Carbamazepine

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Carbamazepine
Carbamazepine.svg
Carbamazepine 3D.png
Systematic (IUPAC) name
5H-dibenzo[b,f]azepine-5-carboxamide
Clinical data
Trade names Tegretol
AHFS/Drugs.com monograph
MedlinePlus a682237
Licence data US Daily Med:link
  • AU: D
  • US: D (Evidence of risk)
Oral
Pharmacokinetic data
Bioavailability ~100%[1]
Protein binding 70-80%[1]
Metabolism Hepatic—by CYP3A4, to active epoxide form (carbamazepine-10,11 epoxide)[1]
Half-life 36 hours (single dose), 16-24 hours (repeated dosing)[1]
Excretion Urine (72%), feces (28%)[1]
Identifiers
298-46-4 YesY 85756-57-6
N03AF01
PubChem CID 2554
DrugBank DB00564 YesY
ChemSpider 2457 YesY
UNII 33CM23913M YesY
KEGG D00252 YesY
ChEBI CHEBI:3387 YesY
ChEMBL CHEMBL108 YesY
Chemical data
Formula C15H12N2O
236.269 g/mol
 YesY (what is this?)  (verify)

Carbamazepine (CBZ), marketed under the tradename Tegretol among others, is a medication used primarily in the treatment of epilepsy and neuropathic pain.[2] For seizures it works as well as phenytoin and valproate.[3][4] It is not effective for absence seizures or myoclonic seizures. It may be used in schizophrenia along with other medications and as a second line agent in bipolar disorder.[2] It is taken two to four times per day.[2] A controlled release formulation is available for which there is tentative evidence showing less side effects.[5]

Common side effects include nausea and sedation. 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 it 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.[2]

Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler.[6] It is available as a generic medication and is not very expensive.[7] It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[8]

Medical uses[edit]

Tegretol 200-mg CR (made in NZ)

Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain.[2] 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.[2][9]

In the United States, the FDA-approved medical uses are epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), trigeminal neuralgia, and manic and mixed episodes of bipolar I disorder.[10]

It is unclear if there is a significant difference in effectiveness between controlled release and immediate release formulations in epilepsy.[11] Controlled release forms might, however, have lower risks of side effects.[11]

Other uses may include attention deficit hyperactivity disorder, schizophrenia, phantom limb syndrome, complex regional pain syndrome, borderline personality disorder, and post-traumatic stress disorder.[citation needed]

Adverse effects[edit]

In the US, the label for carbamazepine contains warnings concerning:

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.[1] Less common side effects may include increased risk of seizures in people with mixed seizure disorders,[13] abnormal heart rhythms, blurry or double vision.[1] 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.[14]

Interactions[edit]

Carbamazepine has a potential for drug interactions; caution should be used in combining other medicines with it, including other antiepileptics and mood stabilizers.[10] Lower levels of carbamazepine are seen when administrated with phenobarbital, phenytoin (Dilantin), or primidone (Mysoline), 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.[15] Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, and valproic acid.[10] Drugs that decrease the metabolism of carbamazepine or otherwise increase its levels include erythromycin,[16] cimetidine, propoxyphene, and calcium channel blockers.[10] Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[10] As a drug that induces cytochrome P450 enzymes, it accelerates elimination of many benzodiazepines and decreases their action.[17]

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (MEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.[18] 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.[1]

Pharmacogenetics[edit]

The FDA has informed health-care professionals that dangerous or even fatal skin reactions (Stevens–Johnson syndrome and toxic epidermal necrolysis) caused by carbamazepine therapy are significantly more common in patients with a particular human leukocyte antigen allele, HLA-B*1502.[19] Indeed, odds ratios for the development of Stevens-Johnson syndrome or toxic epidermal necrolysis in patients who carry the allele can be in the double, triple or even quadruple digits, depending on the population studied.[20][21] HLA-B*1502 occurs almost exclusively in patients with ancestry across broad areas of Asia, but has a very low or absent frequency in European, Japanese, Korean and African populations.[19][22] However, the HLA-A*31:01 allele has been shown to be a strong predictor of both mild and severe adverse reactions to carbamazepine among Japanese and Europeans.[21]

