What are the side effects of phenytoin?

Side Effects of Phenytoin

Phenytoin has numerous side effects affecting multiple body systems, with the most common manifestations being dose-related central nervous system effects including nystagmus, ataxia, slurred speech, decreased coordination, and mental confusion. 1

Central Nervous System Effects

• Dose-related neurological effects:

  • Nystagmus (most common and earliest sign)
  • Ataxia
  • Slurred speech
  • Decreased coordination
  • Mental confusion
  • Dizziness
  • Insomnia
  • Transient nervousness
  • Motor twitchings
  • Paresthesias
  • Somnolence
  • Headaches 1

• Rare but serious neurological effects:

  • Phenytoin-induced dyskinesias (chorea, dystonia, tremor, asterixis)
  • Predominantly sensory peripheral polyneuropathy with long-term therapy 1
  • Depressed conscious state, coma, and seizures in severe intoxication 2

Dermatologic Reactions

• Common skin manifestations:

  • Morbilliform rash (measles-like) - most common
  • Scarlatiniform rashes 1

• Severe cutaneous adverse reactions (SCARs):

  • Stevens-Johnson syndrome (SJS)
  • Toxic epidermal necrolysis (TEN)
  • Exfoliative or purpuric dermatitis
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 1, 3

• Risk factors for SCARs:

  • HLA-B*1502 genetic variant (particularly in patients of Asian ancestry)
  • CYP2C9*3 variant carriers 3

Immunologic Effects

• Anticonvulsant Hypersensitivity Syndrome (AHS) with:

  • Arthralgias
  • Eosinophilia
  • Fever
  • Liver dysfunction
  • Lymphadenopathy
  • Rash 1

• Other immunologic effects:

  • Systemic lupus erythematosus
  • Periarteritis nodosa
  • Immunoglobulin abnormalities 1

Hematologic Effects

• Thrombocytopenia
• Leukopenia
• Granulocytopenia
• Agranulocytosis
• Pancytopenia with or without bone marrow suppression
• Macrocytosis and megaloblastic anemia (usually respond to folic acid therapy)
• Lymphadenopathy including benign lymph node hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease 1

Cardiovascular Effects

• Oral phenytoin: Cardiovascular complications are rare with oral administration 2

• IV administration risks:

  • Hypotension
  • Cardiac arrhythmias (bradycardia, heart block, QT interval prolongation)
  • Ventricular tachycardia and fibrillation
  • Asystole, cardiac arrest, and death (rare) 3, 4

• Risk factors for IV complications:

  • Rapid infusion rate (>50 mg/min)
  • Critical illness
  • Elderly patients
  • Pre-existing hypotension
  • Severe myocardial insufficiency 3, 4

Gastrointestinal Effects

• Nausea
• Vomiting
• Constipation
• Toxic hepatitis
• Liver damage 1

Connective Tissue and Musculoskeletal Effects

• Coarsening of facial features

• Enlargement of lips

• Gingival hyperplasia (common with long-term use)

• Hypertrichosis

• Peyronie's disease 1, 5

• Long-term use effects (>10 years):

  • Bone fractures
  • Osteomalacia
  • Osteoporosis
  • Hypocalcemia
  • Hypophosphatemia
  • Decreased vitamin D metabolites 1

Special Considerations

1. Pregnancy risks:

   • Fetal hydantoin syndrome (structural, developmental, and behavioral changes) 5

2. Pharmacokinetic considerations:

   • Zero-order pharmacokinetics in overdose leading to greatly increased half-life
   • Prolonged duration of symptoms in overdose 2

3. Drug interactions:

   • Numerous drug interactions due to hepatic enzyme induction
   • May alter vitamin and mineral levels
   • Can affect clotting function 1, 5

Management of Phenytoin Toxicity

• Supportive care is the mainstay of therapy
• No specific antidote exists
• Activated charcoal may be beneficial if administered early
• Prevention of injuries due to confusion and ataxia
• Monitoring of vital functions 2

Fosphenytoin Considerations

Fosphenytoin (a phenytoin prodrug) has some advantages over phenytoin:

• Better safety profile with fewer local and systemic adverse effects
• Reduced risk of phlebitis, purple glove syndrome, tissue necrosis
• Fewer cardiac dysrhythmias and hypotension
• Can be administered at faster infusion rates (100-150 mg PE/min vs 50 mg/min)
• Can be administered intramuscularly 6

Understanding these side effects is crucial for appropriate monitoring and management of patients on phenytoin therapy, with particular attention to dose-related CNS effects and the potential for serious dermatologic reactions.