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Phenytoin

Phenytoin (PHT), sold under the brand name Dilantin among others,[1] is an anti-
Phenytoin
seizure medication.[2] It is useful for the prevention of tonic-clonic seizures and
partial seizures, but not absence seizures.[2] The intravenous form is used for status
epilepticus that does not improve with benzodiazepines.[2] It may also be used for
certain heart arrhythmias or neuropathic pain.[2] It can be taken intravenously or by
mouth.[2] The intravenous form generally begins working within 30 minutes and is
effective for 24 hours.[3] Blood levels can be measured to determine the proper
dose.[2]

Common side effects include nausea, stomach pain, loss of appetite, poor
coordination, increased hair growth, and enlargement of the gums.[2] Potentially
serious side effects include sleepiness, self harm, liver problems, bone marrow
suppression, low blood pressure, and toxic epidermal necrolysis.[2] There is evidence
.[2] It appears to be safe
that use during pregnancy results in abnormalities in the baby
to use when breastfeeding.[2] Alcohol may interfere with the medication's effects.[2]

Phenytoin was first made in 1908 by the German chemist Heinrich Biltz and found
useful for seizures in 1936.[4][5] It is on the World Health Organization's List of
Essential Medicines, the most effective and safe medicines needed in a health
system.[6] Phenytoin is available as a generic medication and usually not too
Clinical data
expensive.[7] The wholesale cost in the developing world is between US$0.003 and
Pronunciation /fnton/;
US$0.15 per dose.[8] A month of treatment is about US$30 in the United States.
[2]
/fntn/
Trade names Originally
Dilantin, many
Contents names
worldwide[1]
1 Medical uses
1.1 Seizures
AHFS/Drugs.com Monograph
1.2 Other MedlinePlus a682022
1.3 Special considerations
Pregnancy AU: D
2 Side effects category
2.1 Heart and blood vessels US: D (Evidence of

2.2 Neurological risk)


2.3 Blood
Routes of Oral, parenteral
2.4 Pregnancy administration
2.5 Cancer
ATC code N03AB02 (WHO)
2.6 Mouth
2.7 Skin Legal status
2.8 Immune system
Legal status AU: S4
2.9 Psychological
2.10 Bones (Prescription only)

3 Interactions CA: -only

4 Mechanism of action UK: POM

5 Pharmacokinetics (Prescription only)


6 History US: -only

7 Society and culture


7.1 Cost Pharmacokinetic data
7.2 Trade names Bioavailability 70100% oral,
8 Research 24.4% for rectal
9 References administration
10 External links Protein binding 95%[2]
Metabolism liver
Onset of action 10 to 30 min
Medical uses (IV)[3]
Biological half- 1022 hours[2]
life
Seizures
Duration of 24 hr[3]
Tonic-clonic seizures: Mainly used in the prophylactic management of action
tonic-clonic seizures with complex symptomatology (psychomotor Excretion Primarily through
seizures). A period of 510 days may be required to achieve
anticonvulsant effects. the bile, urinary
Focal seizures: Mainly used to protect against the development of focal Identifiers
seizures with complex symptomatology (psychomotor andtemporal lobe
seizures). Also effective in controlling partialseizures with autonomic IUPAC name
symptoms.
5,5-diphenylimidazolidine-2,4-dione
Absence seizures: Not used in treatment of pure absence seizures due
to risk for increasing frequency of seizures. However , can be used in CAS Number 57-41-0
combination with other anticonvulsants during combined absence and
tonic-clonic seizures. PubChem CID 1775
Seizures during surgery: Used as prevention and treatment of seizures
occurring during and after neurosurgery . IUPHAR/BPS 2624
Status epilepticus: Considered after failed treatment using a
DrugBank DB00252
benzodiazepine due to slow onset of action.[9]
ChemSpider 1710

Other UNII 6158TKW0C5

Abnormal heart rhythms: may be used in the treatment ofventricular KEGG D00512
tachycardia and sudden episodes ofatrial tachycardia after other
antiarrhythmic medicationsor cardioversion has failed. It is aclass 1b ChEBI CHEBI:8107
antiarrhythmic.[10]
ChEMBL CHEMBL16
Digoxin toxicity: IV formulation is drug of choice for arrhythmias caused
by cardiac glycoside toxicity. ECHA InfoCard 100.000.298
Trigeminal neuralgia: Second choice drug to carbamazepine.[11]
Chemical and physical data
Formula C15H12N2O2
Special considerations Molar mass 252.268 g/mol
Monitoring plasma concentrations: Narrowtherapeutic index. 3D model Interactive image
Anticonvulsant effect: 1020 g/mL; Antiarrhythmic effect: 1020 g/mL (JSmol)
Avoid giving intramuscular formulation unlessnecessary due to skin cell
death and local tissue destruction. SMILES
O=C2NC(=O)NC2(c1ccccc1)c3ccccc3
Elderly: May show earlier signs of toxicity
.
Obese: Use ideal body weight for dosing calculations. InChI
Pregnancy: Pregnancy Category D due to risk of fetal hydantoin InChI=1S/C15H12N2O2/c18-13-15(17-14(19)
syndrome and fetal bleeding. However, optimal seizure control is very 16-13,11-7-3-1-4-8-11)12-9-5-2-6-10-12/h1
important during pregnancy so drug may be continued if benefits -10H,(H2,16,17,18,19)
outweigh the risks. Due to decreased drug concentrations during Key:CXOFVDLJLONNDW-UHFFFAOYSA-N
pregnancy, dose of phenytoin may need to beincreased if only option
for seizure control. (what is this?) (verify)
Breast feeding: The manufacturer does not recommend breast feeding
because low concentrations of phenytoin are excreted in breast milk.[12]

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.
IV use is contraindicated in patients withsinus bradycardia, SA block, second- or third-degreeAV block, Stokes-
Adams syndrome, or have known hypersensitivity to phenytoin or any ingredient in the respective formulation or to
other hydantoins.

