|Systematic (IUPAC) name|
|Pregnancy cat.||D (US)|
|Legal status||℞ Prescription only|
|Bioavailability||70-100% oral, 24.4% for rectal and intravenous administration|
|Excretion||Primarily through the bile, urinary|
|Mol. mass||252.268 g/mol|
| (what is this?)
Phenytoin sodium (//) is a commonly used antiepileptic. Phenytoin 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 or other first-line treatment seems inappropriate.
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).
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.
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. 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 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.
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."
At therapeutic doses, phenytoin may produce horizontal gaze nystagmus. At toxic doses, patients experience 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.
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.
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". 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.
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.
In autoimmune disease 
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 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.
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.
- US patent 2409754, Hense HR, "Method for obtaining hydantoins", issued 1946-10-22, assigned to Parke Davis
- Balaji S (2004). "Medical Therapy for Sudden Death". Pediatric Clinics of North America 51 (5): 1379–1387. doi:10.1016/j.pcl.2004.04.002. PMID 15331289.
- Biltz H (1908). "Über die Konstitution der Einwirkungsprodukte von substituierten Harnstoffen auf Benzil und über einige neue Methoden zur Darstellung der 5,5-Diphenyl-hydantoine" [Constitution of the Products of the Interaction of Substituted Carbamides on Benzil and Certain New Methods for the Preparation of 5,5-Diphenylhydantoin]. Chemische Berichte (in German) 41 (1): 1379–1393. doi:10.1002/cber.190804101255.
- Goodman and Gilman's Pharmacological Basis of Therapeutics (10th ed.). New York: McGraw-Hill. 2001.
- Dreyfus J (1998). A Remarkable Medicine Has Been Overlooked: Including an Autobiography and the Clinical Section of the Broad Range of Use of Phenytoin. Continuum International Publishing Group. ISBN 0-8264-1069-3.
- Carl GF, Smith ML (1992). "Phenytoin-folate interactions: differing effects of the sodium salt and the free acid of phenytoin". Epilepsia 33 (2): 372–375. doi:10.1111/j.1528-1157.1992.tb02330.x. PMID 1547769.
- Beckmann CR et al. (2002). Obstetrics and Gynecology (4th ed.). Baltimore: Lippincott Williams & Wilkins.
- CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.
- Adab N, Tudur SC, Vinten J, Williamson P, Winterbottom J (2004). "Common Antiepileptic Drugs in Pregnancy in Women with Epilepsy". Cochrane Database of Systematic Reviews 2004 (3): CD004848. doi:10.1002/14651858.CD004848. PMID 15266543.
- Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.
- Maeda T, Sano N, Togei K, Shibata M, Izumi K, Otsuka H (1988). "Lack of carcinogenicity of phenytoin in (C57BL/6 x C3H)F1 mice". Journal of Toxicology and Environmental Health 24 (1): 111–119. doi:10.1080/15287398809531144. PMID 3373561.
- Arya R, Gulati S, Kabra M, Sahu JK, Kalra V (2011). "Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children". Neurology 76 (15): 1338–1343. doi:10.1212/WNL.0b013e3182152844. PMC 3090066. PMID 21482950.
- FDA warns of risks from epilepsy drugs.
- Scheinfeld N (2003). "Phenytoin in Cutaneous Medicine: Its Uses, Mechanisms and Side Effects". Dermatology Online Journal 9 (3): 6. PMID 12952753.
- Man CB, Kwan P, Baum L, et al. (2007). "Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese". Epilepsia 48 (5): 1015–1018. doi:10.1111/j.1528-1167.2007.01022.x. PMID 17509004.
- Clinical Pharmacology & Therapeutics 66, 563-568 (December 1999) | doi:10.1053/cp.1999.v66.103277001 Article Tools Send to a friend Export citation Rights and permissions Order commercial reprints Bookmark in Connotea Search Pubmed for Stephen Donahue David A. Flockhart Darrell R. Abernethy Ticlopidine inhibits phenytoin clearance*Ticlopidine inhibits phenytoin clearance *Supported in part by grants AG-08226-07 and GM-08386-08 from the National Institutes of Health, Bethesda, Md.
- Chapter 67 - Antiepileptic drug pharmacokinetics and therapeutic drug monitoring pp. 358-366 By Philip N. Patsalos View chapter as PDF Antiepileptic drug pharmacokinetics and therapeutic drug monitoring By Philip N. Patsalos
- Medicines for Epilepsy: Dilantin Epilepsy Foundation.
- Remarkable Medicine, a website about the Dreyfus Foundation's work to expand the indications for phenytoin
- Phenytoin Pharmacokinetics (not a public link)