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phenytoin; diphenylhydantoin; PTN (Dilantin, Dephenylan, Antilepsin)

Tradenames: Dilantin, Dephenylan. (phenytoin sodium) Class 1b antiarrhythmic agent. Indications: 1) partial seizures: a) focal seizures b) partial complex seizures 2) digitalis-induced arrhythmias a) ventricular arrhythmias b) supraventricular arrhythmias 3) ventricular arrhythmias associated with long QT syndrome 4) neurogenic pain 5) treatment of migraine syndrome 6) treatment of trigeminal neuralgia 7) status epilepticus - adjunct therapy with benzodiazepine - phenytoin is the anticonvulant of choice after administration of benzodiazepine [5] Contraindications: Caution: 1) hepatic dysfunction 2) tonic-clonic seizures (grand mal seizures) - no longer recommended; may exacerbate generalized seizures [3] 3) avoid abrupt discontinuation Dosage: 1) intravenous (IV) a) load 15-20 mg/kg up to 1000 mg IV (< 50 mg/min) b) CAUTON: Mix in normal saline; precipitates in D5W 2) maintenance: 5 mg/kg or 300 mg PO QD or divided TID Tabs: 30, 50 100 mg. Elixir: 30 & 125 mg/5 mL. Suppositories: 100 mg. Injection: 50 mg/mL (2 mL, 5 mL). Also topical agent. Dosage adjustment in renal failure: - none - supplemental dose after dialysis uncertain [5] Pharmacokinetics: 1) slowly absorbed from the GI tract 2) the rate & extent of absorption differs among different preparations 3) food delays absorption [9] 4) average 1/2 life is 22 hours 5) 95% protein-bound 6) metabolized by liver by cyt P450 2C9 & cyt P450 2C19 7) major metabolite: parahydroxyphenyl derivative (inactive) 8) undergoes enterohepatic circulation 9) excreted in the urine by glomerular filtration & tubular secretion (< 5% excreted unchanged in urine) 10) metabolism is saturable, thus small increases in the dose may produce large increases in plasma concentrations 11) therapeutic level is 10-20 ug/mL 12) serum level should be checked after 5-7 1/2lives Monitor: - HLA testing for HLA-B*1502 allele prior to administration (Asians) [5] - serum ALT or serum AST within 180 days [14] - CYP2C9 allele testing may be appropriate - variants including CYP2C9*3 may diminish phenytoin clearance by as much as 95% [16] - free phenytoin recommended [5] Adverse effects: 1) common (> 10%) - psychiatric changes, slurred speech, trembling, constipation, nausea/vomiting, dizziness, drowsiness, gingival hyperplasia, dizziness, sedation, ataxia [5] 2) less common (1-10%) - anorexia, weight loss, rash (DRESS), headache, insomnia, leukopenia, hepatitis, increased serum creatinine 3) uncommon (< 1%) - Stevens-Johnson syndrome, lupus-like syndrome, paresthesia, hypotension, bradycardia, cardiac arrhythmias, cardiovascular collapse, confusion, peripheral neuropathy, fever, blood dyscrasias, venous irritation & pain, thrombophlebitis, diplopia, nystagmus, blurred vision, lymphadenopathy 4) intravenous (IV): - cardiac arrhythmias with or without hypotension - CNS depression - sinus bradycardia - thrombophlebitis - occurs as a result of vehicle for delivery - minimized by central venous administration - purple glove syndrome 5) other (PO): - cerebellar-vestibular symptoms - nystagmus, ataxia, diplopia, vertigo - behavioral changes - other neurological manifestations - slurred speech, confusion, insomnia, drowsiness - GI symptoms - nausea/vomiting, diarrhea, cholestasis - osteomalacia/osteoporosis (diminished bone mineral density [10,11]) - megaloblastic anemia - hirsutism or hypertrichosis - drug-induced lupus - phenytoin syndrome - folic acid deficiency - increased risk of Stevens Johnson syndrome & toxic epidermal necrolysis in Asian patients positive for HLA allele, HLA-B*1502 [12] - type B drug reaction - drug reaction with eosinophilia & systemic symptoms (DRESS) - generally occurs 2-8 weeks after phenytoin initiation 6) toxicity - nystagmus develops at 20 ug/mL - ataxia is present at 30 ug/mL - lethargy is present at 40 ug/mL 7) less well tolerated in the elderly [5] Drug interactions: 1) increased phenytoin levels (inhibition of metabolism) with: - chloramphenicol, dicumarol, disulfiram, isoniazid, cimetidine, amiodarone, fluconazole, estrogen, erythromycin, felbamate, some sulfonamides (trimethoprim/sulfamethoxazole) 2) valproic acid increases phenytoin levels 3) decreased levels of phenytoin may be caused by: - carbamazepine, rifampin, folic acid, phenobarbital, cisplatin, vinblastine, bleomycin, continuous NG feedings 4) phenytoin decreases serum levels of: - cyclosporine, valproic acid, ethosuximide, carbamazepine, felbamate, primidone, warfarin, oral contraceptives, corticosteroids, theophylline, chloramphenicol, rifampin, doxycycline, quinidine, mexelitine, disopyramide, dopamine, non-depolarizing skeletal muscle relaxants 5) phenytoin blocks anti-parkinson effect of L-dopa 6) phenytoin may increase Li+ toxicity 7) valproic acid & salicylates may affect phenytoin protein-binding 8) phenytoin induces cyt P450 1A2 (CYP1A2) & cyt P450 3A4 (CYP3A4), thus may diminish levels of drugs metabolized by CYP1A2 & CYP3A4 9) any drug which inhibits cyt P450 2C9 or cyt P450 2C19 can increase phenytoin levels 10) any drug which induces cyt P450 2C9 or cyt P450 2C19 can diminish phenytoin levels 11) may decrease efficacy of oral contraceptives [5] Test interactions: -> in vivo effects -> phenytoin increases alkaline phosphatase activity Laboratory: 1) specimen: a) serum, plasma (EDTA) b) stable at room temperature for several hours c) stable for 1 year at -20 degrees C 2) methods: GLC, HPLC, RIA, EIA, FPIA, FIA 3) interferences: a) RIA & EIA: principal metabolite 5-(p-hydroxyphenyl)- 5-phenylhydantoin may cross-react, epecially with renal insufficiency b) do NOT collect in serum separator tubes; phenytoin may be extracted by separator gel 4) SERUM LEVELS SHOULD BE INTERPRETED IN THE CONTEXT OF SERUM ALBUMIN 5) free phenytoin levels recommended [5] 6) labs with Loincs - phenytoin in specimen - phenytoin in body fluid - phenytoin in saliva - free phenytoin in saliva - phenytoin in serum/plasma - free phenytoin in serum/plasma - phenytoin in urine Mechanism of action: 1) exerts a stabilizing effect on excitable membranes of neurons & myocytes 2) at concentrations < 10 uM, phenytoin can decrease Na+ fluxes at rest or during depolarization secondary to inhibition of voltage-dependent Na+ channels 3) at concentrations > 10 uM, phenytoin delays activation of neuronal outward K+ currents during action potentials, leading to an increased refractory period 4) at 20 uM , phenytoin can reduce the size & duration of Ca+2-dependent action potentials in neurons, secondary to effects on rapidly-inactivating Ca+2 channels

