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 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 SULAR 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 - 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 P 450 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 P 450 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.

Special Populations

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