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Manidipine

A Review of its Use in Hypertension

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Summary

Abstract

Manidipine is a dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. The resulting reduction in blood pressure (BP) in patients with hypertension is maintained over 24 hours.

Manidipine 10 to 40mg once daily for 4 weeks significantly lowered office BP from baseline and compared with placebo, and significantly reduced 24-hour BP compared with placebo in patients with essential hypertension in a well controlled trial. The decline in BP was maintained over 24 hours (trough to peak BP ratios were >50%) without disturbing the circadian BP pattern. BP reductions with therapeutic dosages of manidipine were maintained for up to 1 year in noncomparative trials.

The BP-lowering capacity of manidipine 5 to 20 mg/day appears to be similar to that of other calcium antagonists with which it has been compared in randomised double-blind and nonblind trial.

In a well controlled short term trial, manidipine 10mg daily significantly decreased trough sitting BP compared with placebo in elderly patients with mild to moderate essential hypertension. Decreases in BP were maintained for up to 3 years of treatment.

The drug (10 or 20 mg/day) also significantly lowered sitting BP from baseline in patients with hypertension and type 2 diabetes mellitus in randomised, long term comparative trials. In general, the observed reduction in BP with manidipine was similar to that observed with amlodipine, enalapril or delapril. The effects of manidipine on urinary albumin excretion (UAE) have not been clearly demonstrated in clinical trials in this patient group. BP was also reduced with manidipine in patients with impaired glucose tolerance.

Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Commonly reported events included ankle oedema, headache, palpitation, flushing, dizziness, rash and fatigue. Manidipine appears to have less potential for pedal oedema than amlodipine.

Conclusions: Manidipine has shown antihypertensive efficacy and appears to be well tolerated in adult and elderly patients with mild or moderate essential hypertension. The BP-lowering effects of the drug in patients with hypertension and type 2 diabetes mellitus or impaired glucose tolerance were not associated with any adverse metabolic effects. The effects of manidipine on UAE in this patient group remain unclear. Manidipine provides an additional treatment option for patients for whom dihydropyridine calcium antagonists are appropriate.

Pharmacodynamic Properties

Manidipine is a second generation dihydropyridine calcium antagonist, which inhibits the voltage-dependent calcium inward currents in smooth muscle cells. The subsequent peripheral vasodilation leads to a reduction in blood pressure (BP) in patients with hypertension, which is maintained over a 24-hour period.

The drug is vasoselective and has shown less in vitro negative inotropic activity than nisoldipine, nicardipine, nifedipine, verapamil and diltiazem. Heart rate (HR) did not significantly increase with manidipine 10 to 30mg once daily; however, increases in HR were observed with manidipine 40mg daily. Manidipine 10 or 20mg daily significantly reduced measures of left ventricular mass in patients with essential hypertension and hypertension in diabetes.

Results from experimental animal studies and trials in patients with essential hypertension indicate that manidipine produces vasodilation of the efferent as well as the afferent arterioles, and causes natriuresis and diuresis. Administration of manidipine was also associated with retardation of end-stage renal pathology in rats and a reduction in urinary albumin excretion (UAE) from baseline in patients with essential hypertension and normotensive patients with type 2 diabetes mellitus. However, consistent reductions in UAE have not been demonstrated in patients with type 2 diabetes mellitus and hypertension after manidipine.

The drug has been shown to decrease the incidence of or completely inhibit stroke in stroke-prone rat models. Clinical trials in patients with essential hypertension or patients with hypertension and type 2 diabetes mellitus indicate that manidipine (10 to 40 mg/day) has neutral effects on lipid profiles and glucose metabolism (including atherogenic index in one trial). Therapeutic dosages of the drug significantly improved insulin sensitivity in patients with hypertension in diabetes.

Pharmacokinetic Profile

The mean maximum plasma concentration (Cmax; 7.2 μg/L) of manidipine was reached 1.5 hours after oral administration of a single 20mg dose in 12 fasting healthy volunteers; the area under the plasma concentration-time curve extrapolated to infinity (AUC∞) was 20.8 μg/L Dh. The presence of food increases manidipine absorption (AUC∞ 29.1 μg/L Dh). Manidipine appears to undergo a high degree of plasma protein binding (99%).

After oral administration, manidipine undergoes extensive first-pass hepatic metabolism, with 63% of an oral dose eliminated in the faeces and 31% in the urine as metabolites. In healthy volunteers, the terminal elimination half-lives for a single oral dose of manidipine 5,10 and 20mg varied from 3.9 to 7.95 hours.

The pharmacokinetic profile of manidipine in patients with mild hepatic impairment appears to be similar to that observed in healthy volunteers, whereas elimination is significantly delayed in patients with more severe hepatic impairment. Therapeutic dosages of manidipine appear to have low potential for drug-drug interactions.

