Carbamazepine
Carbamazepine, sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.
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 the medication 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. It is on the World Health Organization's List of Essential Medicines. The wholesale cost in the developing world is about US$0.07 to US$0.24 per day as of 2015. In 2017, it was the 176th most commonly prescribed medication in the United States, with more than three million prescriptions.
The newer but structurally related drugs, Oxcarbazepine and eslicarbazepine acetate, both show similar interactions, adverse events, and mechanisim of action profiles.
Medical uses
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. However, evidence does not support this usage. It is not effective for absence seizures or myoclonic seizures. Although carbamazepine may have a similar effectiveness and efficacy when compared to phenytoin and valproate the choice of medications should be considered for each person individually as further research is needed to determine which medication is most helpful for people with newly-onset seizures.In the United States, the FDA-approved medical uses are epilepsy, trigeminal neuralgia, and manic and mixed episodes of bipolar I disorder.
The drug is also claimed to be effective for ADHD.
As of 2014, a controlled release formulation was available for which there is tentative evidence showing fewer side effects and unclear evidence with regard to whether there is a difference in efficacy.
Adverse 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, but these do not progress to more serious problems.
- increased risks of suicide
- increased risks of hyponatremia and SIADH
- 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.
Interactions
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, 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.
Pharmacogenetics
Serious skin reactions such as Stevens–Johnson syndrome or toxic epidermal necrolysis due to carbamazepine therapy are more common in people with a particular human leukocyte antigen allele, HLA-B*1502. Odds ratios for the development of Stevens-Johnson syndrome or toxic epidermal necrolysis in people 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 people 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, such as the DRESS syndrome form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans. It is suggested that carbamazepine acts as a potent antigen that binds to the antigen-presenting area of HLA-B*1502 alike, triggering an everlasting activation signal on immature CD8-T cells, thus resulting in widespread cytotoxic reactions like SJS/TEN.Pharmacokinetics
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
Carbamazepine is a sodium channel blocker. It binds preferentially to voltage-gated sodium channels in their inactive conformation, which prevents repetitive and sustained firing of an action potential. Carbamazepine has effects on serotonin systems but the relevance to its antiseizure effects is uncertain. There is evidence that it is a serotonin releasing agent and possibly even a serotonin reuptake inhibitor.History
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG 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 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. 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.