Benazepril

Summary

Synopsis

Benazepril is a nonsulfhydryl ACE inhibitor prodrug, which is converted in vivo to its active form, benazeprilat. Data from clinical studies have indicated that benazepril 5 to 80mg (usually 10 to 20mg), administered as a single daily dose, effectively decreases blood pressure in patients with mild to moderately severe hypertension. In a small number of comparative studies, the anti-hypertensive efficacy of benazepril appeared to be at least equivalent to that of captopril, enalapril, hydrochlorothiazide, nifedipine, nitrendipine or propranolol at usual therapeutic doses. Combinations of benazepril and hydrochlorothiazide or nifedipine achieved a greater lowering of blood pressure than benazepril alone, ana this approach may be suitable for patients with more severe hypertension.

Benazepril is reported to have beneficial effects on various indices of cardiac function and to improve clinical symptoms and exercise capacity in patients with congestive heart failure.

The tolerability of benazepril in clinical trials has been very good, with an incidence of adverse effects similar to that observed in placebo recipients.

Thus, benazepril appears to be an effective alternative to other members of its class for the management of hypertension, and further studies will accurately define its usefulness in congestive heart failure.

Pharmacodynamic Properties

Benazepril is a prodrug requiring biotransformation in vivo to the active angiotensin converting enzyme (ACE) inhibitor benazeprilat.

ACE inhibition by benazeprilat results in decreased plasma angiotensin II concentrations, which in turn leads to increased plasma renin activity and decreased plasma aldosterone levels. The beneficial haemodynamic and cardiac effects of benazepril appear to be mediated by ACE inhibition and the resultant reduction in formation of angiotensin II, which in turn decreases vascular resistance. The contribution, if any, of increased tissue bradykinin resulting from ACE inhibition and decreased sympathetic nervous system activity is unknown.

Plasma ACE activity was inhibited by > 90% 24 hours after administration of benazepril 5 to 40mg in healthy volunteers and in patients with hypertension, and the inhibitory effect of benazepril 10mg was of similar magnitude to cilazapril 5mg or perindopril 8mg, while that of benazepril 20mg was greater than that of enalapril 20mg.

Benazepril has little effect on blood pressure or heart rate in normotensive volunteers, but in dosages of 5 to 40mg decreases diastolic and systolic blood pressure in hypertensive patients for up to 24 hours, with peak effects at around 2 to 6 hours.

In patients with congestive heart failure already receiving digoxin and/or diuretics, single doses of benazepril 2, 5 or 10mg increased cardiac output, and decreased systemic and pulmonary resistance and mean arterial, pulmonary arterial and right atrial pressures. Intravenously administered benazeprilat 0.3 to 10mg significantly reduced heart rate and left ventricular systolic pressure and produced a shift in the left ventricular diastolic pressure-volume relationship, with a 30% reduction in mean diastolic wall stress, in patients with left ventricular dysfunction secondary to myocardial infarction. Data from preliminary studies in animals and humans have also suggested that benazepril may attenuate or reverse left ventricular hypertrophy in hypertension.

Renal vascular resistance and filtration fraction were decreased and renal plasma flow increased, while glomerular filtration rate was unchanged, following single or repeated administration of benazepril in healthy volunteers, patients with hypertension and normotensive patients with glomerulonephritis. Benazepril also decreased urinary excretion of protein in patients with glomerulonephritis.

Benazepril appeared to improve glycaemic control in type II diabetic hypertensive patients, and was also reported to lower plasma cholesterol concentrations by 4% in hypertensive patients.

Pharmacokinetic Properties

Benazepril is rapidly but incompletely (at least 37%) absorbed following oral administration to fasting volunteers, reaching maximum plasma concentrations within 0.5 hours. Rapid and extensive hydrolysis to benazeprilat results in peak plasma concentrations of the active metabolite within 1.5 hours of benazepril administration. Administration of benazepril with food decreases the rate, but not the extent, of absorption. In healthy volunteers maximum plasma benazeprilat concentrations of approximately 495 and 970 pmol/g were achieved following administration of benazepril 10mg and 20mg, respectively, with corresponding AUC_0–24 values of 2485 to 2650 and 4690 pmol/g · h. Both benazepril and benazeprilat are ≥ 95% bound to serum proteins and very small amounts of both compounds are secreted into human breast milk.