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. It appears to be okay
during breastfeeding. Alcohol may interfere with the medication's effects.[2]

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 13 mg/kg/min (or 50 mg/min, whichever is slower) in children. Heart monitoring should occur during
[13]
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, cerebellarataxia, and tremor.[14] If phenytoin is stopped abruptly, this may result in increased
seizure frequency, including status epilepticus.[13]

Phenytoin may accumulate in thecerebral cortex over long periods of time which can cause atrophy of the cerebellum. The degree of
[15]
atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication.

Abrupt discontinuation of phenytoin can precipitatestatus epilepticus.[12]

Phenytoin is known to be a causal factor in the development ofperipheral neuropathy.[16]

Blood
It has been suggested that phenytoin causes a reduction in folic acid levels, predisposing patients to megaloblastic anemia. Folate 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.[17] Other side effects may include: agranulocytosis,[18] aplastic anemia,[19]
decreased white blood cell count,[20] and a low platelet count.[21]

Pregnancy
Phenytoin is a known teratogen. The syndrome consists of craniofacial anomalies (broad nasal bridge, cleft lip and palate, smaller
than normal head) and a mild form of mental retardation (average IQ=71).[22] This syndrome resembles the well-described Fetal
Alcohol Syndrome[23] 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.[24] 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 that phenytoin is a humancarcinogen.[25][26]

Mouth
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.[27] 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
Hypertrichosis, 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 StevensJohnson syndrome (SJS) and toxic epidermal
necrolysis (TEN). These conditions are significantly more common in patients with a particular HLA-B allele, HLA-B*1502.[28]
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.[29] The U.S. Food and Drug Administration (FDA) 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
[30]
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-inducedlupus.[31]

Phenytoin is also associated with induction of reversibleIgA deficiency.[32]

Psychological
Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the
[12]
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
.[12]
deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density

Interactions
Phenytoin is an inducer of the CYP3A4 and CYP2C9 families of the P450 enzyme responsible for the liver's degradation of various
drugs.[33]

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
[34]
decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin."

Warfarin (Coumadin) and trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its
[35]
metabolism. Consider using other options if possible.

Mechanism of action
Phenytoin is believed to protect against seizures by causing voltage-dependent block
of voltage gated sodium channels.[36] This blocks 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: the resting state, the open state,
and the 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 The mechanism of action of
by membrane depolarization as well as by repetitive firing, the binding to the phenytoin sodium. Sodium channels
inactive state by phenytoin sodium can produce voltage-dependent, use-dependent are: 1) Closed 2) Open 3) Inactive
[37]
and time-dependent block of sodium-dependent action potentials. (phenytoin effect)

The primary site of action appears to be the motor cortex where spread of seizure
activity is inhibited.[38] 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.[13]

Pharmacokinetics
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.[39][40][41][42]

History
Phenytoin (diphenylhydantoin) was first synthesized by German chemistHeinrich Biltz in 1908.[43] 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 controllingseizures, 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.[44]

It was approved by the United StatesFood and Drug Administrationin 1953 for use in seizures.

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.[45] 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.

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 aboutpurple glove syndromein November 2011.[46]

Society and culture

Cost
Phenytoin is available as a generic medication and usually not too expensive.[7] Wholesale it costs between US$0.003 and US$0.15
per dose.[8] A month of treatment is about US$30 in the United States.
[2]

Since September 2012, the marketing licence in the UK has been held by Flynn Pharma Ltd, of Dublin, Ireland, and the product,
although identical, has been called Phenytoin Sodium xxmg Flynn Hard Capsules. (The xxmg in the name refers to the strengthfor
example 'Phenytoin sodium 25 mg Flynn Hard Capsules').[47] The capsules are still made by Pfizer's Goedecke subsidiary's plant in
Freiburg, Germany and they still have Epanutin printed on them.[48] After Pfizer's sale of the UK marketing licence to Flynn Pharma,
the price of a 28-pack of 25 mg phenytoin sodium capsules marked Epanutin rose from 66p (about $0.88) to 15.74 (about $25.06).
Capsules of other strengths also went up in price by the same factor2384%,[49] costing the UK's National Health Service an extra
43 million (about $68.44 million) a year.[50] The companies were referred to theCompetition and Markets Authoritywho found that
ge excessive and unfair prices.[51]
they had exploited their dominant position in the market to char

The Competition and Markets Authority (CMA) imposed a record 84.2 million fine on the manufacturer Pfizer, and a 5.2 million
[52]
fine on the distributor Flynn Pharma and ordered the companies to reduce their prices.

Trade names
Phenytoin is marketed under manytrade names worldwide.[1]

Research
Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds.[53][54] A meta-
[55]
analysis also supported the use of phenytoin in managing various ulcers.

multiple sclerosis.[56]
Some clinical trials have explored whether phenytoin can be used as neuroprotector in

References
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External links
Medicines for Epilepsy: DilantinEpilepsy Foundation.
Remarkable Medicine, a website about the Dreyfus Foundation's work to expand the indications for phenytoin
Phenytoin Pharmacokinetics(not a public link)
English translation of 1908 German article on phenytoin synthesis by Heinrich Biltz

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