Fosinopril

Fosinopril is the pro-drug (ester) of the long acting active ACE inhibitor fosinoprilat. After oral administration fosinopril is quickly and fully metabolised to the active fosinoprilat. Fosinopril contains a phosphinic group capable of a specific binding to the active site of the angiotensin converting enzyme, preventing the conversion of angiotensin I in angiotensin II. The reduction in angiotensin II leads to a vasoconstriction reduction and a decrease in aldosterone secretion, which might induce a slight increase in serum potassium and a loss of sodium and fluid.

ACE inhibition also interferes with bradykinin degradation, a potent vasodepressant, contributing to the antihypertensive effect; fosinopril presents a therapeutic action in hypertensive patients with renin low levels.

In patients with cardiac failure, it is assumed that fosinopril beneficial effects are mainly resultant of a suppression of the renin-angiotensin-aldosterone system; ACE inhibition produces a reduction in pre-load and post-load.

Administration of fosinopril to patients with hypertension results in a reduction of both supine and standing blood pressure without a significant increase in heart rate. In hypertension, fosinopril reduces blood pressure within one hour of administration, the maximum effect being observed within 3-6 hours. With the usual daily dosage, the anti-hypertensive effect lasts for 24 hours. In some patients receiving lower dosages the effect may be reduced at the end of the dosage interval.
The orthostatic effects and tachycardia are rare but might occur in patients with salt depletion or in hypovolemia. In some patients the development of optimal blood pressure reduction may require 3-4 weeks of therapy. Fosinopril and thiazide diuretics have additive effects.

In heart failure, fosinopril improves symptoms and exercise tolerance and reduces the severity of and frequency of hospitalisation due to cardiac failure. In a study of 8 cirrhotic patients, fosinopril 20 mg/day for one month did not change hepatic (alanine transferase, gamma-glutamyl-transpeptidase, galactose clearance test and antipyrine clearance test) or renal functions.

Absorption

After oral administration, the extension of the absorption of fosinopril averages 30% to 40%. The absorption of fosinopril is not affected by the presence of food in gastrointestinal tract, however the speed of the absorption might be reduced. Rapid and complete hydrolysis to active fosinoprilat occurs in the gastrointestinal mucosa and liver. The time to reach the maximum plasma concentration is approximately three hours and is independent of administered dose. After multiple or single doses, the pharmacokinetic parameters (C_max, AUC) are directly proportional to the fosinopril dose that has been taken.

Distribution

Fosinoprilat is protein bound (>95%), but has a negligible binding to blood cellular components.

Biotransformation

One hour after oral administration of fosinopril sodium, less than 1% fosinopril in plasma remains unchanged; 75% is present as active fosinoprilat, 15-20% as fosinoprilat glucuronide (inactive), and the remainder (~5%) as the 4-hydroxy metabolite of fosinoprilat (active).

Elimination

After intravenous administration, the elimination of fosinopril is by both hepatic and renal routes. In hypertensive patients that receive repeated doses of fosinopril and have normal renal and hepatic functions, the fosinoprilat elimination half-life is 11.5 hours, being of 14 hours in patients with cardiac failure.

Other special populations

Patients with renal impairment

In patients with renal failure (creatinine clearance <80 ml/min/1,73 m²), the total fosinoprilat body clearance is approximately half of that observed in patients with normal renal function, while no significant changes are seen in the absorption, the bioavailability and the plasma protein binding. The fosinoprilat clearance does not vary according with the degree of renal failure; the reduction in renal elimination is compensated by the increase in hepato-biliary elimination. A slight increase in AUC values (less than the double of normal values) has been observed in patients with several degrees of renal failure, including terminal renal failure (creatinine clearance <10 ml/min/1.73 m²).

Patients with hepatic impairment

In patients with hepatic failure (alcoholism or biliary cirrhosis), the fosinopril hydrolysis is not significantly reduced, although the rate of the hydrolysis might be reduced; the total fosinoprilat clearance is almost half of the clearance observed in patients with normal hepatic function.

Paediatric population

Limited pharmacokinetic data in children and adolescents were provided by a single-dose pharmacokinetic study in 19 hypertensive patients 6 to 16 years of age who received 0.3mg/kg of a solution of fosinopril.

Whether AUC and C_max values of fosinoprilat (active form of fosinopril) in children from 6 to 16 years of age were comparable to those seen in adults receiving 20mg of fosinopril as a solution, has to be demonstrated.

The terminal elimination half-life for fosinoprilat was 11-13 hours and similar at all stages studied.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. Reproductive toxicity studies suggest that fosinopril has no negative effects on fertility and reproductive performance in rats, and is not teratogenic. ACE inhibitors, as a class, when given in the second or third trimester, have been shown to induce adverse effects on the late foetal development, resulting in foetal death and congenital effects, in particular affecting the skull. Foetotoxicity, intrauterine growth retardation and patent ductus arteriosus have also been reported. These developmental anomalies are thought to be partly due to a direct action of ACE inhibitors on the foetal reninangiotensin system and partly due to ischaemia resulting from maternal hypotension and decreases in foetal-placental blood flow and oxygen/nutrient delivery to the foetus. In a study in which female rats were dosed with fosinopril prior to mating through gestation, an increased incidence of rat pup deaths occurred during lactation. The substance has been shown to cross the placenta and is secreted in milk.