Carbamazepine
JCY Lo, San Diego, CA, USA
Ó 2014 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by Henry A. Spiller, volume 1, pp 413–414, Ó 2005, Elsevier Inc.
l Name: Carbamazepine
l Chemical Abstracts Service Registry Number: 298-46-4
l Synonyms: CBZ; 5H-dibenz(b,f)-azepine-5-carboxamide;
Tegretol
l Molecular Formula: C15H12N2O
l Chemical Structure: NCONH2
Background
Carbamazepine is a synthetic iminostilbene derivative struc-
turally similar to imipramine, a tricyclic antidepressant. While
unrelated structurally, carbamazepine shares a similar thera-
peutic action with phenytoin. Carbamazepine was first discov-
ered in 1953 by Swiss chemist Walter Schindler. Throughout the
1960s, antimuscarinic was used and marketed for trigeminal
neuralgia and as an anticonvulsant. By the 1970s, it was being
used as a mood stabilizer for patients with bipolar disorder.
Uses
Carbamazepine is used in the treatment of epilepsy and
trigeminal neuralgia. Unlabeled uses include treatment of
postherpetic pain syndrome, neurogenic diabetes insipidus,
bipolar disorder, alcohol withdrawal, and cocaine dependence.
Environmental Fate and Behavior
Environmental exposure occurs via direct release into water or
via vaporization into the air. It is susceptible to photolysis and
is thought to have a half-life of roughly 63 days in lake water in
vitro. However, when dissolved and exposed to direct photol-
ysis, it has a half-life of approximately 1 day.
Exposure Routes and Pathways
The exposure pathway for carbamazepine is exclusively oral
(ingestion of tablets or suspension).
Toxicokinetics
Carbamazepine is slowly and incompletely absorbed during
therapeutic use. With large ingestions, absorption may be
Encyclopedia of Toxicology, Volume 1 http://dx.doi.org/10.1016/B978-0-12-386454-3.00705-3
delayed and unpredictable, producing peak levels from 4 to
72 h after the overdose. The absorption phase in an overdose
is highly variable because of carbamazepine’s poor solubility,
ability to significantly decrease gut motility, and to form
pharmacobezoars. One of the primary metabolites of
carbamazepine is carbamazepine-10,11-epoxide (CBZE),
which also has anticonvulsant activity. A minor pathway
results in iminostilbene formation. Further hydrolysis and
conjugation produce six other known metabolites including
10,11-dihydroxycarbamazepine. Protein binding is 75% for
carbamazepine and 50% for CBZE. However, the percentage
of protein binding may decrease in massive overdose due to
saturable binding sites. The volume of distribution is
0.8–1.9 l kg 1. The hydrolyzed and conjugated metabolites
are eliminated through the kidneys, with only 1.2% free
carbamazepine being found in the urine and 28% is elimi-
nated unchanged in the feces. Carbamazepine induces drug-
metabolizing enzymes so that drug half-life is reduced in
chronic use. The half-life in healthy adults ranges from
18–65 h in a single dose to 8–17 h during chronic adminis-
tration. In newborns and children, the half-life is below 9 h.
Mechanism of Toxicity
Carbamazepine is both an important anticonvulsant in ther-
apeutic doses and a powerful proconvulsant in overdose. The
therapeutic anticonvulsant mechanism is primarily related to
blockade of presynaptic voltage-gated sodium channels.
Blockade of the sodium channels is believed to inhibit the
release of synaptic glutamate and possibly other neurotrans-
mitters. Carbamazepine is also a powerful inhibitor of the
muscarinic and nicotinic acetylcholine receptors, N-methyl-D-
aspartate (NMDA) receptors, and the central nervous system
(CNS) adenosine receptors. In addition, carbamazepine is
structurally related to the cyclic antidepressant imipramine
and in massive overdose, it may affect cardiac sodium
channels.
Acute and Short-Term Toxicity (or Exposure)
Animal
Carbamazepine is not commonly used in animals. Limited
information on toxicity exits. Tachyarrhythmias, hypotension,
and seizures have been seen.
Human
The primary and common toxic event involves the CNS.
Cardiac conduction delays and ventricular arrhythmias can be
seen but are infrequent. Sinus tachycardia and hypotension are
more commonly seen. In the few deaths directly attributable to
carbamazepine toxicity, ventricular dysrhythmias have been
665
666 Carbamazepine
the terminal event. Coma, seizures, and respiratory depression
are commonly seen in adults at levels greater than 40 mg ml 1
(170 mmol l 1). Status epilepticus has been reported. The
incidence of serious toxicity is similar in adults and children.
However, serum levels are less predictive in children. Therefore,
coma, seizures, and apnea may be seen at lower serum levels
than in adults. Other manifestations of neurological toxicity are
nystagmus, ataxia, choreoathetoid movements, encephalop-
athy, absence of corneal reflexes, decreased deep tendon
reflexes, urinary retention, and dystonias. A cyclic clinical
course can be seen, with a waxing and waning of symptoms.
This may be due to the presence of a pharmacobezoar in the gut
or more commonly due to a decrease in gastrointestinal
motility produced by the prominent anticholinergic effects of
carbamazepine.
