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Abstract
Carbamazepine is a mood stabilizer which is approved for use in bipolar disorder with manic and mixed episodes.
It is also approved for use for the treatment of trigeminal neuralgia, temporal lobe epilepsy (complex partial seizures)
and generalized tonic-clonic seizure. It is metabolized in the liver, primarily by CYP450 3A4 and is an inducer of
CYP450 3A4 enzyme. The specific mechanism of action of carbamazepine in stabilizing mood is unknown. It exerts
effects by decreasing dopamine turn over, enhancement of brain γ-aminobutyric acid (GABA) levels via multiple
actions of synthesis and degradation, and modulation of other neurotransmitters, voltage sensitive Na+ channels,
extra hypothalamic neuropeptides, secondary messenger systems, and neuro protection. The most common side
effects are nausea, vomiting, constipation, diarrhea, loss of appetite, sedation, dizziness and ataxia. Serious side
effects may include skin rashes, decreased bone marrow function and confusion. It should not be used in those with
a history of bone marrow problems. Routine blood level monitoring is necessary. There is an increased risk of fetal
abnormalities if carbamaepine taken in pregnancy. Carbamaepine concentrations are known to be increased with
concurrent use of antidepressants (such as fluexetine, fluovoxamine, nefazodone), omeperazole, efavirnaz, ratinovir,
valproate, cemitidine and erythrpmycin. Its level decrease when administrated with Rifampin and Cisplatin.
Keywords: Carbamaepine; Pharmacokinetics; Pharmacodynamics; breastfeeding is not recommended. Care should be taken in those with
Side effects; Drug interactions either kidney or liver problems [1,6].
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Dopaminergic transmission strong inducer of hepatic enzymes and the plasma half-life shortens to
about 15 h when it is given repeatedly [10].
Dopamines are major neurotransmitters involved in the patho-
physiologic mechanism of bipolar disorders. Antimanic and mood- Bioavailability is 80% and its peak plasma levels are reached 2-8 h
stabilizing properties of carbamazepine could be related decrease after a single dose. Carbamazepine is 70-80% bound to plasma protein.
dopamine turnover. Carbamazepine is not a direct antagonist at The average half-life after a single dose is 26 h, with a range of 18-54 h.
dopamine receptors and exerts its actions on the dopamine system However, with long-term administration, the half-life decreases to
through some other series of mechanisms. Chronic administration of approximately 12 h (range, 10-25 h). This change occurs with the
carbamazepine reduced D2 receptor density and D2-like receptor induction of hepatic P450 enzymes, which increase the rate of
phosphorylation. Dopamine levels have been reported to be increased metabolism of Carbamazepine itself (auto induction) [10,11]. The
in the prefrontal cortex after chronic Carbamazepine administration. degree of Carbamazepine auto induction is somewhat dose dependent
Carbamazepine does decrease levels of the dopamine metabolite but is usually complete after 3-5 weeks of treatment [10,11,13].
homovanillic acid (HVA) in the CSF of affectively ill patients following Carbamazepine is metabolized in the liver and then excreted by the
probenecid administration, consistent with its ability to decrease kidneys, as only 1 percent is eliminated by biliary excretion [10,11,13].
dopamine turnover in animals [8-10].
Pre-carbamazepine work up and monitoring
Serotonergic transmission
Before starting carbamazepine treatments other causes of mood
Serotonin are another major neurotransmitters involved in the disorder or manic symptoms, including medical disorders,
patho-physiologic mechanism of bipolar disorders. Carbamazepine is a medications and substances of abuse, should be excluded. Screening
serotonin releasing agent and possibly even a serotonin reuptake laboratory exams should include liver function tests, thyroid function
inhibitor [10-15]. tests, CBC and ECG in patients over 40 years old or with pre-existing
cardiac disease. In females of childbearing age, pregnancy should be
Effects of carbamazepine on G-proteins and inositol excluded due to carbamazepine use during the first trimester is
transporter associated with teratogenic effect (especially neural tube defect) (Table
1). Start folic acid supplement in women (pregnant) who are
Carbamazepine blocks cyclic adenosine monophosphate (cAMP)
carbamazepine [10,16-23].
and G proteins. Carbamazepine may also enhance several inositol
phosphatases. It modalities increase brain-derived neurotrophic factor
(BDNF) Chronic administration of carbamazepine increased levels in Predictors of good carbamazepine response
rat brain of GRK3, which is involved in homologous desensitization of Factors predicting positive response to carbamazepine includes past
agonist-activated G-protein coupled receptors. GRK3 is reduced in the history of good carbamazepine response or family member with good
post-mortem study of bipolar disorders brain [8,10]. response, co morbid anxiety or panic attack, mixed mania and
depression is followed by Mania [10,16-23].
Noradnergic transmission (NE, norepinephrine)
Norepinephrine’s are major neurotransmitters involved in the Summary of predictors for good carbamazepine response
patho-physiologic mechanism of bipolar disorders. Studies
demonstrated that carbamazepine decreases the release of 1) Past history of good carbamazepine response (personal or
norepinephrine [10]. family).
2) History of alcoholism.
Effects on voltage-gated sodium channels
3) Comorbid post-traumatic stress disorders.
Carbamazepine stabilizes the inactivated state of voltage-gated
4) History of trigeminal neuralgia.
sodium channels, making fewer of these channels available to
subsequently open. This leaves the affected cells less excitable until the 5) Irritable mania.
drug dissociates. By doing this carbamazepine like vaproate decreases
6) Comorbid substance issues.
influx of sodium ion and increases efflux of potassium ion [8,10].
7) Sequence: Depression-Mania-Euthymia.
Pharmacokinetics of Carbamazepine 8) Severe mania (severe mania with psychosis).
Metabolized in the liver, primarily by CYP450 3A4. It is renal 9) Mixed mania.
excreted. The active metabolite is (carbamazepine-10,11 epoxide).
Initial half-life 26–65 h (35–40 h for extended release formulation); 10) Secondary mania.
half-life 12–17 h with repeated doses Half-life of active metabolite is 11) Co morbid anxiety and panic attack.
approximately 34 h. It Is not only a substrate for CYP450 3A4, but also
an inducer of CYP450 3A4. Thus, carbamazepine induces its own 12) Co morbid migraine headache.
metabolism, often requiring an upward dosage adjustment.
Carbamazepine is well absorbed after oral administration. Its
plasma half-life is about 30 h when it is given as single dose, but it is a
Page 3 of 5
2) CBC
4) Carbamazepine levels
2) LFTs
3) Weight and height if patient gains weight rapidly (to check for weight gain or obesity)
4) Carbamazepine levels
2) CBC
If patient develop fever, sore throat, etc. while on carbamazepine treatment
Page 4 of 5
Page 5 of 5
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