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.
In randomized, placebo-controlled, double-blind, clinical trials, DynaCirc CR® (isradipine) Controlled Release Tablets have been shown to have antihypertensive effects proportional to doses between 5 and 20 mg, administered once daily. DynaCirc CR® (isradipine) produced statistically significant reductions in supine and standing blood pressure, compared with placebo, 24 hours postdose. The endpoint results of one parallel group dose-ranging trial showed mean responses 24 hours after ingestion of DynaCirc CR® (isradipine) (systolic/diastolic) -5.2/-2.8, -13.4/-9.7, -15.6/-10.2 and -15.5/-11.8 mmHg, for 5, 10, 15 and 20 mg doses, respectively, change from baseline greater than concurrent placebo. The antihypertensive effect of any one dose begins in about 2 hours and reaches a peak at about 8-10 hours postdose. At the recommended starting dose (5 mg) the trough response (24 hours after dosing) was about 76% that of the peak. At doses of 10, 15 and 20 mg, the trough blood pressure response was about equal to that at peak effect. In association with the fall in blood pressure, resting heart rate is slightly increased, on average from 1-3 beats/minute. The antihypertensive response to DynaCirc CR® (isradipine) has not been detected to be influenced by gender or age.
In man, peripheral vasodilation produced by immediate-release DynaCirc® (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.
In general, no detrimental effects on the cardiac conduction system were seen with the use of immediate-release DynaCirc® (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.
Pharmacokinetics and Metabolism
With the immediate-release formulation DynaCirc® (isradipine) Capsules, 90%-95% of the orally administered dose is absorbed. Because of the biotransformation of isradipine during its first-pass through the portal circulation, the bioavailability of DynaCirc CR® (isradipine) ranges from 15%-24%. Isradipine is 95% bound to plasma proteins.
Peak concentrations of approximately 1 ng/mL/mg dosed occur about 1.5 hours after DynaCirc® (isradipine) Capsules administration. The elimination of isradipine is biphasic with an early half-life of 1 ½-2 hours, and a terminal half-life of about 8 hours, resulting in trough concentrations of about 0.1 ng/mL/mg dosed of immediate-release DynaCirc® (isradipine) Capsules.
In single dose studies of DynaCirc CR® (isradipine) Controlled Release Tablets, after a 2-3 hour lag time, concentrations of isradipine plateau between 7 and 18 hours post-dosing (reaching a Cmax of 3-4 ng/mL with an AUC of 62-73 ng•h/mL for a 10 mg dose) and then a concentration >50% of the peak exists for 17-20 hours.
There is no evidence of dose dumping either in the presence or absence of food. Food has been shown to decrease the extent of bioavailability of DynaCirc CR® (isradipine) by up to 25%.
The pharmacokinetics of DynaCirc CR® (isradipine) Controlled Release Tablets are linear over the dose range of 5-20 mg, in that the plasma drug concentrations are proportional to the dose administered.
Isradipine is completely metabolized prior to excretion, and no unchanged drug is detected in the urine. The major routes of isradipine metabolism are ring oxidation of the dihydropyridine moiety to give the corresponding pyridine, and ester cleavage, with or without concomitant oxidation of the dihydropyridine moiety, giving the corresponding carboxylic acids. The cytochrome P-450 IIIA4 system is implicated in the formation of these metabolites, which are hemodynamically inactive. Approximately 60%-65% of an administered dose is excreted in the urine and 25%-30% in the feces. With immediate-release DynaCirc® (isradipine), mild renal impairment (creatinine clearance 30-80 mL/min) increases the 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. In elderly patients administered DynaCirc® (isradipine) Capsules, 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 (see DOSAGE AND ADMINISTRATION).