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Bipolar Disorders and Carbamazepine: Pharmacokinetics, Pharmacodynamics, Therapeutic Effects and Indications of Carbamazepine: Review of Articles

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.


Introduction
Carbamazepine was first synthesized as a potential antidepressant. It is an effective mood stabilizer, is approved for the treatment of mania and the maintenance treatment of bipolar disorder. It is now recognized in most guidelines as a second-line mood stabilizer useful in the treatment and prevention of both phases of bipolar affective disorder. Carbamazepine (CBZ) is a medication used primarily in the treatment of epilepsy and neuropathic pain [1]. For seizures it is effective as phenytoin and valproate. It is not effective for absence seizures or myoclonic seizures where valproate is effective and the drug of choice. It may be used in augmentation for inadequately responding schizophrenia along with other medications and as a second line agent in bipolar disorder [2][3][4].
Carbamazepine (Tegretol) has structural similarity with tricyclic antidepressant imipramine (Tofranil). It is FDA approved medication for the treatment of acute mania in 2002. Carbamazepine is also FDA approved for use for the treatment of trigeminal neuralgia, temporal lobe epilepsy (complex partial seizures), generalized tonic-clonic seizure and bipolar disorder with manic and mixed episodes [4][5][6].
Common side effects include nausea, constipations, diarrhea, and loss of appetite, sedation and drowsiness. 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. Use during pregnancy may cause harm to the baby; however stopping it in pregnant women with seizures is not recommended. Its use during breastfeeding is not recommended. Care should be taken in those with either kidney or liver problems [1,6].

GABA neurotransmission
GABA is an inhibitory neurotransmitter that plays an important role in regulating dopamine and glutamate neurotransmission. It was found that patients with bipolar disorder had lower GABA levels, which results in excitotoxicity and can cause apoptosis (cell loss). It is also of interest that chronic but not acute administration of, Carbamazepine are associated with up regulation of GABA B receptors in the hippocampus, yielding this action as a potential convergent mechanism for mood stabilization. Carbamazepine is a GABA receptor agonist, as it has also been shown to potentiate GABA receptors made up of α1, β2, and γ2 subunits. This mechanism may contribute to its efficacy in neuropathic pain and bipolar disorder [7,8].

Glutamate neurotransmission
Glutamate is the universal excitatory neurotransmitter. Carbamazepines are able to weakly block calcium influx through glutamate receptors of the NMDA subtype. Carbamazepine could exert anti glutamatergic effects both by decreased release of glutamate as well as by relative decreases in glutamate's postsynaptic efficacy by inhibiting calcium influx. Antidepressant and mood-stabilizing effects of carbamazepine is linked to its glutamate antagonism [8][9][10].

Dopaminergic transmission
Dopamines are major neurotransmitters involved in the pathophysiologic mechanism of bipolar disorders. Antimanic and moodstabilizing properties of carbamazepine could be related decrease dopamine turnover. Carbamazepine is not a direct antagonist at dopamine receptors and exerts its actions on the dopamine system through some other series of mechanisms. Chronic administration of carbamazepine reduced D 2 receptor density and D 2 -like receptor phosphorylation. Dopamine levels have been reported to be increased in the prefrontal cortex after chronic Carbamazepine administration. Carbamazepine does decrease levels of the dopamine metabolite homovanillic acid (HVA) in the CSF of affectively ill patients following probenecid administration, consistent with its ability to decrease dopamine turnover in animals [8][9][10].

Effects of carbamazepine on G-proteins and inositol transporter
Carbamazepine blocks cyclic adenosine monophosphate (cAMP) 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 rat brain of GRK3, which is involved in homologous desensitization of agonist-activated G-protein coupled receptors. GRK3 is reduced in the post-mortem study of bipolar disorders brain [8,10].

Noradnergic transmission (NE, norepinephrine)
Norepinephrine's are major neurotransmitters involved in the patho-physiologic mechanism of bipolar disorders. Studies demonstrated that carbamazepine decreases the release of norepinephrine [10].

Effects on voltage-gated sodium channels
Carbamazepine stabilizes the inactivated state of voltage-gated sodium channels, making fewer of these channels available to subsequently open. This leaves the affected cells less excitable until the drug dissociates. By doing this carbamazepine like vaproate decreases influx of sodium ion and increases efflux of potassium ion [8,10].

Pharmacokinetics of Carbamazepine
Metabolized in the liver, primarily by CYP450 3A4. It is renal excreted. The active metabolite is (carbamazepine-10,11 epoxide). Initial half-life 26-65 h (35-40 h for extended release formulation); half-life 12-17 h with repeated doses Half-life of active metabolite is approximately 34 h. It Is not only a substrate for CYP450 3A4, but also an inducer of CYP450 3A4. Thus, carbamazepine induces its own 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 strong inducer of hepatic enzymes and the plasma half-life shortens to about 15 h when it is given repeatedly [10].
Bioavailability is 80% and its peak plasma levels are reached 2-8 h after a single dose. Carbamazepine is 70-80% bound to plasma protein.
The average half-life after a single dose is 26 h, with a range of 18-54 h. However, with long-term administration, the half-life decreases to approximately 12 h (range, 10-25 h). This change occurs with the induction of hepatic P450 enzymes, which increase the rate of metabolism of Carbamazepine itself (auto induction) [10,11]. The degree of Carbamazepine auto induction is somewhat dose dependent but is usually complete after 3-5 weeks of treatment [10,11,13].
Carbamazepine is metabolized in the liver and then excreted by the kidneys, as only 1 percent is eliminated by biliary excretion [10,11,13].

