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Pronunciation | /fəˈnɪtoʊɪn,ˈfɛnɪtɔɪn/ |
Trade names | Dilantin, others [1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682022 |
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Routes of administration | By mouth, intravenous |
Drug class | Anticonvulsant |
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Pharmacokinetic data | |
Bioavailability | 70–100% (oral), 24.4% (rectal) |
Protein binding | 95% [3] |
Metabolism | Liver |
Onset of action | 10–30 min (intravenous) [4] |
Elimination half-life | 10–22 hours [3] |
Duration of action | 24 hours [4] |
Excretion | Urinary (23–70%), bile [5] |
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ECHA InfoCard | 100.000.298 |
Chemical and physical data | |
Formula | C15H12N2O2 |
Molar mass | 252.273 g·mol−1 |
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Phenytoin (PHT), sold under the brand name Dilantin among others, [1] is an anti-seizure medication. [3] It is useful for the prevention of tonic-clonic seizures (also known as grand mal seizures) and focal seizures, but not absence seizures. [3] The intravenous form, fosphenytoin, is used for status epilepticus that does not improve with benzodiazepines. [3] It may also be used for certain heart arrhythmias or neuropathic pain. [3] It can be taken intravenously or by mouth. [3] The intravenous form generally begins working within 30 minutes and is effective for roughly 24 hours. [4] Blood levels can be measured to determine the proper dose. [3]
Common side effects include nausea, stomach pain, loss of appetite, poor coordination, increased hair growth, and enlargement of the gums. [3] Potentially serious side effects include sleepiness, self harm, liver problems, bone marrow suppression, low blood pressure, and toxic epidermal necrolysis. [3] There is evidence that use during pregnancy results in abnormalities in the baby. [3] It appears to be safe to use when breastfeeding. [3] Alcohol may interfere with the medication's effects. [3]
Phenytoin was first made in 1908 by the German chemist Heinrich Biltz and found useful for seizures in 1936. [6] [7] It is on the World Health Organization's List of Essential Medicines. [8] Phenytoin is available as a generic medication. [9] In 2020, it was the 260th most commonly prescribed medication in the United States, with more than 1 million prescriptions. [10] [11]
Though phenytoin has been used to treat seizures in infants, as of 2023, its effectiveness in this age group has been evaluated in only one study. Due to the lack of a comparison group, the evidence is inconclusive. [14]
This section needs more reliable medical references for verification or relies too heavily on primary sources .(June 2019) |
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. Its use appears to be safe during breastfeeding.Alcohol may interfere with the medication's effects. [3]
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 1–3 mg/kg/min (or 50 mg/min, whichever is slower) in children. Heart monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible. [18]
At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience vertical nystagmus, double vision, sedation, slurred speech, cerebellar ataxia, and tremor. [19] If phenytoin is stopped abruptly, this may result in increased seizure frequency, including status epilepticus. [18] [17]
Phenytoin may accumulate in the cerebral cortex over long periods of time which can cause atrophy of the cerebellum. The degree of atrophy is related to the duration of phenytoin treatment and is not related to dosage of the medication. [20]
Phenytoin is known to be a causal factor in the development of peripheral neuropathy. [21]
Folate is present in food in a polyglutamate form, which is then converted into monoglutamates by intestinal conjugase to be absorbed by the jejunum. Phenytoin acts by inhibiting this enzyme, thereby causing folate deficiency, and thus megaloblastic anemia. [22] Other side effects may include: agranulocytosis, [23] aplastic anemia, [24] decreased white blood cell count, [25] and a low platelet count. [26]
Phenytoin is a known teratogen, since children exposed to phenytoin are at a higher risk of birth defects than children born to women without epilepsy and to women with untreated epilepsy. [27] [28] The birth defects, which occur in approximately 6% of exposed children, include neural tube defects, heart defects and craniofacial abnormalities, including broad nasal bridge, cleft lip and palate, and smaller than normal head. [28] [29] The effect on IQ cannot be determined as no study involves phenytoin as monotherapy, however poorer language abilities and delayed motor development may have been associated with maternal use of phenytoin during pregnancy. [27] This syndrome resembles the well-described fetal alcohol syndrome. [30] and has been referred to as "fetal hydantoin syndrome". Some recommend avoiding polytherapy and maintaining the minimal dose possible during pregnancy, but acknowledge that current data fails to demonstrate a dose effect on the risk of birth defects. [27] [28] Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.
There is no good evidence to suggest that phenytoin is a human carcinogen. [31] [32] However, lymph node abnormalities have been observed, including malignancies. [33]
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. [34] 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.
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 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. [35] 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. [36] 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 should be given to avoiding phenytoin as an alternative to carbamazepine in patients carrying this allele. [37]
Phenytoin has been known to cause drug-induced lupus. [38]
Phenytoin is also associated with induction of reversible IgA deficiency. [39]
Phenytoin may increase risk of suicidal thoughts or behavior. People on phenytoin should be monitored for any changes in mood, the development or worsening depression, and/or any thoughts or behavior of suicide. [17]
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 deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density. [17]
Phenytoin is an inducer of the CYP3A4 and CYP2C9 families of the P450 enzyme responsible for the liver's degradation of various drugs. [40]
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." [41]
Warfarin and trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible. [42]
In general, phenytoin can interact with the following drugs:
Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage gated sodium channels. [43] 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 dissassociate 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. [44]
The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. [45] 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. [18]
Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by first order kinetics, and at high concentrations by zero order kinetics. 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. [46] [47] [48] [49]
Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908. [50] Biltz sold his discovery to Parke-Davis, which did not find an immediate use for it. In 1938, other physicians, including H. Houston Merritt and Tracy Putnam, discovered phenytoin's usefulness for controlling seizures, without the sedative effects associated with phenobarbital. [51]
According to Goodman and Gilman's Pharmacological Basis of Therapeutics:
In contrast to the earlier accidental discovery of the antiseizure properties of potassium 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. [52]
It was approved by the FDA in 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 has claimed to have supplied large amounts of the drug to Richard Nixon throughout the late 1960s and early 1970s, although this is disputed by former White House aides [53] and Presidential historians. [54] Dreyfus' experience with phenytoin is outlined in his book, A Remarkable Medicine Has Been Overlooked. [55] 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 with which the FDA has identified potential safety issues, but has not yet 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. [56]
Phenytoin is available as a generic medication. [9]
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 strength—for example "Phenytoin sodium 25 mg Flynn Hard Capsules"). [57] The capsules are still made by Pfizer's Goedecke subsidiary's plant in Freiburg, Germany, and they still have Epanutin printed on them. [58] 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 factor—2,384%, [59] costing the UK's National Health Service an extra £43 million (about $68.44 million) a year. [60] The companies were referred to the Competition and Markets Authority (CMA) who found that they had exploited their dominant position in the market to charge "excessive and unfair" prices. [61]
The CMA imposed a record £84.2 million fine on the manufacturer Pfizer, and a £5.2 million fine on the distributor Flynn Pharma and ordered the companies to reduce their prices. [62]
Phenytoin is marketed under many brand names worldwide. [1]
In the US, Dilantin is marketed by Viatris after Upjohn was spun off from Pfizer. [63] [64] [65]
Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds. [66] [67] A meta-analysis also supported the use of phenytoin in managing various ulcers. [68] Phenytoin is incorporated into compounded medications to optimize wound treatment, often in combination with misoprostol. [69] [70]
Some clinical trials have explored whether phenytoin can be used as neuroprotector in multiple sclerosis. [71]
Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as a second-line agent in bipolar disorder. Carbamazepine appears to work as well as phenytoin and valproate for focal and generalized seizures. It is not effective for absence or myoclonic seizures.
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. An epileptic seizure is the clinical manifestation of an abnormal, excessive, and synchronized electrical discharge in the neurons. The occurrence of two or more unprovoked seizures defines epilepsy. The occurrence of just one seizure may warrant the definition in a more clinical usage where recurrence may be able to be prejudged. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical activity in the brain. These episodes can result in physical injuries, either directly, such as broken bones, or through causing accidents. In epilepsy, seizures tend to recur and may have no detectable underlying cause. Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to the alarming nature of their symptoms.
Valproate are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with absence seizures, partial seizures, and generalized seizures. They can be given intravenously or by mouth, and the tablet forms exist in both long- and short-acting formulations.
Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder and borderline personality disorder, since many seem to act as mood stabilizers, and for the treatment of neuropathic pain. Anticonvulsants suppress the excessive rapid firing of neurons during seizures. Anticonvulsants also prevent the spread of the seizure within the brain.
Lorazepam, sold under the brand name Ativan among others, is a benzodiazepine medication. It is used to treat anxiety, trouble sleeping, severe agitation, active seizures including status epilepticus, alcohol withdrawal, and chemotherapy-induced nausea and vomiting. It is also used during surgery to interfere with memory formation and to sedate those who are being mechanically ventilated. It is also used, along with other treatments, for acute coronary syndrome due to cocaine use. It can be given orally, transdermal, intravenously (IV), or intramuscularly When given by injection, onset of effects is between one and thirty minutes and effects last for up to a day.
