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 an antiepileptic drug. It is useful to treat partial seizures and generalized tonic-clonic seizures but not primary generalized seizures such as absence seizures or myoclonic seizures. Phenytoin is believed to protect against seizures by causing voltage-dependent block of voltage-gated sodium channels.[1] Phenytoin has low affinity for resting sodium channels at hyperpolarized membrane potentials.[2] When neurons are depolarized and the channels transition into the open and inactivated states, greater binding and block occur. The inhibitory potency is strongly use dependent, so that block accumulates with prolonged or repetitive activation, such as occurs during a seizure discharge. The blocking of sodium channels by phenytoin is of slow onset. The time course of fast sodium currents is therefore not altered in the presence of the drug and action potentials evoked by synaptic depolarizations of ordinary duration are not blocked. Thus phenytoin is able to selectively inhibit pathological hyperexcitability in epilepsy without unduly impairing ongoing activity. Phenytoin also blocks persistent sodium current and this may be of particular importance in seizure control. Phenytoin is a class 1b antiarrhythmic.[3]

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 [4] Diphantoine is a brand available in The Netherlands (91% Phenytoin).

History[edit]

Phenytoin (diphenylhydantoin) was first synthesized by German chemist Heinrich Biltz in 1908.[5] 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.[6]

There are some indications that phenytoin has other effects, including anxiety control and mood stabilization, although it has never been approved for those purposes by the FDA. 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.[7] 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. It was approved by the USA Food and Drug Administration in 1953 for use in seizures.

General and vague references to the use of phenytoin for phantosmia can be found by internet browsing, those found have been but tantalizing. One patient with phantosmia (imagined smells) that began in 1995 (including some parosmia (false or distorted smell)) was prescribed phenytoin after other fixes did not work. This caused nearly complete (and very liveable) remission of the phantosmia. In 2012, following both patient and physician concerns (patient: relation to post-phenytoin sleep apnea onset, deteriorating balance; physician: long term neuralogical damage), phenytoin use was stopped and another seizure medicine was prescribed (levetiracetam) with no noticeable control over the phantosmia. Following information obtained from internet browsing, venlafaxine was prescribed, but also with no therapeutic benefit for the patient. Phenytoin remains the only relief found for this patient.

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 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 System (AERS) Phenytoin Injection (Dilantin) has been associated with the risk of Purple Glove Syndrome.

A 1981 study [8] 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."

Side-effects[edit]

Neurologic[edit]

At therapeutic doses, phenytoin may produce horizontal gaze nystagmus. At toxic doses, patients experience vertical nystagmus, sedation, cerebellar ataxia, and ophthalmoparesis, as well as seizures. Idiosyncratic side-effects of phenytoin, as with other anticonvulsants, include rash and severe allergic reactions.

Phenytoin may accumulate in the cerebral cortex over long periods of time, as well as causing atrophy of the cerebellum 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[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.[9] Other side effects may include: agranulocytosis, aplastic anemia, leukopenia[citation needed], thrombocytopenia. [10]

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).[11] This syndrome resembles the well-described Fetal Alcohol Syndrome[12] 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.[13] 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.[14][15]

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.[16] 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.[17]

Dermatologic[edit]

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

In autoimmune disease[edit]

Phenytoin has been known to cause drug-induced lupus.[18]

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

In immunodeficiency disease[edit]

Phenytoin is also associated with induction of reversible IgA deficiency.[19]

Interactions[edit]

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

Warfarin (Coumadin) and Trimethoprim increase serum phenytoin levels and prolong the serum half-life of phenytoin by inhibiting its metabolism.

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 depolarisation 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. [20]

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.[21][22][23][24]

Use[edit]

  • Grand mal - Abolishes grand mal seizure in nearly 60% of the patient and reduces their severity and frequency in another 15-20%. Dose: 100 mg twice daily, 400 mg/day maximum dose, children 5–8 mg/kg/day.
  • Partial seizures - Phenytoin is preferred to phenobarbital in this type of seizure. The drug often controls but does not completely abolish the seizure activity. It is occasionally useful in infantile spasm.
  • Status epilepticus
  • Cardiac dysrhythmia
  • Trigeminal neuralgia - Second choice drug to carbamazepine.[25]
  • Although controversial,[26] but topical Phenytoin has been used as wound healing agent in patients with chronic skin wounds.[27][28][29][30]

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.[5]

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 

In popular culture[edit]

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. ^ Porter RJ, Dhir A, Macdonald RL, Rogawski MA. Mechanisms of action of antiseizure drugs. Handb Clin Neurol. 2012;108:663-681. doi:10.1016/B978-0-444-52899-5.00021-6. PubMed PMID 22939059.
  3. ^ Balaji S (2004). "Medical Therapy for Sudden Death". Pediatric Clinics of North America 51 (5): 1379–1387. doi:10.1016/j.pcl.2004.04.002. PMID 15331289. 
  4. ^ essential pharmacology by KD Tripathi 6E pg:405
  5. ^ 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. 
  6. ^ Goodman and Gilman's Pharmacological Basis of Therapeutics (10th ed.). New York: McGraw-Hill. 2001. 
  7. ^ 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. 
  8. ^ http://www.ncbi.nlm.nih.gov/pubmed/7336470
  9. ^ 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. 
  10. ^ http://www.netdoctor.co.uk/diseases/facts/aplasticanaemia.htm
  11. ^ Beckmann CR et al. (2002). Obstetrics and Gynecology (4th ed.). Baltimore: Lippincott Williams & Wilkins. 
  12. ^ CDC. (2004). Fetal Alcohol Syndrome: Guidelines for Referral and Diagnosis. Can be downloaded at http://www.cdc.gov/fas/faspub.htm.
  13. ^ 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. 
  14. ^ Report on Carcinogens, Eleventh Edition (PB2005-104914, 2004) p III-216.
  15. ^ 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. 
  16. ^ 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. 
  17. ^ FDA warns of risks from epilepsy drugs.
  18. ^ Scheinfeld N (2003). "Phenytoin in Cutaneous Medicine: Its Uses, Mechanisms and Side Effects". Dermatology Online Journal 9 (3): 6. PMID 12952753. 
  19. ^ 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. 
  20. ^ lippincots modern pharmacology with clinical applications pg no:377 5th Edition
  21. ^ 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.
  22. ^ http://ebooks.cambridge.org/chapter.jsf?bid=CBO9781139103992&cid=CBO9781139103992A081
  23. ^ 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
  24. ^ http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/9993
  25. ^ Pharmacology and pharmacotheraputics 22ed edition pg:129 By R S Satoskar
  26. ^ Shaw, J; Hughes, CM; Lagan, KM; Bell, PM (2007 Nov). "The clinical effect of topical phenytoin on wound healing: a systematic review.". The British journal of dermatology 157 (5): 997–1004. PMID 17854378. 
  27. ^ 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. 
  28. ^ Anstead, GM; Hart, LM; Sunahara, JF; Liter, ME (1996 Jul-Aug). "Phenytoin in wound healing.". The Annals of pharmacotherapy 30 (7-8): 768–75. PMID 8826558. 
  29. ^ Bhatia, A; Prakash, S (2004 Jul 15). "Topical phenytoin for wound healing.". Dermatology online journal 10 (1): 5. PMID 15347487. 
  30. ^ 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. 

External links[edit]