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

Pharm 101 700

Pharmacology 101

Top 200 drugs

MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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