Phenytoin
Clinical data | |
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Pronunciation | /fəˈnɪtoʊɪn, ˈfɛnɪtɔɪn/ |
Trade names | Dilantin, others[1] |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682022 |
License data | |
Pregnancy category |
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intravenous | |
Drug class | Anticonvulsant |
ATC code | |
Legal status | |
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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] |
Identifiers | |
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Phenytoin (PHT), sold under the brand name Dilantin among others,
Common side effects include nausea, stomach pain, loss of appetite, poor coordination,
Phenytoin was first made in 1908 by the German chemist
Medical uses
Seizures
- Tonic-clonic seizures: Mainly used in the prophylactic management of tonic-clonic seizures with complex symptomatology (psychomotor seizures). A period of 5–10 days of dosing may be required to achieve anticonvulsant effects.
- temporal lobe seizures). Also effective in controlling focal seizures with autonomic symptoms.
- Absence seizures: Not used in treatment of pure absence seizures due to risk for increasing frequency of seizures. However, can be used in combination with other anticonvulsants during combined absence and tonic-clonic seizures.
- Seizures during surgery: A 2018 meta-analysis found that early antiepileptic treatment with either phenytoin or phenobarbital reduced the risk of seizure in the first week after neurosurgery for brain tumors.[12]
- Status epilepticus: Considered after failed treatment using a benzodiazepine due to slow onset of action.[13]
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]
Other
- Abnormal heart rhythms: may be used in the treatment of ventricular tachycardia and sudden episodes of atrial tachycardia after other antiarrhythmic medications or cardioversion has failed. It is a class Ib antiarrhythmic.[15]
- Digoxin toxicity: Intravenous phenytoin formulation is a medication of choice for arrhythmias caused by cardiac glycoside toxicity.
- Trigeminal neuralgia: Second choice drug to carbamazepine.[16]
Special considerations
- Phenytoin has a narrow therapeutic index. Its therapeutic range for an anticonvulsant effect is 10–20 μg/mL and for an antiarrhythmic effect 10–20 μg/mL.
- Avoid giving intramuscular formulation unless necessary due to skin cell death and local tissue destruction.
- Elderly patients may show earlier signs of toxicity.
- In the obese, ideal body weight should be used for dosing calculations.
- Pregnancy: Pregnancy category D due to risk of fetal hydantoin syndrome and fetal bleeding. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations as a result of plasma volume expansion during pregnancy, dose of phenytoin may need to be increased if only option for seizure control.
- Breastfeeding: The manufacturer does not recommend breastfeeding since low concentrations of phenytoin are excreted in breast milk.[17]
- 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.
- Intravenous use is contraindicated in patients with Stokes-Adams syndrome, or hypersensitivity to phenytoin, other hydantoinsor any ingredient in the respective formulation.
Side effects
This section needs more primary sources. (June 2019) |
Common side effects include nausea, stomach pain, loss of appetite, poor coordination,
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 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]
Neurological
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]
Blood
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]
Pregnancy
Phenytoin is a known
Cancer
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]
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.[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.
Skin
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
Immune system
Phenytoin has been known to cause drug-induced
Phenytoin is also associated with induction of reversible
Psychological
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]
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 deficiency, as well as low calcium and phosphate in the blood cause decreased bone mineral density.[17]
Interactions
Phenytoin is an inducer of the
A 1981 study by the
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:
- Antidepressants drugs
- Antifungal drugs such as fluconazole, ketoconazole
- antibiotics such as metronidazole, chloramphenicol, clarithromycin, azithromycin
- Cortones (such as betamethasone, dexamethasone, hydrocortisone and prednisolone
- L-DOPA (phenytoin can cause the beneficial effect of levodopa to disappear.)
Pharmacology
Mechanism of action
Phenytoin is believed to protect against seizures by causing voltage-dependent block of
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]
Pharmacokinetics
Phenytoin elimination kinetics show mixed-order, non-linear elimination behaviour at therapeutic concentrations. Where phenytoin is at low concentration it is cleared by
History
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.
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.[56]
Society and culture
Economics
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,
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]
Trade names
Phenytoin is marketed under many brand names worldwide.[1]
Research
Tentative evidence suggests that topical phenytoin is useful in wound healing in people with chronic skin wounds.[63][64] A meta-analysis also supported the use of phenytoin in managing various ulcers.[65]
Some clinical trials have explored whether phenytoin can be used as neuroprotector in multiple sclerosis.[66]
References
- ^ a b c "International trade names for phenytoin". Drugs.com. Archived from the original on 23 February 2016. Retrieved 27 February 2016.
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
- ^ a b c d e f g h i j k l m n "Phenytoin". The American Society of Health-System Pharmacists. Archived from the original on 2015-09-08. Retrieved Aug 22, 2015.
- ^ ISBN 9780323054720.
- PMID 5520387.
- ISBN 9780781757775.
- ISBN 9780781789431. Retrieved 9 June 2016.
- hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
- ^ ISBN 9781449673635.
- ^ "The Top 300 of 2020". ClinCalc. Retrieved 7 October 2022.
- ^ "Phenytoin - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
- PMID 29701546.
