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(New page: {{BioPsy}} {{drugbox | IUPAC_name = 5H-dibenzepine-5-carboxamide | image = Carbamazepine.png | width=127 | CAS_number = 298-46-4 | CAS_supplemental = {{CAS|85756-57-6}} dihydrate | A...)
 
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{{BioPsy}}
 
{{BioPsy}}
 
{{drugbox
 
{{drugbox
| IUPAC_name = 5H-dibenzepine-5-carboxamide
+
| IUPAC_name = 5''H''-dibenz[b,f]azepine-5-carboxamide
 
| image = Carbamazepine.png
 
| image = Carbamazepine.png
  +
| image2 = Carbamazepine 3D.png
 
| width=127
 
| width=127
 
| CAS_number = 298-46-4
 
| CAS_number = 298-46-4
| CAS_supplemental = {{CAS|85756-57-6}} dihydrate
+
| CAS_supplemental = {{CAS|85756-57-6}} (dihydrate)
 
| ATC_prefix = N03
 
| ATC_prefix = N03
 
| ATC_suffix = AF01
 
| ATC_suffix = AF01
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| bioavailability = 80%
 
| bioavailability = 80%
 
| protein_bound = 76%
 
| protein_bound = 76%
| metabolism = [[hepatic]] [[CYP3A4]] to active [[epoxide]] form
+
| metabolism = [[Liver|Hepatic]]—by [[CYP3A4]], to active [[epoxide]] form (carbamazepine-10,11 epoxide)
| elimination_half-life = 25-65 hours
+
| elimination_half-life = 25–65 hours
| excretion = 2-3% excreted unchanged in urine
+
| excretion = 2–3% excreted unchanged in urine
 
| pregnancy_US = C
 
| pregnancy_US = C
 
| legal_AU =
 
| legal_AU =
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| legal_US =
 
| legal_US =
 
| legal_status =
 
| legal_status =
| routes_of_administration = oral
+
| 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]]. It is also used to treat [[Attention-deficit hyperactivity disorder|ADD]], [[ADHD]], [[schizophrenia]] and [[trigeminal neuralgia]].
   
'''Carbamazepine''' (sold under the brand-names '''Biston''', '''Calepsin''', '''Carbatrol''', '''Epitol''', '''Equetro''', '''Finlepsin''', '''Sirtal''', '''Stazepine''', '''Tegretol''', '''Telesmin''', '''Timonil''', sometimes abbreviated '''CBZ''') is an [[anticonvulsant]] and [[mood stabilizer|mood stabilizing]] drug, used primarily in the treatment of [[epilepsy]] and [[bipolar disorder]]. It is also used to treat [[schizophrenia]] and [[trigeminal neuralgia]].
+
==Trade names==
  +
'''Carbamazepine''' has been sold under the names '''Tegretol''', '''Biston''', '''Calepsin''', '''Carbatrol''', '''Epitol''', '''Equetro''', '''Finlepsin''', '''Sirtal''', '''Stazepine''', '''Telesmin''','''Teril''', '''Timonil''', '''Trimonil''', '''Epimaz''', and '''Degranol''' (in [[South Africa]])<ref>http://www.intekom.com/pharm/lennon/degranol.html</ref>.
   
== Mechanisms ==
+
== History ==
Carbamazepine and its derivatives' mechanism of action is relatively well understood. Voltage gated [[Sodium ion channel|sodium channels]] are the molecular pores that allow brain cells ([[neurons]]) to generate [[action potentials]], the electrical event that allows [[neurons]] 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 [[sodium channels]] are available to open, making brain cells less excitable.
+
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.
   
== Adverse effects ==
+
Carbamazepine was first marketed as a drug to treat [[trigeminal neuralgia]] in 1962. It has been used as an anticonvulsant in the [[United Kingdom|UK]] since 1965, but only approved in the [[United States|U.S.]] since 1974.
Carbamazepine renders [[Oral contraceptive|birth control pills]] ineffective because it is an enzyme inducer of the cytochrome P450 system which metabolises the oral contraceptive, leaving less active contraceptive in the plasma.
 
   
Common [[adverse drug reaction|side effect]]s include drowsiness, [[motor-coordination]] impairment and/or upset stomach. Taken every twelve hours, the Tegretol XR or Carbatrol preparations can greatly decrease alcohol tolerance.
+
In 1971, Drs. Takezaki and Hanaoka first used carbmazepine 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 1970's.<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=}}</ref>
   
Less common side effects include, cardiac arrythmias, blurry or double [[Visual perception|vision]] and/or the temporary or mild loss of [[blood cell]]s or [[platelet]]s. In rare cases the latter can be life-threatening if unnoticed, so frequent blood tests are required during the first few months' use, followed by three or four tests per year. In the UK testing would be less frequent in long-term use, typically once every year or two. Underactivity of the thyroid gland may be provoked, so thyroid function tests are advisable every year or two.
+
== Adverse effects ==
  +
Carbamazepine is known to render many [[hormonal contraception]] products ineffective, due to its action as a cytochrome P450 enzyme inducer, which is the system that metabolizes many oral contraceptives. Carbamazepine causes more cytochrome P450 enzyme to be produced, which hastens removal of the contraceptive from the blood plasma although the clinical significance of this effect is debatable.
   
