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Mechanism of Action
Fosinopril and fosinoprilat 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 fosinopril alone for an average of 8 weeks had elevations of serum potassium of approximately 0.1 mEq/L. Similar patients treated with hydrochlorothiazide alone had a mean reduction in serum potassium of 0.15 mEq/L, while patients who received combined treatment with 10/12.5 mg or 20/12.5 mg of fosinopril and hydrochlorothiazide had reductions of 0.07 and 0.03 mEq/L, respectively. (See PRECAUTIONS.)
Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
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 MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide tablets) remains to be elucidated.
While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril 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 is unknown.
Pharmacokinetics and Metabolism
The absolute absorption of fosinopril averages 36% of an oral dose. The primary site of absorption is the proximal small intestine. While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.
Following oral administration of hydrochlorothiazide, peak plasma concentrations are achieved in 1–2.5 hours, and the extent of absorption is 50–80%. The reported studies of food effects on hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide is increased by agents that reduce gastrointestinal motility. It is reported to be decreased by 50% in patients with congestive heart failure.
Cleavage of the ester group (primarily in the liver) converts fosinopril to its active metabolite, fosinoprilat. The time to peak plasma concentrations of fosinoprilat is about 3 hours, independent of the administered dose of fosinopril. In patients with hepatic dysfunction due to cirrhosis, conversion of fosinopril to fosinoprilat may be slowed, but the extent of this conversion is unchanged.
Fosinoprilat is highly protein bound (95%), but has negligible binding to cellular components of blood. The peak serum concentration and the area under the concentration-time curve of fosinoprilat is directly proportional to the administered dose of fosinopril.
After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20–30% as a glucuronide conjugate of fosinoprilat, and 1–5% as a p-hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p-hydroxy metabolites. In rats, the p-hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.
Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier, but fosinoprilat does cross the placenta of pregnant animals. In humans, hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to those in the maternal circulation.
Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6–7.8 L/kg, and its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6–1.8 times those measured in plasma.
After intravenous administration, fosinoprilat is eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 and 39 mL/min.
In hypertensive patients with normal renal and hepatic function, the effective half-life of accumulation of fosinoprilat following multiple dosing of fosinopril sodium is 11.5 hours. Thus, steady-state concentrations of fosinoprilat should be reached after 2 or 3 doses of MONOPRIL-HCT given once daily.
In patients with renal insufficiency (creatinine clearance < 80 mL/min/1.73 m²), the total body clearance of fosinoprilat is approximately one half of that in patients with normal renal function, while absorption, bioavailability, and protein binding are not appreciably altered. The clearance of fosinoprilat does not differ appreciably with the degree of renal insufficiency, because the diminished renal elimination is offset by increased hepatobiliary elimination. A modest increase in plasma AUC levels (less than two times that in normals) was observed in patients with various degrees of renal insufficiency, including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m²). (See DOSAGE AND ADMINISTRATION.)
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the apparent total body clearance of fosinoprilat is approximately one half of that in patients with normal hepatic function.
In elderly (male) subjects (65–74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20–35 years old).
Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5–15 hours. In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.
When fosinopril and hydrochlorothiazide are administered concomitantly, the pharmacokinetics of hydrochlorothiazide are essentially unaffected. Serum levels of fosinoprilat are increased after several weeks of coadministration of hydrochlorothiazide and fosinopril, but the increase is not sufficient to warrant any change in dosing.
After single doses of 10–40 mg of fosinopril, serum ACE activity was inhibited by at least 90% from 2–12 hours after dosing. At 24 hours, serum ACE activity remains suppressed by 85–93%.
Administration of fosinopril 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. In studies in hypertensive patients after three months of fosinopril monotherapy, hemodynamic responses to various stimuli (isometric exercise, 45° head-up tilt, mental challenges) were unchanged compared to baseline, suggesting that fosinopril did not affect the activity of the sympathetic nervous system. Instead, fosinopril-induced reduction in blood pressure appears to be mediated by a reduction in peripheral vascular resistance without reflex cardiac effects. In similar studies, renal, splanchnic, cerebral, and skeletal-muscle blood flows were all unchanged compared to baseline, as was glomerular filtration rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS).
Following oral administration of single doses of 10–40 mg, fosinopril lowered blood pressure within one hour, with peak reductions achieved 2–6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Following four weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once-daily doses of 20–80 mg lowered supine or seated blood pressures (systolic/diastolic) 24 hours after dosing by an average of 8–9/6–7 mmHg more than placebo. The trough effect was about 50–60% of the peak diastolic response and about 80% of the peak systolic response.
In clinical studies of various combinations that included 0–40 mg of fosinopril and 0–37.5 mg of hydrochlorothiazide, the antihypertensive effects were increased with increasing dose of either component. Peak blood pressure reductions were achieved 2–6 hours after dosing. The mean reductions in seated blood pressure (systolic/diastolic) associated with MONOPRIL-HCT (fosinopril sodium-hydrochlorothiazide tablets) 10/12.5 after 24 hours were 9–18/5–7 mmHg greater than those associated with placebo; those associated with MONOPRIL-HCT 20/12.5 after 24 hours were 12–17/8–10 mmHg greater than those associated with placebo. These trough effects were 60–90% of the corresponding peak effects.
Although hydrochlorothiazide tends to be more effective in low-renin hypertensive patients (mainly blacks), and fosinopril—like other ACE inhibitors—tends to be more effective in high-renin patients (mainly non-blacks), the effectiveness of MONOPRIL-HCT is independent of race, age, and gender.
Last reviewed on RxList: 7/1/2009
This monograph has been modified to include the generic and brand name in many instances.
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