- ^ "Phenytoin". Lexi-Comp Online. Archived from the original on 4 March 2016. Retrieved 18 April 2014.
- S2CID 254357105. Report No.: 22(23)-EHC004 2021-SR-01.
- ISBN 9781590742495.
- ISBN 9788179916582.
- ^ a b c d Phenytoin [package insert]. New York, NY: Pfizer Inc.; 2013. Accessed November 2, 2014.
- ^ a b c "Parenteral Dilantin (Phenytoin Sodium Injection, USP)" (PDF). Parke-Davis. U.S. Food and Drug Administration. October 2011. Archived (PDF) from the original on 19 April 2014. Retrieved 18 April 2014.
- ^ "Dilantin Toxicity". Family Practice Notebook, LLC. Archived from the original on 2014-04-19.
- PMID 12810345.
- ISBN 978-1-936287-10-9.
- S2CID 40927589.
- PMID 1805490.
- S2CID 25327883.
- ISBN 978-1-4557-3976-9.)
{{cite book}}
: CS1 maint: location missing publisher (link - ^ Hamblin TJ (August 2005). "Aplastic anaemia". NetDoctor. Archived from the original on 2013-02-12. Retrieved 2013-07-08.
- ^ PMID 25354543.
- ^ PMID 37647086.
- ^ Beckmann CR, et al. (2002). Obstetrics and Gynecology (4th ed.). Baltimore: Lippincott Williams & Wilkins.
- ^ National Task Force on Fetal Alcohol Syndrome and Fetal Alcohol Effect (July 2004). "Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis" (PDF). National Center on Birth Defects and Developmental Disabilities. Centers for Disease Control and Prevention; U.S. Department of Health and Human Services.
- ^ Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.
- PMID 3373561.
- S2CID 37504937.
- PMID 21482950.
- S2CID 34728720.
- PMID 25099164.
- ^ "DILANTIN- phenytoin sodium capsule, extended release". Archived from the original on 2 April 2015. Retrieved 12 March 2015.
- from the original on 2008-08-29.
- S2CID 23984720.
- PMID 10901705.
- S2CID 26099092.
- ^ "Lexi-Comp Online Interaction Lookup". Lexi-Comp. Archived from the original on 2014-04-19.
- S2CID 2201038.
- ^ lippincots modern pharmacology with clinical applications pg no:377 5th Edition
- ^ "Dilantin". MIMS. 2015. Archived from the original on 2014-08-10.
- ISBN 9781139103992. Archived from the originalon 2020-09-25. Retrieved 2013-01-17.
- ^ Patsalos PN (2012). "Chapter 67 Antiepileptic drug pharmacokinetics and therapeutic drug monitoring". Antiepileptic drug pharmacokinetics and therapeutic drug monitoring. Cambridge University Press. pp. 358–366.
- ^ "PNYFR - Clinical: Phenytoin, Total and Free, Serum". Archived from the original on 2013-03-01. Retrieved 2013-01-17.
- S2CID 25980868.
- .
- S2CID 7761284.
- ^ Goodman and Gilman's Pharmacological Basis of Therapeutics (10th ed.). New York: McGraw-Hill. 2001.
- ^ Stout D (2000-08-31). "2 Nixon Aides Skeptical About Report That He Took Drug". The New York Times. Retrieved 2020-02-06.
- ^ Campbell J (6 January 2006). Muir D (ed.). "New Nixon Biography Gives Salacious Details". ABC News. New York City, New York, United States of America: American Broadcasting Company (Walt Disney Television). Retrieved 7 August 2021.
- ISBN 978-0-8264-1069-6.
- ^ "AERS data". FDA. Archived from the original on 19 April 2014. Retrieved 18 April 2014.
- ^ "Phenytoin Sodium Flynn Hard Capsules...Marketing authorisation holder". Flynn Pharma patient information leaflet at the electronic Medicines Compendium. 24 April 2014. Archived from the original on 15 January 2017. Retrieved 13 May 2014.
- ^ "Healthcare Professionals Advised That Epanutin Capsules Are Only To Be Available Under The Generic Name". Durham, NC: MediGuard. 2 October 2012. Archived from the original on 14 May 2014. Retrieved 13 May 2014.
- ^ Adams S (12 October 2012). "Pharma firm hikes cost of epilepsy drug 24 times". Daily Telegraph. London. Archived from the original on 2012-10-13. Retrieved 13 May 2014.
- ^ Gould M (21 November 2012). "Price of anti-epilepsy drug rockets". Pulse. London. Archived from the original on 28 November 2012. Retrieved 13 May 2014.
- ^ White M (12 August 2015). "Pharma market abuse isn't picked up fast enough". Health Service Journal. Archived from the original on 7 October 2015. Retrieved 6 October 2015.
- ^ "CMA fines Pfizer and Flynn £90 million for drug price hike to NHS" (Press release). www.gov.uk. Archived from the original on 2016-12-07. Retrieved 2016-12-07.
- S2CID 23862219.
- PMID 15347487.
- S2CID 74076946.
- S2CID 38835886.
Further reading
- Dean L, Kane M (2016). "Phenytoin Therapy and HLA-B*15:02 and CYP2C9 Genotypes". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. PMID 28520374. Bookshelf ID: NBK385287.