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 C 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 C. 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.
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When CARDENE SR was administered with a high-fat breakfast, mean
C 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.
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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, C 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.
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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,
C 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.
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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 C,
T, 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.
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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 under-perfused
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 under-perfused 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.
*PA=conduction time from high to low right atrium, AH=conduction time
from low right atrium to His bundle deflection or AV nodal conduction
time, HV=conduction time through the His bundle and the bundle branch-Purkinje system.
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.
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