Nisoldipine

Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. In vitro studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle. Although, like other dihydropyridine calcium channel blockers, nisoldipine has negative inotropic effects, in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those that affect cardiac contractility.

The effect of nisoldipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance. While nisoldipine, like other dihydropyridines, exhibits a mild diuretic effect, most of the antihypertensive activity is attributed to its effect on peripheral vascular resistance.

Nisoldipine pharmacokinetics are independent of the dose in the range of 20 to 60 mg, with plasma concentrations proportional to dose. Nisoldipine accumulation, during multiple dosing, is predictable from a single dose.

Nisoldipine is relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. Nisoldipine's low bioavailability is due, in part, to pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. Food with a high fat content has a pronounced effect on the release of nisoldipine from the coat-core formulation and results in a significant increase in peak concentration (C_max ) by up to 300%. Total exposure, however, is decreased about 25%, presumably because more of the drug is released proximally. This effect appears to be specific for nisoldipine in the controlled release formulation, as a less pronounced food effect was seen with the immediate release tablet. Concomitant intake of a high fat meal with nisoldipine extended-release should be avoided.

Maximal plasma concentrations of nisoldipine are reached 6 to 12 hours after dosing. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 7 to 12 hours. C_max and AUC increase by factors of approximately 1.3 and 1.5, respectively, from first dose to steady-state. After oral administration, the concentration of (+) nisoldipine, the active enantiomer, is about 6 times higher than the (-) inactive enantiomer. The plasma protein binding of nisoldipine is very high, with less than 1% unbound over the plasma concentration range of 100 ng/mL to 10 mcg/mL.

Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. Although 60 to 80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite, and has about 10% of the activity of the parent compound. Cytochrome P₄₅₀ enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P₄₅₀ IIIA4. Nisoldipine should not be administered with grapefruit juice as this has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in C_max of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several other dihydropyridine calcium channel blockers.

The antihypertensive efficacy of nisoldipine extended-release was studied in five double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with nisoldipine extended-release as monotherapy and about 300 with placebo; 4 of the 5 studies compared 2 or 3 fixed doses while the fifth allowed titration from 10 to 40 mg. Once daily administration of nisoldipine extended-release produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:

In patients receiving atenolol, supine blood pressure reductions with nisoldipine extended-release at 20, 40 and 60 mg once daily were 12/6, 19/8 and 22/10 mm Hg, respectively. The sustained antihypertensive effect of nisoldipine extended-release was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received initial doses of 20 mg to 30 mg nisoldipine extended-release without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of nisoldipine extended-release.

Patient race and gender did not influence the blood pressure lowering effect of nisoldipine extended-release. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the 10 mg dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of nisoldipine extended-release in patients treated for up to one year.

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of nisoldipine extended-release in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.

Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine extended-release tablets should not be administered with a high fat meal. Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with nisoldipine extended-release.

Nisoldipine extended-release is not known to interfere with the interpretation of laboratory tests.

A 30 to 45% increase in AUC and C_max of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 to 20 %). No pharmacodynamic effects of either histamine H₂ receptor antagonist were observed.

Coadministration of phenytoin with 40 mg nisoldipine extended-release tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of nisoldipine extended-release with phenytoin or any known CYP3A4 inducer should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of nisoldipine extended-release tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. The immediate release, but not the coat-core formulation of nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin or digoxin.

Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose {MRHD} on a mg/m² basis, respectively) and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m² basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m² basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.

When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m² basis) nisoldipine had no effect on fertility.

It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue nisoldipine extended-release, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

Clinical studies of nisoldipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.