Phenytoin (Phenytoinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antiarrhythmics

Antiepileptic agents

Included in the formulation
  • Diphenine
    pills inwards 
    LUHANSKY HFZ, OJSC     Ukraine
  • Diphenine
    pills inwards 
    UZOLE-SIBERIAN CHEMICAL PLANT, OJSC     Russia
    • Included in the list (Order of the Government of the Russian Federation No. 2782-r of 30.12.2014):

    VED

    АТХ:

    N.03.A.B.02   Phenytoin

    Pharmacodynamics:

    An anticonvulsant, a hydantoin derivative. Has anticonvulsant, antiarrhythmic, analgesic, miorelaksiruyuschee effect.

    It is believed that the anticonvulsant effect is due to a block of sodium channels, the stabilization of neuronal membranes, axons and synapses, as well as the restriction of the spread of excitation and convulsive activity. Like other hydantoin anticonvulsants, phenytoin has an exciting effect on the cerebellum, activating the inhibitory pathways that spread to the cerebral cortex. This effect can also lead to a decrease in convulsive activity, which is associated with increased discharge in the cerebellum.

    Blocking sodium channels, the drug prolongs only phases 0 and 4. Accordingly, it inhibits the conductivity and automatism of Purkinje fibers and contractile cardiomyocytes. The drug of class IB blocks the sodium channels in the inactivated state and has an association / dissociation rate of less than 1 s, which does not exceed the duration of the normal action potential.Thus, without restraining the heart rhythm, it prevents the generation and carrying out of extraordinary pulses.

    Abnormal ventricular automatism and membrane excitability decrease. Phenytoin also shortens the refractory period, expands the QRS complex. Increases the pain threshold with neuralgia of the trigeminal nerve and shortens the duration of the attack, reducing the excitation and the formation of repeated discharges, that is, it has an analgesic effect.

    Phenytoin is considered the drug of choice for ventricular arrhythmias caused by cardiac glycosides. This is due to the fact that by providing an antiarrhythmic effect, it does not reduce the positive inotropic effect of these cardiotonic drugs and aggravates the violation of atrio-ventricular conduction.

    The mechanism of myorelaxing action, apparently, is similar to the mechanism of anticonvulsant action. Due to membrane-stabilizing activity in motor disorders, it weakens prolonged repeated discharges and potentiation in nerve and muscle cells.

    Derivatives of hydantoin induce microsomal enzymes of the liver, thereby enhancing the metabolism of concomitantly used drugs.

    Pharmacokinetics:

    When ingested, absorption is slow, characterized by variability depending on the dosage form used. With intramuscular injection, the absorption is also slow, but almost complete - 92%.

    Phenytoin penetrates into the cerebrospinal fluid, saliva, semen, gastric and intestinal juice, bile, excreted in breast milk. Penetrates through the placental barrier, the concentrations in the mother's blood plasma are equal to the concentrations in the fetal plasma. Binding to proteins 90% or more.

    Metabolised in the liver with the participation of isoenzymes CYP2C9, CYP2C19 with the formation of inactive metabolites. It has been established that a constant amount of active substance is metabolized in connection with the saturation of the enzyme system responsible for the metabolism of phenytoin, which occurs when therapeutic concentrations are reached. Therefore, a small increase in the dose may lead to a disproportionately large increase in plasma concentrations of the active substance and half-life.

    Phenytoin is the inducer of the isoenzymes CYP1A2, CYP3A4.

    The half-life period depends on the dose, concentration of the active substance in the plasma.

    It is excreted by the kidneys in the form of metabolites and through the intestines.

    Indications:

    Epilepsy (large convulsive seizures); epileptic status with tonic-clonic seizures; epileptic seizures in neurosurgery (prevention and treatment).

    Ventricular arrhythmias (including with glycosidic intoxication or associated with intoxication with tricyclic antidepressants).

    Neuralgia of the trigeminal nerve (as a second-line agent or in combination with carbamazepine).

    ICD-10

    VI.G40-G47.G40   Epilepsy

    VI.G40-G47.G40.3   Generalized idiopathic epilepsy and epileptic syndromes

    VI.G40-G47.G41   Epileptic status

    VI.G50-G59.G50.0   Neuralgia of the trigeminal nerve

    IX.I30-I52.I47.2   Ventricular tachycardia

    IX.I30-I52.I48   Atrial fibrillation and flutter

    IX.I30-I52.I49.3   Premature depolarization of the ventricles

    IX.I30-I52.I49.2   Premature depolarization originating from compound

    IX.I30-I52.I49.1   Premature depolarization of the atria

    IX.I30-I52.I49.9   Disorder of heart rhythm, unspecified

    XVIII.R25-R29.R25.2   Cramp and spasm

    XIX.T36-T50.T46   Poisoning with drugs that act primarily on the cardiovascular system

    Contraindications:HypersensitivityMorganyi-Adams-Stokes, atrioventricular blockade of II and III degree, sinoatrial block, sinus bradycardia, violations of liver and kidney function,heart failure, cachexia, porphyria, hypersensitivity to phenytoin, pregnancy, lactation.
    Carefully:Alcoholism, heart failure, diabetes, fever, liver failure, cachexia, porphyria, systemic lupus erythematosus.
    Pregnancy and lactation:

    Category by FDA - D. Do not use phenytoin at pregnancy, except for cases when the advantage of treatment for mother exceeds risk for a fetus. There are separate data on the formation of tumors (including neuroblastoma), splitting of the upper lip and palate in children whose mothers received phenytoin during pregnancy.

