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HomeProduct name listCarbamazepine

Carbamazepine

Synonym(s):5H-Dibenz[b,f]azepine-5-carboxamide

  • CAS NO.:298-46-4
  • Empirical Formula: C15H12N2O
  • Molecular Weight: 236.27
  • MDL number: MFCD00005073
  • EINECS: 206-062-7
  • SAFETY DATA SHEET (SDS)
  • Update Date: 2024-12-18 14:07:02
Carbamazepine Structural

What is Carbamazepine?

Description

Carbamazepine is a synthetic iminostilbene derivative structurally similar to imipramine, a tricyclic antidepressant. While unrelated structurally, carbamazepine shares a similar therapeutic action with phenytoin. Carbamazepine was first discovered 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.

Chemical properties

White or off-white crystalline powder. Soluble in ethanol, acetone, propylene glycol, insoluble in water. Odorless and tasteless.

Originator

Tegretol,Geigy,W. Germany,1964

The Uses of Carbamazepine

Carbamazepine (CBZ) is a first generation anticonvulsant and mood stabilizing compound that has been used as a therapeutic in the context of neuropathic pain, epilepsy, and affective disorders. It exerts its effects by blocking voltage-gated sodium channels (IC50 = 640 μM), making fewer of these channels available to subsequently open, which leads to decreased high-frequency repetitive firing of action potentials. The estimated IC50 values for inhibition of Nav1.7-, Nav1.3-, and Nav1.8-type channels by CBZ following prolonged inactivation have been reported as 406, 900, and 138 μM, respectively. CBZ can also inhibit L-type Ca2+ channels (IC50 = 974 μM) and has been shown to potentiate GABAA receptors (IC50 >3 mM).

The Uses of Carbamazepine

Used in treatment of pain associated with trigeminal neuralgia. Anticonvulsant

Background

Carbamazepine, also known as Tegretol, is an anticonvulsant drug and analgesic drug used to control seizures and to treat pain resulting from trigeminal neuralgia. It was initially approved by the FDA in 1965. Aside from the above uses, this drug is also given to control the symptoms of bipolar 1. Interestingly, carbamazepine was the first anticonvulsant used to treat individuals with bipolar disorder.

Indications

Carbamazepine is indicated for the treatment of epilepsy and pain associated with true trigeminal neuralgia. In particular, carbamazepine has shown efficacy in treating mixed seizures, partial seizures with complex symptoms, and generalized tonic-clonic seizures. Carbamazepine is also indicated for the treatment of manic episodes and mixed manic-depressive episodes caused by bipolar I disorder. Some off-label, unapproved uses of carbamazepine include the treatment of alcohol withdrawal syndrome and restless leg syndrome.

Definition

ChEBI: Carbamazepine is a dibenzoazepine that is 5H-dibenzo[b,f]azepine carrying a carbamoyl substituent at the azepine nitrogen, used as an anticonvulsant. It has a role as an anticonvulsant, an EC 3.5.1.98 (histone deacetylase) inhibitor, a mitogen, a glutamate transporter activator, an antimanic drug, an analgesic, a non-narcotic analgesic, an environmental contaminant, a xenobiotic, a drug allergen and a sodium channel blocker. It is a dibenzoazepine and a member of ureas.

Manufacturing Process

19.3 parts of iminostilbene are dispersed in 100 parts by volume of toluene. Phosgene is then introduced whereupon the temperature of the reaction mixture rises to 70°C. While boiling under reflux, further phosgene is introduced until all the iminostilbene has dissolved and the hydrogen chloride development is complete. The reaction mixture is then cooled and the 5- chlorocarbonyl iminostilbene which has crystallized out is filtered off under suction. It melts at 168° to 169°C.
12.8 parts of 5-chlorocarbonyl iminostilbene are dispersed in 128 parts by volume of absolute ethanol and ammonia gas is introduced for three hours into this mixture while stirring at boiling temperature. The reaction is complete after this time; the reaction mixture is cooled and the crystals which precipitate are filtered off under suction. The ammonium chloride is washed from the crystals with water and the residue is recrystallized first from absolute ethanol and then from benzene. 5-carbamyl iminostilbene is obtained which melts at 204° to 206°C.

brand name

Carbatrol (Shire); Epitol (Teva); Equetro (Shire); Tegretol (Novartis); Teril (Taro).

Therapeutic Function

Analgesic, Anticonvulsant

Biological Functions

Carbamazepine has become a major drug in the treatment of seizure disorders. It has high efficacy, is well tolerated by most patients, and exhibits fewer long-term side effects than other drugs.
Oral absorption of carbamazepine is quite slow and often erratic. Its half-life is reported to vary from 12 to 60 hours in humans.The development of blood level assays has markedly improved the success of therapy with this drug, since serum concentration is only partially dose related. Carbamazepine is metabolized in the liver, and there is evidence that its continued administration leads to hepatic enzyme induction. Carbamazepine- 10,11-epoxide is a pharmacologically active metabolite with significant anticonvulsant effects of its own.

