View source for Carbamazepine

{{drugbox
 | Watchedfields = changed
| verifiedrevid = 322095827
| IUPAC_name = 5''H''-dibenzo[''b'',''f'']azepine-5-carboxamide
 | image = Carbamazepine Structural Formulae.png
 | width = 250
 | image2 = Carbamazepine 3D.png
 | width2 = 220
 | CASNo_Ref = {{cascite}}
 | InChI = 1/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)
| smiles = O=C(N)N3c1ccccc1\C=C/c2c3cccc2
| InChIKey = FFGPTBGBLSHEPO-UHFFFAOYAM
| CAS_number = 298-46-4
 | ChemSpiderID = 2457
 | CAS_supplemental = {{CAS|85756-57-6}} (dihydrate)
 | ATC_prefix = N03
 | ATC_suffix = AF01
 | ATC_supplemental = 
 | PubChem = 2554
 | DrugBank = DB00564
 | C=15 | H=12 | N=2 | O=1
 | molecular_weight = 236.269 g/mol
 | bioavailability = 80%
 | protein_bound = 76%
 | metabolism = [[Liver|Hepatic]]—by [[CYP3A4]], to active [[epoxide]] form (carbamazepine-10,11 epoxide)
 | elimination_half-life = 25–65 hours
 | excretion = 2–3% excreted unchanged in urine
 | pregnancy_US = D
 | legal_AU = 
 | legal_UK = POM
 | legal_US = Rx-only
 | legal_status = 
 | routes_of_administration = Oral
}}
'''Carbamazepine''' ('''CBZ''') is an [[anticonvulsant]] and [[mood stabilizer|mood stabilizing]] drug used primarily in the treatment of [[epilepsy]] and [[bipolar disorder]], as well as [[trigeminal neuralgia]]. It is also used [[off-label use|off-label]] for a variety of indications, including [[attention-deficit hyperactivity disorder]] (ADHD), [[schizophrenia]], [[phantom limb]] syndrome, [[paroxysmal extreme pain disorder]], and [[post-traumatic stress disorder]].

== History ==
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of [[Novartis]]) in [[Basel]], [[Switzerland]], in 1953.<ref>{{cite journal |author=Schindler W, Häfliger F |title=Über Derivate des Iminodibenzyls |journal=[[Helvetica Chimica Acta]] |year=1954 |volume=37 |issue=2 |pages=472–83. |doi=10.1002/hlca.19540370211}}</ref> Schindler then synthesized the drug in 1960, before its anti-epileptic properties had been discovered.

Carbamazepine was first marketed as a drug to treat [[trigeminal neuralgia]] (formerly known as tic douloureux) in 1962. It has been used as an anticonvulsant in the [[United Kingdom|UK]] since 1965, and has been approved in the [[United States|U.S.]] since 1974.

In 1971, Drs. Takezaki and Hanaoka first used carbamazepine to control mania in patients refractory to antipsychotics ([[Lithium pharmacology|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 anti-aggression effects of this drug. Carbamazepine would be studied for bipolar disorder throughout the 1970s.<ref name="pmid9682927">{{cite journal |author=Okuma T, Kishimoto A |title=A history of investigation on the mood stabilizing effect of carbamazepine in Japan |journal=Psychiatry Clin. Neurosci. |volume=52 |issue=1 |pages=3–12 |year=1998 |month=February |pmid=9682927 |doi=10.1111/j.1440-1819.1998.tb00966.x}}</ref>

==Indications==
In the United States, the [[Food and Drug Administration|FDA]]-approved indications for carbamazepine use are [[epilepsy]] (including [[partial seizure]]s and [[tonic-clonic seizure]]s), [[trigeminal neuralgia]], and [[mania|manic]] and [[mixed state (psychiatry)|mixed episode]]s of [[bipolar I disorder]].<ref name=Lexi-Comp/> Although data are still lacking, carbamazepine appears to be as effective and safe as [[lithium pharmacology|lithium]] for the treatment of bipolar disorder, both in the acute and maintenance phase.<ref name=Ceron-Litvoc>{{cite journal |author=Ceron-Litvoc D, Soares BG, Geddes J, Litvoc J, de Lima MS |title=Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic review of randomized controlled trials |journal=Hum Psychopharmacol |volume=24 |issue=1 |pages=19–28 |year=2009 |month=January |pmid=19053079 |doi=10.1002/hup.990}}</ref>

