertensive effect of quinapril outlasts its inhibitory effect on circulating ACE, whereas tissue ACE inhibition more closely correlates with the duration of its antihypertensive effects.
ACE inhibitors, including quinapril, may enhance insulin sensitivity.
Pharmacokinetics: Following oral administration, peak plasma quinapril concentrations are observed within 1 hour. Based on the recovery of quinapril and its metabolites in the urine, the extent of absorption is approximately 60%. Thirty-eight percent of orally administered quinapril is systemically available as quinaprilat. Quinapril has an apparent half-life in plasma of approximately 1 hour. Peak plasma quinaprilat concentrations are observed approximately 2 hours following an oral dose of quinapril. Quinaprilat is eliminated primarily by renal excretion and has an effective accumulation half-life of approximately 3 hours. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins.
In patients with renal insufficiency, the apparent elimination half-life of quinaprilat increases as creatinine clearance decreases. Pharmacokinetic studies in patients with end-stage renal disease on chronic hemodialysis or continuous ambulatory peritoneal dialysis indicate that dialysis has little effect on the elimination of quinapril and quinaprilat. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. The elimination of quinaprilat is also reduced in elderly patients (≥65 years) and correlates well with their level of renal function (see Dosage & Administration).
Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.
Pharmacokinetics in the Elderly: Elderly patients exhibited increased AUC and peak levels for quinaprilat compared to values in younger patients; this appeared to be related to decreased renal function rather than to age itself. In controlled and uncontrolled studies where 21% of patients were 65 years or older, no overall differences in effectiveness or safety were observed between older and younger patients. However, greater sensitivity of some older individuals cannot be ruled out.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Quinapril hydrochloride was not carcinogenic in mice or rats when given in doses up to 75 or 100 mg/kg/day (50-60 times the maximum human daily dose, respectively) for 104 weeks. Neither quinapril nor quinaprilat was mutagenic in the Ames bacterial assay with or without metabolic activation. Quinapril was also negative in the following genetic toxicology studies: in vitro mammalian cell point mutation, sister-chromatid exchange in cultured mammalian cells, micronucleus test with mice, in vitro chromosome aberration with V79 cultured lung cells, and an in vivo cytogenetic study with rat bone marrow. There were no adverse effects on fertility or reproduction in rats at dose levels up to 100 mg/kg/day (60 times the maximum daily human dose).
No fetotoxic or teratogenic effects were observed in rats at quinapril doses as high as 300 mg/kg/day (180 times the maximum daily human dose), despite maternal toxicity at 150 mg/kg/day. Offspring body weights were reduced in rats treated late in gestation and during lactation with doses of 25 mg/kg/day or more. Quinapril was not teratogenic in the rabbit; however, as noted with other ACE inhibitors, maternal toxicity and embryotoxicity were seen in some rabbits at doses as low as 0.5 mg/kg/day and 1 mg/kg/day, respectively.