Topiramate, sold under the brand name Topamax among others, is a medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence and essential tremor. For epilepsy this includes treatment for generalized or focal seizures. It is taken orally.
Lamotrigine, sold under the brand name Lamictal among others, is a medication used to treat epilepsy and stabilize mood in bipolar disorder. For epilepsy, this includes focal seizures, tonic-clonic seizures, and seizures in Lennox-Gastaut syndrome. In bipolar disorder, lamotrigine has not been shown to reliably treat acute depression in any groups except for the severely depressed; but for patients with bipolar disorder who are not currently symptomatic, it appears to reduce the risk of future episodes of depression.
Absence seizures are one of several kinds of generalized seizures. In the past, absence epilepsy was referred to as "pyknolepsy," a term derived from the Greek word "pyknos," signifying "extremely frequent" or "grouped". These seizures are sometimes referred to as petit mal seizures ; however, usage of this terminology is no longer recommended. Absence seizures are characterized by a brief loss and return of consciousness, generally not followed by a period of lethargy. Absence seizures are most common in children. They affect both sides of the brain.
Oxcarbazepine, sold under the brand name Trileptal among others, is a medication used to treat epilepsy. For epilepsy it is used for both focal seizures and generalized seizures. It has been used both alone and as add-on therapy in people with bipolar disorder who have had no success with other treatments. It is taken by mouth.
Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat anxiety disorders, seizures, bipolar mania, agitation associated with psychosis, OCD and akathisia. It is a long-acting tranquilizer of the benzodiazepine class. It possesses anxiolytic, anticonvulsant, sedative, hypnotic, and skeletal muscle relaxant properties. It is typically taken orally but is also used intravenously. Effects begin within one hour and last between eight and twelve hours in adults.
Nitrazepam, sold under the brand name Mogadon among others, is a hypnotic drug of the benzodiazepine class used for short-term relief from severe, disabling anxiety and insomnia. It also has sedative (calming) properties, as well as amnestic, anticonvulsant, and skeletal muscle relaxant effects.
Phenobarbital, also known as phenobarbitone or phenobarb, sold under the brand name Luminal among others, is a medication of the barbiturate type. It is recommended by the World Health Organization (WHO) for the treatment of certain types of epilepsy in developing countries. In the developed world, it is commonly used to treat seizures in young children, while other medications are generally used in older children and adults. It is also used for veterinary purposes. It may be used intravenously, injected into a muscle, or taken by mouth. The injectable form may be used to treat status epilepticus. Phenobarbital is occasionally used to treat trouble sleeping, anxiety, and drug withdrawal and to help with surgery. It usually begins working within five minutes when used intravenously and half an hour when administered by mouth. Its effects last for between four hours and two days.
Primidone, sold under various brand names, is a barbiturate medication that is used to treat partial and generalized seizures and essential tremors. It is taken by mouth.
Vigabatrin, sold under the brand names Vigafyde, Vigpoder and Sabril among others, is a medication used in the management and treatment of infantile spasms and refractory complex partial seizures.
Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxioselective anxiolytic since 1970, and an anticonvulsant since 1984. The primary drug-development goal was to provide greater anxiolytic, anti-obsessive efficacy with fewer benzodiazepine-related side effects.
Fetal hydantoin syndrome, also called fetal dilantin syndrome, is a group of defects caused to the developing fetus by exposure to teratogenic effects of phenytoin. Dilantin is the brand name of the drug phenytoin sodium in the United States, commonly used in the treatment of epilepsy.
Lacosamide, sold under the brand name Vimpat among others, is a medication used for the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. It is used by mouth or intravenously.
Perampanel, sold under the brand name Fycompa, is an anti-epileptic medication developed by Eisai Co. that is used in addition to other drugs to treat partial seizures and generalized tonic-clonic seizures for people older than twelve years. It was first approved in 2012, and as of 2016, its optimal role in the treatment of epilepsy relative to other drugs was not clear. It was the first antiepileptic drug in the class of selective non-competitive antagonist of AMPA receptors.
Women with epilepsy can have safe, healthy pregnancies and healthy babies. However, proper planning and care is essential. The goal of planning is to minimize the risk of congenital malformations and neurodevelopmental disorders for the fetus while maintaining the mother's seizure control.