Carbamazepine

Article Author:
Jasdave Maan
Article Editor:
Abdolreza Saadabadi
Updated:
10/27/2018 12:31:27 PM
PubMed Link:
Carbamazepine

Indications

Carbamazepine is FDA indicated for epilepsy, trigeminal neuralgia, and acute manic and mixed episodes in bipolar I disorder. Indications for epilepsy are specifically for partial seizures with complex symptomatology (psychomotor, temporal lobe), generalized tonic seizures (grand mal), and mixed seizure patterns. Carbamazepine is not indicted for absence seizures. Carbamazepine is FDA indicated as first-line treatment trigeminal neuralgia or tic douloureux. Randomized control trials have shown that carbamazepine has similar efficacy to lithium in acute manic episodes.

Carbamazepine is used off-label for refractory schizophrenia. Simple well designed trials have shown efficacy in patients with schizophrenia with EEG abnormalities, schizophrenia with violent episodes, and schizoaffective disorder. It improves both positive and negative symptoms in schizophrenic patients. Other off-label uses of this drug include treatment of restless leg syndrome and decreasing agitation and aggression in patients with dementia. Another prominent off-label use of this drug is the treatment of neuropathic pain and fibromyalgia. In patients with moderate to severe alcohol withdrawal syndrome, Carbamazepine has been shown to have clinical efficacy in treatment. However, this is not approved by the FDA, and it has not been shown to prevent alcohol withdrawal seizures as compared to benzodiazepines.

Mechanism of Action

Currently, the mechanism of action for carbamazepine in humans is still not understood completely by researchers. It has been proposed via animal research that this drug works by reducing polysynaptic responses and blocking the post-tetanic potentiation. It was also shown to reduce pain that is caused by stimulation of an infraorbital nerve in cats and rats. Another group of findings was the reduction of the action potential in the nucleus ventralis of the thalamus and depression of the lingual mandibular reflex. This reduction of action potential occurs by carbamazepine binding to voltage-dependent sodium channels and inhibiting the generation of rapid action potentials. This effect increases with increased rates of neuronal firing.

Administration

Carbamazepine is available as conventional tablets, extended-release tablets, suspensions, and solutions. Oral administration is available as conventional chewable tablets in 100 mg, 200 mg and extended-release tablets are available in 100 mg, 200 mg, 300 mg and 400 mg. Suspensions, conventional tablets, and extended-release tablets deliver equivalent amounts of drug to the systemic circulation. The suspension is absorbed faster than the other two modes of administration, and the extended-release tablet is absorbed slightly slower than conventional tablets. Initial dosing is at 200 twice daily in adults and 100 twice daily in children under 12, slowly increased over time to minimum effective level. Minimum effectively levels in adults and children over 12 years is 800 mg to 1200mg daily for treatment of epilepsy. In children from six to 12 years, the effective level for treatment of epilepsy is 400 mg to 800 mg daily.

