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Carbamazepine

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Not to be confused with Carbamazine.

Carbamazepine
Clinical data
Trade namesTegretol, others
Other namesCBZ
AHFS/Drugs.comMonograph
MedlinePlusa682237
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth
Drug classAnticonvulsant[1]
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~100%[4]
Protein binding70–80%[4]
MetabolismLiver (CYP3A4)[4]
MetabolitesActive epoxide form (carbamazepine-10,11 epoxide)[4]
Elimination half-life36 hours (single dose), 16–24 hours (repeated dosing)[4]
ExcretionUrine (72%), feces (28%)[4]
Identifiers
  • 5H-dibenzo[b,f]azepine-5-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.512 Edit this at Wikidata
Chemical and physical data
FormulaC15H12N2O
Molar mass236.274 g·mol−1
3D model (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 anticonvulsant medication used in the treatment of epilepsy and neuropathic pain.[3][1] It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder.[5][1] Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures.[6] It is not effective for absence or myoclonic seizures.[1]

Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler.[7][8] It was first marketed in 1962.[9] It is available as a generic medication.[10] It is on the World Health Organization's List of Essential Medicines.[11] In 2020, it was the 185th most commonly prescribed medication in the United States, with more than 2 million prescriptions.[12][13]

Medical uses

Tegretol 200-mg CR (made in NZ)

Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain.[1] 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.[1][14] However, evidence does not support its usage for schizophrenia.[15] It is not effective for absence seizures or 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.[6]

In the United States, carbamazepine is indicated for the treatment of epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), and trigeminal neuralgia.[3][16] Carbamazepine is the only medication that is approved by the Food and Drug Administration for the treatment of trigeminal neuralgia.[17]

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.[18]


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.[4]

Interactions

Carbamazepine has a potential for drug interactions.[16] Drugs that decrease breaking down of carbamazepine or otherwise increase its levels include erythromycin,[19] cimetidine, propoxyphene, and calcium channel blockers.[16] Grapefruit juice raises the bioavailability of carbamazepine by inhibiting the enzyme CYP3A4 in the gut wall and in the liver.[4] Lower levels of carbamazepine are seen when administrated with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity.[20]

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.[21] 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 cytochrome P450 enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects.[20] Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, valproic acid,[16] many benzodiazepines,[22] and methadone.[23] Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[16]

Pharmacology

Mechanism of action

Carbamazepine is a sodium channel blocker.[24] 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.[25][26][27] It has been suggested that carbamazepine can also block voltage-gated calcium channels, which will reduce neurotransmitter release. [28]

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 blood 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 lower minimum concentrations.[29][30]

In the circulation, carbamazepine itself comprises 20 to 30% of total residues. The remainder is in the form of metabolites; 70 to 80% of residues is bound to plasma proteins. Concentrations in breast milk are 25 to 60% of those in the blood plasma.[30]

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 its glucuronides. Other metabolites include various hydroxyl derivatives and carbamazepine-N-glucuronide.[30]

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.[29][30]

History

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.[31][32] 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.[31] 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.[33]

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[34]: 224  and in streams receiving treated wastewater.[35] 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."[34]: 227 

Brand names

Carbamazepine is available worldwide under many brand names including Tegretol.[36]

Research

References

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  2. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  3. ^ a b c "Tegretol- carbamazepine suspension Tegretol- carbamazepine tablet Tegretol XR- carbamazepine tablet, extended release". DailyMed. 16 May 2022. Retrieved 3 January 2023.
  4. ^ a b c d e f g h Cite error: The named reference carbamazepinelabel was invoked but never defined (see the help page).
  5. ^ Nevitt SJ, Marson AG, Weston J, Tudur Smith C (August 2018). "Sodium valproate versus phenytoin monotherapy for epilepsy: an individual participant data review". The Cochrane Database of Systematic Reviews. 2018 (8): CD001769. doi:10.1002/14651858.CD001769.pub4. PMC 6513104. PMID 30091458.
  6. ^ a b Nevitt SJ, Marson AG, Tudur Smith C (July 2019). "Carbamazepine versus phenytoin monotherapy for epilepsy: an individual participant data review". The Cochrane Database of Systematic Reviews. 2019 (7): CD001911. doi:10.1002/14651858.CD001911.pub4. PMC 6637502. PMID 31318037.
  7. ^ Smith HS (2009). Current therapy in pain. Philadelphia: Saunders/Elsevier. p. 460. ISBN 978-1-4160-4836-7. Archived from the original on 5 March 2016.
  8. ^ US patent 2948718, Walter Schindler, "New n-heterocyclic compounds", published 1960-08-09, issued 1960-08-09, assigned to Geigy Chemical Corporation 
  9. ^ Moshé S (2009). The treatment of epilepsy (3 ed.). Chichester, UK: Wiley-Blackwell. p. xxix. ISBN 978-1-4443-1667-4. Archived from the original on 5 March 2016.
  10. ^ Porter NC (2008). "Trigeminal Neuralgia: Surgical Perspective". In Chin LS, Regine WF (eds.). Principles and practice of stereotactic radiosurgery. New York: Springer. p. 536. ISBN 978-0-387-71070-9. Archived from the original on 5 March 2016.
  11. ^ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  12. ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
  13. ^ "Carbamazepine - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
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  33. ^ 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. PMID 9682927. S2CID 8480811.
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Further reading

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