Pharmacological properties
Pharmacodynamics. Phenytoin is an anticonvulsant used in the treatment of epilepsy. The main site of action is the motor area of the cerebral cortex, where convulsive activity is suppressed. Probably by promoting the outflow of sodium from neurons, phenytoin is able to stabilize the threshold of excitability caused by excessive stimulation or environmental changes that can reduce the membrane sodium gradient. This includes a decrease in posttetanic potentiation at synapses. The absence of posttetanic potentiation prevents the spread of the epileptic focus to adjacent areas of the cerebral cortex. Phenytoin reduces the maximum activity of the brainstem centers responsible for the tonic phase of tonic-clonic seizures (grand mal).
Pharmacokinetics. When taken orally, where absorption is characterized by variability, the peak concentration in blood plasma is noted within 3-12 hours. Actively distributed in tissues, including the central nervous system, penetrates into the cerebrospinal fluid, bile, excreted with saliva, gastric and intestinal juice, penetrates into breast milk, sperm. Penetrates through the placenta, while the drug concentrations in the blood plasma of the mother and fetus are equal. Binding to blood plasma proteins is 70-95%.
Metabolized by liver enzymes to inactive metabolites, about 5% of phenytoin is excreted unchanged by the kidneys. T ½ is about 24 hours, but depends on the dose of the drug and the concentration in the blood plasma. With prolonged use, it completely disappears from the blood plasma 3 days after stopping the drug.
Indication
Epilepsy, mainly grand mal seizures. Status epilepticus with tonic-clonic seizures. Treatment and prevention of epileptic seizures in neurosurgery.
In some cases, it can be prescribed to treat heart rhythm disorders caused by organic CNS lesions or an overdose of cardiac glycosides.
As a second-line drug or in combination with carbamazepine, it is indicated for trigeminal neuralgia.
Application
Inside, during or after meals (to avoid irritation of the gastric mucosa).
In epilepsy (partial and generalized tonic-clonic seizures), a single dose for adults is ½-1 tablet. Take 2-3 times a day. According to indications, to achieve the optimal therapeutic effect, the daily dose can be increased to 3-4 tablets. Maximum doses for adults: single - 3 tablets, daily - 8 tablets.
Children aged 5-8 years are prescribed ½ tablet 2 times a day, those over 8 years old - ½-1 tablet 2 times a day (at the rate of 4-8 mg/kg of body weight per day).
Arrhythmias: adults - 1 tablet 4 times a day (the effect appears on the 3rd-5th day), then the daily dose should be reduced to 3 tablets. To quickly achieve therapeutic concentration (on the 1st-2nd day) - 2 tablets 4 times on the 1st day, 1 tablet 5 times - on the 2nd-3rd day and 1 tablet 2-3 times a day - from the 4th day of treatment.
Trigeminal neuralgia: 1-3 tablets per day.
Contraindication
Hypersensitivity to phenytoin or other components of the drug, as well as to hydantoin anticonvulsants. heart failure, Adams-Stokes syndrome, AV block II-III degree, sinoatrial block, sinus bradycardia; hepatic or renal failure, cachexia, porphyria.
With caution: children with rickets, elderly patients, diabetes mellitus, chronic liver and kidney diseases, chronic alcoholism.
Concomitant administration of phenytoin with delavirdine is contraindicated due to the potential for loss of virological response and possible antagonism of delavirdine or non-nucleoside reverse transcriptase inhibitors.
Side effects
From the nervous system: dizziness, agitation, difficulty breathing, tremor, ataxia, nystagmus, impaired coordination of movements, confusion, diplopia, insomnia, mood changes, drowsiness, headache, muscle weakness, dysarthria; in isolated cases - peripheral neuropathy, dyskinesia (including chorea, dystonia).
On the part of the digestive system: nausea, vomiting, toxic hepatitis, gingival hyperplasia, constipation, liver damage.
From the side of the hematopoietic system: rarely - thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia (with / without bone marrow suppression), megaloblastic anemia, macrocytosis. There is a possible connection between taking the drug and the development of lymphadenopathy, including qualitative hyperplasia of the lymph nodes, pseudolymphoma, lymphoma and Hodgkin's disease.
On the part of the musculoskeletal system: coarsening of facial features, thickening of the lips; with prolonged use - a decrease in bone mineral density (osteopenia, osteoporosis, osteomalacia), bone fractures.
Allergic reactions: skin rash, fever; in isolated cases - bullous, purpuric or exfoliative dermatitis with hepatitis, lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, anaphylaxis. Dermatological manifestations are sometimes accompanied by scarlet fever-like or crust-like rashes.
On the part of the immune system: in isolated cases, there have been reports of the possible development of hypersensitivity syndrome (may include the following symptoms: eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), periarteritis nodosa, changes in immunoglobulin levels.
Others: in rare cases - hypertrichosis, Peyronie's disease; change in taste sensations, including a metallic taste in the mouth.
If side effects are severe, the dose is gradually reduced or the drug is stopped altogether.
Special instructions
Abrupt discontinuation of diphenin treatment in patients with epilepsy may trigger the development of withdrawal syndrome.
In patients with epilepsy, if abrupt drug withdrawal is necessary (for example, if allergic or hypersensitivity reactions develop), anticonvulsants that are not hydantoin derivatives should be used.
In acute alcohol intoxication, the concentration of phenytoin in the blood plasma may increase, and in chronic alcoholism, it may decrease.
If the drug is not effective enough, it is recommended to prescribe another antiepileptic drug.
There have been reports of the possibility of suicidal behavior or thoughts in some patients treated with antiepileptic drugs. Therefore, the occurrence of such cases cannot be ruled out when using Diphenin, which requires appropriate monitoring by doctors and relatives of the patient regarding possible signs or tendencies of the patient to suicidal behavior.
If depression appears or worsens, monitoring of the patient's condition by doctors and relatives is also necessary; relatives or family members of patients with AIDS should be informed about the increased risk of suicidal behavior or thoughts in AIDS patients, so if unusual changes in mood or behavior occur, you should immediately consult a doctor.
Elevated phenytoin levels sustained in the blood plasma may cause conditions characterized by delirium, psychosis, or encephalopathy, or rarely, irreversible cerebellar dysfunction. Accordingly, determination of phenytoin blood levels is recommended at the first signs of acute toxicity. Dosage reduction is necessary if blood levels of the drug are excessive; if symptoms persist, discontinuation of therapy is recommended.
St. John's wort preparations should not be used while taking Diphenin, as there is a risk of reducing the concentration of phenytoin in the blood plasma and the effectiveness of the drug.
Cases of hyperglycemia due to the drug's delay in insulin secretion have been reported. Phenytoin may also increase glucose levels in diabetic patients.
Phenytoin is metabolized primarily in the liver, so patients with impaired liver function or the elderly may require a reduced dose to prevent accumulation and toxicity.
Cases of acute hepatotoxicity, acute hepatic failure, jaundice, hepatomegaly, increased blood transaminase levels, leukocytosis and eosinophilia have been reported; in the event of acute hepatic failure, the drug should be discontinued immediately and not re-administered.
Antiepileptic drug hypersensitivity syndrome is a rare reaction that may occur during anticonvulsant therapy. The syndrome can be potentially fatal and is characterized by fever, rash, lymphadenopathy, and other reactions, often involving the liver. The mechanism of the syndrome is unknown. The interval between the first dose of the drug and the onset of symptoms is usually 2-3 weeks, although there have been reports of the syndrome occurring after 3 or more months of anticonvulsant therapy. Patients at risk include black patients, patients with a family history of the syndrome, and patients with a suppressed immune system. If the syndrome is diagnosed, the drug should be discontinued and appropriate supportive therapy should be provided.
Phenytoin can cause rare serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson syndrome and toxic epidermal necrolysis. The reactions may occur asymptomatically, but patients should be warned about the symptoms of rash, blisters, fever or other signs of hypersensitivity such as itching and to inform the doctor immediately if they occur.
In case of severe skin adverse reactions, the drug should be discontinued and the patient should be given alternative treatment. If a patient develops a rash, it is necessary to evaluate his condition for the development of DRESS syndrome. It is known that the presence of HLA-B * 1502 in patients increases the risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis.
Phenytoin and other anticonvulsants due to the induction of the P450 enzyme can affect bone mineral metabolism, indirectly affecting the metabolism of vitamin D 3. With prolonged use (over 10 years) this can lead to vitamin D 3 deficiency and an increased risk of osteomalacia, fractures, osteoporosis in patients who take the drug constantly. During the period of treatment, especially long-term, UV irradiation is recommended, as well as a diet that satisfies the body's need for vitamin D 3.
There have been isolated reports linking phenytoin administration with exacerbation of porphyria, so caution is required in patients with a history of this disease.
Hematopoietic complications, sometimes fatal, have been reported, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with/without bone marrow suppression, and lymphadenopathy.
Do not prescribe to patients with seizures associated with hypoglycemia or other metabolic disorders.
Use during pregnancy and breastfeeding. During pregnancy, the drug should be prescribed only for vital indications, when the benefit of treatment for the mother outweighs the risk to the fetus.
The drug passes into breast milk in concentrations sufficient to cause side effects in the infant, so its use in the mother is not recommended.
Children. The drug in this dosage form is prescribed to children aged 5 years and older for epilepsy.
It is recommended that children (especially during the growth period) be prescribed Diphenin in combination with vitamins D and K, as the development of osteopathies such as rickets, hypocalcemia, and blood clotting disorders is possible.
Ability to influence the reaction speed when driving vehicles or working with other mechanisms. During the treatment period, a delay in the speed of psychomotor reactions is observed. Persons whose activities require increased attention and speed of psychomotor reactions should be careful when using the drug.
Interactions
Drugs that may increase phenytoin plasma levels
Amiodarone, antiepileptics (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, miconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2 antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazine, salicylates, sertraline, succinimides, sulfonamides (e.g. sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), cyclopidine, tolbutamide, trazodone, warfarin, as well as single administration of phenytoin and alcohol.
Drugs that may decrease serum phenytoin levels
Anticancer drugs, usually in combination (e.g. bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampicin, ritonavir, St. John's wort, sucralfate, theophylline, vigabatrin, as well as chronic alcohol abuse.
The use of phenytoin with drugs that increase gastric pH (for example, dietary supplements or antacids containing calcium carbonate, aluminum hydroxide, and magnesium hydroxide) may affect the absorption of phenytoin. In most cases of this interaction, a decrease in phenytoin plasma levels is observed if the drugs are used at the same time. Therefore, if possible, phenytoin and these drugs should not be used at the same time of day.
Drugs that may increase or decrease phenytoin plasma levels
Phenobarbital, sodium valproate and valproic acid. The effect of phenytoin on the plasma levels of phenobarbital, valproic acid and sodium valproate is unpredictable.
When prescribing or withdrawing these drugs in patients treated with phenytoin, phenytoin dose adjustment may be necessary to achieve optimal therapeutic results.
Drugs contraindicated in phenytoin therapy: delavirdine (see Side effects).
Drugs whose effectiveness is impaired when used with phenytoin
Azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampicin, sertraline, teniposide, theophylline, vitamin D.
The interaction of phenytoin and warfarin may be different, so it is necessary to determine the prothrombin time when combining them.
Phenytoin reduces plasma concentrations of the active metabolites of albendazole, antiviral drugs (including efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic drugs (carbamazepine, felbamate, lamotrigine, topiramate, oxcarbazepine, quetiapine), atorvastatin, chlorpropamide, clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nisoldipine, praziquantel, simvastatin and verapamil.
Concomitant administration of phenytoin with fosamprenavir may reduce the concentration of amprenavir, the active metabolite of the latter; when phenytoin is used simultaneously with a combination of fosamprenavir and ritonavir, an increase in the concentration of amprenavir in the blood plasma is possible.
Patients who have been taking phenytoin for a long time have developed resistance to the neuromuscular blocking effects of nondepolarizing muscle relaxants (pancuronium, vecuronium, rocuronium, and cisatracurium). It is not known whether phenytoin has the same effect on other nondepolarizing muscle relaxants. Patients with such conditions should be closely monitored.
Laboratory Tests. Phenytoin may decrease plasma thyroxine (T4) concentrations. It may also decrease dexamethasone and metapyrone levels in studies. Phenytoin may cause increases in plasma glucose, ALT, and GGT. Phenytoin is a potent inducer of liver enzymes.
Phenytoin is bound to plasma proteins. Caution should be exercised when using immunological methods to measure plasma phenytoin concentrations.
Symptoms: lethal dose for children is unknown; estimated lethal dose for adults is 2-5 g initial symptoms: nystagmus, ataxia and dysarthria; other signs of overdose: tremor, hyperreflexia, drowsiness, slurred speech, nausea, vomiting. Coma and hypotension are possible. Death may occur due to respiratory and cardiovascular failure.
There are differences between individual cases of overdose depending on the concentration of phenytoin in the blood plasma. Thus, nystagmus usually occurs at a dose of 20 μg/ml, ataxia - 30 μg/ml, dysarthria and lethargy occur at a plasma concentration of phenytoin above 40 μg/ml (there are no reports of toxicity at a concentration of 50 μg/ml).
Treatment is symptomatic. There is no specific antidote.
If the patient is conscious, he should be washed with gastric lavage, activated charcoal or other sorbents should be administered. Mechanical ventilation may be necessary in case of CNS, respiratory and cardiovascular depression. Hemodialysis may be prescribed, since phenytoin is fully bound to plasma proteins.
Storage conditions
In a dry place, protected from light.
