Phenytoin

From Anvita Health Wiki

Contents 1 More Specific Terms 2 Introduction 3 Indications 4 Contraindications 5 Dosage 6 Pharmacokinetics 7 Monitor 8 Adverse-effects 9 Drug-interactions 10 Test-interactions 11 Laboratory 12 Mechanism-of-action 13 More General Terms 14 Additional Terms 15 Internet Database 16 References

More Specific Terms

• phenytoin, topical (Dilantin)

Introduction

• Tradenames: Dilantin, Dephenylan. (phenytoin sodium) Class 1b antiarrhythmic agent.

Indications

• seizures:

• tonic-clonic seizures (grand mal sezures)
• focal seizures
• partial complex seizures

• digitalis-induced arrhythmias

• ventricular arrhythmias
• supraventricular arrhythmias

• ventricular arrhythmias associated with long QT syndrome
• neurogenic pain
• treatment of migraine syndrome
• treatment of trigeminal neuralgia

Contraindications

• Caution:
• hepatic dysfunction
• avoid abrupt discontinuation
  

• pregnancy category = d
• safety in lactation = ?

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.
• Elixir: 30 & 125 mg/5 mL.
• Suppositories: 100 mg.
• Injection: 50 mg/mL (2 mL, 5 mL). Also topical agent.

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 (Asians) not yet recommended
• serum ALT or serum AST within 180 days [14]
  
• monitor with anticonvulsants

Adverse-effects

• common (> 10%) - psychiatric changes, slurred speech, trembling, constipation, nausea/vomiting, dizziness, drowsiness, gingival hyperplasia
• less common (1-10%)

• anorexia, weight loss, rash, 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, ataxia, 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

• 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
• hepatitis (rare)
• 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]

• toxicity

• nystagmus develops at 20 ug/mL
• ataxia is present at 30 ug/mL
• lethargy is present at 40 ug/mL
  
• drug adverse effects of anticonvulsants

Drug-interactions

• increased phenytoin levels (inhibition of metabolism) with:

• chloramphenicol, dicumarol, disulfiram, isoniazid, cimetidine, amiodarone, fluconazole, estrogen, erythromycin, some sulfonamides, felbamate

• 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:

• cyclosporine, valproic acid, ethosuximide, carbamazepine, felbamate, primidone, warfarin, oral contraceptives, corticosteroids, theophylline, chloramphenicol, rifampin, doxycycline, quinidine, mexelitine, disopyramide, dopamine, non- depolarizing skeletal muscle relaxants

• 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
  
• 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 may be measured

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

• hydantoin; glycolylurea
• anticonvulsant
• antiarrhythmic agent, Group IB

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

Internet Database

PubChem: 1775
PubChem: 12425
PubChem: 4787

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, American College of Physicians, Philadelphia 1998
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 et al, Bone health in young women with epilepsy after year of antiepileptic drug mopnotherpay/ Neurology 2008, 70:1586 PMID: [1]
12. FDA MedWatch [2]
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#: [3] (subscription needed) [4]
14. Anvita Health guideline :id 1683

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