Small reductions in white cell count and serum sodium are common.
+
Common [[adverse drug reaction|side effect]]s include drowsiness, [[motor coordination]] impairment and/or upset stomach. Carbamazepine preparations may also greatly decrease a person's alcohol tolerance.
   
There are also reports of a bizarre auditory side effect, whereby patients perceive musical notes about a [[semitone]] lower than their actual pitch (so [[middle C]] would be heard as the note [[Scientific pitch notation|B3]] just below it, etc).
+
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. 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.
   
[[Oxcarbazepine]], a derivative of carbamazepine, has fewer and less serious side effects.
+
There are also reports of an auditory side effect for carbamazepine use, whereby patients perceive sounds about a [[semitone]] lower than their actual pitch. Thus, [[middle C]] would be heard as the note [[Scientific pitch notation|B3]] just below it, etc. This unusual side-effect is usually not noticed by most people, and quickly disappears after the person stops taking carbamazepine.
   
Carbamazepine can cause [[Syndrome of inappropriate antidiuretic hormone|SIADH]] (syndrome of inappropriate antidiuretic hormone), since it both increases the release and potentiates the action of ADH ([[vasopressin]]).
+
[[Oxcarbazepine]], a derivative of carbamazepine, reportedly has fewer and less serious side effects.
   
Carbamazepine greatly reduces serum concentrations of [[simvastatin]] and simvastatin acid {{ref_label | Pharmacol2004 | 1 | a}}.
+
Carbamazepine may cause [[Syndrome of inappropriate anti-diuretic hormone|SIADH]] (syndrome of inappropriate anti-diuretic hormone), since it both increases the release and potentiates the action of ADH ([[vasopressin]]).
   
 
Carbamazepine may aggravate [[juvenile myoclonic epilepsy]], so it is important to mention any history of jerking, especially in the morning, before starting to take this drug.
 
Carbamazepine may aggravate [[juvenile myoclonic epilepsy]], so it is important to mention any history of jerking, especially in the morning, before starting to take this drug.
   
== History ==
+
Pregnant women taking carbamazepine put their fetuses at increased risk for teratogenic effects. As a result, they should be given [[folic acid]] supplementation and undergo prenatal ultrasonography for diagnosis.
Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of [[Novartis]]) in [[Basel]], [[Switzerland]], in 1953. 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]] in 1962. It has been used as an anticonvulsant in the [[United Kingdom|UK]] since 1965, but only approved in the [[United States|U.S.]] since 1974.
+
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=}}</ref>
   
If taken as meant as drug, side effects include double vision, euphoric feeling, drowsiness, and other mild side effects.
+
The FDA informed healthcare 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. <ref>{{cite web |author=MedWatch |title=Carbamazepine |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine |date=December 12, 2007 |work=2007 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements |publisher=FDA}}</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 open, making brain cells less excitable.
  +
  +
When Carbamazepine is used in the treatment of Bipolar disorder the mode of action is inhibition of Glycogen synthase kinase-3. (Per Dr Martin Department of Pharmacology ATSU)
  +
  +
== Interactions ==
  +
  +
[[Valproic acid]] and [[valnoctamide]] both interact with carbamazepine, as they 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> ed. |year=2006 |publisher=[[McGraw-Hill]] |location=New York |isbn=978-0071422802|pages=p. 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.
  +
  +
Carbamazepine,as CYP 450 inducer, may increase clearance of many drugs, decreasing their blood levels.
   
 
== See also ==
 
== See also ==
Line 59: Line 61:
   
 
== References ==
 
== References ==
* W Schindler and F Häfliger, ''Über derivate des iminodibenzyls'', [[Helvetica Chimica Acta]] 1954, 37:472-483
+
<references />
== Notes ==
 
#{{note | Pharmacol2004}} {{cite journal
 
| author=M. Ucar ''et al''
 
| title=Carbamazepine markedly reduces serum concentrations of simvastatin and simvastatin acid
 
| journal=Eur J Clin Pharmacol
 
| year=2004
 
| volume=59
 
| issue=
 
| pages= 879–882}}
 
Т
 
   
 
