Download Carbamazepine (Tegretol)

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Carbamazepine (Tegretol)
Carbamazepine is one of the older drugs used for the treatment of
epilepsy . It has a long history of effectiveness & safety . It is structurally
similar to the tricyclic anti depressant agents . It has been the drug of
choice for the treatment of trigeminal neuralgia & is used in treatment of
generalised as well as complex partial seizures . It is most frequently
prescribed for those patients who have failed to respond to other anti
convulsant therapy or for those who have developed significant side
effects from other anti convulsant agents .
Preparation, Dosage & Drug levels:
Tegretol is prepaired as 200mg oral tablets ,100mg chewable tablets &
100mg/5ml suspension . The usual dose of tegretol is 200mg given
3times daily . Like many drugs that to be taken continuously, It takes
from 7 to 14 days to build up the blood level . The range of therapeutic
serum concentration for carbamazepine is 4 to to 12 mg/L .
Toxic Side Effects:
Many patients will develop symptoms of toxicity when plasma
concentration exceed 9mg/L. Therefore , many clinicians prefer to use a
therapeutic range of 4 to 8 mg/L. These side effects are :
- Dizziness: a feeling that the room is spinning around .
- Drunken sensation : a feeling of clumsiness,a staggering gait or feeling
of slowest movement .
- Light headedness :feeling like you might faint.
- Double vision : inability to focus well .
- Slurred speech: feeling of thick or swollen tongue ,inability to control it
while speaking .
- Confusion : inability to think clearly.
- Memory lapses : difficulty remembering the sorts of things you usually
remember.
Common side effects:
Tegretol can damage your liver . If this occurs the whites of your eyes
may turn yellow (jaundice),you may have diarrhea . Tegretol can damage
your bone marrow where white blood cells are produced .
Metabolism:
Tegretol is metabolised by the liver .Therefore, the amount of tegretol
that you need to take depends on how fast your liver metabolizes it
.Anything that adversely affects liver function such as hepatitis or
alcohol abuse will affect its ability to metabolise.
Key parameters :
Therapeutic plasma conc.
4 - 12 mg/L
Bioavailability
80 %
Salt form (S)
1
Volume of distribution
1.4 L/kg
Clearance (CL)
Conc. Dependent
Half Life (t ½)
Conc. Dependent
Uses:
Tegretol is most effective when used to treat generalised tonic-clonic
seizures.These are the type of seizures during which you lose
consciousness & your arms or legs may stiffen or jerk . During complex
partial seizures you will lose consciousness aware -ness of your
surroundings,but you may appear awake to those around you. people who
witness a partial complex seizures often describe the afflicted person as
confused or staring.Tegretol is not very effective in treating other types of
seizures .
Bioavailability(F):
Carbamazepine is a lipid soluble compound which is slowly absorbed
from the G.I.T. Peak plasma conc. Occur approximately 6hrs (range : 2
to 24 hrs) after oral ingestion . Although the bioavailability of carbamazepine has not been directly determined ,it is estimated to be greater
than 70% & may approach 100% . Since carbamazepine is so slowly
absorbed , changes in gastrointestinal function, especially those
associated with rapid transit, could decrease its bioavailability & result in
variable plasma conc. Of carbamazepine .
Volume of distribution (vd):
The volume of distribution of carbamazepine is approximately 1.4 L/Kg .
Carbamazepine ,a neutral compound that is primarily bound to albumin &
α1-acid glycoprotein, has a free fraction (alpha) of approximately 0.2 to
0.3 .
Clearance (Cl):
Carbamazepine is eliminated almost by the metabolic route,with less than
2% of an oral dose being excreted unchanged in the urine .Clearance
values are difficult to estimate because bioavailability is uncertain.
Nevertheless ,the average clearance value appears to be approximately
0.064 L/Kg in patients who have received the drug chronically . In
patients who are taking other enzyme inducing antiepileptic drugs ,the
clearance is increased to approximately 0.1 L/Kg/hr. Single dose studies
suggest a clearance value which is one half to one third of the value
observed in patients on chronic therapy .The increase in clearance
associated with chronic therapy is apparently due to auto-induction of its
metabolic enzymes . Auto-induction of metabolism commonly cause
changes in steady-state carbamazepine levels which are less than
proportional to an increase in the maintenance dose .
