Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. Benazeprilat has much greater ACE inhibitory activity than does benazepril.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium.

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60% to 90% (up to 4 hours post-dose) at the 10 mg dose.

Drug Interactions

Benazepril has been used concomitantly with beta-adrenergic-blocking agents, calcium- channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.

The pharmacokinetics of benazepril are approximately dose-proportional within the dosage range of 10 to 80 mg.

Following oral administration of benazepril, peak plasma concentrations of benazepril, and its active metabolite benazeprilat are reached within 0.5 to1.0 hour and 1 to 2 hours, respectively. While the bioavailability of benazepril is not affected by food, time to peak plasma concentrations of benazeprilat is delayed to 2 to 4 hours.

The serum protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).

Benazepril is almost completely metabolized to benazeprilat by cleavage of the ester group (primarily in liver). Both benazepril and benazeprilat undergo glucuronidation.

Benazepril and benazeprilat are cleared predominantly by renal excretion. About 37% of an orally administered dose was recovered in urine as benazeprilat (20%), benazeprilat glucuronide (8%), benazepril glucuronide (4%) and as trace amounts of benazepril. Nonrenal (i.e., biliary) excretion accounts for approximately 11% to 12% of benazeprilat excretion. The effective half-life of benazeprilat following once daily repeat oral administration of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily.

Accumulation ratio based on AUC of benazeprilat was 1.19 following once daily administration.

Specific Populations

Renal impairment

The pharmacokinetics of systemic exposure to benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance ≤30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady-state may be delayed.

When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not detected in the dialysate.

Hepatic impairment

In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered.

Drug Interactions

The pharmacokinetics of benazepril are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).

Pediatrics

The pharmacokinetics of benazaprilat, evaluated in pediatric patients with hypertension following oral administration of a single dose is presented in table below.