Pharm

Phenytoin

search

Phenytoin, Dilantin, Diphenylhydantoin, DPH, Hydantoin, Mephenytoin, Phenacemide

  • Classification
  • Hydantoin
  1. Phenytoin (Dilantin)
  2. Fosphenytoin (Cerebyx)
  3. Phenytoin congeners (limited use)
    1. Mephenytoin
    2. Ethotoin
    3. Phenacemide
  • Mechanism
  1. Hydantoin anticonvulsant
  2. Alters Sodium and Calcium Ion influx (repolarization, depolarization) and presynaptic Calcium uptake
  3. Stabilizes Neuronal membranes by inhibiting Neuronal firing and prevents the propagation of Seizure activity within the motor cortex
  • History
  1. Phenytoin is the oldest non-Sedative antiepileptic drug (1938)
  2. Developed based on research into Phenobarbital antiseizure effect
  • Indications
  1. Partial Seizures
  2. Generalized tonic-clonic Seizures
  • Contraindications
  1. Pregnancy (See Fetal Hydantoin Syndrome)
  • Pharmacokinetics
  • Phenytoin
  1. Fosphenytoin (Cerebyx) has similar Pharmacokinetics to Phenytoin and is preferred for IV use
  2. Hepatic metabolism
  3. Large volume of distribution (0.7 L/kg)
  4. Highly Protein bound (90%)
    1. Phenytoin levels must be interpreted in relation to the Serum Albumin level
  5. Onset: 10-30 minutes
  6. Therapeutic level: 10-20 mcg/ml
  7. Half-Life: 12 to 24-36 hours
    1. Average half life for moderate dosages: 24 hours
    2. Very long Half-Life (zero order elimination) at toxic concentrations (>40 mcg/ml)
  • Dosing
  • Phenytoin or Dilantin (Adults)
  1. Status Epilepticus
    1. Fosphenytoin is preferred for IV use
    2. Initial: 20 mg/kg IV (at 1 mg/kg/min up to 50 mg/min) up to to 1000 mg maximum
      1. May repeat once at 5-10 mg/kg IV
    3. Maintenance: 50 mg/min or 100 mg IV or orally every 6 to hours
  2. Epilepsy
    1. Start Option 1: Oral dose start
      1. Start 100 mg orally three times daily
      2. Advance dosing based on serum concentrations
    2. Start Option 2: Oral loading regimen
      1. Dose 1: 400 mg orally
      2. Dose 2: 300 mg orally at 2 hours after dose 1
      3. Dose 3: 300 mg mg orally at 4 hours after dose 1
      4. Start subsequent maintenance dosing on next day
    3. Start Option 3: Parenteral loading regimen
      1. Dose: 10-20 mg/kg (average 1 gram) IV
      2. Do not administer faster than 50 mg/min
    4. Maintenance dose
      1. Initial: 5 mg/kg to 300 mg/day divided daily to three times daily
    5. Titrating dose
      1. Avoid increasing dose by >25-30 mg per trial
      2. Wait for steady state (7 days) before level recheck
  • Dosing
  • Phenytoin or Dilantin (Children)
  1. Status Epilepticus
    1. Fosphenytoin is preferred for IV use
    2. Initial: 15 to 20 mg/kg IV (at 1 mg/kg/min up to 50 mg/min)
      1. May repeat once at 5-10 mg/kg IV
  2. Epilepsy
    1. Start 5 mg/kg/day orally divided 2 to 3 times daily
    2. Titrate to therapeutic serum level
    3. Typical range: 4 to 8 mg/kg/day up to 300 mg/day
  • Drug Interactions
  1. Decreases Oral Contraceptive efficacy
  2. Drugs that increase plasma Phenytoin levels
    1. Amiodarone
    2. Clobazam
    3. Fluconazole
    4. Ranitidine
    5. Phenylbutazone
    6. Sulfonamides
    7. Benzodiazepines
    8. Anticoagulants
    9. Isoniazid
  3. Drugs that decrease Phenytoin level or free fraction
    1. Influenza Vaccine
    2. Tolbutamide
    3. Carboplatin
    4. Rifampicin
    5. Theophylline
    6. Phenobarbital
    7. Carbamazepine
  4. Phenytoin decreases plasma level of other drug
    1. Doxorubicin
  • Adverse Effects
  1. See Dilantin Toxicity
  2. Fetal Hydantoin Syndrome
  3. Neurologic effects
    1. Nystagmus
    2. Ataxia
    3. Sedation
  4. Intravenous Effects
    1. CNS Depression
    2. Severe Hypotension
    3. Arrhythmias
  5. Drug Hypersensitivity
    1. Fever
    2. Lymphadenopathy
    3. Drug-Induced Agranulocytosis or Bone Marrow suppression
  6. Common chronic changes associated with Phenytoin
    1. Gingival Hyperplasia
    2. Hirsutism
    3. Coarse facial features
    4. Peripheral Neuropathy (decreased Deep Tendon Reflex)
  7. Other effects
    1. Hepatotoxicity
    2. Drug-Induced Rash
      1. Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis
        1. More common in Asian heritage with HLA-B 1502 Mutation
      2. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
    3. Pancreatitis
    4. Osteoporosis
    5. Folic Acid Deficiency
  • Monitoring
  1. Monitor Phenytoin levels to ensure in therapeuti range
    1. Hypoalbuminemia may increase free fraction of Phenytoin
  2. Routine Labs every 6 to 12 months
    1. Complete Blood Count with Platelet Count (myelosuppression risk)
    2. Liver Function Tests (hepatotoxicity risk)
  3. May decrease circulating Thyroid Hormone
    1. May increase Thyroid Stimulating Hornone (TSH)
  • Safety
  1. Pregnancy: Category D
    1. Fetal Hydantoin Syndrome risk
  2. Lactation: Contraindicated
  • Resources
  1. Phenytoin Injection (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=035a8d4e-2063-4240-83cb-d7eebcabe301
  2. Phenytoin Extended Release Capsule (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8848de76-8d74-4620-bcc7-a86a596e5dd9
  3. Phenytoin Capsule (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=df0bf42b-ce9a-42c3-8c24-46f1ea3bd214
  • References
  1. (2022) Presc Lett, Resource #361206, Antiseizure Medications
  2. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 56-7
  3. Hamilton (2020) Tarascon Pocket Pharmacopoeia