Half life (t1/2):
Single dose studies predict a carbamazepine
half life of approximately 30 to 35 hrs ,steady state data suggest a half life
of approximately 15 hrs in patients receiving carbamazepine
monotherapy & approximately 10hrs in patients receiving other enzyme
inducing anti epileptic drugs .
Time of sampling:
Obtaining carbamazepine plasma samples within the first few weeks of
therapy may be useful to establish a relationship between carbamazepine
concentration & a patients clinical responce . Once steady state has been
achieved , the time of sampling within a dosing interval is arbitrary given
the long half life & relatively short dosing interval for carbamazepine .
Nevertheless ,it is reasonable to obtain carbamazepine plasma samples at
a consistent time within the dosing interval.
Question#1: N.S.,a 36 year old,60 Kg female is to
be given carbamazepine as an anticonvulsant agent.
Calculate a daily dose that will produce an avearage
steady state plasma conc. Of approximately 6 mg/L.
F=0.8 , cl=3.84l/hr (0.064l/kg x 60kg) ,S=1
Maintenance dose = (cl)(cpss ave)(t)
(s) (f)
= (3.84l/hr)(6mg/l)(24hr/1day)
(1) (0.8)
= 691.2 mg/day
This dose (approximately700mg/day)is that which would
be required to achieve the steady state level of 6mg/l after auto
induction of carbamazepine metabolism had taken place .
for this reason ,N.S. should be started on a lower daily
dose initially & increased at one to two week intervals based
upon her clinical
response.the usual initial daily dose for adult patients is 200 to
400mg with increases of approximately 200mg every 7 to 14
days .
Question#2: After 2 months ,N.S.’s carbamazepine
dose had been increased to 300mg BID.On this
regimen she had some reduction in seizure
frequency;however,seizure control was still
considered unsatisfactory.The steady-state carbamazepine level at this time was reported to be 4mg/L.
what are possible explanations for this observed
plasma level? What dose would be required to
achieve a new steady-state carbamazepine level of
6mg/L?
Cl= 3.84L/hr , the anticipated carbamazepine level in N.S.for
a dose of 600mg/day would be approximately
5mg/L .
Cpss ave = (s)(f)(dose/t)
Cl
= (1)(0.8)(300mg/12hr)
3.84L/hr
= 5.2 mg/L
The observed level of 4 mg/L is within the predicted range,
considering the fact that both bioavailability & clearance values
derived from average literature values may not be applicable to
N.S. At this point,it would be difficult to establish whether a
slightly lower than expected bioavailability or a higher than
average clearance was responsible for the observed level of
4mg/L.
Because of carbamazepine’s relatively slow absorption
characteristics & long half life ,it is propable that the measured
concentration of 4 mg/L represents an average value.At steady
state, the average plasma concentration should be proportional
to the daily dose. Therefore,to increase the plasma conc. From
4 to 6 mg/L,one would simply increase the carbamazepine dose
by 50%(from 600 to 900 mg/day).An alternate approach might
be to calculate the apparent carbamazepine clearance for
N.S.using an assumed bioavailability of 0.8
Cl = (s)(f)(dose/t)
cpss ave
= (1)(0.8)(600 mg/24hr)
4 mg/l
= 5 L/hr
This clearance value could then be used to calculate the
maintenance dose as illustrated in question 1.However this time
the clearance value which has been derived from the patient’s
specific data would be used rather than an average value from
the literature .
Maintenance dose = (cl)(cpss ave)(t)
(s)(f)
= (5L/hr)(6mg/L)(24hr/day)
(1)(0.8)
= 900 mg/L
if N.S.were receiving other anticonvulsant agents,it would
be appropriate to monitor their conc. As well,since carbamazepine could induce their metabolism,thereby reducing their
steady state conc.
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