== External links ==
 
== External links ==
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[[Category:Carboxamides]]
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[[Category:Analgesic drugs]]
[[Category:Anticonvulsants]]
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[[Category:Anticonvulsive drugs]]
 
[[Category:Mood stabilizers]]
 
[[Category:Mood stabilizers]]
   
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Latest revision as of 01:03, February 2, 2008

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Carbamazepine chemical structure
Carbamazepine

5H-dibenz[b,f]azepine-5-carboxamide
IUPAC name
CAS number
298-46-4
ATC code

N03AF01

PubChem
2554
DrugBank
APRD00337
Chemical formula {{{chemical_formula}}}
Molecular weight 236.269 g/mol
Bioavailability 80%
Metabolism 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 category {{{pregnancy_category}}}
Legal status
Routes of administration Oral

Carbamazepine ("CBZ") is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorder. It is also used to treat ADD, ADHD, schizophrenia and trigeminal neuralgia.

Trade namesEdit

Carbamazepine has been sold under the names Tegretol, Biston, Calepsin, Carbatrol, Epitol, Equetro, Finlepsin, Sirtal, Stazepine, Telesmin,Teril, Timonil, Trimonil, Epimaz, and Degranol (in South Africa)[1].

History Edit

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.[2] 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 in 1962. It has been used as an anticonvulsant in the UK since 1965, but only approved in the U.S. since 1974.

In 1971, Drs. Takezaki and Hanaoka first used carbmazepine 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 1970's.[3]

Adverse effects Edit

Carbamazepine is known to render many hormonal contraception products ineffective, due to its action as a cytochrome P450 enzyme inducer, which is the system that metabolizes many oral contraceptives. Carbamazepine causes more cytochrome P450 enzyme to be produced, which hastens removal of the contraceptive from the blood plasma although the clinical significance of this effect is debatable.

Common side effects include drowsiness, motor coordination impairment and/or upset stomach. Carbamazepine preparations may also greatly decrease a person's alcohol tolerance.

Less common side effects include cardiac arrhythmias, blurry or double vision and/or the temporary loss of blood cells or platelets. 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 their actual pitch. Thus, middle C would be heard as the note B3 just below it, etc. 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 SIADH (syndrome of inappropriate anti-diuretic hormone), since it both increases the release and potentiates the action of ADH (vasopressin).

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

Pregnant women taking carbamazepine put their fetuses at increased risk for teratogenic effects. As a result, they should be given folic acid supplementation and undergo prenatal ultrasonography for diagnosis.

In addition, carbamazepine has been linked to serious adverse cognitive anomalies, including EEG slowing[4] and cell apoptosis.[5]

The FDA informed healthcare 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. [6]

Mechanism of Action Edit

The mechanism of action of carbamazepine and its derivatives is relatively well understood. Voltage-gated sodium channels are the molecular pores that allow brain cells (neurons) to generate action potentials, the electrical events that allow neurons 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 open, making brain cells less excitable.

When Carbamazepine is used in the treatment of Bipolar disorder the mode of action is inhibition of Glycogen synthase kinase-3. (Per Dr Martin Department of Pharmacology ATSU)

Interactions Edit

Valproic acid and valnoctamide both interact with carbamazepine, as they inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of carbamazepine-10,11 epoxide into inactive metabolites.[7] By inhibiting mEH, valproic acid and valnoctamide cause a buildup of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Carbamazepine,as CYP 450 inducer, may increase clearance of many drugs, decreasing their blood levels.

See also Edit

References Edit

  1. http://www.intekom.com/pharm/lennon/degranol.html
  2. Schindler W, Häfliger F (1954). Über Derivate des Iminodibenzyls. Helvetica Chimica Acta 37 (2): 472–83..
  3. 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.
  4. Salinsky MC, Binder LM, Oken BS, Storzbach D, Aron CR, Dodrill CB (2002). Effects of gabapentin and carbamazepine on the EEG and cognition in healthy volunteers. Epilepsia 43 (5): 482–90.
  5. Gao XM, Margolis RL, Leeds P, Hough C, Post RM, Chuang DM (1995). Carbamazepine induction of apoptosis in cultured cerebellar neurons: effects of N-methyl-D-aspartate, aurintricarboxylic acid and cycloheximide. Brain Res. 703 (1-2): 63–71.
  6. MedWatch. Carbamazepine. 2007 Safety Alerts for Drugs, Biologics, Medical Devices, and Dietary Supplements. FDA.
  7. Gonzalez, Frank J.; Robert H. Tukey (2006). "Drug Metabolism" Laurence Brunton, John Lazo, Keith Parker (eds.) Goodman & Gilman's The Pharmacological Basis of Therapeutics, 11th ed., p. 79, New York: McGraw-Hill.

External links Edit


Anticonvulsants edit





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