==Trade names==
Carbamazepine has been sold under the names Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin, Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze ([[New Zealand]]), Amizepin ([[Poland]]), Hermolepsin ([[Sweden]]), and Degranol ([[South Africa]]).<ref>[http://www.intekom.com/pharm/lennon/degranol.html Degranol Tablets]</ref>

==Pharmacokinetics==

Carbamazepine exhibits autoinduction: it [[regulation of gene expression|induces]] the expression of the hepatic microsomal enzyme system [[CYP3A4]], which metabolizes carbamazepine itself. Upon initiation of carbamazepine therapy, concentrations are predictable and follow their respective baseline clearance/half-life values that have been established for the specific patient. However, after enough carbamazepine has been presented to the liver tissue, the CYP3A4 activity increases, speeding up drug clearance and shortening the half-life. Autoinduction will continue with subsequent increases in dose but will usually reach a plateau within 5–7 days of a maintenance dose. Increases in dose at a rate of 200&nbsp;mg every 1–2 weeks may be required to achieve a stable seizure threshold. Stable carbamazepine concentrations occur usually within 2–3 weeks after initiation of therapy.<ref>{{cite book|last=Bauer |first=Larry A. |title=[[Applied Clinical Pharmacokinetics]] |edition=2<sup>nd</sup> |year=2008 |publisher=[[McGraw-Hill]]|isbn=0838503888}}</ref>

== Mechanism of action ==
The mechanism of action of carbamazepine and its derivatives is relatively well understood. [[Voltage-gated sodium channel]]s are the molecular pores that allow brain cells ([[neuron]]s) to generate [[action potential]]s, the electrical events that allow [[neuron]]s to communicate over long distances. After the sodium channels open to start the action potential, they inactivate, essentially closing the channel. Carbamazepine stabilizes the inactivated state of sodium channels, meaning that fewer of these channels are available to subsequently open, making brain cells less excitable (less likely to fire).
Carbamazepine has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits.<ref>Granger, P. et al.  Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol. Pharmacol. 47, 1189–1196 (1995).</ref>

== Interactions ==

Carbamazepine has a very high potential for [[drug interaction]]s; caution should be used in combining other medicines with it, including other antiepileptics and mood stabilizers.<ref name=Lexi-Comp>{{cite web |url=http://www.merck.com/mmpe/lexicomp/carbamazepine.html |title=Carbamazepine |date=February 2009 |author=Lexi-Comp |work=[[Merck Manual of Diagnosis and Therapy|The Merck Manual Professional]]}} Retrieved on May 3, 2009.</ref> Lower levels of carbamazepine are seen when administrated with [[phenobarbital]], [[phenytoin]] (Dilantin), or [[primidone]] (Mysoline). 
Carbamazepine, as a [[CYP450]] inducer, may increase clearance of many drugs, decreasing their blood levels.<ref name="urleMedicine - Toxicity, Carbamazepine">{{cite web |url=http://www.emedicine.com/emerg/topic77.htm |title=eMedicine - Toxicity, Carbamazepine |work= |accessdate=}}</ref> Drugs that are more rapidly metabolized with carbamazepine include [[warfarin]] (Coumadin), phenytoin (Dilantin), [[theophylline]], and valproic acid (Depakote, Depakote ER, Depakene, Depacon).<ref name=Lexi-Comp/> Drugs that decrease the metabolism of carbamazepine or otherwise increase its levels include [[erythromycin]],<ref>{{cite journal |author=Stafstrom CE, Nohria V, Loganbill H, Nahouraii R, Boustany RM, DeLong GR |title=Erythromycin-induced carbamazepine toxicity: a continuing problem |journal=Arch Pediatr Adolesc Med |volume=149 |issue=1 |pages=99–101 |year=1995 |month=January |pmid=7827672 |doi= |url=http://archpedi.ama-assn.org/cgi/pmidlookup?view=long&pmid=7827672}}</ref> [[cimetidine]] (Tagamet), [[propoxyphene]] (Darvon), and [[calcium channel blocker]]s.<ref name=Lexi-Comp/> Carbamazepine also increases the metabolism of the hormones in [[birth control pill]]s and can reduce their effectiveness, potentially leading to unexpected pregnancies.<ref name=Lexi-Comp/>

