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
Tegretol Pharmacology, Pharmacokinetics, Studies, Metabolism - Carbamazepine
Tegretol Pharmacology, Pharmacokinetics, Studies, Metabolism - Carbamazepine
PHARMACOLOGY
In controlled clinical
trials, carbamazepine
has been shown to be effective in the treatment
of psychomotor and
grand mal seizures, as well
as trigeminal neuralgia.
Mechanism of Action
Carbamazepine has demonstrated anticonvulsant
properties in rats and mice with electrically and chemically induced
seizures. It appears to act by reducing polysynaptic
response and blocking
the post-tetanic potentiation. Carbamazepine greatly reduces or
abolishes pain induced
by stimulation of the infraorbital
nerve in cats and rats.
It depresses thalamic
potential and bulbar
and polysynaptic
reflexes, including the linguomandibular reflex in cats. Carbamazepine
is chemically unrelated to other anticonvulsants or other drugs
used to control the
pain of trigeminal
neuralgia. The mechanism of action
remains unknown.
The principal metabolite
of carbamazepine-10, 11-epoxide, has anticonvulsant activity as
demonstrated in several in vivo animal
models of seizures. Through clinical
activity for the epoxide
has been postulated, the significance of its activity
with respect to the safety and efficacy
of carbamazepine has not been established.
Pharmacokinetics
In clinical studies
suspension, conventional
tablets and XR tablets delivered equivalent
amounts of drug to the
systemic circulation.
However, the suspension
was absorbed somewhat faster, and the XR tablet
slightly slower, than the conventional tablet. The bioavailability
of the XR tablet was 89% compared to suspension. Following a twice
a day dosage regimen,
the suspension provides
higher peak levels and lower trough
levels than those obtained from the conventional tablet
for the same dosage regimen.
On the other hand, following a three times a day dosage
regimen, carbamazepine suspension affords steady-state plasma
levels comparable to carbamazepine tablets given b.i.d.
when administered at the same total mg
daily dose. Carbamazepine chewable tablets may produce higher peak
levels than the same dose
given as regular tablets.
Carbamazepine in blood
is 76% bound to plasma
proteins. Plasma levels of carbamazepine
are variable and may
range from 0.5-25 mcg/ml, with no
apparent relationship
to the daily intake of the drug. Usual adult
therapeutic levels
are between 4 and 12 mcg/ml. Following chronic
oral administration
of suspension, plasma
levels peak at approximately 1.5 hours compared to 4 to 5 hours
after administration of oral
tablets. The CSF/serum ratio
is 0.22, similar to the 22% unbound carbamazepine in serum. Because
carbamazepine
may induce its own metabolism, the half-life
is also variable. Initial half-life
values range from 25-65
hours, with 12-17 hours on repeated doses. Carbamazepine is metabolized
in the liver. After oral
administration
of 14C-carbamazepine, 72% of the administered radioactivity
was found in the urine
and 28% in the feces. This urinary
radioactivity
was composed largely of hydroxylated and conjugated metabolites,
with only 3% of unchanged carbamazepine. Transplacental passage
of carbamazepine
is rapid (30 to 60 minutes), and the drug
is accumulated in fetal
tissues, with higher levels found in liver
and kidney than in brain
and lungs.
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