Phenytoin

Chemical

Hydantoin derivative

Use

  1. Tx seizures
  2. Anti-arrhythmias
  3. Trigeminal neuralgia tx

Presentation

Capsules

Colourless solution

50mg/mL

Dose / Route

PO 200 – 600mg/day

IV 15mg/kg (slow, over 1hr) LOAD

     100mg TDS (maintenance)

Requires load because long t ½ → ∴ takes a while to reach steady state

Route

PO/IV

PO = slow absorption & unpredictable

Onset

IV immediate → peaks 1hr

PO unknown (variable) → Peaks 1 – 3hrs

MoA (mechanism)

  1. Binds & stabilises INACTIVE Na+ channels to prevent further generation of AP
  2. Potentiates GABA
  3. ↓Ca2+ influx → ∴ ↓excitability

Strong affinity for CNS binding

PD

CNS – stabilises membrane → prevents the spread of seizure

CVS

  • Blocks fast Na+ channel
  • ↓slope of Ph 0
  • ↓amplitude of AP
  • ∴ ↓ conduction velocity (-ve inotropy)

GI – ↓BGL, deranged LFTs

PK

*** Narrow therapeutic range: 10 = 20mcg/mL**

A

Slow but good

90% OBA

D

90% PPB high!

Always correct dose with [Albumin]

Low VD 0.6L/kg

M

Liver CYP450

Hydroxylation

  • Saturable
  • First order kinetics then ∆ Zero order kinetics

*** large genetic variation in rate of metabolism

Therapeutic dose & toxic dose are v. close ∴ requires monitoring

E

Metabolites in urine

t ½ B 9 – 24hrs  

↓dose for hepatic impairment but not renal impairment

Adverse Effects

Idiosyncratic reactions

  • Gum hyperplasia
  • Hirsutism
  • Megaloblastic AN
  • Erythroderma
  • SLE

Dose related reactions

  • N&V
  • Cerebral ataxia
  • Nystagmus
  • Dysarthria
  • Tremor

Drug interactions

POTENT ENZYME INDUCER

  • ↓effectiveness BZD, pethidine, warfarin
  • ↑LA CNS toxicity
  • ↑dose of NMBD (except atrac req)
  • Isoniazid & metronidazole (enzyme inhibitors) will ↑risk phenytoin toxicity

Teratogenic