Nicardipine

Nicardipine is a second generation slow calcium channel inhibitor, and belongs to the phenyl-dihydropyridine group. Nicardipine has a greater selectivity for L-type calcium channels in vascular smooth muscle than cardiac myocytes. At very low concentrations it inhibits the influx of calcium into the cell. Its action is produced mainly on arterial smooth muscle. This is reflected in relatively large and rapid changes in blood pressure, with minimal inotropic changes in cardiac function (baroreflex effect). Nicardipine produces smooth muscle relaxation and marked peripheral vasodilatation.

Pharmacodynamic effects

Administered by systemic route, nicardipine is a potent vasodilator which diminishes total peripheral resistance and lowers blood pressure. Heart rate is temporarily increased; as a result of a decrease in after-load, cardiac output is markedly and durably increased.

In humans, the vasodilator action also occurs in both acute dose administration and chronic administration in the large and small arteries, increasing blood flow and improving arterial compliance. Renal vascular resistance is decreased.

Absorption

Nicardipine is rapidly and completely absorbed with plasma levels detectable 20 minutes following an oral dose. Maximal plasma levels are observed within 30 minutes to two hours (mean T_max = 1 hour). When given with a high fat meal peak plasma levels are reduced by 30%. Nicardipine is subject to saturable first-pass metabolism and the bioavailability is about 35% following a 30 mg oral dose at steady state.

Steady state plasma levels are achieved after about 3 days of dosing at 20 and 30 mg tds and remain relatively constant over 28 days of dosing at 30 mg tds. Considerable intersubject variability in plasma levels is observed. Following dosing to steady state using doses of 30 and 40 mg (tds), the terminal plasma half-life of nicardipine averaged 8.6 hours.

Following intravenous administration, nicardipine is rapidly absorbed with studies showing the time to onset ranging between 5-15 minutes. Peak plasma levels can reach 184 ng/ml and steady state plasma concentrations of 157 ng/ml achieved within 24-48 hours of continuous infusion.

Distribution

Nicardipine is highly protein-bound (>99%) in human plasma over a wide concentration range.

Biotransformation

Nicardipine is metabolized by cytochrome P450 3A4. Studies involving either a single dose, or administration 3 times daily for 3 days, have shown that less than 0.03% of unchanged nicardipine is recovered in the urine in humans after oral or intravenous administration. The most abundant metabolite in human urine is the glucuronide of the hydroxy form, which is formed by the oxidative cleaving of the N-methylbenzyl moiety and the oxidation of the pyridine. Nicardipine does not induce its own metabolism and does not induce hepatic microsomal enzymes.

Elimination

Following a radioactive oral solution dose, 60% of the radioactivity was recovered in the urine and 35% in faeces. Most of the dose (>90%) was recovered within 48 hours of dosing.

The elimination profile of the drug following an intravenous dose consists of three phases, with corresponding half-life: distribution 6.4 min, elimination 1.5 hours, terminal elimination 7.9 hours. Studies have shown clinical offset of action to be approximately 15 minutes.

Renal impairment

The pharmacokinetics of orally/intravenously administered nicardipine were studied in subjects with severe renal dysfunction requiring hemodialysis (creatinine clearance <10 ml/min), mild/moderate renal dysfunction (creatinine clearance 10-50 mi/min) and normal renal dysfunction (creatinine clearance >50 ml/min). At steady state, C_max and AUC were significantly higher and clearance significantly lower in subjects with mild/moderate renal dysfunction compared with in subjects with normal renal function. There were no significant differences in the principal pharmacokinetic parameters between severe renal dysfunction and normal renal dysfunction. These results are similar to those seen with other oral formulations.

Linearity/non-linearity

The pharmacokinetics of nicardipine capsule are non-linear due to saturable hepatic first pass metabolism.

Nicardipine has been shown to pass into the milk of lactating animals. It has been reported in animal experiments that the drug is excreted into breast milk.

In animal experiments where this drug was administered at a high dose during the terminal stage of pregnancy, an increase in fetal deaths, delivery disturbances, decrease in the body weight of offsprings, and suppression of post-natal body weight gain were reported.

However, the toxicity to reproduction has not been reported.