Carbamazepine

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Carbamazepine
Carbamazepine.svg
Carbamazepine3Dan.gif
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
Pregnancy cat. D (AU) D (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes 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
CAS number 298-46-4 YesY 85756-57-6
ATC code N03AF01
PubChem CID 2554
DrugBank DB00564
ChemSpider 2457 YesY
UNII 33CM23913M YesY
KEGG D00252 YesY
ChEBI CHEBI:3387 YesY
ChEMBL CHEMBL108 YesY
Chemical data
Formula C15H12N2O 
Mol. mass 236.269 g/mol
 YesY (what is this?)  (verify)

Carbamazepine (CBZ) (Tegretol, Equetro) is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia. Off-label uses include attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, borderline personality disorder, and post-traumatic stress disorder.

Studies on the use of carbamazepine in pregnant women have demonstrated exposure of the fetus to the drug and its metabolites. Intrauterine exposure to carbamazepine has been shown to be teratogenic and is associated with the development of spina bifida,[2] neurodevelopmental problems,[3] craniofacial defects, cardiovascular malformations, hypospadias, and developmental delays.

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]

Medical uses[edit]

Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain.[5] It may be used off-label as a second line treatment for bipolar disorder and as an adjunct, never alone, with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed.[5]

In the United States, the FDA-approved indications are epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), trigeminal neuralgia, and manic and mixed episodes of bipolar I disorder.[6] Although data are still lacking, carbamazepine appears to be as effective and safe as lithium for the treatment of bipolar disorder, both in the acute and maintenance phase.[7]

Adverse effects[edit]

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.

Less common side-effects may include cardiac arrhythmias, blurry or double vision and/or the temporary loss of blood cells or platelets and in rare cases can cause aplastic anemia or agranulocytosis. With normal use, small reductions in white cell count and serum sodium levels are common; however, in rare cases, the loss of platelets may become life-threatening. In this case 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. Additionally, carbamazepine may possibly exacerbate preexisting cases of hypothyroidism, so yearly thyroid function tests are advisable for persons taking the drug.

There are also rare reports of an auditory side-effect for carbamazepine use, whereby patients perceive sounds about a semitone lower than previously.[8][9][10] Thus, middle C would be heard as the note B3 just below it, and so on. The inverse effect (that is, notes sounding higher) has also been recorded.[11][12] 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. It may also aggravate other types of generalized seizure disorder, particularly absence seizures.[13]

In addition, carbamazepine has been linked to serious adverse cognitive anomalies, including EEG slowing[14] and apoptosis of cultured cerebellar neurons.[15]

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-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.[16] In Europeans a large proportion of sensitivity is associated with HLA-B58. Researchers have also identified another genetic variant, HLA-A*3101 which has been shown to be a strong predictor of both mild and severe adverse reactions to carbamazepine among Japanese[17] and Europeans.[18]

Associated birth defects[edit]

If taken during pregnancy, Carbamazepine can cause birth defects that include: cardiovascular and urinary tract anomalies, craniofacial defects such as cleft palate,[19] fingernail hypoplasia, microcephaly, developmental delays, and intrauterine growth restrictions.[20]

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.[6] 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.[21] Drugs that are more rapidly metabolized with carbamazepine include warfarin (Coumadin), lamotrigine (Lamictal), phenytoin (Dilantin), theophylline, and valproic acid (Depakote, Depakote ER, Depakene, Depacon).[6] Drugs that decrease the metabolism of carbamazepine or otherwise increase its levels include erythromycin,[22] cimetidine (Tagamet), propoxyphene (Darvon), and calcium channel blockers.[6] Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[6] As a drug that induces cytochrome P450 enzymes, it accelerates elimination of many benzodiazepines and decreases their action.[23]

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.[24] By inhibiting mEH, valproic acid and valnoctamide cause a buildup 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.

Environmental impact[edit]

Carbamazepine can enter the environment through discharge of wastewater, and has also been shown to persist and accumulate in the organic components of soil and sludge.[25] As carbamazepine is an emerging contaminant,[26] the effects of its bioaccumulation on other living creatures and plants are not well-understood.

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. Some of its metabolites have antiepileptic properties. A slow-release preparation is used for patients who experience transient side effects coinciding with plasma concentration peaks following oral dosing.

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 has also been shown to potentiate GABA receptors made up of alpha1, beta2, gamma2 subunits.[27] 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.[28] 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 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 anti-aggression effects of this drug. Carbamazepine would be studied for bipolar disorder throughout the 1970s.[29]

Brand names[edit]

Carbamazepine has been sold under the names Biston (Czech), Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin, Tegretol, EPITAB XR(of Werrick Pakistan') Teril, Timonil, Trimonil, Epimaz, Carbama/Carbamaze (New Zealand), Amizepin (Poland), Carzine (Kolkata), Mazetol, Tegrital, Tegrita, Zeptol (India), Karbapin (Serbia), Hermolepsin (Sweden), Degranol (South Africa),[30] and Tegretal (Chile, Germany).[31]

Synthesis[edit]

Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide, is synthesized by reacting 5H-dibenz[b,f]azepine and phosgene, which forms 5-chlorcarboxy-5H-dibenz-[b,f]azepine), and its subsequent reaction with ammonia to give the desired carbamazepine. Coll. means collidine.

Preparation of Carbamazepine: U.S. Patent 2,948,718 Schindler, W.; 1960. (Geigy, Delaware)

An alternative method of synthesis is the direct reaction of 5H-dibenz[b,f]azepine with potassium cyanate (KOCN).

  • H. Krahnefeld, H. Wunderlich, DD 133052  (1977).

Carbamazepine is a dibenzazepine.

References[edit]

[32][33]

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  3. ^ Cummings, C; Stewart, M; Stevenson, M; Morrow, J; Nelson, J (2011-03-17). "Neurodevelopment of children exposed in utero to lamotrigine, sodium valproate and carbamazepine". Archives of Disease in Childhood 96 (7): 643–7. doi:10.1136/adc.2009.176990. PMID 21415043. 
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  26. ^ i.e. one that is relatively new, and still unregulated in terms of its discharge to the environment
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  30. ^ Degranol Tablets[dead link]
  31. ^ http://www.farmaciasahumada.cl/fasaonline/fasa/MFT/PRODUCTO/P1163.HTM
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  33. ^ Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan, New England Journal of Medicine, March 2010. http://www.nejm.org/doi/full/10.1056/NEJMoa1009717

External links[edit]