Pharm 101: Phenytoin

Class

Anticonvulsant

Pharmacodynamics

• Works via sodium channel blockade in a manner similar to carbamazepine:
  • Presynaptic blockade of synaptic transmission
  • Inhibits high frequency repetitive firing of neurons
  • Preferential binding to sodium channels in inactive state
• Neuronal blockade is use and voltage dependent, providing ability to preferentially inhibit action potentials during seizure discharges but less effectively interfere with ordinary ongoing action potential firing

Pharmacokinetics

• Bioavailability 90%
• Peak serum concentration at 3-12 hours
• 90% plasma protein bound
• Volume of distribution 0.65L/kg
• Dose-dependent elimination:
  • First order (linear) kinetics at low concentrations
  • Zero order kinetics at higher concentrations due to saturation of hepatic enzymes
  • Half life variable 12-36 hours
  • Small dose adjustments can thus cause significant toxicity
• Liver metabolism to inactive metabolites, excreted by urine (< 2% excreted unchanged)
• CYP enzyme inducer:
  • Increased metabolism of co-administered anti-seizure drugs
  • Insignificant auto-induction of own metabolism

Clinical uses

• Prevention of focal seizures and generalised tonic-clonic seizures in epilepsy
  • Therapeutic level 10-20mg/L
  • At low blood levels, 5-7 days are needed to reach steady-state blood levels after every dose change. At higher levels this may take 4-6 weeks.
• Acute treatment of status epilepticus
  • Loading dose is commonly used in initial seizures management to reach effective target concentration (Vd x target concentration)

Adverse effects

• Nystagmus and loss of smooth extraocular pursuit movements are normal early signs of administration
• Neurological:
  • Diplopia
  • Mild peripheral neuropathy
• Metabolic:
  • Low folate
  • Vitamin D abnormalities with long-term use
• Gingival hyperplasia
• Toxicity:
  • Diplopia and ataxia
  • Sedation, coma
• Pregnancy: fetal hydantoid syndrome
• Intravenous infusion:
  • Hypotension and bradycardia with rapid infusion (due to dilutant)
  • Limits infusion rates to 50mg/min (30-60 minutes)
  • Reduced risk with fosphenytoin sodium injection (preferred)
  • Can cause local necrosis if extravasation

Further Reading

• Long N. Phenytoin Toxicity. LITFL
• Nickson C. Post-Traumatic Seizures. LITFL
• Cadogan M. Seizing and No Access. LITFL