Fosinopril

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Abstract
Fosinopril is the prodrug of the active diacid ACE inhibitor fosinoprilat. In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. The drug has compensatory dual elimination routes via renal and hepatic systems and accumulates to a lesser extent than enalapril and lisinopril in patients with chronic renal insufficiency with or without heart failure. Comparative studies of 3 or 6 months’ duration with fosinopril 10 to 40 mg/day have demonstrated clinical efficacy significantly superior to that of placebo in patients with heart failure [mostly New York Heart Association (NYHA) functional class II or III]. Fosinopril treatment consistently increased exercise duration and improved heart failure symptoms in these patients. Significantly fewer fosinopril than placebo recipients withdrew or were hospitalised because of worsening heart failure. Additionally, significantly more fosinopril than placebo recipients showed improvement, and fewer patients had deteriorated, in terms of NYHA functional class. Fosinopril and enalapril showed similar clinical efficacy over 6 and 12 months’ treatment in patients with NYH A functional class II to IV heart failure. As yet, there are no data showing a mortality benefit with fosinopril. Fosinopril was well tolerated in clinical trials in patients with heart failure. Dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events. In 6- or 12- month comparative studies, fosinopril therapy was associated with a lower incidence of dizziness and hypotension, but a higher incidence of vertigo, than enalapril therapy. 0.8% of patients discontinued the drug because of cough, which occurred to a similar extent with fosinopril and enalapril. Thus, based on available clinical evidence, fosinopril is an effective and well tolerated option for the management of patients with heart failure. Although clinical data are limited, fosinopril may be especially useful in patients with renal or hepatic impairment. Fosinopril is the prodrug of the phosphoryl-containing ACE inhibitor fosinoprilat. In patients with heart failure, single doses of fosinopril produced maximum inhibition of serum ACE (98 to 99%) 4 hours after administration, with substantial inhibition (84 to 86%) still present after 24 hours. Inhibition of ACE reduces the production of angiotensin II, a potent vasoconstrictor. Other pharmacological effects of fosinoprilat include increased bradykinin production, reduced plasma endothelin levels and reduced sympathetic release of noradrenaline (norepinephrine). In patients with heart failure, fosinopril reduces pulmonary capillary wedge pressure, mean arterial blood pressure, mean right atrial pressure and heart rate, and increases stroke volume index and cardiac index. Fosinopril has been associated with reductions in left ventricular mass and cardiac wall thickness in hypertensive patients. In patients with chronic renal insufficiency, fosinopril did not appear to reduce renal blood flow, glomerular filtration rate or effective renal plasma flow. Fosinopril reduced urinary protein excretion in patients in several studies. Most of the 32 to 36% of fosinopril absorbed after oral administration is rapidly de-esterified in the liver and gastrointestinal mucosa to the active diacid, fosinoprilat. Food appears not to affect absorption. The pharmacokinetic properties of fosinoprilat in patients with heart failure resemble those in healthy volunteers, and the pharmacokinetics are largely unaltered in elderly patients. Fosinoprilat undergoes both renal and hepatic elimination, with a plasma elimination half-life of approximately 12 hours in healthy volunteers. In healthy volunteers, approximately equal amounts of fosinoprilat are recovered from urine and faeces. Renal clearance accounted for approximately 40% of total clearance in patients with heart failure. Total body clearance of fosinopril is reduced in patients with renal impairment, but because of a compensatory increase in hepatic elimination, the extent of the reduction does not correlate with the degree of renal impairment. Accumulation of fosinoprilat is lower than that of enalaprilat and lisinopril in patients with chronic renal insufficiency with or without concurrent heart failure. Because of its dual and compensatory routes of elimination, the pharmacokinetic profile of fosinopril in patients with hepatic impairment appears to be similar to that in healthy volunteers (although the rate, but not the extent, of fosinopril de-esterification may be reduced in the former group). In 3 double-blind placebo-controlled studies of 3 or 6 months’ duration in patients with mild to moderately severe heart failure, fosinopril 10 to 40 mg/day consistently increased exercise duration and improved symptoms (e.g. dyspnoea, fatigue, paroxysmal nocturnal dyspnoea) relative to placebo. Analysis of adverse outcomes showed that fosinopril-treated patients had significantly fewer withdrawals or hospitalisations because of worsening heart failure. Significantly more fosinopril than placebo recipients showed improvement, and fewer patients had worsened, in terms of New York Heart Association (NYHA) functional class. The clinical efficacy of fosinopril has been compared with that of enalapril (both titrated to 20 mg/day as tolerated) in patients with NYHA functional class II to IV heart failure in 2 comparative studies of 6 or 12 months’ duration. There were no significant differences between the 2 drugs at end-point in change in exercise duration, adverse outcomes (e.g. withdrawal or hospitalisation because of worsening heart failure), change in NYHA functional class or heart failure symptoms. Compared with enalapril recipients, fosinopril recipients showed a trend towards greater improvement in exercise duration in the 6-month study. There was also a trend towards a longer time to first adverse event, a lower rate of adverse outcomes and earlier improvement in NYHA functional class in the 12-month study, although the difference in the latter parameter was not sustained. However, both drugs provided similar effects overall. Fosinopril is well tolerated in patients with heart failure. In placebo-controlled trials of 3 to 6 months duration, dizziness (11.9 vs 5.4% for placebo), cough (9.7 vs 5.1%) and hypotension (4.4 vs 0.8%) were the most commonly reported adverse events with fosinopril. The incidence of drug withdrawal because of adverse events was 8 and 7.5% for fosinopril and placebo recipients, respectively, in these studies. ACE inhibitor-induced cough caused the discontinuation of fosinopril in 0.8% of patients. First-dose hypotension occurred in 2.4% of fosinopril recipients and 0.8% of placebo recipients. No patients in these studies withdrew because of abnormal laboratory test values. Data from 2 comparative studies suggest that fosinopril may cause a lower incidence of hypotension or dizziness and a higher incidence of vertigo than enalapril; the incidence of cough was similar. There were few significant differences between fosinopril and enalapril with respect to incidence of, or withdrawals due to, laboratory test abnormalities. The initial recommended dosage of fosinopril in patients with heart failure is 10mg once daily, which should be increased according to response to a maximum of 40mg daily. The usual effective dosage is 20 to 40 mg/day in patients also receiving diuretics with or without digitalis. Dosage adjustment is not required in patients with hepatic or renal dysfunction. Concurrent administration of fosinopril and lithium may increase serum lithium concentrations. Antacids may reduce the absorption of fosinopril.