[[Valproic acid]] and [[valnoctamide]] both inhibit [[epoxide hydrolase|microsomal epoxide hydrolase]] (mEH), the [[enzyme]] responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.<ref>{{cite book |last=Gonzalez |first=Frank J. |coauthors=Robert H. Tukey |editor=Laurence Brunton, John Lazo, Keith Parker (eds.) |title=[[Goodman & Gilman's The Pharmacological Basis of Therapeutics]] |edition=11<sup>th</sup> |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0071422802|pages=79 |chapter=Drug Metabolism }}</ref> By inhibiting mEH, valproic acid and valnoctamide cause a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

== Adverse effects ==

Common [[adverse drug reaction|adverse effect]]s include drowsiness, headaches and migraines, [[motor coordination]] impairment and/or upset stomach. Carbamazepine preparations typically greatly decrease a person's alcohol tolerance.

Less common side effects include cardiac arrhythmias, blurry or double [[Visual perception|vision]] and/or the temporary loss of [[blood cell]]s or [[platelet]]s and in rare cases can cause aplastic anemia. With normal use, small reductions in white cell count and serum sodium are common, however, in rare cases, the loss of platelets may become life-threatening. This occurs commonly enough that a doctor may recommend frequent blood tests during the first few months of use, followed by three to four tests per year for established patients. In the UK, testing is generally performed much less frequently for long-term carbamazepine patients—typically once per year. Additionally, carbamazepine may exacerbate preexisting cases of hypothyroidism, so yearly thyroid function tests are advisable for persons taking the drug.

There are also reports of an auditory side effect for carbamazepine use, whereby patients perceive sounds about a [[semitone]] lower than previously.<ref name="pmid12581810">{{cite journal |author=Yoshikawa H, Abe T |title=Carbamazepine-induced abnormal pitch perception |journal=Brain Dev. |volume=25 |issue=2 |pages=127–9 |year=2003 |month=March |pmid=12581810 |doi= 10.1016/S0387-7604(02)00155-9|url=http://linkinghub.elsevier.com/retrieve/pii/S0387760402001559}}</ref><ref name="pmid14518681">{{cite journal |author=Konno S, Yamazaki E, Kudoh M, Abe T, Tohgi H |title=Half pitch lower sound perception caused by carbamazepine |journal=Intern. Med. |volume=42 |issue=9 |pages=880–3 |year=2003 |month=September |pmid=14518681 |doi= 10.2169/internalmedicine.42.880|url=http://joi.jlc.jst.go.jp/JST.Journalarchive/internalmedicine1992/42.880?from=PubMed |format={{dead link|date=January 2010}}}}</ref><ref name="pmid9804087">{{cite journal |author=Kashihara K, Imai K, Shiro Y, Shohmori T |title=Reversible pitch perception deficit due to carbamazepine |journal=Intern. Med. |volume=37 |issue=9 |pages=774–5 |year=1998 |month=September |pmid=9804087 |doi= 10.2169/internalmedicine.37.774|url=http://joi.jlc.jst.go.jp/JST.Journalarchive/internalmedicine1992/37.774?from=PubMed |format={{dead link|date=January 2010}}}}</ref> Thus, [[middle C]] would be heard as the note [[Scientific pitch notation|B3]] just below it, etc. The inverse effect (that is, notes sounding higher) has also been recorded.<ref name="pmid11020128">{{cite journal |author=Miyaoka T, Seno H, Itoga M, Horiguchi J |title=Reversible pitch perception deficit caused by carbamazepine |journal=Clin Neuropharmacol |volume=23 |issue=4 |pages=219–21 |year=2000 |pmid=11020128 |doi= 10.1097/00002826-200007000-00010|url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0362-5664&volume=23&issue=4&spage=219}}</ref><ref name="pmid15446396">{{cite journal |author=Wakamoto H, Kume A, Nakano N |title=Elevated pitch perception owing to carbamazepine-activating effect on the peripheral auditory system: auditory brainstem response study |journal=J. Child Neurol. |volume=19 |issue=6 |pages=453–5 |year=2004 |month=June |pmid=15446396 |doi= |url=http://jcn.sagepub.com/cgi/pmidlookup?view=long&pmid=15446396}}</ref> This unusual side effect is usually not noticed by most people, and quickly disappears after the person stops taking carbamazepine.

[[Oxcarbazepine]], a derivative of carbamazepine, reportedly has fewer and less serious side effects.

Carbamazepine may cause [[Syndrome of inappropriate antidiuretic hormone]] (SIADH), since it both increases the release and potentiates the action of ADH ([[vasopressin]]).

Carbamazepine may aggravate [[juvenile myoclonic epilepsy]], so it is important to uncover any history of jerking, especially in the morning, before starting the drug.

In addition, carbamazepine has been linked to serious adverse cognitive anomalies, including EEG slowing<ref name="pmid12027908">{{cite journal |author=Salinsky MC, Binder LM, Oken BS, Storzbach D, Aron CR, Dodrill CB |title=Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers |journal=Epilepsia |volume=43 |issue=5 |pages=482–90 |year=2002 |pmid=12027908 |doi=10.1046/j.1528-1157.2002.22501.x |url=http://www.blackwell-synergy.com/doi/full/10.1046/j.1528-1157.2002.22501.x?cookieSet=1}}</ref> and cell apoptosis.<ref name="pmid8719616">{{cite journal |author=Gao XM, Margolis RL, Leeds P, Hough C, Post RM, Chuang DM |title=Carbamazepine induction of apoptosis in cultured cerebellar neurons: effects of N-methyl-D-aspartate, aurintricarboxylic acid and cycloheximide |journal=Brain Res. |volume=703 |issue=1-2 |pages=63–71 |year=1995 |pmid=8719616 |doi=10.1016/0006-8993(95)01066-1}}</ref>

The FDA informed health care professionals that dangerous or even fatal skin reactions ([[Stevens Johnson syndrome]] and [[toxic epidermal necrolysis]]), that can be caused by carbamazepine therapy, are significantly more common in patients with a particular [[human leukocyte antigen]] (HLA) allele, [[HLA-B75|HLA-B*1502]]. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians. <ref>{{cite web |author=MedWatch |title=Carbamazepine  |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine |date=2007-12-12 |work=2007 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements |publisher=FDA}}</ref> In Europeans a large proportion of sensitivity is associated with [[HLA-B58]].

== See also ==
* [[Oxcarbazepine]]

==Chemistry==
[[File:Carbamazepine syn.png|600px]]

Schindler, W.; 1960, {{US Patent|2,948,718}}.

Carbamazepine is a [[dibenzazepine]].

== References ==
{{reflist|2}}

== External links ==
{{Commons cat}}
* [http://www.carbatrol.com Carbatrol website]
* [http://www.equetro.com Equetro website]
* [http://www.pubpk.org/index.php?title=Carbamazepine Carbamazepine Pharmacokinetics - PubPK]
* [http://www.rxlist.com/cgi/generic/carbam.htm TA warning]
* [http://www.psycheducation.org/depression/meds/carbamazepine.htm Carbamazepine overview] from PsychEducation.org
* [http://www.medscape.com/viewarticle/410736_4 Extensive review of the effects of carbamazepine in pregnancy and breastfeeding] (free full text with registration)
* [http://patimg1.uspto.gov/.piw?Docid=02948718&homeurl=http%3A%2F%2Fpatft.uspto.gov%2Fnetacgi%2Fnph-Parser%3FSect1%3DPTO1%2526Sect2%3DHITOFF%2526d%3DPALL%2526p%3D1%2526u%3D%2Fnetahtml%2Fsrchnum.htm%2526r%3D1%2526f%3DG%2526l%3D50%2526s1%3D2,948,718.WKU.%2526OS%3DPN%2F2,948,718%2526RS%3DPN%2F2,948,718&PageNum=&Rtype=&SectionNum=&idkey=2A0649DBED16 U.S. Patent 2,948,718, August 1960]

{{Anticonvulsants}}
{{Mood stabilizers}}
{{Bipolar disorder}}
{{Tricyclics}}

[[Category:Anticonvulsants]]
[[Category:Mood stabilizers]]
[[Category:Prodrugs]]
[[Category:Ureas]]
[[Category:World Health Organization essential medicines]]
[[Category:Dibenzazepines]]

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