Adverse Effects

The most common side effects of carbamazepine include dizziness, drowsiness, ataxia nausea, and vomiting. Although rarer in occurrence, this comes with a black box warning for several severe dermatologic reactions. In patients of Han Chinese ancestry studies have indicated a strong association between the HLA-B*1502 gene and Steven Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Studies have shown no increased risk with this gene and SJS/TEN in Iranian patients. A meta-analysis of 11 studies with 343 cases of carbamazepine-induced SJS/TEN showed HLB-B*4001, HLB*4601, and HLB*5801 genes were strong protective factors. Another risk factor for these dermatologic reactions was the HLA-B*1511 gene in the Asian population. HLA-B*1502 is largely absent in the non-Asian origins. Patients with Han Chinese ancestry should undergo testing for the HLA-B*1502 gene. Up to 90 % of patients on carbamazepine who have this reaction experience it within the first few months of treatment. Another important allele to consider with this medication is HLA*3101. This allele is found in Japanese, Korean, and European ancestry. Retrospective studies show a significantly increased incidence of dermatologic reactions such as Steven Johnson syndrome, Toxic epidemic necrolysis, maculopapular eruptions, and drug reaction with eosinophilia and systemic symptoms (Dress syndrome). Other serious side effects include aplastic anemia, agranulocytosis, central nervous system depression, hepatotoxicity, confusion, renal toxicity, suicidal ideation, and hyponatremia. Hyponatremia is mild, transient, and reversible. Mild anticholinergic effects such as urinary retention, increased intraocular pressure, and constipation have also been reported. Carbamazepine can exacerbate heart failure patients or even lead to cardiac dysfunction in healthy patients due to its tendency to cause homocysteinemia. Homocysteine is commonly known to increase the risk for cardiovascular disease. Patients with cardiac conduction issues have a higher risk of undergoing atrioventricular (AV) heart block. Use of this drug in patients with an abnormal ECG should be avoided to elude potential second and third degree AV heart block. This drug is teratogenic and is established as a category D drug in pregnancy. Although carbamazepine is not contraindicated in pregnancy, it should only be used if the benefits outweigh the increased risk of congenital malformation. Such malformations include spina bifida, craniofacial defection, cardiovascular cutaneous malformation, hypospadias, and developmental delays. This drug can be transferred through the breast milk in nursing infants, prompting a design to make of whether to discontinue nursing or discontinue the drug in the mother. Precautions should be taking in mixed seizure disorder that includes atypical absence seizures. There is an increased frequency of generalized convulsions in this group of patients with this drug.

Contraindications

Carbamazepine has been contraindicated in patients who have bone marrow depression and are hypersensitive to this drug or tricyclic compounds such as amitriptyline. Before administration, monoamine oxidizes inhibitors should be discontinued for a minimum of 14 days. Usage carbamazepine and nefazodone together may result in insufficient plasma concentration of nefazodone. Carbamazepine is contraindicated in use with non-nucleoside reverse transcriptase inhibitors due to interaction with CYP3A4.

Monitoring

Carbamazepine is metabolized in the liver to carbamazepine-10, 11-epoxide which is the active metabolite the leads to pharmacological action. Before administration of this drug, a few labs should be taken into consideration. Screening for HLA-A*3101 and HLA-B*1502 genotypes should be conducted alongside a pregnancy test. Complete blood counts (CBC)  should be obtained at baseline and the drug should be discontinued if low white blood count or platelet count is encountered on subsequent lab results. Liver enzymes should be assessed to avoid acute liver failure. This drug shows an increased risk for suicidal thoughts and behavior, prompting psychiatric assessment of patients of this drug if possible. Patients with increased intraocular pressure should have periodic eye examinations to look out for certain ocular changes, focusing on the slit lamp, fundoscopy, and tonometry.  This drug has shown increased porphyrin production in rodents. Patients with a history of porphyrias, such as acute intermittent porphyry, variegate porphyria, and porphyria cutanea tarda, should be carefully monitored to avoid acute attacks.

This drug should be discontinued at first sign of a drug-related rash. Withdrawal should be gradual as immediate withdrawal severely increases the risk for status epilepticus. This leads to severe hypoxia that can be fatal, especially to a pregnant woman. Even smaller seizures form withdrawing the drug too fast can lead to significant damage to the fetus. Routine screening should be ordered with a pregnant woman to assess for possible defects.

Toxicity

In adults, doses of carbamazepine exceeding 24 grams have been associated with fatal outcomes. Acute toxicity appears after 1 to 3 hours of intake and presents with neuromuscular disturbances.  Patients have impaired consciousness leading to coma, tremor, restlessness, athetoid movements, psychomotor disturbances, dizziness, drowsiness, mydriasis, and nystagmus. Initially, patients experience hyperreflexia, but during intoxication, they progress into a state of hyporeflexia. Cardiac, vascular signs are generally mild with low toxicity, but with doses higher than 60 grams severe cardiac dysfunction can occur. During acute toxicity respiratory depression, ECG abnormalities, tachycardia, shock, and urinary retention should all be monitored and managed to avoid end-organ damage. Treatment of an overdose is focused on the elimination of the drug by inducing vomiting, gastric lavage, activated charcoal, and forced diuresis. Gastric lavage is indicated even after 4 hours of indigestion. Seizures caused by carbamazepine poisoning should be treated with benzodiazepines such as diazepam.



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