Pharmacokinetics[edit]

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.[medical citation needed]

Mechanism of action[edit]

The mechanism of action of carbamazepine and its derivatives is relatively well understood. Carbamazepine stabilizes the inactivated state of voltage-gated sodium channels, making fewer of these channels available to subsequently open. This leaves the affected cells less excitable until the drug dissociates.[citation needed] Carbamazepine is also a GABA receptor agonist, as it has also been shown to potentiate GABA receptors made up of alpha1, beta2, and gamma2 subunits.[23] This mechanism may contribute to its efficacy in neuropathic pain and manic-depressive illness.

History[edit]

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.[24] Schindler then synthesized the drug in 1960, before its antiepileptic properties had been discovered. It was first marketed as a drug to treat trigeminal neuralgia (formerly known as tic douloureux) in 1962. It has been used as an anticonvulsant and antiepileptic in the UK since 1965, and has been approved in the US since 1974.

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.[25]

Environmental fate[edit]

Carbamazepine has been detected in wastewater effluent.[26]:224 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 normally found, a 2014 review found 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."[26]:227

Brand names[edit]

Carbamazepine has been sold under the names Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Seizunil, Telesmin, Tegretol, Epitab XR, Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze, Amizepin, Carzine, Mazetol, Neurotop, Tegrital, Tegrita, Zeptol, Karbapin, Hermolepsin, Degranol, and Tegretal.[27]

References[edit]

