Mechanism of Action
In animals and humans, fosinopril sodium is hydrolyzed by esterases to the pharmacologically active form, fosinoprilat, a specific competitive inhibitor of angiotensin converting enzyme (ACE).
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.
In 647 hypertensive patients treated with fosinopril alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with fosinopril, including those receiving concomitant diuretic therapy. 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 fosinopril sodium tablets remains to be elucidated.
While the mechanism through which fosinopril sodium tablets lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril sodium tablets have an antihypertensive effect even in patients with low-renin hypertension. Although fosinopril sodium tablets were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.
In patients with heart failure, the beneficial effects of fosinopril sodium tablets are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin converting enzyme produces decreases in both preload and afterload.
Pharmacokinetics and Metabolism
Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/jejunum). 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.
Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs) and peak concentrations (Cmaxs) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.
After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20 to 30% as a glucuronide conjugate of fosinoprilat, and 1 to 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.
After intravenous administration, fosinoprilat was 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 healthy subjects, the terminal elimination half-life (t1/2) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1/2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1/2 was 14 hours.
In patients with mild-to-severe renal insufficiency (creatinine clearance 10 to 80 mL/ min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with end-stage renal disease (creatinine clearance < 10 mL/min/1.73m2), the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function. (See DOSAGE AND ADMINISTRATION.)
Fosinopril is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one-half of that in patients with normal hepatic function.
In elderly (male) subjects (65 to 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 to 35 years old).
In pediatric patients - Information related to the pharmacokinetics in pediatric patients is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug products. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product, produced by Ranbaxy is not labeled for pediatric use.
Fosinoprilat was found to cross the placenta of pregnant animals.
Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Serum ACE activity was inhibited by ≥ 90% at 2 to 12 hours after single doses of 10 to 40 mg of fosinopril. At 24 hours, serum ACE activity remained suppressed by 85%, 93%, and 93% in the 10, 20, and 40 mg dose groups, respectively.
Administration of fosinopril sodium tablets 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). Use of fosinopril sodium tablets in combination with thiazide diuretics gives a blood pressure-lowering effect greater than that seen with either agent alone.
Following oral administration of single doses of 10 to 40 mg, fosinopril sodium tablets lowered blood pressure within one hour, with peak reductions achieved 2 to 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 to 80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8 to 9/6 to 7 mmHg more than placebo. The trough effect was about 50 to 60% of the peak diastolic response and about 80% of the peak systolic response.
In most trials, the antihypertensive effect of fosinopril sodium tablets increased during the first several weeks of repeated measurements. The antihypertensive effect of fosinopril sodium tablets has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of fosinopril sodium tablets has not resulted in a rapid increase in blood pressure.
Limited experience in controlled and uncontrolled trials combining fosinopril with a calcium channel blocker or a loop diuretic has indicated no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
ACE inhibitors are generally less effective in blacks than in non-blacks. The effectiveness of fosinopril sodium tablets was not influenced by age, sex, or weight.
In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that fosinopril sodium tablets do not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate.
Information related to clinical trials of fosinopril in the treatment of hypertension in pediatric patients is available in the approved labeling for Bristol-Myers Squibb Company’s fosinopril sodium drug products. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product, produced by Ranbaxy, is not labeled for pediatric use.
In a randomized, double-blind, placebo-controlled trial, 179 patients with heart failure, all receiving diuretics and some receiving digoxin, were administered single doses of 1, 20, or 40 mg of fosinopril sodium tablets or placebo. Doses of 20 and 40 mg of fosinopril sodium tablets resulted in acute decreases in pulmonary capillary wedge pressure (preload) and mean arterial blood pressure and systemic vascular resistance (afterload). One hundred fifty-five of these patients were re-randomized to once-daily therapy with fosinopril sodium tablets (1, 20, or 40 mg) for an additional 10 weeks. Hemodynamic measurements made 24 hours after dosing showed (relative to baseline) continued reduction in pulmonary capillary wedge pressure, mean arterial blood pressure, right atrial pressure and an increase in cardiac index and stroke volume for the 20 and 40 mg dose groups. No tachyphylaxis was seen.
Fosinopril sodium tablets was studied in 3 double-blind, placebo-controlled, 12 to 24 week trials including a total of 734 patients with heart failure, with fosinopril sodium tablets doses from 10 to 40 mg daily. Concomitant therapy in 2 of these 3 trials included diuretics and digitalis; in the third trial patients were receiving only diuretics. All 3 trials showed statistically significant benefits of fosinopril sodium tablet therapy, compared to placebo, in one or more of the following: exercise tolerance (one study), symptoms of dyspnea, orthopnea and paroxysmal nocturnal dyspnea (2 studies), NYHA classification (2 studies), hospitalization for heart failure (2 studies), study withdrawals for worsening heart failure (2 studies), and/or need for supplemental diuretics (2 studies). Favorable effects were maintained for up to two years. Effects of fosinopril sodium tablets on long-term mortality in heart failure have not been evaluated. The once daily dosage for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic responses.