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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 (nisoldipine) 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.
Renal Dysfunction: Because renal elimination is not an important pathway, bioavailability and pharmacokinetics of SULAR (nisoldipine) were not significantly different in patients with various degrees of renal impairment. Dosing adjustments in patients with mild to moderate renal impairment are not necessary.
Geriatric: Elderly patients have been found to have 2 to 3 fold higher plasma concentrations (Cmax and AUC) than young subjects. This should be reflected in more cautious dosing (See DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency: In patients with liver cirrhosis given 10 mg SULAR (nisoldipine) , plasma concentrations of the parent compound were 4 to 5 times higher than those in healthy young subjects. Lower starting and maintenance doses should be used in cirrhotic patients (See DOSAGE AND ADMINISTRATION).
Gender and Race: The effect of gender or race on the pharmacokinetics of nisoldipine has not been investigated.
Disease States: Hypertension does not significantly alter the pharmacokinetics of nisoldipine.
Administration of a single dose of nisoldipine leads to decreased systemic vascular resistance and blood pressure with a transient increase in heart rate. The change in heart rate is greater with immediate release nisoldipine preparations. The effect on blood pressure is directly related to the initial degree of elevation above normal. Chronic administration of nisoldipine results in a sustained decrease in vascular resistance and small increases in stroke index and left ventricular ejection fraction. A study of the immediate release formulation showed no effect of nisoldipine on the renin-angiotensin-aldosterone system or on plasma norepinephrine concentration in normals. Changes in blood pressure in hypertensive patients given SULAR (nisoldipine) were dose related over the range of 10 - 60 mg/day. Nisoldipine does not appear to have significant negative inotropic activity in intact animals or humans, and did not lead to worsening of clinical heart failure in three small studies of patients with asymptomatic and symptomatic left ventricular dysfunction. There is little information, however, in patients with severe congestive heart failure, and all calcium channel blockers should be used with caution in any patient with heart failure.
Nisoldipine has no clinically important chronotropic effects. Except for mild shortening of sinus cycle, SA conduc- tion time and AH intervals, single oral doses up to 20 mg of immediate release nisoldipine did not significantly change other conduction parameters. Similar electrophysiologic effects were seen with single iv doses, which could be blunted in patients pre-treated with beta-blockers. Dose and plasma level related flattening or inversion of T-waves have been observed in a few small studies. Such reports were concentrated in patients receiving rapidly increased high doses in one study; the phenomenon has not been a cause of safety concern in large clinical trials.
Clinical Studies in Hypertension
The antihypertensive efficacy of SULAR (nisoldipine) was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with SULAR (nisoldipine) as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from 10 - 40 mg. Once daily administration of SULAR (nisoldipine) 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:
MEAN SUPINE TROUGH SYSTOLIC AND DIASTOLIC BLOOD PRESSURE CHANGES (mm Hg)
| SULAR Dose
In patients receiving atenolol, supine blood pressure reductions with SULAR (nisoldipine) at 20, 40 and 60 mg once daily were 12/6, 19/8 and 22/10 mm Hg, respectively. The sustained antihypertensive effect of SULAR (nisoldipine) 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 - 30 mg SULAR (nisoldipine) without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of SULAR (nisoldipine) . Patient race and gender did not influence the blood pressure lowering effect of SULAR. 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 SULAR (nisoldipine) in patients treated for up to one year.
Last reviewed on RxList: 2/7/2008
This monograph has been modified to include the generic and brand name in many instances.
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