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NORPACE®Clinical Pharmacology (disopyramide phosphate capsules)

CLINICAL PHARMACOLOGY

Mechanisms of Action

Norpace (disopyramide phosphate) is a Type 1 antiarrhythmic drug (i.e., similar to procainamide and quinidine). In animal studies Norpace decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.

Electrophysiology

In man, Norpace at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.

Hemodynamics

At recommended oral doses, Norpace rarely produces significant alterations of blood pressure in patients without congestive heart failure (see Warnings). With intravenous Norpace, either increases in systolic/diastolic or decreases in systolic blood pressure have been reported, depending on the infusion rate and the patient population. Intravenous Norpace may cause cardiac depression with an approximate mean 10% reduction of cardiac output, which is more pronounced in patients with cardiac dysfunction.

Anticholinergic Activity

The in vitro anticholinergic activity of Norpace is approximately 0.06% that of atropine; however, the usual dose for Norpace is 150 mg every 6 hours and for Norpace CR 300 mg every 12 hours, compared to 0.4 to 0.6 mg for atropine (see Warnings and Adverse Reactions for anticholinergic side effects).

Pharmacokinetics

Following oral administration of immediate-release Norpace, disopyramide phosphate is rapidly and almost completely absorbed, and peak plasma levels are usually attained within 2 hours. The usual therapeutic plasma levels of disopyramide base are 2 to 4 mcg/ml, and at these concentrations protein binding varies from 50% to 65%. Because of concentration-dependent protein binding, it is difficult to predict the concentration of the free drug when total drug is measured.

The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours). In six patients with impaired renal function (creatinine clearance less than 40 ml/min), disopyramide half-life values were 8 to 18 hours.

After the oral administration of 200 mg of disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration of 2.3 ± 1.5 hours (mean ± SD) was increased, and the mean peak serum concentration of 4.8 ± 1.6 mcg/ml was higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7 ± 4.2 hours (range in healthy volunteers of 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8 ± 1.9 hours (range of 5 to 9.5 hours).

In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite, and 10% as the other metabolites. The plasma concentration of the major metabolite is approximately one tenth that of disopyramide. Altering the urinary pH in man does not affect the plasma half-life of disopyramide.

In a crossover study in healthy subjects, the bio-availability of disopyramide from Norpace CR capsules was similar to that from the immediate-release capsules. With a single 300-mg oral dose, peak disopyramide plasma concentrations of 3.23 ± 0.75 mcg/ml (mean ± SD) at 2.5 ± 2.3 hours were obtained with two 150-mg immediate-release capsules and 2.22 ± 0.47 mcg/ml at 4.9 ± 1.4 hours with two 150-mg Norpace CR capsules. The elimination half-life of disopyramide was 8.31 ± 1.83 hours with the immediate-release capsules and 11.65 ± 4.72 hours with Norpace CR capsules. The amount of disopyramide and mono-N-dealkylated metabolite excreted in the urine in 48 hours was 128 and 48 mg, respectively, with the immediate-release capsules, and 112 and 33 mg, respectively, with Norpace CR capsules. The differences in the urinary excretion of either constituent were not statistically significant.

Following multiple doses, steady-state plasma levels of between 2 and 4 mcg/ml were attained following either 150 mg every-6-hour dosing with immediate-release capsules or 300 mg every-12-hour dosing with Norpace CR capsules.

Drug Interactions

Effects of other drugs on disopyramide pharmacokinetics

In vitro metabolic studies indicated that disopyramide is metabolized by cytochrome P450 3A4 and that inhibitors of this enzyme may result in elevation of plasma levels of disopyramide. Although specific drug interaction studies have not been done, cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin.

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