Mechanism of Action

Nicardipine HCl is a calcium entry blocker (slow channel blocker or calcium ion antagonist) which 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 HCl are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine HCl produces relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect.

Pharmacokinetics and Metabolism

Nicardipine HCl is completely absorbed following oral doses administered as capsules. Plasma levels are detectable as early as 20 minutes following an oral dose and maximal plasma levels are observed within 30 minutes to two hours (mean T_max = 1 hour). While nicardipine HCl is completely absorbed, it is subject to saturable first pass metabolism and the systemic bioavailability is about 35% following a 30 mg oral dose at steady state.

When nicardipine HCl was administered one (1) or three (3) hours after a high fat meal, the mean Cmax and mean AUC were lower (20% to 30%) than when nicardipine HCl was given to fasting subjects. these decreases in plasma observed following a meal may be significant but the clinical trials establishing the efficacy and safety of nicardipine HCl were done in patients without regard to the timing of meals. Thus the results of these trials reflect the effects of meal-induced variability.

The pharmacokinetics of nicardipine HCl are nonlinear due to saturable hepatic first pass metabolism. Following oral administration, increasing doses result in a disproportionate increase in plasma levels. Steady state Cmax values following 20, 30, and 40 mg doses every 8 hours averaged 36, 88, and 133 ng/ml, respectively. Hence, increasing the dose from 20 to 30 mg every 8 hours more than doubled Cmax and increasing the dose from 20 to 40 mg every 8 hours increased Cmax more than 3-fold. A similar disproportionate increase in AUC with dose was observed. Considerable inter-subject variability in plasma levels was also observed.

Post-absorption kinetics of nicardipine HCl are also non-linear, although there is a reproducible terminal plasma half-life that averaged 8.6 hours following 30 and 40 mg doses at steady state (TID). The terminal half-life represents the elimination of less than 5% of the absorbed drug (measured by plasma concentrations). Elimination over the first 8 hours after dosing is much faster with a half-life of 3-4 hours. Steady state plasma levels are achieved after 2 to 3 days of TID dosing (every 8 hours) and are 2-fold higher than after a single dose.

Nicardipine HCl is highly protein bound (>95%) in human plasma over a wide concentration range.

Nicardipine HCl is metabolized extensively by the liver; less than 1% of intact drug is detected in the urine. Following a radioactive oral dose in solution, 60% of the radioactivity was recovered in the urine and 35% in feces. Most of the dose (over 90%) was recovered within 48 hours of dosing. Nicardipine HCl does not induce its own metabolism and does not induce hepatic microsomal enzymes.

The steady-state pharmacokinetics of nicardipine HCl in elderly hypertensive patients ( ≥65 years) are similar to those obtained in young normal adults. After one week of nicardipine HCl dosing at 20 mg three times a day, the Cmax, Tmax, A.C. terminal plasma half-life, and the extent of protein binding of nicardipine HCl observed in healthy elderly hypertensive patients did not differ significantly from those observed in young normal volunteers.

Bookmark this page: