Mechanism of action of carbamazepine
According to its chemical structure, carbamazepine belongs to the group of tricyclic antidepressants.
In clinical practice, it is used as a sedative, normothymic and anticonvulsant substance. Pharmaceutical preparations based on it are characterized by low toxicity and low potential for addiction. Unfortunately, the mechanism of action of the substance is still not fully understood. It has been established that its administration makes it possible to stabilize the cell membranes (membranes) of hyperstimulated cells of the nervous system, for example, in epilepsy or acute psychosis with convulsive syndrome. At the same time, it suppresses the development of repeated excitation and inhibits the conduction of neuronal impulses.
Use for alcoholism
In the treatment of any pathological conditions associated with long-term alcohol abuse, one-size-fits-all medications are never used. The choice of each medicine is approached with the utmost rigor, since in some cases it can only worsen the situation. The patient is thoroughly examined, after which the benefit/risk factor is assessed.
Indications
The main spectrum of action of the drug is the relief of seizures; to a lesser extent, the emotional background is normalized. Carbamazepine is used for alcoholism if the following indications exist:
- The structure of the syndrome of pathological craving for alcohol contains affective (psycho-emotional) disorders.
- Relief of withdrawal symptoms - “withdrawal” during the period of cessation of abuse in fully formed true binge drinking.
- Prevention of the development of convulsive attacks in cases of aggravated medical history.
- The patient is not suitable for other antidepressants or antiepileptic drugs.
Carbamazepine has been shown to be as effective as or superior to barbital, tiapride, clomethiazole, oxazepam, and placebo in open-label and double-blind studies. A double-blind study conducted by Malcolm et al. and repeated by Stuppaeck et al. demonstrated equal effectiveness of carbamazepine and oxazepam in relieving alcohol withdrawal. However, no differences were found in laboratory testing of liver and blood function, although carbamazepine may worsen these indicators. In addition to relieving withdrawal symptoms, carbamazepine, compared to oxazepam, more effectively improves the general condition of the patient, assessed according to the SCL-90-R criteria.”
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Carbamazepine also enhances the positive effects of other neurotropic drugs that are used during the period of active anti-relapse treatment. In small dosages, it improves the emotional background, eliminates dysphoric symptoms (anxiety, depression, apathy) and reduces convulsive readiness. At the same time, the craving for drinking alcohol is suppressed.
Side effects and contraindications
The dose of the anticonvulsant is selected individually; the drug is usually well tolerated. Carbamazepine is contraindicated in case of clinically significant cardiac rhythm and conduction disturbances, hypersensitivity to tricyclic antidepressants, acute porphyria and a history of myelosuppression. The following side effects are possible:
- disturbance of taste and speech
- headache
- relapse of psychosis
- depression
- appearance of hallucinations
- dizziness
- excessive psychomotor agitation
- nystagmus – multi-frequency involuntary eye movements
- diplopia - double vision
- noise in ears
- conjunctivitis
- peripheral neuropathy
- muscle weakness up to paresis
- atrioventricular block
- worsening heart failure, including due to hemodynamic disorders (hypo- or hypertension)
- kidney damage
- nausea
- vomit
- toxic hepatitis
- thromboembolic complications if there is a predisposition
- electrolyte disorders
- allergic reactions
CARBAMAZEPINE
special instructions
The drug is usually ineffective for absence seizures (petit mal) and myoclonic seizures.
The drug should only be used under the condition of regular medical supervision. During use of the drug with varying frequency, a transient or persistent decrease in the number of platelets or leukocytes is observed. However, in most cases these phenomena are transient and usually do not predict the onset of aplastic anemia or agranulocytosis.
Before starting treatment, as well as periodically during treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the concentration of iron in the blood serum.
Patients should be informed of early signs of toxicity associated with possible hematological disorders, as well as skin and liver symptoms. The patient is informed of the need to immediately consult a doctor in case of adverse reactions such as fever, sore throat, rash, mouth ulcers, unexplained hemorrhages, hemorrhages in the form of petechiae or purpura.
Severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), have been very rarely observed with the use of Carbamazepine. If severe (in some cases life-threatening) skin reactions develop, the patient should be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed in the first months of drug therapy.
According to a retrospective analysis of the use of the drug in Chinese patients, there is a correlation between the frequency of severe dermatological reactions and the presence of the HLA-B*1502 allele of the human leukocyte antigen (HLA) gene in the patient’s genome.
When carbamazepine was used in patients in the countries of the Asian region (Taiwan, Malaysia, the Philippines), where there is a high prevalence of the HLA-B* 1502 allele, an increase in the incidence of Stevens-Johnson syndrome was detected (from “very rare” to “rare”). The frequency of distribution of the HLA-B* 1502 allele is: in the Philippines and among some groups of the population of Malaysia - more than 15%. The prevalence of the HLA-BM502 allele in Korea and India is 2% and 6%, respectively.
The prevalence of this allele in people of Caucasian, Negroid races, Latin Americans, Indians and Japanese is insignificant.
When prescribing carbamazepine to possible carriers of the HLA-B*1502 allele (for example, persons of Chinese nationality), it is recommended to carry out genotyping for this allele. The drug should be prescribed to carriers of this allele only if the benefits of therapy outweigh the possible risks. In persons of Caucasian, Negroid and Americanoid races, genotyping for the HLA-B*1502 allele is not necessary before prescribing Carbamazepine.
For patients already receiving therapy with Carbamazepine, genotyping for this allele is not recommended, since severe skin reactions in most cases were observed in the first months of drug use (regardless of the presence of the HLA-B* 1502 allele). However, the results of genotyping for the HLA-B*1502 allele should not affect the degree of control over the patient’s condition and the doctor’s alertness regarding severe skin reactions. The development of Stevens-Johnson and Lyell syndromes is possible in patients negative for the H-LAB* 1502 allele. Also, in many cases, in people of Chinese nationality positive for the HLA-B*1502 allele, the development of Stevens-Johnson and Lyell syndromes was not observed when using Carbamazepine.
The influence of other factors, such as the dose of anticonvulsants, patient compliance, concomitant therapy with other drugs, concomitant diseases, or the level of control of dermatological reactions, on the incidence and prevalence of severe skin reactions has not been established.
Mild skin reactions, for example, isolated macular or maculopapular exanthema, are in most cases transient and mild, usually disappearing within a few days or weeks with continued treatment or after reducing the dose of the drug. However, since differential diagnosis between early manifestations of severe skin reactions and mild, transient skin rashes can be difficult, if any skin reactions develop, the patient should be under medical supervision (with a view to timely discontinuation of drug therapy if the patient's condition worsens).
The relationship between the presence of the HLA-A*3101 allele in the genome and the development of mild skin reactions (such as hypersensitivity syndrome, isolated macular or maculopapular exanthema) has not been established.
With the development of hypersensitivity to Carbamazepine, patients may experience either individual lesions of the skin, liver, circulatory and lymphatic systems or other organs, or a combination of them, which should be considered as a systemic reaction.
Patients with known hypersensitivity to carbamazepine should be informed of the possibility of developing hypersensitivity reactions to oxcarbazepine in 25-30% of cases.
Cross-hypersensitivity reactions also occur between carbamazepine and phenytoin.
Before starting treatment with the drug and periodically during therapy, it is recommended to study a general urine test and the level of urea in the blood.
Before prescribing Carbamazepine and during treatment, liver function testing is necessary, especially in patients with a history of liver disease, as well as in elderly patients. If pre-existing liver dysfunction worsens or active liver disease develops, carbamazepine should be discontinued immediately.
The drug has weak m-anticholinergic activity. Therefore, when using the drug in patients with increased intraocular pressure, constant monitoring of this indicator is necessary.
To date, there have been isolated reports of disturbances in male fertility and/or disturbances in spermatogenesis. However, the causal relationship of these disorders with taking the drug has not yet been proven.
The drug may reduce the effectiveness of medications containing estrogens and/or progesterone, so women of childbearing age should use alternative methods of birth control during treatment with the drug.
Although the relationship between drug dose, carbamazepine plasma concentration, clinical efficacy or tolerability is very small, regular determination of carbamazepine concentration may be advisable in the following situations: when there is a sharp increase in the frequency of attacks, in order to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of the drug; if toxic reactions are suspected if the patient is taking several medications.
Sudden cessation of the drug may provoke epileptic seizures. If it is necessary to discontinue the drug in a patient with epilepsy, switching to another antiepileptic drug should be carried out under the cover of the drug indicated in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).
Before prescribing the drug, MAO inhibitors should be discontinued at least 2 weeks in advance or, if the clinical situation allows, even longer.
Patients receiving antiepileptic drugs are at increased risk of suicidal behavior, including thoughts of suicide. In this regard, the patient's condition should be carefully monitored in order to promptly detect the progression of depression, suicidal behavior, other changes in mood or unusual behavior of the patient.
