Fosinopril

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Abstract
Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day, amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy. with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment. Fosinopril, a phosphinic acid derivative, is the prodrug of the active diacid ACE inhibitor fosinoprilat. In normotensive volunteers and hypertensive patients, single oral doses of fosinopril ≥40mg, after rapid hydrolysis of the drug to fosinoprilat, inhibited plasma ACE activity for 24 hours and increased plasma renin activity. Plasma aldosterone levels were reduced or remained unchanged. Decreases in resting mean arterial blood pressure (10 to 14%), systolic blood pressure (10 to 14%), diastolic blood pressure (6 to 17%) and systemic vascular resistance (14 to 27%) were seen in hypertensive patients receiving fosinopril 10 to 40 mg/day. Peak antihypertensive effects occurred 5 to 7 hours after the dose, and significant antihypertensive effects were evident after 24 hours. The mean trough to peak blood pressure response ratios in responding patients (decrease in supine diastolic blood pressure from baseline 24 hours after fosinopril administration of ≥5mm Hg) were ≥50%. Fosinopril caused regression of left ventricular hypertrophy and improvements in diastolic function in hypertensive patients, without altering heart rate. Cerebral blood flow was maintained despite substantial reductions in blood pressure in hypertensive patients. Fosinopril significantly reduced renal vascular resistance but had no significant effects on filtration fraction, glomerular filtration rate or renal plasma flow in hypertensive patients. Serum total cholesterol, low density lipoprotein cholesterol and plasma lipoprotein(a) protein levels were decreased in conjunction with a partial reduction in proteinuria in patients with renal disease. 32 to 36% of an oral dose of fosinopril is absorbed and rapidly hydrolysed to fosinoprilat in healthy volunteers. Further metabolism to p-hydroxy-fosinoprilat and the acyl β-glucuronide of fosinoprilat also occurs. Food appears not to affect absorption. With fosinopril doses of 10mg maximum plasma concentrations of fosinoprilat of 99 to 144 μg/L are reached in 2.4 to 4.2 hours in healthy volunteers. These values are not significantly altered in patients with renal or hepatic impairment. The elimination half-life associated with the terminal slope of the concentration-time curve is about 12 hours in healthy volunteers and 14 to 32 hours in patients with renal impairment. Total body clearance is not significantly changed in patients with renal impairment from values of 1.6 to 2.4 L/h in healthy volunteers. Fosinopril differs from other ACE inhibitors in its compensatory dual clearance system. Both renal and biliary routes of elimination are involved, and in the presence of renal impairment the capacity for hepatic elimination appears to be increased, while in patients with hepatic impairment renal elimination is increased. The pharmacokinetics of fosinopril appear to be largely unaltered in elderly patients. Noncomparative trials of fosinopril 10 to 20 mg/day for 4 to 12 weeks have demonstrated normalisation of diastolic blood pressure (to ≤90mm Hg) in 62 to 89% of hypertensive patients. A dose-response relationship is apparent over the dose range 5 to 80 mg/day. In comparative trials, monotherapy with fosinopril 5 to 40 mg/day had a similar antihypertensive effect to that of hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day, amlodipine 5 to 10 mg/day, sustained release nifedipine 40 mg/day, and sustained release verapamil 240 to 480 mg/day. Slightly superior efficacy over isradipine 5 mg/day was noted. The combination of fosinopril 20 mg/day and hydrochlorothiazide 12.5 mg/day tended to produce greater blood pressure lowering than fosinopril 20 mg/day alone and resulted in statistically significantly superior efficacy over hydrochlorothiazide 12.5 mg/day alone. Similar efficacy between the combination fosinopril/hydrochlorothiazide 10 to 20/12.5 mg/day and sustained release nifedipine 40 mg/day alone hsa been reported. Patients receiving fosinopril 20 to 40 mg/day in combination with chlorthalidone 25 mg/day achieved similar reductions in blood pressure to those receiving propranolol 80 to 160 mg/day plus chlorthalidone 25 mg/day. Fosinopril appears to be equally effective in elderly and younger patients. Pharmacoeconomic data specifically relating to fosinopril are few, but there is evidence to suggest that the cost of effective fosinopril therapy is similar to that of most other ACE inhibitors. Fosinopril is well tolerated. The incidence of adverse events in patients receiving the drug in placebo-controlled trials was similar to that in patients receiving placebo. The most common adverse events reported include headache, cough, dizziness, fatigue and diarrhoea. Preliminary evidence suggests that the incidence of cough may be lower in fosinopril recipients than in patients receiving enalapril or other ACE inhibitors. The initial dosage of fosinopril as monotherapy or in combination with thiazide diuretics in patients with hypertension is 10mg once daily. This can be adjusted according to response to 20 to 40 mg/day in most patients, but 80 mg/day may be required in some. Alteration of the dosage may not be required in patients with renal or hepatic impairment.

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