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 and amlodipine for up
to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see WARNINGS
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 Lotrel 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.
Amlodipine is a dihydropyridine calcium antagonist
(calcium ion antagonist or slow channel blocker) that inhibits the transmembrane
influx of calcium ions into vascular smooth muscle and cardiac muscle.
Experimental data suggest that amlodipine binds to both dihydropyridine and
nondihydropyridine binding sites. The contractile processes of cardiac muscle
and vascular smooth muscle are dependent upon the movement of extracellular
calcium ions into these cells through specific ion channels. Amlodipine
inhibits calcium ion influx across cell membranes selectively, with a greater effect
on vascular smooth muscle cells than on cardiac muscle cells. Negative
inotropic effects can be detected in vitro but such effects have not been seen
in intact animals at therapeutic doses. Serum calcium concentration is not
affected by amlodipine. Within the physiologic pH range, amlodipine is an
ionized compound (pKa=8.6), and its kinetic interaction with the calcium
channel receptor is characterized by a gradual rate of association and
dissociation with the receptor binding site, resulting in a gradual onset of
Amlodipine is a peripheral arterial vasodilator that acts
directly on vascular smooth muscle to cause a reduction in peripheral vascular
resistance and reduction in blood pressure.
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. For up to 4 hours after a 10 mg dose, pressor responses to
exogenous angiotensin I were inhibited by 60% to 90%.
Administration of benazepril to patients with
mild-to-moderate hypertension results in a reduction of both supine and standing
blood pressure to about the same extent, with no compensatory tachycardia.
Symptomatic postural hypotension is infrequent, although it can occur in
patients who are salt and/or volume depleted [see WARNINGS AND PRECAUTIONS].
The antihypertensive effects of benazepril were not
appreciably different in patients receiving high- or low-sodium diets.
In normal human volunteers, single doses of benazepril
caused an increase in renal blood flow but had no effect on glomerular
Following administration of therapeutic doses to patients
with hypertension, amlodipine produces vasodilation resulting in a reduction of
supine and standing blood pressures. These decreases in blood pressure are not
accompanied by a significant change in heart rate or plasma catecholamine
levels with chronic dosing.
With chronic once-daily administration, antihypertensive
effectiveness is maintained for at least 24 hours. Plasma concentrations
correlate with effect in both young and elderly patients. The magnitude of
reduction in blood pressure with amlodipine is also correlated with the height
of pretreatment elevation; thus, individuals with moderate hypertension (diastolic
pressure 105–114 mmHg) had about 50% greater response than patients with mild
hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects
experienced no clinically significant change in blood pressure (+1/-2 mmHg).
In hypertensive patients with normal renal function,
therapeutic doses of amlodipine resulted in a decrease in renal vascular
resistance and an increase in glomerular filtration rate and effective renal
plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic
measurements of cardiac function at rest and during exercise (or pacing) in
patients with normal ventricular function treated with amlodipine have generally
demonstrated a small increase in cardiac index without significant influence on
dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic
studies, amlodipine has not been associated with a negative inotropic effect
when administered in the therapeutic dose range to intact animals and humans,
even when coadministered with beta blockers to humans.
Amlodipine does not change sinoatrial (SA) nodal function
or atrioventricular (AV) conduction in intact animals or humans. In clinical
studies in which amlodipine was administered in combination with beta blockers
to patients with either hypertension or angina, no adverse effects on
electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects
in patients with chronic stable angina, vasospastic angina and angiographically
documented coronary artery disease.
The rate and extent of absorption of benazepril and
amlodipine from Lotrel are the same as when administered as individual tablets.
Absorption from the individual tablets is not influenced by the presence of
food in the gastrointestinal tract; food effects on absorption from Lotrel have
not been studied.
Following oral administration of Lotrel, peak plasma
concentrations of amlodipine are reached in 6 to 12 hours. Absolute
bioavailability has been calculated as between 64% and 90%. Following oral
administration of Lotrel, the peak plasma concentrations of benazepril are
reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver)
converts benazepril to its active metabolite, benazeprilat, which reaches peak
plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril
is at least 37%. Amlodipine and benazepril exhibit dose proportional pharmacokinetics
between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg,
The apparent volume of distribution of amlodipine is
about 21 L/kg. In vitro studies indicate that approximately 93% of circulating
amlodipine is bound to plasma proteins in hypertensive patients. The apparent
volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of
circulating amlodipine is bound to plasma proteins, and the bound fraction of
benazeprilat is slightly higher. On the basis of in vitro studies,
benazeprilat's degree of protein binding should be unaffected by age, by
hepatic dysfunction, or—over the therapeutic concentration range—by concentration.
Amlodipine is extensively (approximately 90%) metabolized
in the liver to inactive metabolites. Benazepril is extensively metabolized to
form benazeprilat as the main metabolite, which occurs by enzymatic hydrolysis,
mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates
of benazepril and benazeprilat.
Amlodipine elimination from plasma is biphasic with a
terminal elimination half-life of approximately 30 to 50 hours. Steady-state
plasma levels are reached after once-daily dosing for 7 to 8 days. Ten percent
of unchanged drug and 60% of amlodipine metabolites are excreted in urine.
Effective elimination half-life of amlodipine is 2 days. Benazepril is
eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the
kidneys and the bile; renal excretion is the main route in patients with normal
renal function. In the urine, benazepril accounts for less than 1 % and benazeprilat
for about 20% of an oral dose. Elimination of benazeprilat is biphasic with an
initial half-life of about 3 hours and a terminal half-life of about 22 hours.
