|ATC code||N03AF01 (WHO)|
|Metabolism||Hepatic—by CYP3A4, to active epoxide form (carbamazepine-10,11 epoxide)|
|Biological half-life||36 hours (single dose), 16-24 hours (repeated dosing)|
|Excretion||Urine (72%), feces (28%)|
|CAS Number||298-46-4 85756-57-6|
|Chemical and physical data|
|Molar mass||236.269 g/mol|
|3D model (Jmol)||Interactive image|
Carbamazepine (CBZ), sold under the tradename Tegretol among others, is a medication used primarily in the treatment of epilepsy and neuropathic pain. For seizures it works as well as phenytoin and valproate. It is not effective for absence seizures or myoclonic seizures. It may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder. It is taken two to four times per day. A controlled release formulation is available for which there is tentative evidence showing fewer side effects.
Common side effects include nausea and drowsiness. Serious side effects may include skin rashes, decreased bone marrow function, suicidal thoughts, or 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.
Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler. It was first marketed in 1962. It is available as a generic medication and is not very expensive. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. The wholesale cost in the developing world is between 0.01 and 0.07 USD per dose as of 2014.
Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain. It is used off-label as a second-line treatment for bipolar disorder and in combination with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed.
In the United States, the FDA-approved medical uses are epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), trigeminal neuralgia, and manic and mixed episodes of bipolar I disorder.
It is unclear if there is a significant difference in effectiveness between controlled release and immediate release formulations in epilepsy. Controlled release forms might, however, have lower risks of side effects.
In the US, the label for carbamazepine contains warnings concerning:
- effects on the body's production of red blood cells, white blood cells, and platelets: rarely, there are major effects of aplastic anemia and agranulocytosis reported and more commonly, there are minor changes such as decreased white blood cell or platelet counts, that do not progress to more serious problems.
- increased risks of suicide
- risk of seizures, if the person stops taking the drug abruptly
- risks to the fetus in women who are pregnant, specifically congenital malformations like spina bifida, and developmental disorders.
Common adverse effects may include drowsiness, dizziness, headaches and migraines, motor coordination impairment, nausea, vomiting, and/or constipation. Alcohol use while taking carbamazepine may lead to enhanced depression of the central nervous system. Less common side effects may include increased risk of seizures in people with mixed seizure disorders, abnormal heart rhythms, blurry or double vision. Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about a semitone lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine.
Carbamazepine has a potential for drug interactions; caution should be used in combining other medicines with it, including other antiepileptics and mood stabilizers. Lower levels of carbamazepine are seen when administrated with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity. Carbamazepine, as a CYP450 inducer, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects. Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, and valproic acid. Drugs that decrease the metabolism of carbamazepine or otherwise increase its levels include erythromycin, cimetidine, propoxyphene, and calcium channel blockers. Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies. As a drug that induces cytochrome P450 enzymes, it accelerates elimination of many benzodiazepines and decreases their action.
Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (MEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites. By inhibiting MEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Grapefruit juice raises the bioavailability of carbamazepine by inhibiting CYP3A4 enzymes in the gut wall and in the liver. Carbamazepine increases the processing of methadone resulting in lower blood levels.
Dangerous and potentially fatal skin reactions, including Stevens–Johnson syndrome and toxic epidermal necrolysis, caused by carbamazepine therapy are significantly more common in patients with a particular human leukocyte antigen allele, HLA-B*1502. Odds ratios for the development of Stevens-Johnson syndrome or toxic epidermal necrolysis in patients who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied. HLA-B*1502 occurs almost exclusively in patients with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations. However, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions to carbamazepine among Japanese and Europeans.
Carbamazepine is relatively slowly but well absorbed after oral administration. Its plasma half-life is about 30 hours 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 hours when it is given repeatedly.
Mechanism of action
The mechanism of action of carbamazepine and its derivatives is relatively well understood. Carbamazepine is a use-dependant blocker of voltage-gated sodium channels. It is ionised within intracellular fluid, and is then able to bind to activated voltage-gated sodium channels, preventing repetitive and sustained firing of an action potential.This leaves the affected cells less excitable until the drug dissociates. Carbamazepine is also a GABA receptor agonist, as it has also been shown to potentiate GABA receptors made up of alpha1, beta2, and gamma2 subunits. This mechanism may contribute to its efficacy in neuropathic pain and bipolar disorder. Laboratory research has further demonstrated that carbamazepine is a serotonin releasing agent and possibly even a serotonin reuptake inhibitor.
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953. It was first marketed as a drug to treat epilepsy in Switzerland in 1963 under the brand name "Tegretol"; its use for trigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time. It has been used as an anticonvulsant and antiepileptic in the UK since 1965, and has been approved in the US since 1968.
In 1971, Drs. Takezaki and Hanaoka first used carbamazepine to control mania in patients refractory to antipsychotics (lithium was not available in Japan at that time). Dr. Okuma, working independently, did the same thing with success. As they were also epileptologists, they had some familiarity with the antiaggression effects of this drug. Carbamazepine was studied for bipolar disorder throughout the 1970s.
Carbamazepine has been detected in wastewater effluent.:224 Field and laboratory studies have been conducted to understand the accumulation of carbamazepine in food plants grown in soil treated with sludge, which vary with respect to the concentrations of carbamazepine present in sludge and in the concentrations of sludge in the soil; taking into account only studies that used concentrations normally found, a 2014 review found that "the accumulation of carbamazepine into plants grown in soil amended with biosolids poses a de minimis risk to human health according to the approach.":227
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|Wikimedia Commons has media related to Carbamazepine.|
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