Phenytoin

Pharmacological properties

phenytoin is an anticonvulsant used in the treatment of epilepsy. the main place of action is the motor zone of the cerebral cortex, where convulsive activity is inhibited. probably contributing to 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 gradient of sodium. this includes reducing post-tetanic potentiation at synapses. the absence of post-tetanic potentiation prevents the spread of the epileptic focus to adjacent areas of the cerebral cortex. phenytoin reduces the maximum activity of the centers of the brain stem responsible for the tonic phase of tonic-clonic seizures (grand mal).

Pharmacokinetics When ingested, where absorption is characterized by variability, a peak in plasma concentration is observed within 3-12 hours. It is actively distributed in tissues, including the central nervous system, penetrates the CSF, bile, excreted in saliva, gastric and intestinal juice, penetrates into breast milk, sperm. It penetrates the placenta, while the concentration of the drug in the blood plasma of the mother and fetus are equal. Binding to plasma proteins 70–95%.

It is metabolized by liver enzymes to inactive metabolites, about 5% of phenytoin is excreted unchanged by the kidneys. T_½ - 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 intake.

Indications

Epilepsy, mainly large epileptic seizures (grand mal). epileptic status with tonic-clonic seizures. treatment and prevention of epileptic seizures in neurosurgery.

In some cases, it can be prescribed for the treatment of cardiac arrhythmias caused by organic lesions of the central nervous system, 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 a meal (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, in order to achieve the optimal therapeutic effect, the daily dose can be adjusted to 3-4 tablets. Maximum doses for adults: single - 3 tablets, daily - 8 tablets.

Children aged 5–8 years are prescribed ½ tablets 2 times a day, and over 8 years of age - ½ – 1 tablet 2 times a day (based on 4–8 mg / kg body weight per day).

Arrhythmias: for adults - 1 tablet 4 times a day (the effect is manifested on the 3rd and 5th day), then the daily dose should be reduced to 3 tablets. To quickly achieve therapeutic concentration (on the 1-2nd day) - 2 tablets 4 times on the 1st day, 1 tablet 5 times on the 2nd – 3rd day and 1 tablet 2-3 times day - from the 4th day of treatment.

Trigeminal neuralgia: 1-3 tablets per day.

Contraindications

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 with diabetes mellitus, chronic liver and kidney diseases, chronic alcoholism.

Concomitant use of phenytoin with delavirdine is contraindicated because of the potential for loss of the virologic response and possible antagonism of delavirdine or non-nucleoside reverse transcriptase inhibitors.

Side effects

From the nervous system: dizziness, agitation, difficulty breathing, tremors, 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).

From the digestive system: nausea, vomiting, toxic hepatitis, gingival hyperplasia, constipation, liver damage.

From the hemopoietic system: rarely - thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia (with / without bone marrow depression), megaloblastic anemia, macrocytosis. There may be a connection between taking the drug and the development of lymphadenopathy, including benign lymph node hyperplasia, pseudolymphoma, lymphoma and Hodgkins disease.

From 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, purple or exfoliative dermatitis with hepatitis, lupus erythematosus, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, anaphylaxis. Dermatological manifestations are sometimes accompanied by scarlet-like or measles-like rashes.

On the part of the immune system: in isolated cases, there have been reports of a possible development of hypersensitivity syndrome (may include such symptoms, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), periarteritis nodosa, and changes in immunoglobulin levels.

On the part of the liver and hepatocellular system: acute liver failure.

Others: in isolated cases - hypertrichosis, Peyronies disease; a change in taste, including a metallic taste in the mouth.

With severe side effects, the dose is gradually reduced or the drug is completely stopped.

special instructions

The sudden cessation of diphenin treatment in patients with epilepsy can trigger the withdrawal syndrome.

In patients with epilepsy, if it is necessary to abruptly discontinue the drug (for example, with the development of allergic reactions or hypersensitivity reactions), anticonvulsants other than hydantoin derivatives should be used.

In acute alcohol intoxication, the concentration of phenytoin in blood plasma may increase, in chronic alcoholism - decrease.

If the drug is not effective enough, it is recommended to prescribe another antiepileptic drug.

There are reports of the possibility of suicidal behavior or ideas in some patients who were treated with antiepileptic drugs. Therefore, the occurrence of such cases with the use of Diphenin cannot be ruled out, which requires appropriate monitoring by doctors and relatives of the patient regarding possible signs or tendency of the patient to suicidal behavior.

With the onset or exacerbation of depression, it is also necessary to monitor the condition of the patient by doctors and relatives; relatives or family members of patients with AIDS should be informed about the increased risk of suicidal behavior or thoughts in AIDS patients, therefore, if unusual changes in mood or behavior occur, you should immediately consult a doctor.

Elevated levels of phenytoin, which is maintained in blood plasma, can cause conditions characterized by delirium, psychosis or encephalopathy, or rarely, irreversible cerebellar dysfunction. Accordingly, at the first signs of acute toxicity, the determination of the level of phenytoin in the blood is recommended.It is necessary to reduce the dose with an excessive level of the drug in the blood, if the symptoms do not disappear, it is recommended that drug therapy be discontinued.

Hypericum preparations should not be used while taking diphenin, since there is a risk of a decrease in the concentration of phenytoin in blood plasma and the effectiveness of the drug.

Cases of hyperglycemia caused by delayed insulin release have been reported. Phenytoin can also increase glucose levels in patients with diabetes.

Phenytoin is metabolized mainly in the liver, so for patients with impaired function or the elderly, a dose reduction may be necessary to prevent cumulation and toxicity.

Cases of acute hepatotoxicity, acute liver failure, jaundice, hepatomegaly, increased levels of blood transaminases, leukocytosis and eosinophilia have been reported; in the case of acute liver failure, the use of the drug should be stopped immediately and not prescribed again.

Hypersensitivity syndrome to antiepileptic drugs is a reaction that rarely can occur during anticonvulsant therapy. The syndrome can be potentially fatal and be characterized by fever, rash, lymphadenopathy, and other reactions, often from 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; there have been reports of the occurrence of the syndrome after 3 or more months of taking anticonvulsants. The risk group includes patients of the Negroid race, patients with this syndrome in a family history and patients with a suppressed immune system. With the diagnosed syndrome, it is necessary to stop taking the drug and provide the necessary supportive therapy.

Phenytoin can cause rare serious skin adverse reactions, such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Reactions may occur asymptomatically, but patients should be warned of the symptoms of a rash, blistering, fever, or other signs of hypersensitivity, such as pruritus, and urgently inform the doctor if they occur.

In case of severe skin adverse reactions, the use of the drug should be discontinued and an alternative treatment should be prescribed to the patient. If the patient has a rash, it is necessary to assess his condition regarding the occurrence 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 enzyme P450 can affect the mineral metabolism of bone tissue, indirectly affecting the metabolism of vitamin D₃. With prolonged use (more than 10 years), this can lead to vitamin D deficiency.₃ and an increased risk of osteomalacia, fractures, osteoporosis in patients who take the drug constantly. During the treatment period, especially the long one, UV radiation is recommended, as well as a diet that satisfies the bodys need for vitamin D₃.

There have been separate reports linking phenytoin intake with exacerbation of porphyria, therefore caution is required in patients with a history of this disease.

Hematopoietic complications were reported, sometimes fatal, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia with / without bone marrow suppression, lymphadenopathy.

Phenytoin is ineffective for small seizures (petit mal).

Do not prescribe to patients with convulsions associated with hypoglycemia or other metabolic disorders.

Use during pregnancy and lactation.During pregnancy, the drug should be prescribed only for health reasons, 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, therefore its use in the nursing mother is not recommended.

Children. The drug in this dosage form is prescribed for children aged 5 years and over with epilepsy.

Children (especially during the growth period) are recommended to prescribe Diphenin in combination with vitamins D and K, since the development of osteopathies such as rickets, hypocalcemia, and blood clotting disorders is possible.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. During the treatment period, a delay in the speed of psychomotor reactions is noted. Persons whose activities require increased attention and speed of psychomotor reactions should be careful when using the drug.

Interactions

Medicines that can increase plasma phenytoin levels

Amiodarone, antiepileptics (ethosuximide, felbamate, oxcarbazepine, metsuksimid, 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, sulfanilamides (e.g. sulfamethisole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), cyclopidine, tolbutonate, tarabutonotamide, tarabutonitrate, tarabutonotamide, tarabutonitrate, tarabutonitrate, also and alcohol.

Medicines that can lower serum phenytoin levels

Antineoplastic drugs, usually in combination (e.g. bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, diazepam, diazoxide, folic acid, fosamprenavir, nelfinavir, reserpine, rifampicin, ritonavirfin, zver, zver also chronic alcohol abuse.

The use of phenytoin with drugs that increase the pH of the stomach (for example, food additives or antacids containing calcium carbonate, aluminum hydroxide and magnesium hydroxide) can affect the absorption of phenytoin. In most cases of this interaction, a decrease in the level of phenytoin in the blood plasma 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.

Medicines that can increase or decrease plasma phenytoin levels

Phenobarbital, sodium valproate and valproic acid. The effect of phenytoin on the levels of phenobarbital, valproic acid and sodium valproate in blood plasma is unpredictable.

When prescribing or canceling these drugs to patients treated with phenytoin, dose adjustment of phenytoin may be necessary to achieve the optimal treatment outcome.

Medicines, the use of which is contraindicated in the case of phenytoin therapy: delavirdine (see CONTRAINDICATIONS).

Medicines whose effectiveness is impaired when phenytoin is used

Azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contraceptives, paclitaxel, paroxetine, quinidine, rifampicin, sertraline D. tenip,

The interaction of phenytoin and warfarin can 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 (in particular, efavirenza, lopinavir / ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), antiepileptic drugs (carbamazepine, felbamate, lamotrigine, chloropatapapate apramate, apiapapate apramate, apiapapate clozapine, cyclosporine, digoxin, fluvastatin, folic acid, methadone, mexiletine, nifedipine, nimodipine, nizoldipine, praziquantel, simvastatin and verapamil .

The concomitant use of phenytoin with fosamprenavir can reduce the concentration of amprenavir, the active metabolite of the latter; when using phenytoin simultaneously with the combination of fosamprenavir and ritonavir, an increase in the concentration of amprenavir in the blood plasma is possible.

Patients who used phenytoin for a long time developed resistance to the neuromuscular blocking effect of non-depolarizing muscle relaxants (pancuronium, vecuronium, rocuronium, and cisatracuria). It is not known whether phenytoin has the same effect on other non-depolarizing muscle relaxants. Patients with such conditions should be under close medical supervision.

Laboratory research. Phenytoin may reduce the concentration of thyroxine (T4) in blood plasma. It can also lower levels of dexamethasone and metapiron in studies. The use of phenytoin can lead to an increase in plasma glucose, alkaline phosphatase and GGT. Phenytoin is a powerful inducer of liver enzymes.

Phenytoin binds to plasma proteins. Caution should be exercised when using immunological methods for measuring plasma phenytoin concentration.

Overdose

Symptoms: the lethal dose for children is unknown; expected lethal dose for adults - 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 can occur due to respiratory and cardiovascular failure.

There are differences between individual cases of overdose depending on the concentration of phenytoin in blood plasma. So, nystagmus usually occurs when taking a dose of 20 μg / ml, ataxia - 30 μg / ml, dysarthria and lethargy occur when the concentration of phenytoin in the blood plasma is more than 40 μg / ml (there are no reports regarding toxicity of the concentration of 50 μg / ml )

The treatment is symptomatic. There is no specific antidote.

If the patient is conscious, he needs to rinse the stomach, prescribe activated charcoal or other sorbents. May be necessary mechanical ventilation for inhibition of the central nervous system, respiratory and cardiovascular systems. Hemodialysis may be prescribed because phenytoin does not completely bind to plasma proteins.

Storage conditions

In a dry, dark place.