Moexipril Hydrochloride

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 0.25 mEq/L were seen when moexipril was used alone).

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 smaller in black patients, a predominantly low-renin population, than in nonblack hypertensive patients. Although moexipril monotherapy is less effective in blacks than in nonblacks, the efficacy of combination therapy appears to be independent of race.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic and antihypertensive. Thiazides affect the distal 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 is unknown.

Moexipril-Hydrochlorothiazide

 Following oral administration of uniretic®, the moexipril peak plasma concentration was reached within 0.8 hour and the peak plasma concentration of moexiprilat occurred 1.6 hours after administration. After reaching the peak plasma level (Cmax), moexiprilat plasma concentrations decreased biphasically. After administration of uniretic®, renal excretion of unchanged hydrochlorothiazide is about 60% in 24 hours. The pharmacokinetics of moexipril and hydrochlorothiazide after administration of uniretic® are not different, respectively, from the pharmacokinetics of moexipril and hydrochlorothiazide from immediate-release monotherapy formulations.

Moexipril Hydrochloride

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 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 1 ½ 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 proportional.

Hydrochlorothiazide

Moexipril - Hydrochlorothiazide

In uniretic® clinical trials using moexipril doses of 3.75-30 mg and hydrochlorothiazide doses of 3.125-50 mg, the antihypertensive effects were sustained for at least 24 hours and they increased with increasing dose of either component. The extent of blood pressure reduction seen with uniretic® was approximately additive as compared to monotherapy of each component. The antihypertensive effects of uniretic® continue during therapy for up to 24 months. The effectiveness of uniretic® was not significantly influenced by patient age or gender. Although moexipril monotherapy is less effective in blacks than in nonblacks, the efficacy of uniretic® appears to be independent of race.

By blocking the renin-angiotensin-aldosterone axis, administration of moexipril tends to reduce the potassium loss associated with hydrochlorothiazide. In uniretic® controlled clinical trials, the average change in serum potassium was near zero in subjects who received 3.75 mg / 6.25 mg or 7.5 mg / 12.5 mg, but subjects who received 15 mg / 12.5 mg or 15 mg / 25 mg experienced a mild decrease in serum potassium, similar to that experienced by subjects who received the same dose of hydrochlorothiazide monotherapy.

Moexipril Hydrochloride

Single and multiple doses of 15 mg or more of moexipril give sustained inhibition of plasma ACE activity of 80-90%, beginning within 2 hours and lasting 24 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 24-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, moexipril lowered sitting blood pressure at trough by 4-11/3-6 mmHg more than placebo, a tendency toward increased response with higher doses. These effects are typical of ACE inhibitors; there are no trials of adequate size comparing moexipril with other antihypertensive agents.

Higher doses of moexipril generally 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 moexipril is generally evident within 2 weeks of treatment, with maximal reduction after 4 weeks. The antihypertensive effects of moexipril have been proven to continue during therapy for up to 24 months.

Moexipril, like other ACE inhibitors, is less effective in decreasing trough blood pressures in blacks than in nonblacks. Placebo-corrected trough group diastolic blood pressure effects in blacks in the proposed dose range were +1 to -3 mmHg compared with responses in nonblacks of -4 to -6 mmHg.

The effectiveness of moexipril was not significantly influenced by patient age, gender, or weight. Moexipril has been shown to have antihypertensive activity in both pre- and postmenopausal women who have participated in placebo-controlled clinical trials.