Phenytoin

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Phenytoin
Phenytoin structure.svg
Phenytoin-3D-balls.png
Systematic (IUPAC) name
5,5-diphenylimidazolidine-2,4-dione
Clinical data
Trade names Dilantin
AHFS/Drugs.com monograph
MedlinePlus a682022
Pregnancy cat. D (US)
Legal status Prescription only
Routes Oral, parenteral
Pharmacokinetic data
Bioavailability 70-100% oral, 24.4% for rectal and intravenous administration
Protein binding 90%
Metabolism hepatic
Half-life 6–24 hours
Excretion Primarily through the bile, urinary
Identifiers
CAS number 57-41-0 YesY
ATC code N03AB02
PubChem CID 1775
DrugBank DB00252
ChemSpider 1710 YesY
UNII 6158TKW0C5 YesY
KEGG D00512 YesY
ChEBI CHEBI:8107 N
ChEMBL CHEMBL16 N
Chemical data
Formula C15H12N2O2 
Mol. mass 252.268 g/mol
 N (what is this?)  (verify)

Phenytoin sodium /fəˈnɪtɨn/ is a hydantoin-derivative anticonvulsant drug used primarily in the management of complex partial seizures and generalized tonic-clonic seizures. Phenytoin is also used to prevent seizures following neurosurgery. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage-gated sodium channels.[1] Additionally, phenytoin is a class 1b antiarrhythmic that can be used to treat cardiac arrhythmias when conventional options have failed or after cardiac glycoside intoxication.[2]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[3]

Medical uses[edit]

Information in this section adapted from Lexi-Comp [4]

  • Grand mal - Mainly used in the prophylactic management of tonic-clonic grand mal seizures with complex symptomatology (psychomotor seizures). A period of 5–10 days may be required to achieve anticonvulsant effects.
  • Partial seizures - Mainly used in the prophylactic management of partial seizures with complex symptomatology (psychomotor and temporal lobe seizures). Also effective in controlling partial 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- Used as prevention and treatment of seizures occurring during and after neurosurgery.
  • Status epilepticus- Considered after failed treatment using a benzodiazepine due to slow onset of action. IV formulation must be used but must be infused slowly due to black box warning. Consider using with IV benzodiazepine or barbiturate in order to rapidly control seizures. Oral therapy should replace parenteral administration as soon as possible. Determination of serum phenytoin concentrations is recommended when IV phenytoin is used for the management of status epilepticus.
  • Cardiac dysrhythmia-IV formulation used in the treatment of ventricular tachycardia and paroxysmal atrial tachycardia after first-line antiarrhythmic agents or cardioversion has failed.
  • Digoxin toxicity- IV formulation is drug of choice for arrhythmias caused by cardiac glycoside toxicity.
  • Trigeminal neuralgia - Second choice drug to carbamazepine.[5]
  • Wound healing- Although controversial,topical Phenytoin has been used as wound healing agent in patients with chronic skin wounds [6][7][8][9][10]

Special considerations[edit]

  • Monitoring plasma concentrations: Narrow therapeutic index. Anticonvulsant effect: 10–20 mcg/mL; Antiarrhythmic effect: 10–20 mcg/mL
  • Avoid giving intramuscular formulation unless necessary due to skin necrosis and local tissue destruction.
  • Geriatric- May show earlier signs of toxicity.
  • Obese- Use ideal body weight for dosing calculations.
  • Pregnancy- Pregnancy Category D due to risk of fetal hydantoin syndrome and fetal hemorrhage. However, optimal seizure control is very important during pregnancy so drug may be continued if benefits outweigh the risks. Due to decreased drug concentrations during pregnancy, dose of phenytoin may need to be increased if only option for seizure control.
  • Hepatic Impairment- Do not use oral loading dose. Consider using decreased maintenance dose.
  • Renal Impairment- Do not use oral loading dose. Can begin with standard maintenance dose and adjust as needed.
  • IV use is contraindicated in patients with sinus bradycardia, SA block, second- or third-degree AV block, Adams-Stokes syndrome, or have known hypersensitivity to phenytoin or any ingredient in the respective formulation or to other hydantoins.

Side-effects[edit]

Cardiovascular[edit]

Severe hypotension and cardiac arrhythmias 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 pediatric patients. Cardiac monitoring should occur during and after IV infusion. Due to these risks, oral phenytoin should be used if possible.[11]

Neurologic[edit]

At therapeutic doses, phenytoin may produce nystagmus on lateral gaze. At toxic doses, patients experience vertical nystagmus, diplopia, sedation, slurred speech, cerebellar ataxia, and tremor.[12] Abrupt discontinuation of phenytoin may result in increased seizure frequency, including status epilepticus[11]

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. [13]

Hematologic[edit]

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.[14] Other side effects may include: agranulocytosis, aplastic anemia, leukopenia[citation needed], thrombocytopenia. [15]

Teratogenicity[edit]

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).[16] This syndrome resembles the well-described Fetal Alcohol Syndrome[17] 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.[18] Data now being collected by the Epilepsy and Antiepileptic Drug Pregnancy Registry may one day answer this question definitively.

Carcinogenicity[edit]

There is no good evidence that phenytoin is a human carcinogen.[19][20]

Gingival[edit]

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.[21] 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[edit]

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.[22]

Dermatologic[edit]

Hypertrichosis, purple glove syndrome, rash, exfoliative dermatitis, pruritis, hirsutism, and coarsening of facial features

Autoimmune disease[edit]

Phenytoin has been known to cause drug-induced lupus.[23]

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.[24] This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.

