Phenytoin

Phenytoin, sold under the brand name Dilantin among others, is an anti-seizure medication. It is useful for the prevention of tonic-clonic seizures and focal seizures, but not absence seizures. The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. It may also be used for certain heart arrhythmias or neuropathic pain. It can be taken intravenously or by mouth. The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. Blood levels can be measured to determine the proper dose.
Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, toxic epidermal necrolysis, and atrophy of the cerebellum. There is evidence that use during pregnancy results in abnormalities in the baby. It appears to be safe to use when breastfeeding. Alcohol may interfere with the medication's effects.
Phenytoin was first made in 1908 by the German chemist Heinrich Biltz and found useful for seizures in 1936. It is on the World Health Organization's List of Essential Medicines. Phenytoin is available as a generic medication. In 2020, it was the 260th most commonly prescribed medication in the United States, with more than 1million prescriptions.

Medical uses

Seizures

Tonic-clonic seizures: Mainly used in the prophylactic management of tonic-clonic seizures with complex symptomatology. A period of 5–10 days of dosing may be required to achieve anticonvulsant effects.
Focal seizures: Mainly used to protect against the development of focal seizures with complex symptomatology. Also effective in controlling focal seizures with autonomic symptoms.
Absence seizures: Not used in treatment of pure absence seizures due to risk for increasing frequency of seizures. However, can be used in combination with other anticonvulsants during combined absence and tonic-clonic seizures.
Seizures during surgery: A 2018 meta-analysis found that early antiepileptic treatment with either phenytoin or phenobarbital reduced the risk of seizure in the first week after neurosurgery for brain tumors.
Status epilepticus: Considered after failed treatment using a benzodiazepine due to slow onset of action.

Though phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive.

Other

Abnormal heart rhythms: may be used in the treatment of ventricular tachycardia and sudden episodes of atrial tachycardia after other antiarrhythmic medications or cardioversion has failed. It is a class Ib antiarrhythmic.
Digoxin toxicity: Intravenous phenytoin formulation is a medication of choice for arrhythmias caused by cardiac glycoside toxicity.
Trigeminal neuralgia: Second choice drug to carbamazepine.
Special considerations
Phenytoin has a narrow therapeutic index. Its therapeutic range for both anticonvulsant and antiarrhythmic effect is 10–20 μg/mL.
Avoid giving intramuscular formulation unless necessary due to skin cell death and local tissue destruction.
Elderly patients may show earlier signs of toxicity.
In the obese, ideal body weight should be used for dosing calculations.
Pregnancy: Pregnancy category D due to risk of fetal hydantoin syndrome and fetal bleeding. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations as a result of plasma volume expansion during pregnancy, dose of phenytoin may need to be increased if only option for seizure control.
Breastfeeding: The manufacturer does not recommend breastfeeding since low concentrations of phenytoin are excreted in breast milk.
Liver disease: Do not use oral loading dose. Consider using decreased maintenance dose.
Kidney disease: Do not use oral loading dose. Can begin with standard maintenance dose and adjust as needed.
Intravenous use is contraindicated in patients with sinus bradycardia, sinoatrial block, second- or third-degree atrioventricular block, Stokes-Adams syndrome, or hypersensitivity to phenytoin, other hydantoins or any ingredient in the respective formulation.
Side effects

Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis. There is evidence that use during pregnancy results in abnormalities in the baby. Its use appears to be safe during breastfeeding. Alcohol may interfere with the medication's effects.

Heart and blood vessels

Severe low blood pressure and abnormal heart rhythms can be seen with rapid infusion of IV phenytoin. IV infusion should not exceed 50 mg/min in adults or 1–3 mg/kg/min in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible.

Neurological

At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience vertical nystagmus, double vision, sedation, slurred speech, cerebellar ataxia, and tremor. If phenytoin is stopped abruptly, this may result in increased seizure frequency, including status epilepticus.
Phenytoin may accumulate in the cerebral cortex over long periods of time which can cause atrophy of the cerebellum. The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication.
Phenytoin is known to be a causal factor in the development of peripheral neuropathy.

Blood

Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency, and thus megaloblastic anemia.
Other side effects may include: agranulocytosis, aplastic anemia, decreased white blood cell count, and a low platelet count.

Pregnancy

Phenytoin is a known teratogen, since children exposed to phenytoin are at a higher risk of birth defects than children born to women without epilepsy and to women with untreated epilepsy. The birth defects, which occur in approximately 6% of exposed children, include neural tube defects, heart defects and craniofacial abnormalities, including broad nasal bridge, cleft lip and palate, and smaller than normal head. The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and delayed motor development may have been associated with maternal use of phenytoin during pregnancy. This syndrome resembles the well-described fetal alcohol syndrome. and has been referred to as "fetal hydantoin syndrome". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

Cancer

There is no good evidence to suggest that phenytoin is a human carcinogen. However, lymph node abnormalities have been observed, including malignancies.

Mouth

Phenytoin has been associated with drug-induced gingival enlargement, probably due to above-mentioned folate deficiency; indeed, evidence from a randomized controlled trial suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin. Plasma concentrations needed to induce gingival lesions have not been clearly defined. Effects consist of the following: bleeding upon probing, increased gingival exudate, pronounced gingival inflammatory response to plaque levels, associated in some instances with bone loss but without tooth detachment.

Skin

, Stevens–Johnson syndrome, purple glove syndrome, rash, exfoliative dermatitis, itching, excessive hairiness, and coarsening of facial features can be seen in those taking phenytoin.
Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome and toxic epidermal necrolysis. These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.
Phenytoin is primarily metabolized to its inactive form by the enzyme CYP2C9. Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. The U.S. Food and Drug Administration notes on the phenytoin drug label that since strong evidence exists linking HLA-B*1502 with the risk of developing SJS or TEN in patients taking carbamazepine, consideration should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele.

Immune system

Phenytoin has been known to cause drug-induced lupus.
Phenytoin is also associated with induction of reversible IgA deficiency.

Psychological

Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide.

Bones

Chronic phenytoin use has been associated with decreased bone density and increased bone fractures. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D, thus decreased vitamin D levels. Vitamin D deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density.