Carbamazepine

Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain.[3][4] It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder.[5][4] Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures.[6] It is not effective for absence or myoclonic seizures.[4]

Carbamazepine was discovered in 1953 by Swiss chemist Walter Schindler.[7][8] It was first marketed in 1962.[9] It is available as a generic medication.[10] It is on the World Health Organization's List of Essential Medicines.[11] In 2023, it was the 185th most commonly prescribed medication in the United States, with more than 2million prescriptions.[12][13]

Photoswitchable analogues of carbamazepine have been developed to control its pharmacological activity locally and on demand using light (photopharmacology), with the purpose of reducing the adverse systemic effects of the drug.[14] One of these light-regulated compounds (carbadiazocine, based on a bridged azobenzene or diazocine) has been shown to produce analgesia with noninvasive illumination in vivo in a rat model of neuropathic pain.

Medical uses

Carbamazepine is typically used for the treatment of seizure disorders and neuropathic pain.[4] It is used off-label as a second-line treatment for bipolar disorder and in combination with an antipsychotic in some cases of schizophrenia when treatment with a conventional antipsychotic alone has failed.[4][15] However, evidence does not support its usage for schizophrenia.[16] It is not effective for absence seizures or myoclonic seizures.[4] Although carbamazepine may have a similar effectiveness (as measured by people continuing to use a medication) and efficacy (as measured by the medicine reducing seizure recurrence and improving remission) when compared to phenytoin and valproate,[6] it is not well-researched which medication is most helpful for people with newly-onset seizures.[17][18][19]

In the United States, carbamazepine is indicated for the treatment of epilepsy (including partial seizures, generalized tonic-clonic seizures and mixed seizures), and trigeminal neuralgia.[3] Carbamazepine is the only medication that is approved by the Food and Drug Administration for the treatment of trigeminal neuralgia.[20]

As of 2014, a controlled release formulation was available for which there is tentative evidence showing fewer side effects and unclear evidence with regard to whether there is a difference in efficacy.[21]

In 2016, the FDA approved an intravenous formulation of carbamazepine, also granting it orphan drug status under the trade name Carnexiv, as a short-term replacement therapy for oral carbamazepine in adults with specific types of seizure disorders, who are unable to tolerate the oral formulation.[22] Carnexiv is indicated for short-term treatment of up to seven days for partial seizures with complex symptomatology, generalized tonic–clonic seizures and mixed seizure patterns, in patients who are temporarily unable to take or tolerate oral medications.[1][23]

It has also been shown to improve symptoms of "typewriter tinnitus", a type of tinnitus caused by the neurovascular compression of the cochleovestibular nerve.[24]

Adverse effects

In the US, the label for carbamazepine contains warnings concerning:[3]

Common adverse effects may include drowsiness, dizziness, headaches and migraines, ataxia, nausea, vomiting, and/or constipation. Alcohol use while taking carbamazepine may lead to enhanced depression of the central nervous system.[25] Less common side effects may include increased risk of seizures in people with mixed seizure disorders,[29] abnormal heart rhythms, blurry or double vision.[25] Also, rare case reports of an auditory side effect have been made, whereby patients perceive sounds about a semitone lower than previously; this unusual side effect is usually not noticed by most people, and disappears after the person stops taking carbamazepine.[30]

• effects on the body's production of red blood cells, white blood cells, and platelets: rarely, there are major effects of aplastic anemia and agranulocytosis reported and more commonly, there are minor changes such as decreased white blood cell or platelet counts, but these do not progress to more serious problems.[25]
• Bone marrow suppression
• increased risks of suicide[26]
• increased risks of hyponatremia and SIADH[25][27]
• risk of seizures, if the person stops taking the drug abruptly[25]
• risks to the fetus in women who are pregnant, specifically congenital malformations like spina bifida, and developmental disorders.[25][28]
• Pancreatitis
• Hepatitis
• Dizziness
• Stevens–Johnson syndrome
• SHBG elevation with effects on free testosterone
• dyslipidemia

Interactions

Carbamazepine has a potential for drug interactions.[36] Drugs that decrease breaking down of carbamazepine or otherwise increase its levels include erythromycin,[37] cimetidine, propoxyphene, and calcium channel blockers.[36] Grapefruit juice raises the bioavailability of carbamazepine by inhibiting the enzyme CYP3A4 in the gut wall and in the liver.[25] Lower levels of carbamazepine are seen when administered with phenobarbital, phenytoin, or primidone, which can result in breakthrough seizure activity.

Valproic acid and valnoctamide both inhibit microsomal epoxide hydrolase (mEH), the enzyme responsible for the breakdown of the active metabolite carbamazepine-10,11-epoxide into inactive metabolites.[38] By inhibiting mEH, valproic acid and valnoctamide cause a build-up of the active metabolite, prolonging the effects of carbamazepine and delaying its excretion.

Carbamazepine, as an inducer of cytochrome P450 enzymes, may increase clearance of many drugs, decreasing their concentration in the blood to subtherapeutic levels and reducing their desired effects.[39] Drugs that are more rapidly metabolized with carbamazepine include warfarin, lamotrigine, phenytoin, theophylline, valproic acid,[36] many benzodiazepines,[40] and methadone.[41] Carbamazepine also increases the metabolism of the hormones in birth control pills and can reduce their effectiveness, potentially leading to unexpected pregnancies.[36]

Pharmacology

History

Carbamazepine was discovered by chemist Walter Schindler at J.R. Geigy AG (now part of Novartis) in Basel, Switzerland, in 1953.[49][50] It was first marketed as a drug to treat epilepsy in Switzerland in 1963 under the brand name Tegretol; its use for trigeminal neuralgia (formerly known as tic douloureux) was introduced at the same time.[49] It has been used as an anticonvulsant and antiepileptic in the United Kingdom since 1965, and has been approved in the United States since 1968.[4]

Carbamazepine was studied for bipolar disorder throughout the 1970s.[51]

Society and culture

Further reading

External links

• Carbamazepine. UK National Health Service