Common side effects includenausea anddrowsiness.[1] Serious side effects may include skin rashes, decreasedbone marrow function,suicidal thoughts, or confusion.[1] It should not be used in those with a history of bone marrow problems.[1] Use duringpregnancy may cause harm to the baby; however, stopping the medication in pregnant women with seizures is not recommended.[1] Its use duringbreastfeeding is not recommended.[1] Care should be taken in those with either kidney or liver problems.[1]
Carbamazepine is typically used for the treatment ofseizure disorders andneuropathic pain.[1] It is usedoff-label as a second-line treatment for bipolar disorder and in combination with anantipsychotic in some cases ofschizophrenia when treatment with a conventional antipsychotic alone has failed.[1][14] However, evidence does not support this usage.[15] It is not effective forabsence seizures ormyoclonic seizures.[1] Although carbamazepine may have a similar effectiveness (people continue on medication) and efficacy (medicine reduces seizure recurrence and improves remission) 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.[5]
The drug is also claimed to be effective forADHD.[17]
As of 2014, acontrolled 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.[18]
The typical dose for seizures in adults; however, ranges from 400 mg per day to 1,200 mg per day.[1] Lower doses of 200 mg per day may be used for trigeminal neuralgia and increased up to 200 mg three times per day.[1][20]
Side effects
a)Palpable purpuric lesions b) lesions around ankle
In the US, the label for carbamazepine contains warnings concerning:
risk of seizures, if the person stops taking the drug abruptly[3]
risks to the fetus in women who are pregnant, specifically congenital malformations likespina bifida, and developmental disorders.[3][23]
Commonadverse 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 thecentral nervous system.[3] Less common side effects may include increased risk of seizures in people withmixed seizure disorders,[24]abnormal heart rhythms, blurry ordouble vision.[3] Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about asemitone lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine.[25]
Interactions
Carbamazepine has a potential fordrug interactions; caution should be used in combining other medicines with it, including other antiepileptics and mood stabilizers.[16] Lower levels of carbamazepine are seen when administrated withphenobarbital,phenytoin, orprimidone, which can result in breakthrough seizure activity. Carbamazepine, as aCYP450 inducer, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects.[26] Drugs that are more rapidly metabolized with carbamazepine includewarfarin,lamotrigine,phenytoin,theophylline, andvalproic acid.[16] Drugs that decrease the metabolism of carbamazepine or otherwise increase its levels includeerythromycin,[27]cimetidine,propoxyphene, andcalcium channel blockers.[16] Carbamazepine also increases the metabolism of the hormones inbirth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[16] As a drug that inducescytochrome P450 enzymes, it accelerates elimination of manybenzodiazepines and decreases their action.[28]
Valproic acid andvalnoctamide both inhibitmicrosomal epoxide hydrolase (MEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.[29] 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 thebioavailability of carbamazepine by inhibiting CYP3A4 enzymes in the gut wall and in the liver.[3] Carbamazepine increases the processing ofmethadone resulting in lower blood levels.[30]
Pharmacogenetics
Serious skin reactions such asStevens–Johnson syndrome ortoxic epidermal necrolysis due to carbamazepine therapy are more common in people with a particularhuman leukocyte antigen allele,HLA-B*1502.[3]Odds ratios for the development of Stevens-Johnson syndrome ortoxic epidermal necrolysis (SJS/TEN) in people who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied.[31][32]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.[3][33] However, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions, such as theDRESS syndrome form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans.[32][34] 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.[35]
Mechanism of action
Candidate genes involved in the pharmacokinetics of carbamazepine.[36]
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 aserotonin releasing agent and possibly even aserotonin reuptake inhibitor.[38][39][40]
Pharmacokinetics
Carbamazepine is relatively slowly but well absorbed after oral administration.[41]
Its plasma half-life is about 36 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 8-12 hours when it is given repeatedly.[41]
History
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part ofNovartis) inBasel,Switzerland, in 1953.[42][43] It was first marketed as a drug to treat epilepsy inSwitzerland in 1963 under the brand name "Tegretol"; its use fortrigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time.[42] It has been used as an anticonvulsant and antiepileptic in theUK since 1965, and has been approved in theUS since 1968.[1]
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.[44]
The wholesale cost in thedeveloping world is about US$0.07 to US$0.24per day as of 2015.[11] In 2017, it was the 176th most commonly prescribed medication in the United States, with more than three million prescriptions.[12][13]
Carbamazepine and its (bio-)transformation products have been detected in wastewater treatment planteffluent[45]: 224 and in streams receiving treated wastewater.[46] Field and laboratory studies have been conducted to understand the accumulation of carbamazepine in food plants grown in soil treated withsludge, 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 ade minimis risk to human health according to the approach."[45]: 227
Brand names
Carbamazepine is available worldwide under many brand names including Tegretol.[47]
↑World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
↑11.011.1"Carbamazepine".International Medical Products Price Guide.Archived from the original on 29 July 2020. Retrieved26 November 2019.
