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Imidapril (Tanatril™), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP).
In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.
The active metabolite of imidapril is imidaprilat, which inhibits the conversion of angiotensin I to angiotensin II. Lowering of plasma and tissue angiotensin II levels results in peripheral vasodilation, reduced systemic BP, renoprotective effects in patients with type 1 diabetes, and decreased renal sodium and water retention.
After multidose oral administration in patients with hypertension, steady-state maximum plasma concentrations of imidapril (≈30 ng/mL) and imidaprilat (≈20 ng/mL) are achieved in a median time of 2 and 5 hours. In healthy men 25.5% of a single dose of imidapril 10mg was excreted in the urine within 24 hours. Elimination occurs primarily through excretion in the urine (≈40%) and faeces (≈50%); after oral administration in healthy volunteers, the terminal elimination half-life of imidaprilat is ≈24 hours.
In randomised controlled trials, oral imidapril was effective in the treatment of adults with mild to moderate essential hypertension. In short-term (2- and 4-week) dose-finding trials, imidapril dosages of 10–40 mg/day were significantly more effective than placebo, inducing 11–15mm Hg reductions in sitting diastolic BP (sDBP; primary endpoint). In comparative 12- and 24-week trials, imidapril 5–20 mg/day induced reductions in mean sDBP of 10–15mm Hg that did not differ significantly from those induced by hydrochlorothiazide 12.5–50 mg/day or captopril 50–100 mg/day (primary endpoint), nor those induced by enalapril 5–10 mg/day or nifedipine sustained release (SR) 40–80 mg/day (secondary endpoint). In addition, reductions in sDBP and sitting systolic BP (co-primary endpoints) with imidapril did not differ from those induced by candesartan 4–16 mg/day. Favourable reductions in sDBP were maintained during 6-month and 52-week noncomparative trials.
In patients with type 1 diabetes, the urinary albumin excretion rate (a marker of nephropathy) increased by 72% in placebo recipients, but declined by 41% in imidapril 5 mg/day and by 6% in captopril 37.5 mg/day recipients during a mean treatment period of 1.5 years.
In patients with CHF, mean total exercise time increased from baseline in imidapril 2.5–10 mg/day recipients in a dose-related manner after 12-weeks of treatment; a 9.7% increase with imidapril 10 mg/day was significantly greater than the change with placebo (+0.7%).
Overall, imidapril was relatively well tolerated, with an incidence of adverse events in pooled analyses of data from clinical trials and post-marketing surveillance (n = 6632) of 6.6%. The most commonly reported adverse events were cough, hypotension, dizziness and pharyngeal discomfort. During 2- and 4-week trials, the overall incidence of adverse events was 26% and 40% in recipients of imidapril 2.5–40 mg/day compared with 35% and 37% in placebo recipients. In comparative trials, the incidence of treatment-related adverse events in imidapril versus enalapril recipients in two 12-week trials were 5.6% versus 12.2% and 12.0% versus 14.1%; in other 12-week trials treatment-related adverse events were observed in 24.2% of imidapril versus 41.7% of nifedipine SR, and 20.7% of imidapril versus 46.4% of captopril recipients, while the overall incidence of adverse events in imidapril versus candesartan recipients was 11.7% versus 16.1%. The incidences of adverse events in a 24-week trial were 46.0% with imidapril and 52.8% with hydrochlorothiazide. In longer-term trials, adverse events were reported by 61.6% of imidapril recipients in the 52-week trial; however, only 1.7% of imidapril recipients in a 6-month field trial experienced adverse events considered related to ACE inhibitor treatment.
In prospective investigations in hypertensive patients, switching to imidapril did not reduce the incidence of cough (a class effect of ACE inhibitors) in a small open-label trial in hypertensive patients already experiencing ACE-inhibitor induced cough; however, in a large crossover trial, the incidence of cough with imidapril (15.2%) was less than half that with enalapril (38.6%). In addition, cough disappeared in 52.9% of enalapril recipients switched to imidapril, and in patients without cough during imidapril treatment, switching to enalapril induced cough in 20.9%. In contrast, in patients without cough during initial enalapril treatment, only 0.9% developed cough during subsequent imidapril treatment. In a second large, double-blind crossover trial, the incidence of cough was significantly lower in imidapril than benazepril recipients.
Volume 67, Issue 9 , pp 1359-1378
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- 1. Wolters Kluwer Health / Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore, Auckland, 0754, New Zealand
- 2. Wolters Kluwer Health, Conshohocken, Pennsylvania, USA