Interactions

drug interactions drug adverse effects of anticonvulsants monitor with anticonvulsants

Related

cytochrome p450 1A2 (cytochrome P3-450, phenacetin deethylase, cytochrome p450-4, CYP1A2) cytochrome P450 2C19 (cytochrome P450 2C17, cytochrome P450 11A, mephenytoin 4-hydroxylase, cytochrome P450 254C, CYP2C19) cytochrome P450 2C9; cytochrome P450 BP-1; cytochrome P450 MP-4; S-mephenytoin-4-hydroxylase; limonene 6-monooxygenase; limonene 7-monooxygenase (CYP2C9, CYP2C10) cytochrome P450 3A4 (cytochrome P450 C3, nifedipine oxidase, P450-PCN1, NF-25, CYP3A4) fosphenytoin (Cerebyx) phenytoin in serum/plasma phenytoin syndrome phenytoin teratogenesis

Specific

phenytoin, topical (Dilantin)

General

antiarrhythmic agent, Group IB anticonvulsant hydantoin; glycolylurea

Properties

MISC-INFO: elimination route LIVER PO-absorption 3-12 HOURS 1/2life 6-24 HOURS << 10 ug/mL> 20-60 HOURS <10-20 ug/mL> protein-binding 90% therapeutic-range 10-20 UG/ML 40-80 UM elimination by hemodialysis - pregnancy-category D safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill pg 439
  2. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  3. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 700
  4. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  5. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17. American College of Physicians, Philadelphia 1998, 2012, 2015.
  6. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  7. Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 10
  8. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  9. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
  10. Prescriber's Letter 10(1):4 2003
  11. Pack A, Morrell MJ, Randall A, McMahon DJ, Shane E. Bone health in young women with epilepsy after year of antiepileptic drug mopnotherapy. Neurology 2008, 70:1586 PMID: 18443309
  12. FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#Phenytoin
  13. Prescriber's Letter 16(1): 2009 COMMENTARY: Serious Skin Reactions Associated with Phenytoin Use in HLA-B*1502 Positive Patients CHART: Labs for HLA (Human Leukocyte Antigen) Testing Detail-Document#: 250109 (subscription needed) http://www.prescribersletter.com
  14. deprecated reference
  15. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  16. Chung WH et al Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions. JAMA. 2014;312(5):525-534 PMID: 25096692 http://jama.jamanetwork.com/article.aspx?articleid=1892248

Component-of

carbamazepine/lamotrigine/phenobarbital/phenytoin/primidone/valproic acid pentobarbital/phenytoin