Diphenylhydantoin: Formula, Presentation, Indications, Mechanism of Action, Dosage, Side Effects and Interactions

It is a first-generation drug with more clinical and laboratory studies than other antiepileptic drugs.

Its regular use is a treatment for epilepsy and prevents or treats seizures, but it also has antiarrhythmic effects.

Diphenilhydantoin is indicated for all forms of epilepsy, except for absence crises.

It is recommended for generalized focal seizures and performs antiepileptic activity but without causing general depression in the central nervous system.

This drug can induce a total remission of the tonic-clonic seizures and some partial-type seizures. Still, it can not wholly eliminate the sensory symptoms or other initial symptoms that precede the development of the attack.

Chemical formula

  • C15H12N2O2.
  • 5,5-diphenylimidazolidine-2,4-dione.


This drug is found in ampules of sodium diphenylhydantoin only for intramuscular or intravenous use and diphenylhydantoin in suspension and prolonged-release capsules for oral use.


Diphenylhydantoin is given to control some seizures and treat or prevent attacks that can begin during or after brain surgery or in the nervous system.


Besides being a treatment for seizures during neurosurgery or severe head trauma, it is treated after the carbamazepine is used for neuralgia, Trigeminal, and cardiac arrhythmias.

Mechanism of action

Its activity is at the brain and heart levels for its antiepileptic, anticonvulsant, and antiarrhythmic uses. The main action is in the motor cortex of the brain, which is responsible for inhibiting convulsive activity.

And in its cardiac antiarrhythmic action stabilizes the myocardial cells, just as it happens with the central nervous system.

This drug increases the threshold of seizures and limits the spread of discharges and their space.

Its effects are related to its action on the sodium channels of the neuronal cell membranes. Because of this effect on the sodium channels, diphenylhydantoin is also slightly antiarrhythmic and acts on the Purkinje fibers.

Stabilizes the excitable membranes of various cells, such as neurons and cardiac myocytes.


Injectable sodium diphenylhydantoin

The doses applied to the patients have to be individualized. It is recommended to start with tiny amounts and then make gradual increments until seizure control is achieved or when the onset of toxic effects is perceived.

It is necessary to establish plasma levels to achieve a dosage as accurately as possible in some cases.

The most effective serum levels clinically, in general, are in the range of 10 to 20 grams per milliliter, although there are cases that can be controlled with lower serum levels.

It takes seven to ten days to achieve equilibrium in the state of blood concentrations.

The dose in adults is 3 to 4 mg/kg per day and with maintenance doses of 200 to 500 mg per day, administered in one or multiple doses.

In children, the initial dose is 5 mg/kg per day with a maximum amount of 300mg per day and with a maintenance dose of 4 to 8 mg/kg per day.

In the case of neonates, doses will be indicated according to serum levels.

Diphenylhydantoin in extended-release capsules and suspension

In general, these presentations are administered two to three times a day, and it is recommended to take them at approximately the same time every day.

Side effects

Side effects can occur in:

The central nervous system

The collateral exposures of the treatment of Diphenylhydantoin are observed in the central nervous system and are intimately affected by concentrations in the blood.

Side effects have been reported as nystagmusataxia, and mental confusion.

Others include dizziness, periods of insomnia, crisis or transient nervousness, headaches, and the presence of tremors.

As well as dyskinesias, irreversible brain dysfunction, and peripheral neuropathy.

Gastrointestinal tract

Presence of constipation, nausea, and vomiting.

Mucosa and skin

Fever and manifestations of morphiform or scarlatiniform rash have often occurred.

Rarely cases of lupus erythematosus, bullous dermatitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been observed.

Connective tissue

In the course of treatment have appeared side effects such as Peyronie’s disease, lip thickening, gingival hyperplasia, and hirsutism.


There have been reports of agranulocytosis, spinal cord aplasia, granulocytopenia, leukopenia, pancytopenia, and thrombocytopenia.

As well as local and general lymphadenopathy development, including lymphomas, pseudolymphomas, benign nodular hyperplasia, and Hodgkin’s disease .


Other side effects observed are immunoglobulin abnormalities, polyarteritis nodosa, toxic hepatitis, systemic lupus erythematosus, and polyarthropathy.

Warnings and contraindications

Particular attention should be paid to the case of the suspension of the treatment of Diphenylhydantoin since the sudden break can precipitate a bad epileptic state.

In cases where the drug should be discontinued, replaced, or reduced by another antiepileptic, this modification in the treatment should be carried out gradually.

In patients with hepatic insufficiency, the dose should be reviewed to avoid an accumulation and the symptoms of toxicity.

In the case of uremia, the doses of diphenylhydantoin are reduced.

Prevention should be taken in the administration of the drug in women who are of childbearing age due to the risk of pregnancy since congenital malformations in the fetus may manifest as:

Cleft lip, cleft palate, cardiac malformations, fetal microcephaly syndrome, prenatal growth deficit, and mental deficiency.

During breastfeeding periods, research has reported that small amounts of diphenylhydantoin are passed into breast milk.

Caution should be exercised in patients with blood dyscrasia, diabetes, liver dysfunction, renal dysfunction, systemic lupus erythematosus, and arterial hypotension.


Drugs that increase serum levels of Diphenylhydantoin include cimetidine, chloramphenicol, disulfiram, phenylbutazone, dicumarol, isoniazid, and sulfonamides.

Among the drugs that reduce serum levels of diphenylhydantoin are carbamazepine and excessive alcohol intake.

Other drugs that decrease or increase serum levels of Diphenilhidantoin are valproic acid, phenobarbital, and some antacids.

Also, diphenylhydantoin decreases the effect of some medications such as corticosteroids, dicumarol, oral contraceptives, quinidine, and vitamin D.

It can increase or decrease the effects of warfarin. Determining serum levels is particularly useful when there are suspicions of some drug interactions.

In the laboratory, diphenylhydantoin can cause an increase in serum glucose levels, alkaline phosphatase, hepatic enzyme gamma-glutamyl transpeptidase, and reduce calcium and folic acid levels.