Benazeprilat is eliminated from plasma in a bipnasic pattern, with initial and terminal half-lives of approximately 3 and 22 hours, respectively, in healthy volunteers; the effective half-life for accumulation was calculated to be 10 to 11 hours. Elimination of benazeprilat appears to occur by both urinary and biliary routes, approximately 18% of a benazepril dose being recovered in the urine as benazeprilat. In healthy subjects renal clearance of benazeprilat is about 1.4 to 1.7 L/h.

The pharmacokinetics of benazepril and/or benazeprilat are only slightly altered by advanced age, hepatic cirrhosis, mild to moderate renal dysfunction or nephrotic syndrome. However, renal clearance of benazeprilat decreases in parallel with renal function, resulting in substantial increases in AUC values in patients with severe renal impairment (creatinine clearance < 1.8 L/h; 30 ml/min).

Therapeutic Use

Several short term studies (of up to 8 weeks’ duration) have demonstrated that benazepril 10 to 80 mg/day (usually 10 to 40mg) is effective in lowering blood pressure in patients with mild to moderately severe hypertension. Compared with placebo, mean reductions of approximately 5 to 10 and 10 to 15mm Hg, respectively, are generally achieved in diastolic and systolic blood pressure in such patients. The antihypertensive efficacy of benazepril was maintained during 1 to 2 years’ therapy. Benazepril appeared to be a suitable treatment for hypertensive mature or elderly patients and those with concomitant renal dysfunction.

Data from studies comparing benazepril with other antihypertensive drugs are somewhat limited at present. Benazepril 10 mg/day was as effective as enalapril 20 mg/day and at least as effective as captopril 50 mg/day. Titrated doses of benazepril 20 to 40 mg/day produced comparable reductions in blood pressure to nifedipine 40 to 80mg or propranolol 80 to 160 mg/day, and benazepril 10 to 20 mg/day was at least as effective as hydrochlorothiazide 25 to 50mg or nitrendipine 20 to 40 mg/day.

Further reductions in blood pressure, have been achieved by addition of hydrochlorothiazide 6.25 to 50 mg/day or nifedipine 40 mg/day to benazepril monotherapy.

Limited clinical experience with benazepril in congestive heart failure has indicated that the drug may be useful as adjunctive therapy in the management of this condition; beneficial changes reported following administration of benazepril included decreased systemic and pulmonary resistance, and systemic, pulmonary arterial and right atrial pressures and increased cardiac output, resulting in improved signs and symptoms and exercise tolerance.

Tolerability

Benazepril has been well tolerated in clinical trials, with adverse effects considered to be related to study drug occurring in 20% of patients treated with benazepril alone vs 18% of placebo recipients. Headache was the most common symptom (5% of patients), but occurred as frequently in placebo-treated patients. Other adverse effects included dizziness, fatigue, cough, nausea and postural dizziness, which were reported by ≤ 3% of benazepril recipients. Serious adverse effects were rare, although swelling or oedema of the face or lip occurred in a small proportion of patients.

In comparative studies, benazepril was at least as well tolerated as hydrochlorothiazide and better tolerated than nifedipine. Moreover, concomitant benazepril administration appeared to decrease adverse symptoms associated with nifedipine treatment, and may attenuate the metabolic effects of thiazide diuretics.

Laboratory parameter changes observed in a small proportion of patients during benazepril monotherapy included decreased haemoglobin concentration, leucopenia and hyperkalaemia, as observed with other ACE inhibitors.

Dosage and Administration

The usual recommended initial dosage of benazepril for the treatment of hypertension in patients not receiving diuretics is 10mg once daily, which may be increased to a maximum of 40 mg/day if blood pressure is not sufficiently lowered. A twice-daily regimen may be used for patients in whom blood pressure control is not adequate over 24 hours with once-daily administration. If necessary, an additional antihypertensive drug may also be given concomitantly. Discontinuation of diuretic therapy 2 to 3 days before introduction of benazepril is advisable in order to minimise the risk of first-dose hypotension. A lower starting dose of 5 mg/day is recommended for patients with severe renal dysfunction [creatinine clearance < 1.8 L/h (30 ml/ min)], or heart failure and those in whom existing diuretic therapy cannot be discontinued. The maximum recommended dose in severe renal dysfunction is 10 mg/day.

A dosage of 2.5 to 20 mg/day has been suggested as adjunctive therapy in patients with congestive heart failure.