Carbamazepine

Source: Wikipedia, the free encyclopedia.
Not to be confused with
Carbamazine
.

Carbamazepine
Clinical data
Trade namesTegretol, others
Other namesCBZ
AHFS/Drugs.comMonograph
MedlinePlusa682237
License data
Pregnancy
category
  • AU: D
By mouth
Drug classAnticonvulsant[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%[5]
Protein binding70–80%[5]
MetabolismLiver (CYP3A4)[5]
MetabolitesActive epoxide form (carbamazepine-10,11 epoxide)[5]
Elimination half-life36 hours (single dose), 16–24 hours (repeated dosing)[5]
ExcretionUrine (72%), feces (28%)[5]
Identifiers
  • 5H-dibenzo[b,f]azepine-5-carboxamide
JSmol)
  • c1ccc2c(c1)C=Cc3ccccc3N2C(=O)N
  • InChI=1S/C15H12N2O/c16-15(18)17-13-7-3-1-5-11(13)9-10-12-6-2-4-8-14(12)17/h1-10H,(H2,16,18) checkY
  • Key:FFGPTBGBLSHEPO-UHFFFAOYSA-N checkY
  (verify)

Carbamazepine, sold under the brand name Tegretol among others, is an

myoclonic seizures.[1]

Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler.

generic medication.[11] It is on the World Health Organization's List of Essential Medicines.[12] In 2020, it was the 185th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14]

Medical uses

Tegretol 200-mg CR (made in NZ)

Carbamazepine is typically used for the treatment of

myoclonic 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 to phenytoin and valproate, 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]

In the United States, carbamazepine is

mixed seizures), and trigeminal neuralgia.[4][17] Carbamazepine is the only medication that is approved by the Food and Drug Administration for the treatment of trigeminal neuralgia.[18]

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.[19]

Adverse effects

In the US, the label for carbamazepine contains warnings concerning:[4]

Common

abnormal heart rhythms, blurry or double vision.[5] 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.[24]

Pharmacogenetics

Serious skin reactions such as

DRESS form of severe cutaneous reactions, to carbamazepine among Japanese, Chinese, Korean, and Europeans.[26][28] 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.[29]

Interactions

Carbamazepine has a potential for

propoxyphene, and calcium channel blockers.[17] Grapefruit juice raises the bioavailability of carbamazepine by inhibiting the enzyme CYP3A4 in the gut wall and in the liver.[5] Lower levels of carbamazepine are seen when administered with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity.[31]

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of the active metabolite carbamazepine-10,11-epoxide into inactive metabolites.[32]
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 of

birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[17]

Pharmacology

Mechanism of action

Carbamazepine is a

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.[36][37][38] It has been suggested that carbamazepine can also block voltage-gated calcium channels, which will reduce neurotransmitter release.[39]

Pharmacokinetics

Metabolism. Top: carbamazepine • middle: carbamazepine-10,11-epoxide, the active metabolite • bottom: carbamazepine-10,11-diol, an inactive metabolite, which is then glucuronidized

Carbamazepine is relatively slowly but practically completely absorbed after administration by mouth. Highest concentrations in the

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 lower minimum concentrations.[40][41]

In the circulation, carbamazepine itself comprises 20 to 30% of total residues. The remainder is in the form of

plasma proteins. Concentrations in breast milk are 25 to 60% of those in the blood plasma.[41]

Carbamazepine itself is not pharmacologically active. It is activated, mainly by CYP3A4, to carbamazepine-10,11-

hydroxyl derivatives and carbamazepine-N-glucuronide.[41]

The

plasma half-life is about 35 to 40 hours when carbamazepine is given as single dose, but it is a strong inducer 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 as phenytoin or phenobarbital. About 70% are excreted via the urine, almost exclusively in form of its metabolites, and 30% via the faeces.[40][41]

History

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.[42][43] 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.[42] 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.[44]

Society and culture

Environmental impact

Main article: Environmental impact of pharmaceuticals and personal care products

Carbamazepine and its bio-transformation products have been detected in wastewater treatment plant effluent[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 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 commonly found in the environment, a 2014 review concluded 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."[45]: 227 

Brand names

Carbamazepine is available worldwide under many brand names including Tegretol.[47]

Research

References

  1. ^ a b c d e f g h "Carbamazepine". The American Society of Health-System Pharmacists. Archived from the original on 27 February 2015. Retrieved 28 March 2015.
  2. FDA
    . Retrieved 22 October 2023.
  3. ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  4. ^ a b c d "Tegretol- carbamazepine suspension Tegretol- carbamazepine tablet Tegretol XR- carbamazepine tablet, extended release". DailyMed. 16 May 2022. Retrieved 3 January 2023.
  5. ^ a b c d e f g h i j k l m n o "Carbamazepine Drug Label". Archived from the original on 8 December 2014.
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  9. ^ US patent 2948718, Walter Schindler, "New n-heterocyclic compounds", published 1960-08-09, issued 1960-08-09, assigned to Geigy Chemical Corporation 
  10. ISBN 978-1-4443-1667-4. Archived
    from the original on 5 March 2016.
  11. ISBN 978-0-387-71070-9. Archived
    from the original on 5 March 2016.
  12. hdl:10665/325771
    . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  13. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  14. ^ "Carbamazepine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
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  17. ^ a b c d e Lexi-Comp (February 2009). "Carbamazepine". The Merck Manual Professional. Archived from the original on 3 November 2010. Retrieved on 3 May 2009.
  18. ^ Pino MA (19 January 2017). "Trigeminal Neuralgia: A "Lightning Bolt" of Pain". US Pharmacist. 42: 41–44.
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  31. ^ a b "Carbamazepine Toxicity". eMedicine. 2 February 2019. Archived from the original on 4 July 2008.
  32. ISBN 978-0-07-142280-2
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  34. PMID 10506872
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  35. PMID 26801895
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  40. ^ a b "Carbamazepine". PubChem. National Library of Medicine, National Institutes of Health, U.S. Department of Health and Human Services. Retrieved 6 May 2021.
  41. ^ a b c d Haberfeld H, ed. (2021). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Tegretol retard 400 mg-Filmtabletten.
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  47. ^ "Carbamazepine". Drugs.com. Retrieved 27 October 2019.

Further reading

External links

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