Mechanism Of Action
Benazepril and benazeprilat inhibit
angiotensin-converting enzyme (ACE) in human subjects and in animals. 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. Hypertensive patients treated with benazepril alone for up to 52
weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients
treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent
changes in their serum potassium (see PRECAUTIONS).
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 Lotensin HCT remains to be
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.
Hydrochlorothiazide is a thiazide diuretic. Thiazides
affect the renal tubular mechanisms of electrolyte reabsorption, directly
increasing excretion of sodium and chloride in approximately equivalent
amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma
volume, with consequent increases in plasma renin activity, increases in
aldosterone secretion, increases in urinary potassium loss, and decreases in
serum potassium. The renin-aldosterone link is mediated by angiotensin, so
coadministration of an ACE inhibitor tends to reverse the potassium loss
associated with these diuretics.
The mechanism of the antihypertensive effect of thiazides
Pharmacokinetics And Metabolism
Following oral administration of Lotensin HCT, peak
plasma concentrations of benazepril are reached within 0.5-1.0 hours. As
determined by urinary recovery, the extent of absorption is at least 37%. In
fasting subjects, the rate and extent of absorption of benazepril and
hydrochlorothiazide from Lotensin HCT are not different, respectively, from the
rate and extent of absorption of benazepril and hydrochlorothiazide from
immediate-release monotherapy formulations.
The estimated absolute bioavailability of
hydrochlorothiazide after oral administration is about 70%. Peak plasma
hydrochlorothiazide concentrations (Cmax) are reached within 2 to 5 hours after
oral administration. Hydrochlorothiazide binds to albumin (40 to 70%) and
distributes into erythrocytes.
The absorption of benazepril from Lotensin® tablets
is not influenced by the presence of food in the gastrointestinal tract. There
is no clinically significant effect of food on the bioavailability of
Cleavage of the ester group (primarily in the liver)
converts benazepril to its active metabolite, benazeprilat. Peak plasma
concentrations of benazeprilat are reached 1-2 hours after drug intake in the
fasting state and 2-4 hours after drug intake in the nonfasting state. 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 – over the concentration range of 0.24-23.6 μmol/L –
In studies of rats given 14C-benazepril,
benazepril and its metabolites crossed the blood-brain barrier only to an
extremely low extent. Multiple doses of benazepril did not result in
accumulation in any tissue except the lung, where, as with other ACE inhibitors
in similar studies, there was a slight increase in concentration due to slow
elimination in that organ.
Benazepril is almost completely metabolized to
benazeprilat, which has much greater ACE inhibitory activity than benazepril,
and to the glucuronide conjugates of benazepril and benazeprilat. Only trace
amounts of an administered dose of benazepril can be recovered unchanged in the
urine; about 20% of the dose is excreted as benazeprilat, 4% as benazepril
glucuronide, and 8% as benazeprilat glucuronide.
In patients with hepatic dysfunction due to cirrhosis,
levels of benazeprilat are essentially unaltered. Similarly, the
pharmacokinetics of benazepril and benazeprilat do not appear to be influenced
The kinetics of benazepril are dose-proportional within
the dosage range of 5-20 mg. Small deviations from dose proportionality were
observed when the broader range of 2-80 mg was studied, possibly due to the
saturable binding of the compound to ACE.
The effective half-life of accumulation of benazeprilat
following multiple dosing of benazepril is 10-11 hours. Thus, steady-state
concentrations of benazeprilat should be reached after 2 or 3 doses of
benazepril given once daily.
During chronic administration (28 days) of once-daily
doses of benazepril between 5 mg and 20 mg, the kinetics did not change, and
there was no significant accumulation. Accumulation ratios based on AUC and
urinary recovery of benazeprilat were 1.19 and 1.27, respectively.
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.
Benazepril and benazeprilat are cleared predominantly by
renal excretion in healthy subjects with normal renal function. Nonrenal (i.e.,
biliary) excretion accounts for approximately 11%-12% of benazeprilat excretion
in healthy subjects. In patients with renal failure, biliary clearance may
compensate to an extent for deficient renal clearance.
The disposition of 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 (see DOSAGE AND ADMINISTRATION).
Following oral administration, plasma hydrochlorothiazide
concentrations decline biexponentially, with a mean distribution half-life of
about 2 hours and an elimination half-life of about 10 hours. About 70% of an
orally administered dose of hydrochlorothiazide is eliminated in the urine as
unchanged drug. In a study in individuals with impaired renal function, the
mean elimination half-life of hydrochlorothiazide was increased to 2 fold in
individuals with mild/moderate renal impairment (30 < CLcr < 90 mL/min)
and 3 fold and severe renal impairment ( ≤ 30 mL/min), when compared to
individuals with normal renal function (CLcr > 90 mL/min).
Single and multiple doses of 10 mg or more of benazepril
cause inhibition of plasma ACE activity by at least 80%-90% for at least 24
hours after dosing. For up to 4 hours after a 10-mg dose, pressor responses to
exogenous angiotensin I were inhibited by 60%-90%.
In normal human volunteers, single doses of benazepril
caused an increase in renal blood flow but had no effect on glomerular
After oral administration of hydrochlorothiazide,
diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12
Lotensin HCT potentiates the antihypertensive action of
other antihypertensive drugs (e.g., curare derivatives, guanethidine,
methyldopa, beta-blockers, vasodilators, calcium channel blockers ACE
inhibitors and ARBs and DRIs).
In single-dose studies, benazepril lowered blood pressure
within 1 hour, with peak reductions achieved 2-4 hours after dosing. The
antihypertensive effect of a single dose persisted for 24 hours. In
multiple-dose studies, once-daily doses of 20-80 mg decreased seated pressure
(systolic/diastolic) 24 hours after dosing by about 6-12/4-7 mmHg. The
reductions at trough are about 50% of those seen at peak.
Four dose-response studies of benazepril monotherapy
using once-daily dosing were conducted in 470 mild-to-moderate hypertensive
patients not using diuretics. The minimal effective once-daily dose of
benazepril was 10 mg; further falls in blood pressure, especially at morning
trough, were seen with higher doses in the studied dosing range (10-80 mg). In
studies comparing the same daily dose of benazepril given as a single morning
dose or as a twice-daily dose, blood pressure reductions at the time of morning
trough blood levels were greater with the divided regimen.
The antihypertensive effects of benazepril were not
appreciably different in patients receiving high-or low-sodium diets.
In 15 controlled clinical trials, 1453 healthy or
hypertensive patients were exposed to benazepril and hydrochlorothiazide of
which 459 were exposed for at least 6 months, 214 for at least 12 months and 25
for at least 24 months.
The combination of benazepril-hydrochlorothiazide
resulted in mean placebo-adjusted decreases in sitting systolic and diastolic
blood pressures of 10/6 mm Hg with 5-6.25 mg and 10-12.5 mg doses, and 20/10 mm
Hg with 20-25 mg dose.
In clinical trials of benazepril/hydrochlorothiazide using
benazepril doses of 5-20 mg and hydrochlorothiazide doses of 6.25-25 mg, the
antihypertensive effects were sustained for at least 24 hours, and they
increased with increasing dose of either component. Although benazepril
monotherapy is somewhat less effective in blacks than in nonblacks, the
efficacy of combination therapy appears to be independent of race.