Nicardipine Hydrochloride

NICARDIPINE HYDROCHLORIDE- nicardipine hydrochloride capsule


Nicardipine hydrochloride capsules for oral administration each contain 20 mg or 30 mg of nicardipine hydrochloride. Nicardipine hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium channel blocker).

Nicardipine hydrochloride is a dihydropyridine structure with the IUPAC (International Union of Pure and Applied Chemistry) chemical name 2-(benzyl-methyl amino)ethyl methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate monohydrochloride, and it has the following structural formula:

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Nicardipine hydrochloride is a greenish-yellow, odorless, crystalline powder that melts at about 169°C. It is freely soluble in chloroform, methanol, and glacial acetic acid, sparingly soluble in anhydrous ethanol, slightly soluble in n-butanol, water, 0.01 M potassium dihydrogen phosphate, acetone, and dioxane, very slightly soluble in ethyl acetate, and practically insoluble in benzene, ether and hexane. It has a molecular weight of 515.99.

Each capsule, for oral administration, contains 20 mg or 30 mg nicardipine hydrochloride. In addition, each capsule contains the following inactive ingredients: magnesium stearate and pregelatinized starch. The capsule shell consists of FD&C Blue #1, gelatin, and titanium dioxide and is printed with black ink containing FD&C Blue #2, FD&C Red #40, FD&C Blue #1, and D&C Yellow #10.


Mechanism of Action

Nicardipine 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 are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produces relaxation of coronary vascular smooth muscle at drug levels which cause little or no negative inotropic effect.

Pharmacokinetics and Metabolism

Nicardipine is completely absorbed following oral doses administered as capsules. Plasma levels are detectable as early as 20 minutes following as oral dose and maximal plasma levels are observed within 30 minutes to two hours (mean Tmax = 1 hour). While nicardipine 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 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 was given to fasting subjects. These decreases in plasma levels observed following a meal may be significant but the clinical trials establishing the efficacy and safety of nicardipine 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 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 are also non-linear, although there is a reproducible terminal plasma halflife 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 2 to 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 is highly protein bound (>95%) in human plasma over a wide concentration range.

Nicardipine 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 does not induce its own metabolism and does not induce hepatic microsomal enzymes. Nicardipine plasma levels were higher in patients with mild renal impairment (baseline serum creatinine concentration ranged from 1.2 to 5.5 mg/dL) than in normal subjects. After 30 mg nicardipine hydrochloride TID at steady state, Cmax and AUC were approximately 2-fold higher in these patients.

Because nicardipine is extensively metabolized by the liver, the plasma levels of the drug are influenced by changes in hepatic function. Nicardipine plasma levels were higher in patients with severe liver disease (hepatic cirrhosis confirmed by liver biopsy or presence of endoscopically-confirmed esophageal varices) than in normal subjects. After 20 mg nicardipine hydrochloride BID at steady state, Cmax and AUC were 1.8 and 4-fold higher, and the terminal half-life was prolonged to 19 hours in these patients.

Geriatric Pharmacokinetics

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


In man, nicardipine produces a significant decrease in systemic vascular resistance. The degree of vasodilation and the resultant hypotensive effects are more prominent in hypertensive patients. In hypertensive patients, nicardipine reduces the blood pressure at rest and during isometric and dynamic exercise. In normotensive patients, a small decrease of about 9 mmHg in systolic and 7 mmHg in diastolic blood pressure may accompany this fall in peripheral resistance. An increase in heart rate may occur in response to the vasodilation and decrease in blood pressure, and in a few patients this heart rate increase may be pronounced. In clinical studies mean heart rate at time of peak plasma levels was usually increased by 5 to 10 beats per minute compared to placebo, with the greater increases at higher doses, while there was no difference from placebo at the end of the dosing interval. 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 the left ventricular end-diastolic pressure (LVEDP). Although there is evidence that nicardipine increases coronary blood flow, there is no evidence that this property plays any role in its effectiveness in stable angina. In patients with coronary artery disease, intracoronary administration of nicardipine caused no direct myocardial depression. Nicardipine does, however, have a negative inotropic effect in some patients with severe left ventricular dysfunction and could, in patients with very impaired function, lead to worsened failure.

“Coronary Steal”, the detrimental redistribution of coronary blood flow in patients with coronary artery disease (diversion of blood from underperfused areas toward better perfused areas), has not been observed during nicardipine treatment. On the contrary, nicardipine has been shown to improve systolic shortening in normal and hypokinetic segments of myocardial muscle, and radio-nuclide angiography has confirmed that wall motion remained improved during an increase in oxygen demand. Nonetheless, occasional patients have developed increased angina upon receiving nicardipine. Whether this represents steal in those patients, or is the result of increased heart rate and decreased diastolic pressure, is not clear.

In patients with coronary artery disease nicardipine improves L.V. diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction, and reduced ischemia. Nicardipine has no negative effect on myocardial relaxation at therapeutic doses. The clinical consequences of these properties are as yet undemonstrated.

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