Immunodeficiency disease[edit]

Phenytoin is also associated with induction of reversible IgA deficiency.[24]

Interactions[edit]

Phenytoin is an inducer of the CYP3A4 and CYP2C19 families of the P450 enzyme responsible for the hepatic degradation of various drugs.[25]

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." [26]

Warfarin (Coumadin) and Trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism. Consider using other options if possible.[27]

Mechanism of action[edit]

Phenytoin produces its anticonvulsant activity through blocking 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 1.Resting state 2.Open state 3.Inactive state

The mechanism of action of phenytoin sodium. Sodium channels are 1.Closed channels 2.Open channels 3.inactive channel (phenytoin effect)

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 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. [28]

The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. 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.[11]

Pharmacokinetics[edit]

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.[29][30][31][32]

Chemistry[edit]

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.[33]

Phenytoin synthesis.png

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 

History[edit]

Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908.[33] 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.[34]

It was approved by the USA Food and Drug Administration 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 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.[35] 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 about purple glove syndrome in November 2011.[36]


Society and culture[edit]

Trade names[edit]

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). FENTOIN-ER,EPSOLIN are brands available in India [37] Diphantoine is a brand available in The Netherlands (91% Phenytoin).

Popular culture[edit]

Dilantin made an appearance in the 1962 novel One Flew Over the Cuckoo's Nest by Ken Kesey, both as an anticonvulsant and as a mechanism to control inmate behavior.

In the 2013 science fiction film Elysium, the protagonist (played by Matt Damon) takes Miporol, a fictional brand name for diphenylhydantoin, after having been exposed to a lethal dose of radiation.

References[edit]

  1. ^ Rogawski MA, Löscher W. The neurobiology of antiepileptic drugs. Nat Rev Neurosci. 2004 Jul;5(7):553-564 PubMed PMID 15208697.
  2. ^ McEvoy, GK (2004). "AHFS drug information 2004". American Society of Health-System Pharmacists: 2117–2120. 
  3. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ "Phenytoin". Lexi-Comp Online. Retrieved 18 April 2014. 
  5. ^ Pharmacology and pharmacotheraputics 22ed edition pg:129 By R S Satoskar
  6. ^ Shaw, J; Hughes, CM; Lagan, KM; Bell, PM (Nov 2007). "The clinical effect of topical phenytoin on wound healing: a systematic review.". The British journal of dermatology 157 (5): 997–1004. PMID 17854378. 
  7. ^ Prathvi, Shetty (2013). "A Comparative Study of Efficacy of Topical Phenytoin vs Conventional Wound Care in Diabetic Ulcers". International Journal of Molecular Medical Science. doi:10.5376/ijmms.2013.03.0008. 
  8. ^ Anstead, GM; Hart, LM; Sunahara, JF; Liter, ME (Jul–Aug 1996). "Phenytoin in wound healing.". The Annals of pharmacotherapy 30 (7-8): 768–75. PMID 8826558. 
  9. ^ Bhatia, A; Prakash, S (Jul 15, 2004). "Topical phenytoin for wound healing.". Dermatology online journal 10 (1): 5. PMID 15347487. 
  10. ^ Sinha SN & Amarasena I (February 2008). "Does phenytoin have a role in the treatment of pressure ulcers?". Wound Practice and Research 16 (1): 37–41. 
  11. ^ a b c "FDA drug label". FDA. Retrieved 18 April 2014. 
  12. ^ "Dilantin Toxicity". 
  13. ^ De Marco, Felipe A; et al (July 2003). "Cerebellar Volume and Long-Term Use of Phenytoin". European Journal of Epilepsy 12 (5): 312–315. PMID 12810345. Retrieved 20 April 2014. 
  14. ^ 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. 
  15. ^ http://www.netdoctor.co.uk/diseases/facts/aplasticanaemia.htm
  16. ^ Beckmann CR et al. (2002). Obstetrics and Gynecology (4th ed.). Baltimore: Lippincott Williams & Wilkins. 
  17. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.
  18. ^ Adab N, Tudur SC, Vinten J, Williamson P, Winterbottom J (2004). "Common Antiepileptic Drugs in Pregnancy in Women with Epilepsy". In Adab, Naghme. Cochrane Database of Systematic Reviews 2004 (3): CD004848. doi:10.1002/14651858.CD004848. PMID 15266543. 
  19. ^ Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.
  20. ^ 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. 
  21. ^ 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. 
  22. ^ FDA warns of risks from epilepsy drugs.
  23. ^ Scheinfeld N (2003). "Phenytoin in Cutaneous Medicine: Its Uses, Mechanisms and Side Effects". Dermatology Online Journal 9 (3): 6. PMID 12952753. 
  24. ^ a b 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. 
  25. ^ Cuttle, L; et al (August 2000). "Phenytoin metabolism by human cytochrome P450: involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation". Drug Metabolism and Disposition 28 (8): 945–950. PMID 10901705. Retrieved 20 April 2014. 
  26. ^ Carter, BL; et al (1981). "Effect of antacids on phenytoin availability". Therapeutic Drug Monitoring 3 (4): 333–340. PMID 7336470. Retrieved 20 April 2014. 
  27. ^ "Lexi-Comp Online Interaction Lookup". Lexi-Comp. 
  28. ^ lippincots modern pharmacology with clinical applications pg no:377 5th Edition
  29. ^ 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.
  30. ^ http://ebooks.cambridge.org/chapter.jsf?bid=CBO9781139103992&cid=CBO9781139103992A081
  31. ^ 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
  32. ^ http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9993
  33. ^ a b 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. 
  34. ^ Goodman and Gilman's Pharmacological Basis of Therapeutics (10th ed.). New York: McGraw-Hill. 2001. 
  35. ^ 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. 
  36. ^ "AERS data". FDA. Retrieved 18 April 2014. 
  37. ^ essential pharmacology by KD Tripathi 6E pg:405

External links[edit]