Isradipine pharmacokinetics and molecular data

Pharmacokinetics and molecular data
Description Mechanism of Action Clinical Effects Hemodynamics Electrophysiologic Effects Pharmacokinetics and Metabolism

Description
Isradipine is a calcium antagonist available for oral administration in capsules containing 2.5 mg or 5 mg.

The structural formula of Isradipine is:



Chemically, Isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-,methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water (<10 mg/L at 37°C), but is soluble in ethanol and freely soluble in acetone, chloroform and methylene chloride.

Active Ingredient: Isradipine

Inactive Ingredients: colloidal silicon dioxide, corn starch, gelatin, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, red iron oxide (5 mg), sodium lauryl sulfate and titanium dioxide.

Black ink contains the following ingredients: Black Iron Oxide, D&C Yellow # 10 Aluminum Lake, FD&C Blue # 1 Aluminum Lake, FD&C Blue # 2 Aluminum Lake, FD&C Red # 40 Aluminum Lake, n-Butyl Alcohol, Propylene Glycol, and Shellac Glaze in SD-45 Alcohol.

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Mechanism of Action
Isradipine is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. The effects observed in mechanistic experiments in vitro and studied in intact animals and man are compatible with this mechanism of action and are typical of the class.

Except for diuretic activity, the mechanism of which is not clearly understood, the pharmacodynamic effects of Isradipine observed in whole animals can also be explained by calcium channel blocking activity, especially dilating effects in arterioles which reduce systemic resistance and lower blood pressure, with a small increase in resting heart rate. Although like other dihydropyridine calcium channel blockers, Isradipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those which affect contractility. In patients with normal ventricular function, Isradipine’s afterload reducing properties lead to some increase in cardiac output.

Effects in patients with impaired ventricular function have not been fully studied.

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Clinical Effects
Dose-related reductions in supine and standing blood pressure are achieved within 2-3 hours following single oral doses of 2.5 mg, 5 mg, 10 mg, and 20 mg Isradipine, with a duration of action (at least 50% of peak response) of more than 12 hours following administration of the highest dose.

Isradipine has been shown in controlled, double-blind clinical trials to be an effective antihypertensive agent when used as monotherapy, or when added to therapy with thiazide-type diuretics. During chronic administration, divided doses (b.i.d.) in the range of 5-20 mg daily have been shown to be effective, with response at trough (prior to next dose) over 50% of the peak blood pressure effect. The response is dose-related between 5-10 mg daily. Isradipine is equally effective in reducing supine, sitting, and standing blood pressure.

On chronic administration, increases in resting pulse rate averaged about 3-5 beats/min. These increases were not dose-related.

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Hemodynamics
In man, peripheral vasodilation produced by Isradipine is reflected by decreased systemic vascular resistance and increased cardiac output. Hemodynamic studies conducted in patients with normal left ventricular function produced, following intravenous Isradipine administration, increases in cardiac index, stroke volume index, coronary sinus blood flow, heart rate, and peak positive left ventricular dP/dt. Systemic, coronary, and pulmonary vascular resistance was decreased. These studies were conducted with doses of Isradipine which produced clinically significant decreases in blood pressure. The clinical consequences of these hemodynamic effects, if any, have not been evaluated.

Effects on heart rate are variable, dependent upon rate of administration and presence of underlying cardiac condition. While increases in both peak positive dP/dt and LV ejection fraction are seen when intravenous Isradipine is given, it is impossible to conclude that these represent a positive inotropic effect due to simultaneous changes in preload and afterload. In patients with coronary artery disease undergoing atrial pacing during cardiac catheterization, intravenous Isradipine diminished abnormalities of systolic performance. In patients with moderate left ventricular dysfunction, oral and intravenous Isradipine in doses which reduce blood pressure by 12%-30%, resulted in improvement in cardiac index without increase in heart rate, and with no change or reduction in pulmonary capillary wedge pressure. Combination of Isradipine and propranolol did not significantly affect left ventricular dP/dt max. The clinical consequences of these effects have not been evaluated.

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Electrophysiologic Effects
In general, no detrimental effects on the cardiac conduction system were seen with the use of Isradipine. Electrophysiologic studies were conducted on patients with normal sinus and atrioventricular node function. Intravenous Isradipine in doses which reduce systolic blood pressure did not affect PR, QRS, AH* or HV* intervals.

No changes were seen in Wenckebach cycle length, atrial, and ventricular refractory periods. Slight prolongation of QTc interval of 3% was seen in one study. Effects on sinus node recovery time (CSNRT) were mild or not seen.

In patients with sick sinus syndrome, at doses which significantly reduced blood pressure, intravenous Isradipine resulted in no depressant effect on sinus and atrioventricular node function.


 * AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time;


 * HV = conduction time through His bundle and the bundle branch-Purkinje system.

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Pharmacokinetics and Metabolism
Isradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. Isradipine is detectable in plasma within 20 minutes after administration of single oral doses of 2.5-20 mg, and peak concentrations of approximately 1 ng/mL/mg dosed occur about 1.5 hours after drug administration. Administration of Isradipine with food significantly increases the time to peak by about an hour, but has no effect on the total bioavailability (area under the curve) of the drug. Isradipine is 95% bound to plasma proteins. Both peak plasma concentration and AUC exhibit a linear relationship to dose over the 0-20 mg dose range. The elimination of Isradipine is biphasic with an early half-life of 1½-2 hours, and a terminal half-life of about 8 hours. The total body clearance of Isradipine is 1.4 L/min and the apparent volume of distribution is 3 L/kg.

Isradipine is completely metabolized prior to excretion, and no unchanged drug is detected in the urine. Six metabolites have been characterized in blood and urine, with the mono acids of the pyridine derivative and a cyclic lactone product accounting for >75% of the material identified. Approximately 60%-65% of an administered dose is excreted in the urine and 25%-30% in the feces. Mild renal impairment (creatinine clearance 30-80 mL/min) increases the bioavailability (AUC) of Isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance <10 mL/min) who have been on hemodialysis show a 20%-50% lower AUC than healthy volunteers. No pharmacokinetic information is available on drug therapy during hemodialysis. In elderly patients, Cmax and AUC are increased by 13% and 40%, respectively; in patients with hepatic impairment, Cmax and AUC are increased by 32% and 52%, respectively.

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