↑Ceron-Litvoc D, Soares BG, Geddes J, Litvoc J, de Lima MS (January 2009). "Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials".Human Psychopharmacology.24 (1):19–28.doi:10.1002/hup.990.PMID19053079.
↑Liu L, Zheng T, Morris MJ, Wallengren C, Clarke AL, Reid CA, et al. (November 2006). "The mechanism of carbamazepine aggravation of absence seizures".The Journal of Pharmacology and Experimental Therapeutics.319 (2):790–8.doi:10.1124/jpet.106.104968.PMID16895979.S2CID7693614.
↑Tateno A, Sawada K, Takahashi I, Hujiwara Y (August 2006). "Carbamazepine-induced transient auditory pitch-perception deficit".Pediatric Neurology.35 (2):131–4.doi:10.1016/j.pediatrneurol.2006.01.011.PMID16876011.
↑Schlatter J, Madras JL, Saulnier JL, Poujade F (September 1999). "[Drug interactions with methadone]" [Drug interactions with methadone].Presse Médicale (in French).28 (25):1381–4.PMID10506872.{{cite journal}}: CS1 maint: unrecognized language (link)
↑32.032.1Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al. (April 2014). "Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions".Epilepsia.55 (4):496–506.doi:10.1111/epi.12564.hdl:2429/63109.PMID24597466.
↑Dailey JW, Reith ME, Steidley KR, Milbrandt JC, Jobe PC (October 1998). "Carbamazepine-induced release of serotonin from rat hippocampus in vitro".Epilepsia.39 (10):1054–63.doi:10.1111/j.1528-1157.1998.tb01290.x.PMID9776325.
↑Dailey JW, Reith ME, Yan QS, Li MY, Jobe PC (June 1997). "Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+".European Journal of Pharmacology.328 (2–3):153–62.doi:10.1016/s0014-2999(97)83041-5.PMID9218697.
↑41.041.1Rogawski, Michael A. (2020). "24. Antiseizure drugs". In Katzung, Bertram G.; Trevor, Anthony J. (eds.).Basic and Clinical Pharmacology (15th ed.). New York: McGraw-Hill. pp. 4427–430.ISBN978-1-260-45231-0.Archived from the original on 10 October 2021. Retrieved7 November 2021.
↑42.042.1D.F. Scott. "Carbamazepine". Chapter 8 in The History of Epileptic Therapy: An Account of How Medication was Developed. History of Medicine Series. CRC Press, 1993ISBN9781850703914
↑Okuma T, Kishimoto A (February 1998). "A history of investigation on the mood stabilizing effect of carbamazepine in Japan".Psychiatry and Clinical Neurosciences.52 (1):3–12.doi:10.1111/j.1440-1819.1998.tb00966.x.PMID9682927.
↑45.045.1Prosser RS, Sibley PK (February 2015). "Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation".Environment International.75:223–33.doi:10.1016/j.envint.2014.11.020.PMID25486094.
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