Phenytoin Phenytoin sodium is a commonly used
antiepileptic. Phenytoin (fen-i-TOE-in) acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels. Aside from seizures, it is an option in the treatment of
trigeminal neuralgia in the event that carbamazepine is deemed inappropiate.
It is sometimes considered a
class 1b antiarrhythmic Trade names
Phenytoin sodium has been marketed as
Phenytek by
Mylan Laboratories, previously Bertek Pharmaceuticals, and
Dilantin;
Australia also
Dilantin Kapseals and
Dilantin Infatabs in the
USA,
Eptoin by Abbott Group in India and as
Epanutin in the
UK and
Israel, by
Parke-Davis, now part of
Pfizer. In the USSR and post-USSR countries, it was/is marketed as
Дифенин (
Diphenin,
Dipheninum),.
HistoryPhenytoin (diphenylhydantoin) was first synthesized by German chemist
Heinrich Biltz in 1908. Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, outside scientists including
H. Houston Merritt and
Tracy Putnam discovered phenytoin's usefulness for controlling
seizures, without the sedative effects associated with
phenobarbital.
According to
Goodman and Gilman's Pharmacological Basis of Therapeutics,
In contrast to the earlier accidental discovery of the antiseizure properties of bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals. There are some indications that phenytoin has other effects, including
anxiety control and
mood stabilization, although it has never been approved for those purposes by the FDA.
Jack Dreyfus, founder of the
Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and
depression when he received a prescription for Dilantin in 1966. He is believed to have supplied large amounts of the drug to
Richard Nixon throughout the late 1960s and early 1970s.
Dreyfus' experience with phenytoin is outlined in his book,
A Remarkable Medicine Has Been Overlooked,
[3]. Despite more than $70 million in personal financing, his push to see phenytoin evaluated for alternative uses has had little lasting effect on the medical community. This was partially because
Parke-Davis was reluctant to invest in a drug nearing the end of its patent life, and partially due to mixed results from various studies. It was approved by the
USA Food and Drug Administration in 1953 for use in
seizures.
Dilantin made an appearance in the 1962 novel
One Flew Over the Cuckoo's Nest by
Ken Kesey, both as an
anticonvulsant and as a mechanism to control inmate behavior.
In 2008, the drug was put on the FDA's
Potential Signals of Serious Risks List to be further evaluated for approval. The list means that the FDA has identified a potential safety issue, but does not mean that FDA has identified a causal relationship between the drug and the listed risk.
According to the FDA's New Safety Information Identified by the
Adverse Event Reporting System (AERS) Phenytoin Injection (Dilantin) has been associated with the risk of
Purple Glove Syndrome.
Side-effects NeurologicAt therapeutic doses, phenytoin produces horizontal gaze
nystagmus, which is harmless but occasionally tested for by
police as a marker for
alcohol intoxication (which can also produce nystagmus). At toxic doses, patients experience
sedation, cerebellar
ataxia, and
ophthalmoparesis, as well as paradoxical
[clarification needed] seizures. Idiosyncratic side-effects of phenytoin, as with other
anticonvulsants, include rash and severe
allergic reactions.
Phenytoin may accumulate in the
cerebral cortex over long periods of time, as well as causing atrophy of the
cerebellum when administered at chronically high levels. Despite this, the drug has a long history of safe use, making it one of the more popular anti-convulsants prescribed by doctors, and a common "first line of defense" in seizure cases.
HematologicIt has been suggested that phenytoin causes a reduction in
folic acid levels, predisposing patients to
megaloblastic anemia. Folic acid is presented in foods as polyglutamate, which is then converted into monoglutamates by
intestinal conjugase. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency. Other side effects may include: agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia.
TeratogenicityPhenytoin is a known
teratogen. The syndrome consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, microcephaly) and a mild form of mental retardation (average IQ=71).This syndrome resembles the well-described
Fetal Alcohol Syndrome and has also been called the "
fetal hydantoin syndrome".
[citation needed] Data now being collected by the
Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.
Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data do not provide clear answers.
[7] CarcinogenicityThere is no good evidence that phenytoin is a human
carcinogen GingivalPhenytoin has been associated with drug induced
gingival enlargement (hyperplasia) in the oral cavity probably due to above mentioned folate defiency. Plasma concentrations needed to induce gingival lesions has 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.
Suicide riskFollowing almost 200 studies of 11 anti-seizure drugs, the FDA has also warned of an increased suicide risk for any patients treated with certain anti-seizure drugs. The study of 44,000 patients found that patients whose epilepsy is treated with drugs face about twice the risk of suicidal thoughts compared to placebo-takers. Although phenytoin was not named in the study, the FDA announced that it expected the risk applied to every epilepsy drug
DermatologicHypertrichosis, rash, exfoliative dermatitis,
pruritis.
In autoimmune diseasePhenytoin has been known to cause drug-induced
lupus.
Phenytoin therapy has been linked to the life-threatening skin reactions
Stevens-Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN). These conditions are significantly more common in patients with a particular
HLA-B allele,
HLA-B*1502This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.
In immunodeficiency diseasePhenytoin is also associated with induction of reversible IgA deficiency
InteractionsPhenytoin is an inducer of the CYP3A4 and CYP2C19 families of the P450 enzyme responsible for the hepatic elimination and degradation of various drugs.