A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Adalat Pharmacology, Pharmacokinetics, Studies, Metabolism - Nifedipine
Adalat Pharmacology, Pharmacokinetics, Studies, Metabolism - Nifedipine
CLINICAL PHARMACOLOGY
Nifedipine is a calcium
ion influx inhibitor
(slowchannel blocker
or calcium ion antagonist)
which inhibits the transmembrane influx of calcium ions into vascular
smooth muscle and cardiac
muscle. The contractile
processes of vascular
smooth muscle and cardiac
muscle are dependent
upon the movement of extracellular
calcium ions into these
cells through specific
ion channels. Nifedipine
selectively inhibits calcium
ion influx across the cell
membrane of vascular
smooth muscle and cardiac
muscle without altering
serum calcium concentrations.
Mechanism of Action: The mechanism
by which nifedipine reduces arterial blood pressure
involves peripheral
arterial vasodilatation
and consequently, a reduction
in peripheral vascular
resistance. The increased peripheral vascular resistance
that is an underlying cause
of hypertension
results from an increase in active tension
in the vascular smooth
muscle. Studies have demonstrated that the increase in active tension
reflects an increase in cytosolic free calcium.
Nifedipine is a peripheral
arterial vasodilator
which acts directly on vascular
smooth muscle. The binding of nifedipine to voltage-dependent and
possibly receptor-operated channels in vascular
smooth muscle results
in an inhibition
of calcium influx through
these channels. Stores of intracellular calcium in vascular
smooth muscle are limited
and thus dependent upon the influx of extracellular
calcium for contraction
to occur. The reduction in calcium
influx by nifedipine causes arterial
vasodilation and
decreased peripheral vascular
resistance which
results in reduced arterial
blood pressure.
Pharmacokinetics and Metabolism: Nifedipine is completely absorbed
after oral administration. The bioavailability
of nifedipine as A.A.A.
CC relative to immediate
release nifedipine is
in the range of 84%-89%.
After ingestion of A.A.A.
CC tablets under fasting
conditions, plasma concentrations
peak at about 2.5-5 hours with a second small peak or shoulder
evident at approximately 6-12 hours post
dose. The elimination
half-life of nifedipine
administered as A.A.A.
CC is approximately 7 hours in contrast
to the known 2 hour elimination half-life of nifedipine administered
as an immediate release
capsule.
When A.A.A. CC is administered
as multiples of 30 mg tablets
over a dose range of 30
mg to 90 mg, the area
under the curve (AUC)
is dose proportional; however,
the peak lasma concentration
for the 90 mg dose
given as 3 x 30 m is 29% greater than predicted from the 30 mg
and 80 mg doses.
Two 30 mg A.A.A.
CC tablets may be interchanged with a 60 mg
ADALAT CC tablet. Three 30 mg
A.A.A. CC tablets, however,
result in substantially higher Cmax values than those
after a single 90 mg A.A.A.
CC tablet. Three 30 mg tablets
therefore should not be considered interchangeable with a 90 mg
tablet. Once daily dosing of A.A.A.
CC under fasting conditions
results in decreased fluctuations in the plasma
concentration
of nifedipine when compared to t. i. d. dosing with immediate
release nifedipine capsules.
The mean peak plasma
concentration
of nifedipine following a 90 mg
ADALAT CC tablet, administered
under fasting conditions,
is approximately 115 ng/mL. When A.A.A.
CC is given immediately after a high fat
meal in healthy volunteers,
there is an average
increase of 60% in the peak plasma
nifedipine concentration, a prolongation in the time
to peak concentration,
but no significant change in the A.C.
Plasma concentrations of nifedipine when ADALAT CC is taken after
a fatty meal result in
slightly lower peaks compared to the same daily dose
of the immediate release
formulation administered in three divided doses. This may be, in
part, because A.A.A.
CC is less bioavailable than the immediate
release formulation.
Nifedipine is extensively metabolized to highly water
soluble, inactive metabolites accounting for 60% to 80% of the dose
excreted in the urine. Only traces (less than 0.1% of the dose)
of the unchanged form can
be detected in the urine. The remainder is excreted in the feces
in metabolized form, most likely as a result of biliary excretion.
