CLINICAL PHARMACOLOGY
Mechanism of Action
Nicardipine is a calcium entry blocker (slow channel blocker or calcium ion antagonist) that 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 that cause little or no negative inotropic effect.
Pharmacokinetics and Metabolism
Nicardipine is completely absorbed following oral doses administered as capsules, and the systemic bioavailability is about 35% following a 30-mg oral dose at steady-state. The pharmacokinetics of nicardipine are nonlinear due to saturable hepatic first-pass metabolism.
Following oral administration of CARDENE SR, plasma levels are detectable as early as 20 minutes and maximal plasma levels are achieved as a broad peak generally between 1 and 4 hours. The average terminal plasma half-life of nicardipine is 8.6 hours. Following oral administration increasing doses result in disproportionate increases in plasma levels. Steady-state Cmax values following 30-, 45-, and 60-mg doses every 12 hours averaged 13.4, 34.0, and 58.4 ng/mL, respectively. Hence, increasing the dose twofold increases maximum plasma levels 4-fold to 5-fold. A similar disproportionate increase is observed with AUC. In comparison with equivalent daily doses of CARDENE capsules, CARDENE SR shows a significant reduction in Cmax. CARDENE SR also has somewhat lower bioavailability than CARDENE except at the highest dose. Minimum plasma levels produced by equivalent daily doses are similar. CARDENE SR thus exhibits significantly reduced fluctuation in plasma levels in comparison to CARDENE capsules.
When CARDENE SR was administered with a high-fat breakfast, mean Cmax was 45% lower, AUC was 25% lower and trough levels were 75% higher than when CARDENE SR was given in the fasting state. Thus, taking CARDENE SR with the meal reduced the fluctuation in plasma levels. Clinical trials establishing the safety and efficacy of CARDENE SR were carried out in patients without regard to the timing of meals.
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 following administration of CARDENE SR in hypertensive patients with moderate renal impairment (creatinine clearance 10 to 55 mL/min) were significantly higher following a single-oral dose and at steady-state than in hypertensive patients with mildly impaired renal function (creatinine clearance >55 mL/min). After 45-mg CARDENE SR bid at steady-state, Cmax and AUC were 2-fold to 3-fold higher in the patients with moderate renal impairment. Plasma levels in patients with mildly impaired renal function were similar to those in normal subjects.
In patients with severe renal impairment undergoing routine hemodialysis, plasma levels following a single dose of CARDENE SR were not significantly different from those patients with mildly impaired renal function.
Because nicardipine is extensively metabolized by the liver, the plasma levels of the drug are influenced by changes in hepatic function. Following administration of CARDENE capsules, 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 CARDENE bid at steady-state, Cmax and AUC were 1.8-fold and 4-fold higher, and the terminal half-life was prolonged to 19 hours in these patients. CARDENE SR has not been studied in patients with severe liver disease.
Geriatric Pharmacokinetics
The pharmacokinetics of CARDENE SR in elderly hypertensive subjects (mean age 70 years) were compared to those in younger hypertensive subjects (mean age 44 years). After a single dose and after 1 week of dosing with CARDENE SR there were no significant differences in Cmax, Tmax, AUC or clearance between the young and elderly subjects. In both groups of subjects, steady-state plasma levels were significantly higher than following a single dose. In the elderly subjects, a disproportional increase in plasma levels with dose was observed similar to that observed in normal subjects.
Hemodynamics
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 mm Hg in systolic and 7 mm Hg 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 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. CARDENE 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 radionuclide 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.
Electrophysiologic Effects
In general, no detrimental effects on the cardiac conduction system were seen with the use of CARDENE.
Nicardipine increased the heart rate when given intravenously during acute electrophysiologic studies and prolonged the corrected QT interval to a minor degree. The sinus node recovery times and SA conduction times were not affected by the drug. The PA, AH and HV intervals and the functional and effective refractory periods of the atrium were not prolonged by nicardipine and the relative and effective refractory periods of the His-Purkinje system were slightly shortened after intravenous nicardipine.
Renal Function
There is a transient increase in electrolyte excretion, including sodium. CARDENE does not cause generalized fluid retention, as measured by weight changes.
Effects in Hypertension
CARDENE SR produced decreases in both systolic and diastolic blood pressure throughout the dosing interval in clinical trials. The antihypertensive efficacy of CARDENE SR administered twice daily has been demonstrated using in-clinic blood pressure measures in placebo-controlled trials involving patients with mild to moderate hypertension and in trials using 12 or 24 hour ambulatory blood pressure monitoring.
|