General Description

Certified pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to pharmacopeia primary standards.
Carbamazepine is a tricyclic lipophilic compound, with mild anticholinergic activity. It is widely used as an antiepileptic drug for the treatment of simple and complex partial tonic-clonic seizures.

Biochem/physiol Actions

Anticonvulsant; ligand for the GABAA receptor benzodiazepine modulatory site. Sodium channel inhibitor.

Mechanism of action

In animals, the profile of antiseizure properties for CBZ is similar to that of phenytoin. CBZ is effective in the maximal electroshock (MES) test (electrically induced seizure test) but is ineffective against pentylenetetrazole-induced seizures. It is not effective for absence or myoclonic seizures and, indeed, may exacerbate their onset. Like phenytoin, CBZ acts on voltage-dependent sodium channels to prevent the spread of seizures. CBZ depresses synaptic transmission in the reticular activating system, thalamus, and limbic structures. In a double-blind, crossover study in patients whose seizures were not controlled completely by combinations of AED, CBZ was equal in efficacy to phenobarbital and phenytoin in controlling seizure frequency, and side effects were minimal.

Pharmacokinetics

Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels. In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS). Carbamazepine has a narrow therapeutic index.

Pharmacokinetics

Following the administration of an oral dose, CBZ is slowly absorbed, with the attainment of peak concentration from immediate-release tablets in 4 to 5 hours and from extended-release tablets in 3 to 12 hours. The normal half-life averages between 12 and 17 hours; however, because of autoinduction, the half-life may range from 8 to 29 hours. The half-life for CBZ-10,11-epoxide is 5 to 8 hours. Therapeutic plasma concentrations range from 4 to 12 μg/mL (in adults) and may require a month to achieve a stable therapeutic concentration for the desired antiseizure effect because of induction of hepatic metabolizing enzymes.
CBZ is principally metabolized by CYP3A4 its 10,11-epoxide, with CYP2C8 and CYP1A2 having minor roles. CBZ epoxide is hydrolyzed to inactive 10,11-dihydroxy CBZ by epoxide hydrolase. CBZ epoxide is active and appears to be more toxic than CBZ. However, CBZ not only induces CYP3A4 activity but also its own metabolism (an autoinducer) as well as UGT and the increased formation of glucuronide metabolites. Like phenytoin, CBZ has been associated with a number of toxic effects, including a drug-induced hypersensitivity syndrome. Although phenytoin-induced hypersensitivity reactions are relatively rare events, they can be potentially life-threatening. Although the mechanism by which CBZ induces hypersensitivity reactions has not been well characterized, recent studies have suggested that the immune reaction may be caused, at least in part, by its metabolism into chemically reactive metabolites, which may be the critical step in the formation of protein adducts and subsequent immune responses.

Clinical Use

Carbamazepine is an effective agent for the treatment of partial seizures and generalized tonic–clonic seizures; its use is contraindicated in absence epilepsy. Carbamazepine is also useful in the treatment of trigeminal neuralgia and is an effective agent for the treatment of bipolar disorders.

Side Effects

Like most of the agents that block sodium channels, side effects associated with carbamazepine administration involve the central nervous system (CNS). Drowsiness is the most common side effect, followed by nausea, headache, dizziness, incoordination, vertigo, and diplopia.These effects occur particularly when the drug is first taken, but tolerance often develops over a few weeks. There appears to be little risk of cognitive impairment with carbamazepine.
Carbamazepine causes a variety of rashes and other allergic reactions including fever, hepatosplenomegaly, and lymphadenopathy, but the incidence of serious hypersensitivity reactions is rare. Systemic lupus erythematosus can occur, but discontinuation of the drug leads to eventual disappearance of the symptoms. Idiosyncratic hematological reactions to carbamazepine may occur, but serious blood dyscrasias are rare. Carbamazepine has been shown to exacerbate or precipitate seizures in some patients, particularly those exhibiting generalized atypical absences.
While the number of side effects may be fairly large, most are not serious and can be managed. Severe adverse reactions occur less commonly than with phenytoin and similar drugs. The overall incidence of toxicity seems to be fairly low at usual therapeutic doses. Most of the drug interactions with carbamazepine are related to its effects on microsomal drug metabolism. Carbamazepine can induce its own metabolism (autoinduction) after prolonged administration, decreasing its clearance rate, half-life, and serum concentrations. The possibility of autoinduction requires the clinician to reevaluate the patient’s blood levels after a month of carbamazepine therapy. The autoinduction phenomenon is over in about a month.
Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine; the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug–drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and troleandomycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop; this is readily reversible if either the antibiotic or carbamazepine is discontinued.