No studies have been performed with A.A.A.
CC in patients with renal failure; however, significant
alterations in the pharmacokinetics
of nifedipine immediate release
capsules have not been reported in patients undergoing hemodialysis
or chronic ambulatory
peritoneal dialysis.
Since the absorption of nifedipine from A.A.A.
CC could be modified by renal
disease, caution should
be exercised in treating such
patients.
Because hepatic biotransformation
is the predominant route for the disposition of nifedipine, its
pharmacokinetics
may be altered in patients with chronic liver disease. A.A.A.
CC has not been studied in patients with hepatic disease; however,
in patients with hepatic
impairment (liver
cirrhosis) nifedipine has a longer elimination
half-life and higher
bioavailability than in healthy
volunteers. The degree
of protein binding of
nifedipine is high (92%-98%). Protein binding may be greatly reduced
in patients with renal
or hepatic impairment.
After administration
of A.A.A. CC to healthy
elderly men and women (age 60 years), the mean
Cmax is 36% higher and the average
plasma concentration
is 70% greater than in younger patients.
Clinical Studies: A.A.A.
CC produced dose-related decreases in systolic
and diasiolic blood pressure
as demonstrated in two double-blind, randomized, placebo-controlled
trials in which over 350 patients were treated with A.A.A.
CC 30, 60, or 90mg once daily for 6 weeks. In
the first study, A.A.A.
CC was given as monotherapy
and in the second study, ADALAT CC was added to a beta-blocker in
patients not controlled on a beta-blocker alone. The mean
trough (24 hours post-dose)
blood pressure results
from these studies are shown below:
MEAN REDUCTIONS IN TROUGH SUPINE BLOOD PRESSURE (mmHg)
SYSTOLIC/ DIASTOLIC
|
STUDY 1
|
|
ADALAT CC DOSE
|
N
|
MEAN TROUGH REDUCTION*
|
|
30 MG
|
60
|
5.3/2.9
|
|
60 MG
|
57
|
8.0/4.1
|
|
90 MG
|
55
|
12.5/8.1
|
|
STUDY 2
|
|
ADALAT CC DOSE
|
N
|
MEAN TROUGH REDUCTION
|
|
30 MG
|
58
|
7.6/3.8
|
|
60 MG
|
63
|
10.1/5.3
|
|
90 MG
|
62
|
10.2/5.8
|
*Placebo response subtracted.
The trough/peak ratios estimated from 24 hour blood
pressure monitoring
ranged from 41%-78% for diastolic
and 46%-91% for systolic
blood pressure.
Hemodynamics: Like other slow-channel blockers, nifedipine exerts
a negative inotropic
effect on isolated myocardial
tissue. This is rarely, if ever, seen in intact animals or man,
probably because of reflex
responses to its vasodilating effects. In
man, nifedipine decreases peripheral
vascular resistance which leads to a fall
in systolic and diastolic
pressures, usually minimal in normotensive
volunteers (less than 5-10 mm
Hg systolic), but sometimes
larger. With A.A.A. CC,
these decreases in blood
pressure are not accompanied
by any significant
change in heart rate.
Hemodynamic studies of the immediate
release nifedipine formulation
in patients with normal ventricular function
have generally found a small increase in cardiac
index without major effects on ejection
fraction, left ventricular
end- diastolic pressure (LVEDP) or volume
(LVEDV). In patients with
impaired ventricular function, most acute
studies have shown some increase in ejection
fraction and reduction
in left ventricular
filling pressure.
Electrophysioiogic Effects: Although, like other members of its
class, nifedipine causes a slight depression
of sinoatrial node
function and atrioventricular
conduction in isolated myocardial
preparations, such effects
have not been seen in studies in intact animals or in man. In
formal electrophysiologic studies, predominantly in patients with
normal conduction
systems, nifedipine administered as the immediate
release capsule
has had no tendency to prolong
atrioventricular conduction
or sinus node
recovery time, or to
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