    Phenytoin is excreted in breast milk in concentrations sufficient to cause side effects in the infant. In this regard, the use of phenytoin during lactation is not recommended.

    Dosing and Administration:

    For oral administration for adults, the initial dose is 3-4 mg / kg per day, followed by an increase in dose to achieve the optimal therapeutic effect. In most cases, the maintenance dose is 200-500 mg per day in one or more doses.

    Children - 5 mg / kg per day in two doses followed by a dose increase of not more than 300 mg per day. The maintenance dose is 4-8 mg / kg per day.

    For intravenous administration to adults and children, the initial dose is 15-20 mg / kg. Depending on the clinical situation, a single dose can be 50-100 mg / kg. For newborns, the initial dose is also 15-20 mg / kg.

    Intramuscularly, adults can be administered in a single dose of 100-300 mg.

    Side effects:

    From the side CNS and peripheral nervous system: nystagmus, ataxia, confusion, mood changes, muscle weakness, movement coordination disorders, dizziness, sleep disorders, blurred speech or stammering, trembling of hands, transient nervousness; peripheral neuropathy.

    From the side digestive system: nausea, vomiting, constipation, toxic hepatitis, liver damage. Hyperplasia of the gums can occur during the first 6 months of therapy and begins with gingivitis, is more common in patients under the age of 23 years.

    From the side hematopoiesis system: thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, pancytopenia, megaloblastic anemia.

    From the side endocrine system: hypertrichosis, enlargement of facial features, including thickening of the lips, extension of the tip of the nose and extension of the lower jaw.

    From the side metabolism: impaired glucose absorption due to inhibition of the release of insulin, a violation of vitamin D metabolism and the development of hypocalcemia.

    From the side musculoskeletal system: Dupuytren's contracture; peripheral polyarthropathy. With prolonged use, the lack of an adequate diet that satisfies the need for vitamin D, or sufficient sunlight during the treatment period, osteomalacia and rickets may develop.

    Allergic reactions: skin rash, which can be a prodromal sign of more severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), eosinophilia, fever, drug lymphadenopathy.

    Other: Peyronie's disease.

    Overdose:

    Symptoms: ataxia, diplopia, drowsiness, dysarthria, hyperreflexia, convulsions, nausea, vomiting. Lethal dose for adults 2-5 g.

    Treatment: symptomatic.

    Interaction:

    Alcohol and other drugs that depress the central nervous system - increased oppression.For chronic alcohol use, decrease the concentration and effectiveness of phenytoin; with simultaneous single administration of phenytoin and alcohol - an increase in the concentration of phenytoin.

    Amiodarone, anticoagulants (coumarin or indanedione), disulfiram, isoniazid, itraconazole, ketoconazole, miconazole, omeprazole, ranitidine, sulfonamides, phenylbutazone, chloramphenicol, cimetidine, fluconazole, fluoxetine - Increased concentration and toxicity of phenytoin.

    Valproic acid - inhibition of the metabolism of phenytoin, an increased risk of developing hepatic toxicity of valproic acid, a decrease in its concentration. Monitoring of drug concentrations is necessary.

    Glucocorticoids, estrogen-containing contraceptives, estrogens, theophylline and other xanthines, vitamin D - a decrease in their concentration and efficiency due to increased metabolism.

    Carbamazepine and phenobarbital enhance the elimination of phenytoin.

    Lamotrigine - a decrease in efficiency due to the induction of metabolism.

    Lidocaine, β-adrenoblockers - increased cardiodepressive effect.

    Paracetamol is an increase in hepatotoxicity.

    Rifampicin - a decrease in the effectiveness of phenytoin due to the induction of metabolism.

    Special instructions:

    If hypersensitivity to one of the hydantoin anticonvulsant drugs is susceptible to hypersensitivity to other drugs of this group.

    A sudden cessation of phenytoin treatment in patients with epilepsy can provoke the development of withdrawal syndrome.

    In patients with epilepsy, if an abrupt withdrawal of phenytoin is necessary (for example, with the development of allergic reactions or hypersensitivity reactions) anticonvulsants other than hydantoin derivatives should be used.

    Phenytoin undergoes intensive metabolism in the liver, so patients with impaired liver function, as well as the elderly, need a correction of the dosing regimen.

    During the treatment, especially long, a diet that satisfies the need for vitamin D is recommended, exposure to UV radiation.

    When using the drug in children during growth, the risk of side effects from the connective tissue increases.

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

    Impact on the ability to drive vehicles and manage mechanisms.

    During the treatment period, the speed of psychomotor reactions slows down. This should be taken into account by persons engaged in potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

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