Quinapril

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Abstract
Quinapril is rapidly de-esterified after absorption to quinaprilat (the active diacid metabolite), a potent angiotensin converting enzyme (ACE) inhibitor. Quinapril produces favourable haemodynamic changes, and improves ventricular and endothelial function in patients with various cardiovascular disorders; these effects are mediated through the binding of quinaprilat to both tissue and plasma ACE. Quinapril 10 to 40 mg/day provided effective blood pressure control in most patients with essential hypertension in clinical trials, but some patients required dosages of 80 mg/day and/or concomitant diuretic therapy. In general, quinapril provided similar blood pressure control to other standard antihypertensive therapies including other ACE inhibitors, calcium antagonists and β-adrenoceptor antagonists in comparative clinical trials. Combined therapy with quinapril and hydrochlorothiazide had a significantly greater antihypertensive effect than either drug as monotherapy in two well designed studies. Quinapril has also been shown to reduce microalbuminuria in patients with hypertension and/or diabetes mellitus. In patients with congestive heart failure, quinapril ≤40 mg/day produced beneficial haemodynamic and echocardiographic changes and improved exercise tolerance, symptoms and functional class. Effects of quinapril on survival have not been investigated, but quinapril 10 to 20 mg/day showed comparable efficacy to captopril 25 to 50mg twice daily in two well designed trials. In patients with coronary artery disease, quinapril 40 mg/day significantly reduced the incidence of ischaemic events after coronary artery bypass grafting (CABG) in a well controlled study (n = 148). However, a lower dosage of quinapril (20 mg/day) showed no effect on ischaemic events or atherosclerotic progression with 3 years of treatment in a similarly designed study involving 1750 patients undergoing coronary angioplasty. The tolerability of quinapril is similar to that of other ACE inhibitors. In placebo-controlled trials, cough occurred in 2 and4.3% and hypotension occurred in 50% inhibition of plasma ACE over 24 hours. Quinapril has also been shown to inhibit angiotensin II formation in human vasculature following several weeks of administration. In humans, the hypotensive effect of exogenous bradykinin is potentiated by ACE inhibitor therapy, and the bradykinin antagonist icatibant reduces the hypotensive effect of ACE inhibitors in humans. Similar effects have been demonstrated with quinapril in animal studies. In patients with hypertension, once-daily administration of quinapril 10 to 40mg provided good 24-hour blood pressure control as assessed by ambulatory blood pressure monitoring in some, but not all studies. Generally, quinapril had no significant effect on heart rate, cardiac output or left ventricular (LV) ejection fraction. In patients with moderate to severe congestive heart failure, quinapril produced a number of favourable haemodynamic effects including improved cardiac output and reduced systemic vascular resistance and pulmonary capillary wedge pressure, without an increase in heart rate. Quinapril ≤40 mg/day reduced LV hypertrophy in patients with hypertension or chronic valvular regurgitation, and reduced progressive ventricular remodelling in patients with distant myocardial infarction in one small investigation. Quinapril 10 to 40mg once daily improved endothelial function (as measured by improved flow-mediated dilation or reduced vasoconstrictive response to acetylcholine) in patients with coronary artery disease and hypertension over 2 to 6 months of therapy; improved endothelial function was also observed in patients with congestive heart failure receiving a single infusion of quinaprilat. In contrast, the angiotensin II antagonist losartan (50 mg/day), calcium antagonists amlodipine (5 mg/day) and nitrendipine (10 mg/day), and the ACE inhibitor enalapril (10 mg/day) did not improve endothelial function. Quinapril 5 to 10 mg/day increased heart rate variability and reduced sympathetic overactivity after myocardial infarction in patients with coronary artery disease. In general, quinapril showed neutral or beneficial effects on lipid profiles, glycaemia and renal haemodynamics. Following oral administration of quinapril in healthy volunteers, approximately 60% of the dose is absorbed and peak plasma concentration (Cmax) is reached within 1 hour. Quinapril then undergoes rapid de-esterfication to quinaprilat, the active diacid metabolite, which reaches Cmax within 2 hours. Both quinapril and quinaprilat are highly bound to plasma proteins (≈97%), and mean elimination half-lives are ≈1 and 2 hours, respectively. Quinaprilat has a long terminal half-life of ≈25 hours, which may be associated with its slow release from ACE. The main route of elimination is via the kidney: quinaprilat accounts for 30% of the oral dose recovered in the urine, quinapril accounts for 3% and two other inactive metabolites account for 6% each. The remainder of the oral dose is eliminated in the faeces as unabsorbed quinapril or by biliary excretion of quinapril and its metabolites. The pharmacokinetics of quinapril and quinaprilat are affected by renal and hepatic impairment. In addition, elimination of quinapril may be reduced in patients with congestive heart failure and/or advanced age; however, this reduction is typically a result of decreased renal function in these patients. In lactating mothers receiving a 20mg dose of quinapril, only 1.6% of the maternal dose was estimated to reach the infant. Hypertension The antihypertensive efficacy of quinapril is well documented, with dosages of 10 to 80 mg/day consistently producing significant reductions in blood pressure in patients with mild to moderate hypertension (patients