Photoswitchable analogues of carbamazepine have been developed to control its pharmacological activity locally and on demand using light (photopharmacology), with the purpose of reducing the adverse systemic effects of the drug.[15] One of these light-regulated compounds (carbadiazocine, based on a bridgedazobenzene ordiazocine) has been shown to produce analgesia with noninvasive illuminationin vivo in a rat model ofneuropathic pain.
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][16] However, evidence does not support its usage for schizophrenia.[17] It is not effective forabsence seizures ormyoclonic seizures.[1] Although carbamazepine may have a similar effectiveness (as measured by people continuing to use a medication) and efficacy (as measured by the medicine reducing seizure recurrence and improving remission) when compared tophenytoin andvalproate, choice of medication should be evaluated on an individual basis as further research is needed to determine which medication is most helpful for people with newly-onset seizures.[7]
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.[20]
It has also been shown to improve symptoms of "typewriter tinnitus", a type of tinnitus caused by the neurovascular compression of the cochleovestibular nerve.[21]
Commonadverse effects may include drowsiness, dizziness, headaches and migraines,ataxia, nausea, vomiting, and/or constipation.Alcohol use while taking carbamazepine may lead to enhanced depression of thecentral nervous system.[5] Less common side effects may include increased risk of seizures in people withmixed seizure disorders,[25]abnormal heart rhythms, blurry ordouble vision.[5] 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.[26]
Serious skin reactions such asStevens–Johnson syndrome (SJS) ortoxic epidermal necrolysis (TEN) due to carbamazepine therapy are more common in people with a particularhuman leukocyte antigen gene-variant (allele),HLA-B*1502.[5]Odds ratios for the development of SJS or TEN in people who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied.[27][28]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.[5][29] 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 form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans.[28][30] 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.[31]
Valproic acid andvalnoctamide both inhibitmicrosomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of theactive metabolite carbamazepine-10,11-epoxide into inactive metabolites.[34] By inhibiting mEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.
Carbamazepine, as an inducer ofcytochrome P450 enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects.[33] Drugs that are more rapidly metabolized with carbamazepine includewarfarin,lamotrigine,phenytoin,theophylline,valproic acid,[18] manybenzodiazepines,[35] andmethadone.[36] Carbamazepine also increases the metabolism of the hormones inbirth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[18]
Metabolism. Top: carbamazepine • middle: carbamazepine-10,11-epoxide, theactive metabolite • bottom: carbamazepine-10,11-diol, an inactive metabolite, which is thenglucuronidized
Carbamazepine is relatively slowly but practically completely absorbed after administration by mouth. Highest concentrations in theblood plasma are reached after 4 to 24 hours depending on the dosage form.Slow release tablets result in about 15% lower absorption and 25% lower peak plasma concentrations than ordinary tablets, as well as in less fluctuation of the concentration, but not in significantly lowerminimum concentrations.[42][43]
In the circulation, carbamazepine itself comprises 20 to 30% of total residues. The remainder is in the form ofmetabolites; 70 to 80% of residues is bound toplasma proteins. Concentrations in breast milk are 25 to 60% of those in the blood plasma.[43]
Carbamazepine itself is not pharmacologically active. It is activated, mainly by CYP3A4, to carbamazepine-10,11-epoxide, which is solely responsible for the drug's anticonvulsant effects. The epoxide is then inactivated by microsomal epoxide hydrolase (mEH) to carbamazepine-trans-10,11-diol and further to itsglucuronides. Other metabolites include varioushydroxyl derivatives and carbamazepine-N-glucuronide.[43]
Theplasma half-life is about 35 to 40 hours when carbamazepine is given as single dose, but it is a stronginducer of liver enzymes, and the plasma half-life shortens to about 12 to 17 hours when it is given repeatedly. The half-life can be further shortened to 9–10 hours by other enzyme inducers such asphenytoin orphenobarbital. About 70% are excreted via the urine, almost exclusively in form of its metabolites, and 30% via the faeces.[42][43]
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part ofNovartis) inBasel,Switzerland, in 1953.[44][45] It was first marketed as a drug to treat epilepsy in Switzerland in 1963 under the brand name Tegretol; its use fortrigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time.[44] It has been used as an anticonvulsant and antiepileptic in the United Kingdom since 1965, and has been approved in the United States since 1968.[1]
Carbamazepine was studied for bipolar disorder throughout the 1970s.[46]
Carbamazepine and its bio-transformation products have been detected in wastewater treatment planteffluent[47]: 224 and in streams receiving treated wastewater.[48] 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 commonly found in the environment, a 2014 review concluded that "the accumulation of carbamazepine into plants grown in soil amended with biosolids poses ade minimis risk to human health according to the approach."[47]: 227
^US patent 2948718, Walter Schindler, "New n-heterocyclic compounds", published 9 August 1960, issued 9 August 1960, assigned to Geigy Chemical Corporation
^Organization WH (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.
^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.S2CID5684931.
^Sunwoo, W., Jeon, Y., Bae, Y. et al. Typewriter tinnitus revisited: The typical symptoms and the initial response to carbamazepine are the most reliable diagnostic clues. Sci Rep 7, 10615 (2017).https://doi.org/10.1038/s41598-017-10798-w
^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.
^abAmstutz 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.S2CID41565230.
^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.
^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.
^ab"Carbamazepine".PubChem. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved6 May 2021.
^abScott DF (1993). "Chapter 8: Carbamazepine".The History of Epileptic Therapy: An Account of How Medication was Developed. History of Medicine Series. CRC Press.ISBN978-1-85070-391-4.
^abProsser 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.Bibcode:2015EnInt..75..223P.doi:10.1016/j.envint.2014.11.020.PMID25486094.
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