Therapeutic Efficacy

Manidipine 10 to 20 mg/day for 4 to 48 weeks reduced office SBP by 15 to 32mm Hg and DBP by 7 to 16mm Hg in randomised trials of adult patients with mild to moderate hypertension. Manidipine (10, 20 or 40mg once daily) significantly lowered office BP compared with baseline and placebo, and significantly lowered 24-hour BP compared with placebo after 4 weeks in adult patients with mild to moderate hypertension in a double-blind, randomised placebo-controlled trial. The decline in BP was maintained over 24 hours [trough to peak ratios ranged between 0.62 and 0.79 for systolic BP (SBP) and 0.54 to 0.67 for diastolic BP (DBP)] without disturbing the circadian BP pattern.

Manidipine 10 to 20mg once daily appears to have a similar BP-lowering capacity to that of other calcium antagonists with which it has been compared (once daily amlodipine 2.5 to 10mg, felodipine 5 or 10mg, lacidipine 4 or 6mg or nicardipine 10 or 20mg, or twice daily controlled release nifedipine (20 or 40mg). In contrast, in a randomised trial of 40 patients with mild to moderate essential hypertension, manidipine 10 to 40mg daily significantly reduced DBP compared with delapril 15 to 60mg daily at months 5, 6, 9 and 12.

Several long term, noncomparative studies in patients with mild to/or moderate hypertension suggest that BP reductions with recommended dosages of manidipine (10 or 20mg daily) are maintained for up to 1 year with no development of tolerance.

Special Patient Populations

Long term randomised, comparative trials indicate that manidipine 10 or 20mg once daily significantly lowers sitting BP from baseline in patients with hypertension and concomitant type 2 diabetes mellitus by 16 to 21mm Hg (SBP) and by 9 to 16mm Hg (DBP). The observed reduction in BP with manidipine was similar to that observed with other standard antihypertensive therapies (amlodipine, enalapril and delapril) in randomised multicentre trials.

Trough sitting SBP and DBP significantly decreased (by 16/7mm Hg) with manidipine 10mg once daily for 8 weeks compared with placebo in a study of 54 elderly patients (aged 76 to 89 years) with mild to moderate essential hypertension in a double-blind, randomised, placebo-controlled trial. In addition, BP normalised (DBP ≤ 90mm Hg) in more manidipine (63%) than placebo (4%) recipients. Decreases in BP from baseline were maintained for up to 3 years of treatment in a long term, nonrandomised, nonblind comparative trial in elderly patients.

BP was significantly reduced from baseline after 4 weeks’ treatment with manidipine 10 or 20mg once daily in a 12-week noncomparative trial in 16 patients with renal impairment of various causes; these reductions were maintained until study completion. Similar long term efficacy was demonstrated with manidipine 5 to 20mg once daily in a 48-week study in 32 patients with renal impairment. BP reductions from baseline with manidipine 10 or 20 mg/day were similar to those with nifedipine gastrointestinal therapeutic system (GITS) 30 or 60 mg/day in 83 patients with chronic renal failure.

Tolerability

Manidipine was well tolerated in clinical trials, with most adverse effects related to vasodilation. Ankle oedema (6%), headache (3.8%), palpitation (2.7%), flushing (2.2%), dizziness (1.6%), rash (0.5%) and fatigue (0.5%) were the most commonly reported adverse events in a noncomparative trial involving 183 patients ith mild to moderate hypertension treated with manidipine 10 or 20mg daily for up to 12 months.

Adverse events with manidipine treatment (10 or 20 mg/day) appeared to occur with a similar incidence overall to those with placebo, amlodipine (5 or 10 mg/day), felodipine (5 or 10 mg/day), lacidipine (4 or 6 mg/day), controlled release nifedipine (20 to 40mg twice daily) or enalapril (10 or 20 mg/day) in randomised or nonrandomised clinical trials in patients with essential hypertension(including some patients with type 2 diabetes mellitus). However, manidipine appears to have less potential for oedema than amlodipine.

Dosage and Administration

Manidipine is indicated for the treatment of essential hypertension at a recommended initial dosage of 10mg once daily. In patients with an initial unsatisfactory response after 1 or 2 weeks, the dosage should be increased to 20mg oncedaily.

Manidipine is contraindicated in paediatric patients and women who are pregnant or breast feeding. In addition, dosage reductions are recommended for patients with hepatic impairment and patients over the age of 65 years, but not for patients with renal function impairment.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Susan M. Cheer & Karen McClellan

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  1. Susan M. Cheer
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  2. Karen McClellan
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Correspondence to Susan M. Cheer.

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Cheer, S.M., McClellan, K. Manidipine. Drugs 61, 1777–1799 (2001). https://doi.org/10.2165/00003495-200161120-00010

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