Chronic Toxicity (or Exposure)
Animal
Male albino rats given injections of carbamazepine over
3 months demonstrated decreased prostate weight and
decreased sperm motility. These changes did not affect fertility.
Human
Idiopathic hepatotoxicity has been reported as a rare manifes-
tation of chronic therapy and is not dose related. Hyponatremia
is a common adverse effect associated with carbamazepine
exposure. Increased antidiuretic hormone secretion and
increased aquaporin 2 expression are proposed mechanism.
Hypersensitivity syndrome, or drug rash with eosinophilia
and systemic symptoms, and Stevens–Johnson syndrome/toxic
epidermal necrolysis (SJS/TEN) have been described with
carbamazepine administration.
In vitro toxicity studies of carbamazepine on rat cerebellar
granule cells have shown inhibition of NMDA-stimulated
calcium entry in a rapid and reversible manner. These find-
ings occurred in therapeutic concentrations of carbamazepine,
which may help explain the antiseizure activity of carbamaze-
pine. It is believed that the toxic cerebellar effects of carba-
mazepine may be due to this mechanism.
Immunotoxicity
Isolated cases of transient hypogammaglobulinemia have been
reported with carbamazepine administration. IgG, IgA, and
IgM were not found to be significantly reduced in patients
treated with carbamazepine in comparison to control subjects
who did not receive carbamazepine. An increase in cytotoxic
activity of natural killer cells was noted in patients treated with
carbamazepine.
Carbamazepine has been associated with a potentially fatal
idiosyncratic reaction known at antiepileptic hypersensitivity
syndrome. This is characterized by eosinophilia, fever, rash,
coagualopathy, and hepatotoxicity.
Pancytopenia has also been reported with carbamazepine
including neutropenia and agranulocytosis.
Reproductive Toxicity
Animal
Rats born to mothers chronically fed carbamazepine during
gestation demonstrated challenges with maintaining balance
and had more difficulty lifting their hind legs than controls.
Mice born to mothers who received intraperitoneal adminis-
tration of carbamazepine demonstrated eye malformation.
Human
Carbamazepine is highly teratogenic. Neural tube defects are
associated with carbamazepine exposure during pregnancy
and can lead to spina bifida. Carbamazepine is pregnancy
category D.
Genotoxicity
Animal
High dose carbamazepine resulted in increased number of
mutations per Drosophila wing.
Human
Associations have been shown for carbamazepine and human
leukocyte antigen (HLA)-B*1502 and HLA-A*3101-induced
cutaneous adverse drug reactions. HLA-B*1502 is present in
certain Asian populations who are predisposed to SJS/TEN.
Carcinogenicity
High-dose (25 mg kg 1 day 1) carbamazepine administra-
tion for more than 2 years caused hepatocellular tumors in
female rats and benign interstitial tumors of the testes in
male rats.
Clinical Management
Basic and advanced life-support measures should be utilized as
necessary. Gastrointestinal decontamination procedures should
be used as appropriate. Activated charcoal effectively binds
carbamazepine. Multiple-dose activated charcoal (0.5 g kg 1
every 4 h) has been shown to decrease the half-life of carba-
mazepine. Generally, supportive measures are all that is required
in carbamazepine overdose. Seizures initially should be
managed with diazepam or lorazepam. However, persistent
seizures may require advancement to phenobarbital or pento-
barbital. Ventricular arrhythmias should be managed with
lidocaine. Patients that present with widening of the QRS
complex can be given sodium bicarbonate in 50 meq boluses.
The presence of persistently high serum levels or fluctuating
elevated serum levels may suggest the presence of a pharma-
cobezoar in the gut. Removal should be attempted, in the
presence of an active bowel, with whole bowel irrigation using
a polyethylene glycol–electrolyte solution. Hemodialysis and
charcoal hemoperfusion have been used in carbamazepine
overdose.

Ecotoxicology
Carbamazepine is not expected to produce acute ecotoxico-
logical effects.
Other Hazards
Carbamazepine is an inducer of CYP 3A4. Coadministration of
carbamazepine and contraceptive drugs may result in decreased
level of contraceptive drugs and permit ovulation.
See also: Diazepam; Lidocaine; Polyethylene Glycol.
Carbamazepine 667
Further Reading
Bridge, T.A., Norton, R.L., Robertson, W.O., 1994. Pediatric carbamazepine over-
doses. Pediatr. Emerg. Care 10, 260–263.
Donner, E., Kosjek, T., Qualmann, S., Kusk, K.O., Heath, E., Revitt, D.M., Ledin, A.,
Andersen, H.R., January 15, 2013. Ecotoxicity of carbamazepine and its UV
photolysis transformation products. Sci. Total Environ. 443, 870–876.
Kasarskis, E.J., Kuo, C.S., Berger, R., 1992. Carbamazepine-induced cardiac
dysfunction: characterization of two distinct clinical syndromes. Arch. Intern. Med.
152, 186–191.
Spiller, H.A., 2001. Management of carbamazepine overdose. Pediatr. Emerg. Care
17, 452–456.
van den Brandhof, E.J., Montforts, M., November 2010. Fish embryo toxicity of carba-
mazepine, diclofenac and metoprolol. Ecotoxicol. Environ. Saf. 73 (8), 1862–1866.