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Phenytoin sodium is an antiepileptic drug used primarily in the management of complex partial seizures and generalized tonic-clonic seizures. Phenytoin is also used to prevent seizures following neurosurgery. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage-gated sodium channels. Additionally, phenytoin is a class 1b antiarrhythmic that can be used to treat cardiac arrhythmias when conventional options have failed or after cardiac glycoside intoxication.

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). FENTOIN-ER,EPSOLIN are brands available in India Diphantoine is a brand available in The Netherlands (91% Phenytoin).

History
Phenytoin (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.

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. 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.

In 2008, the drug was put on the FDA's Potential Signals of Serious Risks List to be further evaluated for approval. The list identifies medications 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. To address this concern, the Warnings and Precautions section of the labeling for Dilantin injection was updated to include additional information about purple glove syndrome in November 2011.

Mechanism of action
Phenytoin produces its anticonvulsant activity through blocking sustained high frequency repetitive firing of action potentials. This is accomplished by reducing the amplitude of sodium-dependent action potentials through enhancing steady state inactivation. Sodium channels exist in three main conformations 1.Resting state 2.Open state 3.Inactive state Phenytoin binds preferentially to the inactive form of the sodium channel. Because it takes time for the bound drug to dissociate from the inactive channel, there is a time dependent block of the channel. Since the fraction of inactive channels is increased by membrane depolarization as well as by repetitive firing, the binding to the inactive state by phenytoin sodium can produce voltage-dependent, use-dependent and time-dependent block of sodium-dependent action potentials.

The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of post-tetanic potentiation at synapses which prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of generalized tonic-clonic seizures.

Pharmacology
Phenytoin elimination kinetics show mixed-order behaviour at therapeutic concentrations. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. The time to reach steady state is often longer than 2 weeks.

Use

 * Grand mal - Abolishes grand mal seizure in nearly 60% of the patient and reduces their severity and frequency in another 15-20%. Dose: 100 mg twice daily, 400 mg/day maximum dose, children 5–8 mg/kg/day.
 * Partial seizures - Phenytoin is preferred to phenobarbital in this type of seizure. The drug often controls but does not completely abolish the seizure activity. It is occasionally useful in infantile spasm.
 * Status epilepticus
 * Cardiac dysrhythmia
 * Trigeminal neuralgia - Second choice drug to carbamazepine.
 * Although controversial, but topical Phenytoin has been used as wound healing agent in patients with chronic skin wounds.

Neurologic
At therapeutic doses, phenytoin may produce horizontal gaze nystagmus. At toxic doses, patients experience vertical nystagmus, sedation, cerebellar ataxia, and ophthalmoparesis, as well as 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.

Hematologic
It 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.

Teratogenicity
Phenytoin 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". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data do not provide clear answers. Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

Carcinogenicity
There is no good evidence that phenytoin is a human carcinogen.

Gingival
Phenytoin has been associated with drug-induced gingival enlargement (overgrowth of the gums), 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.

Suicide risk
Following 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.

Dermatologic
Hypertrichosis, rash, exfoliative dermatitis, pruritis, hirsutism, and coarsening of facial features

In autoimmune disease
Phenytoin 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*1502. This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.

In immunodeficiency disease
Phenytoin is also associated with induction of reversible IgA deficiency.

Interactions
A 1981 study by the National Institutes of Health showed that antacids administered concomitantly with phenytoin "altered not only the extent of absorption but also appeared to alter the rate of absorption. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin."

Phenytoin is an inducer of the CYP3A4 and CYP2C19 families of the P450 enzyme responsible for the hepatic degradation of various drugs.

Warfarin (Coumadin) and Trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism.


 * hydantoins
 * fosphenytoin
 * mephenytoin
 * ethotoin

Chemistry
Phenytoin, 5,5-diphenylimidazolidinedione is synthesized in two different ways. The first involves a base catalyzed addition of urea to benzil followed by a benzilic acid rearrangement (1,2 phenyl migration) to form the desired product. This is known as the Biltz Synthesis of phenytoin.

The second method involves the reaction of benzophenone with potassium cyanide in the presence of ammonium carbonate, followed by the simultaneous cyclization of the resulting product (carboxyaminonitrile) and its rearrangement under the reaction conditions to form phenytoin.



In popular culture
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 the 2013 science fiction film Elysium, the protagonist (played by Matt Damon) takes Miporol, a fictional brand name for diphenylhydantoin, after having been exposed to a lethal dose of radiation.