phenytoin; diphenylhydantoin; PTN (Dilantin, Dephenylan, Antilepsin)
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Introduction
Tradenames: Dilantin, Dephenylan. (phenytoin sodium) Class 1b antiarrhythmic agent.
Indications
- partial seizures:
- digitalis-induced arrhythmias
- ventricular arrhythmias associated with long QT syndrome
- neurogenic pain
- treatment of migraine syndrome
- treatment of trigeminal neuralgia
- status epilepticus
- adjunct therapy with benzodiazepine
- phenytoin is the anticonvulant of choice after administration of benzodiazepine[5]
Contraindications
Caution:
- hepatic dysfunction
- tonic-clonic seizures (grand mal seizures)
- no longer recommended; may exacerbate generalized seizures[3]
- avoid abrupt discontinuation
Dosage
- intravenous (IV)
- load 15-20 mg/kg up to 1000 mg IV (< 50 mg/min)
- CAUTON: Mix in normal saline; precipitates in D5W
- maintenance: 5 mg/kg or 300 mg PO QD or divided TID
Tabs: 30, 50 100 mg.
Suppositories: 100 mg.
Injection: 50 mg/mL (2 mL, 5 mL). Also topical agent.
Dosage adjustment in renal failure
Pharmacokinetics
- slowly absorbed from the GI tract
- the rate & extent of absorption differs among different preparations
- food delays absorption[9]
- average 1/2 life is 22 hours
- 95% protein-bound
- metabolized by liver by cyt P450 2C9 & cyt P450 2C19
- major metabolite: parahydroxyphenyl derivative (inactive)
- undergoes enterohepatic circulation
- excreted in the urine by glomerular filtration & tubular secretion (< 5% excreted unchanged in urine)
- metabolism is saturable, thus small increases in the dose may produce large increases in plasma concentrations
- therapeutic level is 10-20 ug/mL
- serum level should be checked after 5-7 1/2lives
elimination via liver
1/2life = 6-24 hours < 10 ug/mL
1/2life = 20-60 hours 10-20 ug/mL
protein binding = 90 % mostly albumin
elimination by hemodialysis = -
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
- free phenytoin recommended[5]
Adverse effects
- common (> 10%)
- psychiatric changes, slurred speech, trembling, constipation, nausea/vomiting, dizziness, drowsiness, gingival hyperplasia, dizziness, sedation, ataxia[5]
- less common (1-10%)
- anorexia, weight loss, rash (DRESS), headache, insomnia, leukopenia, hepatitis, increased serum creatinine
- 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
- 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
- other (PO):
- cerebellar-vestibular symptoms
- behavioral changes
- other neurological manifestations
- GI symptoms
- 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
- drug reaction with eosinophilia & systemic symptoms (DRESS)
- toxicity
- less well tolerated in the elderly[5]
Drug interactions
- increased phenytoin levels (inhibition of metabolism) with:
- valproic acid increases phenytoin levels
- decreased levels of phenytoin may be caused by:
- carbamazepine, rifampin, folic acid, phenobarbital, cisplatin, vinblastine, bleomycin, continuous NG feedings
- phenytoin decreases serum levels of:
- phenytoin blocks anti-parkinson effect of L-dopa
- phenytoin may increase Li+ toxicity
- valproic acid & salicylates may affect phenytoin protein-binding
- phenytoin induces cyt P450 1A2 (CYP1A2) & cyt P450 3A4 (CYP3A4), thus may diminish levels of drugs metabolized by CYP1A2 & CYP3A4
- any drug which inhibits cyt P450 2C9 or cyt P450 2C19 can increase phenytoin levels
- any drug which induces cyt P450 2C9 or cyt P450 2C19 can diminish phenytoin levels
- may decrease efficacy of oral contraceptives[5]
- drug interaction(s) anticonvulsants with anti-bacterial agents
- drug interaction(s) anticonvulsants with statins
- drug interaction(s) of antiarrhythmic agents in combination with diuretics
Test interactions
- in vivo effects
- phenytoin increases alkaline phosphatase activity
Laboratory
- specimen:
- serum, plasma (EDTA)
- stable at room temperature for several hours
- stable for 1 year at -20 degrees C
- methods: GLC, HPLC, RIA, EIA, FPIA, FIA
- interferences:
- RIA & EIA: principal metabolite 5-(p-hydroxyphenyl)- 5-phenylhydantoin may cross-react, epecially with renal insufficiency
- do NOT collect in serum separator tubes; phenytoin may be extracted by separator gel
- SERUM LEVELS SHOULD BE INTERPRETED IN THE CONTEXT OF SERUM ALBUMIN
- free phenytoin levels recommended[5]
- labs with Loincs
Mechanism of action
- exerts a stabilizing effect on excitable membranes of neurons & myocytes
- at concentrations < 10 uM, phenytoin can decrease Na+ fluxes at rest or during depolarization secondary to inhibition of voltage-dependent Na+ channels
- at concentrations > 10 uM, phenytoin delays activation of neuronal outward K+ currents during action potentials, leading to an increased refractory period
- 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
More general terms
More specific terms
Additional terms
- 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
Component of
References
- ↑ The Pharmacological Basis of Therapeutics, 8th ed. Gilman et al, eds. Permagon Press/McGraw Hill pg 439
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ 3.0 3.1 Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 700
- ↑ Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17. American College of Physicians, Philadelphia 1998, 2012, 2015.
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ Clinical Diagnosis & Management by Laboratory Methods, 19th edition, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1996, pg 10
- ↑ Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
- ↑ 9.0 9.1 Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 470
- ↑ 10.0 10.1 Prescriber's Letter 10(1):4 2003
- ↑ 11.0 11.1 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: https://www.ncbi.nlm.nih.gov/pubmed/18443309
- ↑ 12.0 12.1 FDA MedWatch http://www.fda.gov/medwatch/safety/2008/safety08.htm#Phenytoin
- ↑ 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#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=250109&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 14.0 14.1 deprecated reference
- ↑ Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
- ↑ 16.0 16.1 Chung WH et al Genetic Variants Associated With Phenytoin-Related Severe Cutaneous Adverse Reactions. JAMA. 2014;312(5):525-534 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/25096692 <Internet> http://jama.jamanetwork.com/article.aspx?articleid=1892248