Benazeprilat's effective elimination half-life is 10 to 11 hours, while that of
amlodipine is about 2 days, so steady-state levels of the 2 components are
achieved after about a week of once-daily dosing.
No specific clinical studies were performed to understand
the impact of age on the pharmacokinetics of amlodipine and benazepril as fixed
dose combination. As individual component amlodipine is extensively metabolized
in the liver. In the elderly, clearance of amlodipine is decreased with
resulting increases in peak plasma levels, elimination half-life and
area-under-the-plasma-concentration curve [see Use In Specific Populations].
Patients with hepatic insufficiency have decreased
clearance of amlodipine with a resulting increase in AUC of approximately 40 to
60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment
[see Use In Specific Populations].
The disposition of benazepril and benazeprilat in
patients with mild-to-moderate renal insufficiency (CrCl greater than 30
mL/min) is similar to that in patients with normal renal function. In patients
with CrCl less than or equal to 30 mL/min, peak benazeprilat levels and the
effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics
of amlodipine is not significantly influenced by renal impairment [see
DOSAGE AND ADMINISTRATION, Use In Specific Populations and WARNINGS
In vitro data in human plasma indicate that amlodipine
has no effect on the protein binding of digoxin, phenytoin, warfarin, and
Coadministration of amlodipine with cimetidine did not
alter the pharmacokinetics of amlodipine.
Coadministration of 240 mL of grapefruit juice with a
single oral dose of amlodipine 10 mg in 20 healthy volunteers had no
significant effect on the pharmacokinetics of amlodipine.
Coadministration of the antacid Maalox with a single dose
of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
A single 100 mg dose of sildenafil in subjects with
essential hypertension had no effect on the pharmacokinetic parameters of
amlodipine. When amlodipine and sildenafil were used in combination, each agent
independently exerted its own blood pressure lowering effect.
Coadministration of multiple 10 mg doses of amlodipine
with 80 mg of atorvastatin resulted in no significant change in the
steady-state pharmacokinetic parameters of atorvastatin.
Coadministration of amlodipine with digoxin did not
change serum digoxin levels or digoxin renal clearance in normal volunteers.
Single and multiple 10 mg doses of amlodipine had no
significant effect on the pharmacokinetics of ethanol.
Coadministration of amlodipine with warfarin did not
change the warfarin prothrombin response time.
Coadministration of multiple doses of 10 mg of amlodipine
with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin
compared to simvastatin alone.
Coadministration of a 180 mg daily dose of diltiazem with
5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in
amlodipine systemic exposure. Erythromycin coadministration in healthy
volunteers did not significantly change amlodipine systemic exposure. However,
strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase
the plasma concentrations of amlodipine to a greater extent.
The pharmacokinetic properties of benazepril are not
affected by 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.
When rats received benazepril:amlodipine at doses ranging
from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing
dose-related incidence at all doses tested. On a body surface area basis, the
2.5 mg/kg/day dose of amlodipine is 3.6 times the amlodipine dose delivered
when the maximum recommended dose of Lotrel is given to a 50 kg woman. Similarly,
the 5 mg/kg/day dose of benazepril is approximately twice the benazepril dose
delivered when the maximum recommended dose of Lotrel is given to a 50 kg
woman. No teratogenic effects were seen when benazepril and amlodipine were
administered in combination to pregnant rats or rabbits. Rats received doses of
up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the MRHD on a body
surface area basis, assuming a 50 kg woman). Rabbits received doses of up to
1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of Lotrel given
to a 50 kg woman).
No teratogenic effects of benazepril were seen in studies
of pregnant rats, mice, and rabbits. On a body surface area basis, the maximum
doses used in these studies were 60 times (in rats), 9 times (in mice), and
about equivalent to (in rabbits) the MRHD (assuming a 50 kg woman).
No evidence of teratogenicity or other embryo/fetal
toxicity was found when pregnant rats and rabbits were treated orally with
amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively,
about 10 and 20 times the MRHD of 10 mg amlodipine on a body surface area
basis) during their respective periods of major organogenesis. (Calculations
based on a patient weight of 60 kg.) However, litter size was significantly
decreased (by about 50%) and the number of intrauterine deaths was
significantly increased (about 5-fold) for rats receiving amlodipine maleate at
a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and
throughout mating and gestation. Amlodipine maleate has been shown to prolong
both the gestation period and the duration of labor in rats at this dose. There
are no adequate and well-controlled studies in pregnant women. Amlodipine
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Over 950 patients received Lotrel once-daily in 6
double-blind, placebo-controlled studies. The antihypertensive effect of a
single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours
Once-daily doses of benazepril/amlodipine using
benazepril doses of 10 to 20 mg and amlodipine doses of 2.5 to 10 mg decreased
seated pressure (systolic/diastolic) 24 hours after dosing by about 10–25/6–13
In 2 studies in patients not adequately controlled on
either benazepril 40 mg alone (n=329) or amlodipine 10 mg alone (n=812)
once-daily doses of Lotrel 10/40 mg further decreased seated blood pressure
compared to the respective monotherapy alone.
Combination therapy was effective in blacks and
nonblacks. Both components contributed to the antihypertensive efficacy in
nonblacks, but virtually all of the antihypertensive effect in blacks could be
attributed to the amlodipine component. Among nonblack patients in
placebo-controlled trials comparing Lotrel to the individual components, the
blood pressure lowering effects of the combination were shown to be additive
and in some cases synergistic.
During chronic therapy with Lotrel, the maximum reduction
in blood pressure with any given dose is generally achieved after 1 to 2 weeks.
The antihypertensive effects of Lotrel have continued during therapy for at
least 1 year. Abrupt withdrawal of Lotrel has not been associated with a rapid
increase in blood pressure.