Mechanism Of Action

Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect.

Pharmacokinetics And Metabolism

Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (α-half-life of 2.7 minutes), an intermediate phase ((β-half-life of 44.8 minutes), and a slow terminal phase (γ-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr•kg, and the apparent volume of distribution (V_d) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of Cardene® l.V. are linear over the dosage range of 0.5 to 40.0 mg/hr.

Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of Cardene® I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations.

Nicardipine is highly protein bound ( > 95%) in human plasma over a wide concentration range. Cardene® I.V. has been shown to be rapidly and extensively metabolized by the liver. After coadministration of a radioactive intravenous dose of Cardene® I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine.

Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes.

The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients ( > 65 years) and young healthy adults.

Hemodynamics

Cardene® I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arteri-ally administered Cardene® I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers. Administration of Cardene® I.V. to normotensive volunteers at dosages of 0.25 to 3.0 mg/hr for eight hours produced changes of < 5 mmHg in systolic blood pressure and < 3 mmHg in diastolic blood pressure. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7 ± 1 bpm in postoperative patients and 8 ± 1 bpm in patients with severe hypertension at the end of the maintenance period.

Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Cardene® increases blood flow. Coronary dilatation induced by Cardene® I.V. improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, Cardene® I.V., administered after beta-blockade, significantly improved systolic and diastolic left ventricular function.

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