Mechanism of Action
Moexipril hydrochloride is a prodrug for moexiprilat, which
inhibits ACE in humans and animals. The mechanism through which moexiprilat
lowers blood pressure is believed to be primarily inhibition of ACE activity.
ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive
decapeptide angiotensin I to the vasoconstrictor substance angiotensin II.
Angiotensin II is a potent peripheral vasoconstrictor that also stimulates
aldosterone secretion by the adrenal cortex and provides negative feedback on
renin secretion. ACE is identical to kininase II, an enzyme that degrades
bradykinin, an endothelium-dependent vasodilator. Moexiprilat is about 1000
times as potent as moexipril in inhibiting ACE and kininase II. Inhibition of
ACE results in decreased angiotensin II formation, leading to decreased
vasoconstriction, increased plasma renin activity, and decreased aldosterone
secretion. The latter results in diuresis and natriuresis and a small increase
in serum potassium concentration (mean increases of about 0.2 5 mEq/L were seen
when moexipril was used alone, see PRECAUTIONS).
Whether increased levels of bradykinin, a potent
vasodepressor peptide, play a role in the therapeutic effects of moexipril
remains to be elucidated. Although the principal mechanism of moexipril in
blood pressure reduction is believed to be through the
renin-angiotensin-aldosterone system, ACE inhibitors have some effect on blood
pressure even in apparent low-renin hypertension. As is the case with other ACE
inhibitors, however, the antihypertensive effect of moexipril is considerably
smaller in black patients, a predominantly low-renin population, than in
non-black hypertensive patients.
Pharmacokinetics and Metabolism
Moexipril's antihypertensive activity is almost entirely due
to its deesterified metabolite, moexiprilat. Bioavailability of oral moexipril
is about 13% compared to intravenous (I.V.) moexipril (both measuring the
metabolite moexiprilat), and is markedly affected by food, which reduces the
peak plasma level (Cmax) and AUC (see Absorption). Moexipril should therefore
be taken in a fasting state. The time of peak plasma concentration (Tmax) of
moexiprilat is about 1½ hours and elimination half-life (t½) is estimated at 2 to
9 hours in various studies, the variability reflecting a complex elimination
pattern that is not simply exponential. Like all ACE inhibitors, moexiprilat
has a prolonged terminal elimination phase, presumably reflecting slow release
of drug bound to the ACE. Accumulation of moexiprilat with repeated dosing is
minimal, about 30%, compatible with a functional elimination t½ of about 12 hours.
Over the dose range of 7.5 to 30 mg, pharmacokinetics are approximately dose
Moexipril is incompletely absorbed, with bioavailability as
moexiprilat of about 13%. Bioavailability varies with formulation and food
intake which reduces Cmax and AUC by about 70% and 40% respectively after the
ingestion of a low-fat breakfast or by 80% and 50% respectively after the
ingestion of a high-fat breakfast.
The clearance (CL) for moexipril is 441 mL/min and for
moexiprilat 2 32 mL/min with a t½ of 1.3 and 9.8 hours, respectively.
Moexiprilat is about 50% protein bound. The volume of distribution of
moexiprilat is about 183 liters.
Metabolism and Excretion
Moexipril is relatively rapidly converted to its active
metabolite moexiprilat, but persists longer than some other ACE inhibitor
prodrugs, such that its t½ is over one hour and it has a significant AUC. Both
moexipril and moexiprilat are converted to diketopiperazine derivatives and
unidentified metabolites. After I.V. administration of moexipril, about 40% of
the dose appears in urine as moexiprilat, about 2 6% as moexipril, with small
amounts of the metabolites; about 2 0% of the I.V. dose appears in feces,
principally as moexiprilat. After oral administration, only about 7% of the
dose appears in urine as moexiprilat, about 1% as moexipril, with about 5% as
other metabolites. Fifty-two percent of the dose is recovered in feces as
moexiprilat and 1% as moexipril.
Decreased Renal Function: The effective elimination t½
and AUC of both moexipril and moexiprilat are increased with decreasing renal
function. There is insufficient information available to characterize this
relationship fully, but at creatinine clearances in the range of 10 to 40
mL/min, the t½ of moexiprilat is increased by a factor of 3 to 4.
Decreased Hepatic Function: In patients with mild to
moderate cirrhosis given single 15 mg doses of moexipril, the Cmax of moexipril
was increased by about 50% and the AUC increased by about 12 0%, while the Cmax
for moexiprilat was decreased by about 50% and the AUC increased by almost
Elderly Patients: In elderly male subjects (65-80
years old) with clinically normal renal and hepatic function, the AUC and Cmax of
moexiprilat is about 30% greater than those of younger subjects (19-42 years
Pharmacokinetic Interactions With Other Drugs
No clinically important pharmacokinetic interactions
occurred when univasc® was administered concomitantly with
hydrochlorothiazide, digoxin, or cimetidine.
Pharmacodynamics and Clinical Effect
Single and multiple doses of 15 mg or more of univasc® gives
sustained inhibition of plasma ACE activity of 80-90%, beginning within 2 hours
and lasting 2 4 hours (80%).
In controlled trials, the peak effects of orally
administered moexipril increased with the dose administered over a dose range
of 7.5 to 60 mg, given once a day. Antihypertensive effects were first
detectable about 1 hour after dosing, with a peak effect between 3 and 6 hours
after dosing. Just before dosing (i.e., at trough), the antihypertensive
effects were less prominently related to dose and the antihypertensive effect
tended to diminish during the 2 4-hour dosing interval when the drug was
administered once a day.
In multiple dose studies in the dose range of 7.5 to 30 mg
once daily, univasc® lowered sitting diastolic and systolic blood
pressure effects at trough by 3 to 6 mmHg and 4 to 11 mmHg more than placebo,
respectively. There was a tendency toward increased response with higher doses
over this range. These effects are typical of ACE inhibitors but, to date,
there are no trials of adequate size comparing moexipril with other
The trough diastolic blood pressure effects of moexipril
were approximately 3 to 6 mmHg in various studies. Generally, higher doses of
moexipril leave a greater fraction of the peak blood pressure effect still
present at trough. During dose titration, any decision as to the adequacy of a
dosing regimen should be based on trough blood pressure measurements. If
diastolic blood pressure control is not adequate at the end of the dosing
interval, the dose can be increased or given as a divided (BID) regimen.
During chronic therapy, the antihypertensive effect of any
dose of univasc® is generally evident within 2 weeks of treatment,
with maximal reduction after 4 weeks. The antihypertensive effects of univasc®
have been proven to continue during therapy for up to 2 4 months.
univasc®, like other ACE inhibitors, is less effective
in decreasing trough blood pressures in blacks than in non-blacks.
Placebo-corrected trough group mean diastolic blood pressure effects in blacks
in the proposed dose range varied between +1 to -3 mmHg compared with responses
in non-blacks of -4 to -6 mmHg.
The effectiveness of univasc® was not
significantly influenced by patient age, gender, or weight. univasc® has
been shown to have antihypertensive activity in both pre- and postmenopausal
women who have participated in placebo-controlled clinical trials.
Formal interaction studies with moexipril have not been
carried out with antihypertensive agents other than thiazide diuretics. In
these studies, the added effect of moexipril was similar to its effect as
monotherapy. In general, ACE inhibitors have less than additive effects with
betaadrenergic blockers, presumably because both work by inhibiting the renin-angiotensin