Mechanism of Action

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.

Pharmacokinetics and Metabolism

Nisoldipine pharmacokinetics are independent of the dose across the clinical dosage range of 17 mg to 51 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. A pronounced food-effect is observed when nisoldipine extended-release is administered with a high-fat meal resulting in an increased peak concentration (Cmax) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, nisoldipine extended-release should be taken on an empty stomach (one hour before or 2 hours after a meal).

Maximal plasma concentrations of nisoldipine are reached 9.2 ± 5.1 hours after dosing. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 13.7 ± 4.3 hours. After oral administration, the concentration of (+)- nisoldipine, the active enantiomer, is about 6 times higher than the inactive (-)- nisoldipine 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; five 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 Cmax 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.

Special Populations

Pharmacodynamics

Clinical Studies in Hypertension

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 doses bioequivalent to 8.5 mg to 34 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 doses bioequivalent to 17 mg and 34 mg once daily were 12/6 and 19/8 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 bioequivalent to 17 mg to 25.5 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 lowest clinical 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.

Increased Angina and/or Myocardial Infarction in Patients with Coronary Artery Disease

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.