Phenytoin sodium is a commonly used antiepileptic. Phenytoin (fœnit'oin, IPA) 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 neuralgiaTrigeminal neuralgia , tic douloureux is a neuropathic disorder characterized by episodes of intense pain in the face, originating from the trigeminal nerve. It has been described as among the most painful conditions known...
in the event that
carbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
or other first-line treatment seems inappropriate.
It is sometimes considered a class 1b antiarrhythmic.
Trade names
Phenytoin sodium has been marketed as
Phenytek by
Mylan LaboratoriesMylan Inc. is a global generic and specialty pharmaceuticals company headquartered in Canonsburg, Pennsylvania. In 2007, Mylan acquired a controlling interest in India-based Matrix Laboratories Limited, a top producer of active pharmaceutical ingredients for generic drugs, and the generics...
, previously Bertek Pharmaceuticals, and
Dilantin;
AustraliaAustralia , officially the Commonwealth of Australia, is a country in the Southern Hemisphere comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands in the Indian and Pacific Oceans. It is the world's sixth-largest country by total area...
also
Dilantin Kapseals and
Dilantin Infatabs in the
USAThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
,
Eptoin by Abbott Group in India and as
Epanutin in the
UKThe United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
and
IsraelThe State of Israel is a parliamentary republic located in the Middle East, along the eastern shore of the Mediterranean Sea...
, by
Parke-DavisParke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
, now part of
PfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. In the USSR and post-USSR countries, it was/is marketed as
Дифенин (
Diphenin,
Dipheninum),.
History
Phenytoin (diphenylhydantoin) was first synthesized by German chemist
Heinrich BiltzHeinrich Biltz was a German chemist and professor. Heinrich Biltz was the son of Karl Friedrich Biltz who was a scientist of literature and theatre critic and married to Freya de la Motte Fouqué, a daughter of a physician in Kiel...
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 MerrittH. Houston Merritt was one of the pre-eminent academic neurologists of his day. As the chair of the Neurological Institute of New York from 1948 to 1967, he oversaw the training of hundreds of neurologists; 35 of his former students have become chairs of academic neurology departments across the...
and
Tracy PutnamTracy Jackson Putnam was the co-discoverer, together with H. Houston Merritt, of Dilantin for controlling epilepsy.He graduated from Harvard College in 1915. Later from Harvard medical school in 1920. He worked by the Boston City Hospital and in the New York Neurological Institute at Columbia...
discovered phenytoin's usefulness for controlling
seizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s, without the sedative effects associated with
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
According to
Goodman and Gilman's Pharmacological Basis of Therapeutics,
- In contrast to the earlier accidental discovery of the antiseizure properties of bromide
A bromide is a chemical compound containing bromide ion, that is bromine atom with effective charge of −1. The class name can include ionic compounds such as caesium bromide or covalent compounds such as sulfur dibromide.-Natural occurrence:...
and phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, 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
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
control and
mood stabilizationA mood stabilizer is a psychiatric medication used to treat mood disorders characterized by intense and sustained mood shifts, typically bipolar disorder.-Uses:...
, although it has never been approved for those purposes by the FDA.
Jack DreyfusJohn J. "Jack" Dreyfus, Sr. was an American financial expert and the founder of the Dreyfus Funds.Born in Montgomery, Alabama, Dreyfus was a graduate of Lehigh University in Pennsylvania...
, founder of the Dreyfus Fund, became a major proponent of phenytoin as a means to control nervousness and
depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
when he received a prescription for Dilantin in 1966. He is believed to have supplied large amounts of the drug to
Richard NixonRichard Milhous Nixon was the 37th President of the United States, serving from 1969 to 1974. The only president to resign the office, Nixon had previously served as a US representative and senator from California and as the 36th Vice President of the United States from 1953 to 1961 under...
throughout the late 1960s and early 1970s.
Dreyfus'John J. "Jack" Dreyfus, Sr. was an American financial expert and the founder of the Dreyfus Funds.Born in Montgomery, Alabama, Dreyfus was a graduate of Lehigh University in Pennsylvania...
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-DavisParke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
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 AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
in 1953 for use in
seizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s.
Dilantin made an appearance in the 1962 novel
One Flew Over the Cuckoo's NestOne Flew Over the Cuckoo's Nest is a novel written by Ken Kesey. Set in an Oregon asylum, the narrative serves as a study of the institutional process and the human mind, as well as a critique of Behaviorism and a celebration of humanistic principles. Written in 1959, the novel was adapted into a...
by
Ken KeseyKenneth Elton "Ken" Kesey was an American author, best known for his novel One Flew Over the Cuckoo's Nest , and as a counter-cultural figure who considered himself a link between the Beat Generation of the 1950s and the hippies of the 1960s. "I was too young to be a beatnik, and too old to be a...
, both as an
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
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 SystemThe Adverse Event Reporting System is a computerized information database designed to support the U.S. Food and Drug Administration's post-marketing safety surveillance program for all approved drug and therapeutic biologic products...
(AERS) Phenytoin Injection (Dilantin) has been associated with the risk of
Purple Glove SyndromePurple Glove Syndrome is a poorly understood skin disease in which the extremities become swollen, discoloured and painful. PGS is potentially serious, and may require amputation...
.
Neurologic
At therapeutic doses, phenytoin produces horizontal gaze
nystagmusNystagmus is a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.There are two key forms of Nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorders,...
. At toxic doses, patients experience
sedationSedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, cerebellar
ataxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, and
ophthalmoparesisOphthalmoparesis or ophthalmoplegia refers to paralysis of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic illnesses.-Classification:...
, as well as seizures. Idiosyncratic side-effects of phenytoin, as with other
anticonvulsantThe anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
s, include rash and severe
allergicAn Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
reactions.
Phenytoin may accumulate in the
cerebral cortexThe cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
over long periods of time, as well as causing atrophy of the
cerebellumThe cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
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 acidFolic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
levels, predisposing patients to
megaloblastic anemiaMegaloblastic anemia is an anemia that results from inhibition of DNA synthesis in red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the G2 growth stage to the mitosis stage...
. 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 SyndromeFetal alcohol syndrome is a pattern of mental and physical defects that can develop in a fetus in association with high levels of alcohol consumption during pregnancy. Current research also implicates other lifestyle choices made by the prospective mother...
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.
Gingival
Phenytoin has been associated with drug-induced
gingival enlargementGingival enlargement, the currently accepted terminology for an increase in the size of the gingiva, is a common feature of gingival disease. This is strictly a clinical description of the condition and avoids the erroneous pathologic connotations of terms used in the past such as hypertrophic...
(overgrowth of the gums), probably due to above-mentioned folate deficiency; indeed, evidence from a
randomized controlled trialA randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
suggests that folic acid supplementation can prevent gingival enlargement in children who take phenytoin. 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 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 has been known to cause drug-induced
lupusSystemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
.
Phenytoin therapy has been linked to the life-threatening skin reactions Stevens–Johnson syndrome (SJS) and
toxic epidermal necrolysisToxic epidermal necrolysis is a rare, life-threatening dermatological condition that is usually induced by a reaction to medications...
(TEN). These conditions are significantly more common in patients with a particular
HLA-BHLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen complex...
alleleAn allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
,
HLA-B*1502HLA-B75 is an HLA-B serotype. The serotype identifies certain B*15 gene-allele protein products of HLA-B.B75 is one of many split antigens of the broad antigen, B15...
. 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
Phenytoin is an inducer of the
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
and
CYP2C19Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
families of the P450 enzyme responsible for the hepatic degradation of various drugs.
WarfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
(Coumadin) increases serum phenytoin levels and prolongs the serum half-life of phenytoin by inhibiting its metabolism.
- hydantoin
Hydantoin, which is also known as glycolylurea, is a heterocyclic organic compound that can be thought of as a cyclic "double-condensation reaction" product of glycolic acid and urea...
s
- fosphenytoin
Fosphenytoin is a water-soluble phenytoin prodrug used only in hospitals for the treatment of epileptic seizures....
- mephenytoin
Mephenytoin is a hydantoin, used as an anticonvulsant. It was introduced approximately 10 years after phenytoin, in the late 1940s. The significant metabolite of mephenytoin is nirvanol , which was the first hydantoin...
- ethotoin
Ethotoin is an anticonvulsant drug used in the treatment of epilepsy. It is a hydantoin, similar to phenytoin. Ethotoin lacks phenytoin's side effects of gingival hyperplasia and hirsutism, however it is less effective. This, combined with the need for frequent dosing has limited its usefulness...
Pharmacokinetic
Phenytoin kinetics are nonlinear and saturable, resulting in highly variable concentrations even with minor dosage changes. A small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated.
Chemistry
Phenytoin, 5,5-diphenylimidazolidinedione is synthesized in two different ways. The first involves a base catalyzed addition of
UreaUrea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
to
benzilBenzil is the organic compound with the formula 2, generally abbreviated 2. This yellow solid is one of the most common diketones...
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
benzophenoneBenzophenone is the organic compound with the formula 2CO, generally abbreviated Ph2CO. Benzophenone is a widely used building block in organic chemistry, being the parent diarylketone.-Uses:...
with
sodium cyanideSodium cyanide is an inorganic compound with the formula NaCN. This highly toxic colorless salt is used mainly in gold mining but has other niche applications...
in the presence of
ammonium carbonateAmmonium carbonate is a commercial salt with the chemical formula 2CO3. It is used when crushed as a smelling salt. It can be crushed when needed in order to revive someone who has fainted...
, followed by the simultaneous cyclization of the resulting product (carboxyaminonitrile) and its rearrangement under the reaction conditions to form phenytoin.
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