Pre-carbamazepine work up and monitoring
Before starting carbamazepine treatments other causes of mood disorder or manic symptoms, including medical disorders, medications and substances of abuse, should be excluded. Screening laboratory exams should include liver function tests, thyroid function tests, CBC and ECG in patients over 40 years old or with pre-existing cardiac disease. In females of childbearing age, pregnancy should be excluded due to carbamazepine use during the first trimester is associated with teratogenic effect (especially neural tube defect) ( Table  1). Start folic acid supplement in women (pregnant) who are carbamazepine [10,[16][17][18][19][20][21][22][23].

Summary of predictors for good carbamazepine response
1) Past history of good carbamazepine response (personal or family).
2) History of alcoholism. Carbamazepine use may associate with severe liver damage especially after 6 month.
In cases of aggravated liver dysfunction or acute liver disease discontinue carbamazepine. or If adequate response not obtained. Trough levels >7 mg/L are associated with therapeutic response in bipolar disorder.

2) CBC
If patient develop fever, sore throat, etc. while on carbamazepine treatment

Hematological side effects
• Carbamazepine may cause life-threatening thrombocytopenia, agranulocytosis, and aplastic anemia in 0.005% of patients. Carbamazepine should be discontinued if the WBC declines to less than 3000 mm, absolute neutrophil count <1500 mm or platelet count decreases to <100,000 cells per mm [10,19]. • In the early phase of treatment transient and minor decreases in blood cell indices may occur and do not warrant discontinuation of carbamazepine [10,19,22].

Liver (hepatic side effects)
Carbamazepine has been associated with rare reports of severe hepatitis and cholestatic jaundice has been associated with enzyme elevations. If patient develop hepatitis the medication should be discontinued immediately [10].

Weight gain and carbamazepine
Long-term treatment with carbamazepine is associated with small degrees of weight gain, which are significantly less than those observed on valproate [10].

Pregnancy and carbamazepine
Use of carbamazepine during pregnancy especially associated with teratogenic effect including neural tube defects, such as spina bifida. Preconceptual education and folate-vitamin b complex supplementation for all for pregnant women is necessary. The tearatogenic side effect less in carbamazepine as compared to valproate but higher than lithium [10,24].

Overdose and toxicity of carbamazepine
In overdose, carbamazepine produces seizures, confusion, stupor, motor restlessness, drowsiness, ataxia, dilated pupils, muscle twitching, tremor, hypotension or hypertension, athetoid movements, nystagmus, abnormal reflexes, oliguria, nausea and vomiting. Cardiac arrhythmias do not generally occur unless very large doses are ingested and few fatalities have been reported even after ingestion of as high as 10-20 g of carbamazepine [10,19,22].

Drug Interactions
Carbamazepine is a potent inducer of cytochrome P450 oxidase enzymes, particularly of the 3A4 category so that it reduces in the levels of a variety of other compounds concurrently used with it [31]. Carbamazepine concentrations are known to be increased with concurrent use of antidepressants (such as fluexetine, fluovoxamine, nefazodone), omeperazole, efavirnaz, ratinovir, valproatecarthromycin, cemitidine and erythrpmycin [32]. Its level decrease when administrated with rifampicin. Here are common drug interactions of carbamazepine [10,31,32].

Drug interactions which increase serum levels of carbamazepine
Medications such as erythromycin, fluoxetine, cimetidine, isoniazid, ketoconazole, loratadine, verapamil, diltiazem and danazol inhibit the metabolism of carbamazepine with resultant increase in serum levels and neurotoxicity.
Drug interactions which in decrease serum levels of carbamazepine: Rifampin and Cisplatin cause cytochrome P450 enzyme induction and decreased carbamazepine levels.
Drug interactions of carbamazepine which increase serum levels of other drugs: Carbamazepine will induce hepatic microsomal enzymes and enhance the metabolism (decrease serum levels and decrease the effectiveness) of drugs such as acetaminophen, clozapine haloperidol, benzodiazepines (especially alprazolam, triazolam), oral contraceptives, corticosteroids, cyclosporine, doxycycline, mebendazole, methadone, theophylline, thyroid supplements, valproate and warfarin.

Other Interactions
1) Diuretics may cause hypo natremia can occur with carbamazepine alone.
2) MAOI need to be given after minimum 14-day washout due to the molecular similarity between tricyclic antidepressants and carbamazepine.