  1. ^ a b c d e f g h i j k l "Carbamazepine Drug Label". 
  2. ^ a b c d e f "Carbamazepine". The American Society of Health-System Pharmacists. Retrieved Mar 2015. 
  3. ^ Nolan, SJ; Marson, AG; Pulman, J; Tudur Smith, C (23 August 2013). "Phenytoin versus valproate monotherapy for partial onset seizures and generalised onset tonic-clonic seizures.". The Cochrane database of systematic reviews 8: CD001769. doi:10.1002/14651858.CD001769.pub2. PMID 23970302. 
  4. ^ Tudur Smith, C; Marson, AG; Clough, HE; Williamson, PR (2002). "Carbamazepine versus phenytoin monotherapy for epilepsy.". The Cochrane database of systematic reviews (2): CD001911. doi:10.1002/14651858.CD001911. PMID 12076427. 
  5. ^ Powell, G; Saunders, M; Marson, AG (3 February 2014). "Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy.". The Cochrane database of systematic reviews 2: CD007124. doi:10.1002/14651858.CD007124.pub3. PMID 24488654. 
  6. ^ Smith, Howard S. (2009). Current therapy in pain. Philadelphia: Saunders/Elsevier. p. 460. ISBN 9781416048367. 
  7. ^ Principles and practice of stereotactic radiosurgery. New York: Springer. 2008. p. 536. ISBN 9780387710709. 
  8. ^ "WHO Model List of Essential Medicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  9. ^ 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". Hum Psychopharmacol 24 (1): 19–28. doi:10.1002/hup.990. PMID 19053079. 
  10. ^ a b c d e Lexi-Comp (February 2009). "Carbamazepine". The Merck Manual Professional. Archived from the original on 2010-11-18.  Retrieved on May 3, 2009.
  11. ^ a b Powell, G; Saunders, M; Rigby, A; Marson, AG (3 December 2014). "Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy.". The Cochrane database of systematic reviews 12: CD007124. doi:10.1002/14651858.CD007124.pub4. PMID 25470302. 
  12. ^ Jentink, J; Dolk, H, Loane, MA, Morris, JK, Wellesley, D, Garne, E, de Jong-van den Berg, L, EUROCAT Antiepileptic Study Working, Group (2010-12-02). "Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study". BMJ (Clinical research ed.) 341: c6581. doi:10.1136/bmj.c6581. PMC 2996546. PMID 21127116. 
  13. ^ Lige Liu, Thomas Zheng, Margaret J. Morris, Charlott Wallengren, Alison L. Clarke, Christopher A. Reid, Steven Petrou and Terence J. O'Brien (2006). "The Mechanism of Carbamazepine Aggravation of Absence Seizures". JPET 319 (2): 790–798. doi:10.1124/jpet.106.10496. PMID 16895979. 
  14. ^ "Carbamazepine-induced transient auditory pitch-perception deficit.". Pediatr Neurol 35: 131–4. Aug 2006. doi:10.1016/j.pediatrneurol.2006.01.011. PMID 16876011. 
  15. ^ "eMedicine - Toxicity, Carbamazepine". Archived from the original on 2008-08-04. 
  16. ^ Stafstrom CE, Nohria V, Loganbill H, Nahouraii R, Boustany RM, DeLong GR (January 1995). "Erythromycin-induced carbamazepine toxicity: a continuing problem". Arch Pediatr Adolesc Med 149 (1): 99–101. doi:10.1001/archpedi.1995.02170130101025. PMID 7827672. Archived from the original on 2010-11-18. 
  17. ^ Moody D (2004). "Drug interactions with benzodiazepines". In Raymon LP, Mozayani A (eds.). Handbook of Drug Interactions: a Clinical and Forensic Guide. Humana. pp. 3–88. ISBN 1-58829-211-8. 
  18. ^ Gonzalez, Frank J.; Robert H. Tukey (2006). "Drug Metabolism". In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. p. 79. ISBN 978-0-07-142280-2. 
  19. ^ a b "Carbamazepine Drug Label". http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7a1e523a-b377-43dc-b231-7591c4c888ea. 
  20. ^ Kaniwa, N; Saito, Y (June 2013). "Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury.". Journal of human genetics 58 (6): 317–26. doi:10.1038/jhg.2013.37. PMID 23635947. 
  21. ^ a b Amstutz, U; Shear, NH; Rieder, MJ; Hwang, S; Fung, V; Nakamura, H; Connolly, MB; Ito, S; Carleton, BC; CPNDS clinical recommendation, group (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. PMID 24597466. 
  22. ^ Leckband, SG; Kelsoe, JR; Dunnenberger, HM; George AL, Jr; Tran, E; Berger, R; Müller, DJ; Whirl-Carrillo, M; Caudle, KE; Pirmohamed, M; Clinical Pharmacogenetics Implementation, Consortium (September 2013). "Clinical Pharmacogenetics Implementation Consortium guidelines for HLA-B genotype and carbamazepine dosing.". Clinical pharmacology and therapeutics 94 (3): 324–8. doi:10.1038/clpt.2013.103. PMID 23695185. 
  23. ^ Granger P. et al. (1995). "Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin". Mol. Pharmacol 47: 1189–1196. 
  24. ^ Schindler W, Häfliger F (1954). "Über Derivate des Iminodibenzyls". Helvetica Chimica Acta 37 (2): 472–83. doi:10.1002/hlca.19540370211. 
  25. ^ Okuma T, Kishimoto A (February 1998). "A history of investigation on the mood stabilizing effect of carbamazepine in Japan". Psychiatry Clin. Neurosci. 52 (1): 3–12. doi:10.1111/j.1440-1819.1998.tb00966.x. PMID 9682927. 
  26. ^ a b Prosser RS, Sibley PK2. Human health risk assessment of pharmaceuticals and personal care products in plant tissue due to biosolids and manure amendments, and wastewater irrigation. Environ Int. 2014 Dec 5;75C:223-233. doi: 10.1016/j.envint.2014.11.020. PMID 25486094
  27. ^ Tegretal

External links[edit]