Pharmacology of phenytoin

• Sodium salt has decent water solubility
• The injectable solution has a pH of 12, and is 40% propylene glycol (and 10% alcohol)

• Cannot be given IM: as a depot, the phenytoin precipotates and is absorbed slowly and erratically
• When given IV, can be very irritating, and needs to be diluted
• Can only be administered together with saline

• A derivative of hydantoin
• Other relatives are danrolene and fosphenytoin

• Cross-hypersensitivity may occur

• IV or PO/NG

• Conveniently available as an oral suspension for NG administration

• Well absorbed orally
• Bioavailability is ~ 85% (but varies depending on the manufacturer)
• Food influences absorption

• Usually no need to adjust dose when changing from IV to oral
• Need to cease feeds when administering (2hrs before, 2hrs after) - enterally fed patients should be getting IV phenytoin.

• Volume of distribution: 0.5-1.0L/kg

• Susceptible to removal by plasmapheresis and haemoperfusion

• Highly protein bound: 90%

• Not susceptible to haemodialysis
• Higher free levels are to be expected in patients with low albumin (even though total levels may be normal or low)

• Hydroxylated in the liver by a saturable enzyme system
• Enhances its own elimination through enzyme induction
• After administration, most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestine and excreted in the urine
• Zero-order kinetics after enzymes are saturated, and first-order before.

• Enterohepatic recirculation means there may be a theoretical benefit to multiple dose activate charcoal administration
• Small dose increases may significantly increase the half-life and levels once the enzyme system is saturated

• mean plasma half-life is 22 hours

• Optimal for once daily dosing

• "membrane stabiliser"
• blocks voltage gated sodium channels
• Most of the antiepileptic effect takes place at the motor cortex, where it inhibits the spread of seizure activity possibly by promoting sodium efflux from neuron

• Can also be used as a Class 1 antiarrhythmic

• Control of generalised tonic-clonic seizures
• Prevention of post-TBI seizures

• Cheap and familiar

• Hypersensitivity
• Adams-Stokes syndrome
• Concomitant use with delavirdine
• Heart block
• Bradycardia

• Levitiracetam is an (expensive) alternative

• Rash (5% to 10% )
• Gum hypertrophy
• Ataxia, nystagmus, slurred speech
• Confusion
• Drug-induced lupus
• Agranulocytosis
• Aplastic anemia
• Hepatitis
• Anticonvulsant hypersensitivity syndrome

• May consider another agent in a patient with already poor bone marrow function

• Phenytoin is an inducer of the hepatic cytochrome P450 microsomal isoenzymes CYP3A4, CYP2D6, CYP1A2, CYP2C9 and CYP2C19
• Phenytoin is metabolised primarily by
  CYP2C9 (major) and CYP2C19 (minor), thus several drugs may inhibit or induce the
  metabolism of phenytoin

Common ICU drugs which interfere with phenytoin:

• Amiodarone (increased level)
• Erythromycin (increased level)
• Fluconazole (increased level)
• Rifampicin (decreased level)
• Folate supplements (decreased level)
• Fluoroquinolones (decreased level)

• Nystagmus appears at 20 µg/mL
• Ataxia appears at 30 µg/mL
• Nystagmus appears at 20 µg/mL
• The lethal dose in adults is estimated to be 2 to 5g. 
• In overdose settings, saturation of the hepatic hydroxylation system occurs and zero order kinetics predominate

• Activated charcoal is recommended in life-threatening overdose
• Dialysis is of no benefit
• Haemoperfusion or plasmapheresis may have some benefit