with DBP 95 to 120mm Hg and/or SBP >140mm Hg) in placebo-controlled trials. In comparative, randomised clinical trials, quinapril (10 to 80 mg/day) displayed similar antihypertensive efficacy to other ACE inhibitors captopril (25 to 200 mg/day) and enalapril (10 to 80 mg/day), but inconsistent results have been reported in studies comparing quinapril with lisinopril (2.5 to 20 mg/day). Quinapril 20 to 40mg once daily showed similar efficacy to β-adrenoceptor antagonist atenolol 50 to 100 once daily; however, lower dosages of quinapril (10 to 20 mg/day) did not appear to be as effective as atenolol 50 to 100 mg/day in patients with a history of moderate to severe hypertension. Quinapril 10 to 40 mg/day produced similar response rates to metoprolol 50 to 200 mg/day in patients with hypertension, but quinapril 20 mg/day was slightly less effective than metoprolol 100 mg/day in reducing diastolic blood pressure in patients with type 2 diabetes mellitus in another study. Quinapril (5 to 40 mg/day) also showed similar antihypertensive efficacy to twice-daily sustained release nifedipine (20 to 80 mg/day), once-daily amlodipine (5 to 10 mg/day) and once-daily nitrendipine (10 to 40 mg/day). The addition of a diuretic [usually hydrochlorothiazide (HCTZ)] to quinapril monotherapy increases the response rate from ≥50% to ≈70 to 90% in patients with hypertension. Two large, randomised, double-blind studies showed that quinapril and HCTZ combination therapy was significantly more effective at lowering blood pressure than either drug as monotherapy over 8 weeks of treatment in patients with moderate to severe hypertension. Quinapril 10 to 40 mg/day reduced urinary albumin excretion rate (UAE) to a similar extent as captopril 50 to 150 mg/day and metoprolol 100 mg/day, and was significantly better than atenolol 50 to 100 mg/day and/or HCTZ 25 to 50 mg/day at reducing UAE in randomised, comparative trials. Quinapril 10 to 40 mg/day also significantly decreased UAE in patients with hypertension with or without type 2 diabetes mellitus in two noncomparative studies. Congestive Heart Failure In patients with congestive heart failure, quinapril ≤40 mg/day produced favourable haemodynamic and echocardiographic parameters and improved symptoms, exercise tolerance and disease severity. These favourable effects have been maintained for up to 1 year of nonblind therapy. Although the effect of quinapril on survival in patients with congestive heart failure has not been determined, treatment with other ACE inhibitors has resulted in improved mortality rates, and a recent meta-analysis suggests a class effect for these agents in reducing morbidity and mortality in these patients. In two recent double-blind, randomised, placebo-controlled investigations (n = 131 and 146), quinapril 10 to 20mg once daily showed comparable efficacy to captopril 25 to 50mg twice daily in reducing symptoms of heart failure (e.g. dyspnoea, ventricular gallop or pulmonary congestion), improving echocardiographic parameters (e.g. LV ejection fraction or LV diastolic/systolic diameters) and improving exercise tolerance in patients with mild to moderate congestive heart failure [New York Heart Association (NYHA) functional classes I to III] over 10 or 12 weeks of treatment. In one study, NYHA functional class was also improved with both therapies but quinapril had a greater effect than captopril in patients with more severe disease. Similar effects were observed in another study in elderly patients (aged ≥65 years) with NYHA functional class II or III with an aetiology of ischaemic heart disease. Coronary Artery Disease The results of two large, double-blind, placebo-controlled, randomised trials investigating the potential use of quinapril in patients with coronary artery disease have recently become available: the effects of QUinapril On Vascular Ace and Determinants of Ischemia (QUO VADIS) study and the QUinapril Ischemic Event Trial (QUIET). In the QUO VADIS trial (n = 148), a significant reduction in cardiac events was observed in patients receiving quinapril 40 mg/day versus placebo for 1 year following coronary artery bypass surgery. In contrast, in the QUIET trial, treatment with quinapril 20 mg/day over 3 years had no significant effect on reducing cardiac events or the progression of atherosclerosis in 1750 normolipidaemic, normotensive patients with normal LV function (LV ejection fraction >40%) following coronary angioplasty. Flaws in the design of the QUIET investigation, including insufficient sample size, inadequate quinapril dosage and use of lipidlowering therapy, may have contributed to the lack of effect seen with quinapril in this study. In other investigations in patients undergoing coronary angioplasty and/or coronary stent implantation, quinapril has shown some efficacy in reducing restenosis; however, additional trials are necessary to define the role of quinapril in these patients. Quinapril is generally well tolerated and adverse experiences are usually mild and transient and seldom require treatment withdrawal. In placebo-controlled trials in patients with hypertension or congestive heart failure, discontinuation of quinapril therapy because of adverse events was required in 4.7 and 6.8% of patients, respectively. The most commonly occurring adverse events seen in these studies were dizziness, headache, cough and fatigue, each occurring in 65 years) tolerated quinapril as well as younger patients (aged 80mg furosemide), multiple diuretics or high dose vasodilator therapy, patients with hypovolaemia, hyponatraemia (serum sodium <130 mgEq/L), systolic blood pressure 150 μmol/L and those aged ≥70 years. In the US, it is recommended that all patients with congestive heart failure be supervised for at least 2 hours following the initial dose of quinapril to monitor for the development of hypotension.