Synthesis

Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide (9.5.2), is synthesized by reacting 5H-dibenz[b,f]azepine and phosgene, which forms 5-chlorcarboxy- 5H-dibenz-[b,f]azepine (9.5.1), and its subsequent reaction with ammonia to give the desired carbamazepine (9.5.2) [16]. An alternative method of synthesis is the direct reaction of 5H-dibenz[b,f]azepine with potassium cyanate [17].

Synthesis_298-46-4

Drug interactions

Carbamazepine may be affected by other medicines, such as blood clot preventers and antibiotics. It may also interact with medications used to treat bipolar disorder. Some medications can decrease carbamazepine levels and others can increase carbamazepine levels. Valproate may increase carbamazepine-10,11-epoxide levels, while carbamazepine may decrease the levels of various medications including corticosteroids, clozapine, and lamotrigine. It is important to inform your doctor if you are taking any of these medicines to avoid potential interactions and to ensure carbamazepine works effectively.
Taking carbamazepine with other medicines and herbal supplements
What drug-drug interactions should you be vigilant for when someone is prescribed carbamazepine
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c13bc0b8-7900-4ef4-98ed-e1315a08d95d

Absorption

The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL. The Tmax was reduced to 5.9 ± 1.8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg.
Effect of food on absorption
A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption.

Environmental Fate

Carbamazepine is both an important anticonvulsant in therapeutic 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 neurotransmitters. Carbamazepine is also a powerful inhibitor of the muscarinic and nicotinic acetylcholine receptors, N-methyl-Daspartate (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.

Metabolism

Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine.

Metabolism

Carbamazepine is metabolised in the liver by cytochrome P450 3A4, where the epoxide pathway of biotransformation yields the 10, 11-transdiol derivative and its glucuronide as the main metabolites. 9-Hydroxy-methyl-10-carbamoyl acridan is a minor metabolite related to this pathway. Other important biotransformation pathways for carbamazepine lead to various monohydroxylated compounds, as well as to the N-glucuronide of carbamazepine produced by UGT2B7. After administration of a single oral dose of 400 mg carbamazepine, 72% is excreted in the urine and 28% in the faeces. In the urine, about 2% of the dose is recovered as unchanged drug and about 1% as the pharmacologically active 10,11-epoxide metabolite.

Toxicity

Toxicity information Oral LDLO (female): 1920 mg/kg/17W (intermittent); Oral LDLO (male): 54 mg/kg/9D (intermittent) Oral LD50 (rat): 1957 mg/kg
Overdose information
The initial signs of carbamazepine overdose occur 1-3 hours post ingestion. These signs and symptoms may vary in case of an overdose between carbamazepine and other drugs. Carbamazepine may cause various cardiovascular, neurological, respiratory, urinary symptoms as well as laboratory abnormalities including leukocytosis, reduced leucocytes, acetonuria, and glycosuria.
Neuromuscular symptoms may occur initially, followed by mild cardiac symptoms such as tachycardia, hypertension, or hypotension. Higher doses of carbamazepine may cause more severed cardiovascular effects. Restlessness, muscular twitching, tremor, dilated pupils, nystagmus, psychomotor disturbances, and other neurological symptoms may occur. Hyperreflexia in the initial stages of overdose may be followed by hyporeflexia. Nausea, vomiting, urinary retention, dizziness or drowsiness may also occur. In cases of overdose, contact the local poison control center. Ensure to provide supportive and symptomatic treatment, which may include monitoring and careful supervision by a medical professional. The possibility of overdose with multiple drugs must be considered in the case of carbamazepine overdose. Maintain an adequate airway, oxygen, in addition to ventilation. Vital signs should be monitored.

storage

Store at +4°C

Toxicity evaluation

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 photolysis, it has a half-life of approximately 1 day.

Properties of Carbamazepine

Melting point: 191-192 °C (lit.)
Boiling point: 378.73°C (rough estimate)
Density  1.1099 (rough estimate)
refractive index  1.5906 (estimate)
Flash point: 9℃
storage temp.  2-8°C
solubility  45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: soluble29mg/mL
pka 13.94±0.20(Predicted)
form  Crystals
color  Almost white
Water Solubility  pract. insoluble
Merck  14,1781
CAS DataBase Reference 298-46-4(CAS DataBase Reference)
NIST Chemistry Reference Carbamazepine(298-46-4)
EPA Substance Registry System 5H-Dibenz[b,f]azepine-5-carboxamide (298-46-4)

Safety information for Carbamazepine

Signal word Danger
Pictogram(s)
ghs
Exclamation Mark
Irritant
GHS07
ghs
Health Hazard
GHS08
GHS Hazard Statements H302:Acute toxicity,oral
H317:Sensitisation, Skin
H336:Specific target organ toxicity,single exposure; Narcotic effects
Precautionary Statement Codes P201:Obtain special instructions before use.
P280:Wear protective gloves/protective clothing/eye protection/face protection.
P302+P352:IF ON SKIN: wash with plenty of soap and water.
P308+P313:IF exposed or concerned: Get medical advice/attention.

Computed Descriptors for Carbamazepine

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