List the pharmacological characteristics of phenytoin and outline how these impacts on its clinical use.

[Click here to toggle visibility of the answers]

College Answer

Pharmacology

Impact on clinical use

Formulation: oral tablets or suspension 
or colourless solution (with a carrier 
agent). Intravenous preparation is 
stable in normal saline for a short time.

Administration: oral or slow intravenous injection 
(over 20 min). Should not be given IM as 
precipitates in tissue, with erratic absorption. 
Carrier agent thought to be responsible for some 
of the adverse effects of parenteral phenytoin 
and fosphenytoin may be preferable where 
available.

Good oral bioavailability (85%). Rate 
of absorption (although not total 
absorption) reduced by enteral 
feeding.

Enteral and intravenous doses are the same

Distribution: approximately 90% 
protein bound (to albumin).

Free drug concentration may be therapeutic in 
the face of low total drug concentration in 
hypoalbuminaemic patients.

Elimination predominantly hepatic
Half life approx 22 hours (7-42 hours)

Several days to reach a new steady state and 
loading dose is required for patients in whom 
rapid attainment of therapeutic concentrations is 
required. Adjustments to maintenance doses 
should only be made every 4-7 days.

Kinetics: first order at low 
concentrations but zero order within 
the therapeutic range.

Changes in maintenance doses should be small.

Mode of action: 
Blocks voltage gated neuronal sodium 
channels.

Clinical use as antiepileptic drug predominantly 
for generalized or partial seizures (particularly 
status epilepticus) 
Also for prevention/treatment of torsades in long 
QT syndrome

Hepatic enzyme inducer

Increased metabolism and lower drug 
concentrations of many drugs including other
anti-epileptics, warfarin, benzodiazepines, 
cyclosporine, theophylline

Other interactions

Phenytoin concentrations may be increased by 
fluconazole, omeprazole

Adverse effects: 
IV administration: heart block, 
hypotension 
Dose related neurotoxicity: slurred
speech, impaired memory, headache, 
nystagmus, impaired coordination,
confusion 
Haematological effects 
Blood dyscrasias 
Megaloblastic anaemia 
Acute hypersensitivity reactions – rare
(anticonvulsant hypersensitivity 
syndrome [AHS} hepatotoxicity, 
DRESS, Stevens Johnson syndrome) 
Less important to mention: rash, acne, 
gingival hyperplasia

Decrease rate of infusion, monitor blood pressure 
and ECG during infusion 
Check phenytoin concentration and reduce dose 
if appropriate 
Responds to folate supplementation 
Stop drug promptly with severe hypersensitivity 
reactions and avoid other aromatic anticonvulsants.

Discussion

Phenytoin
Properties Influence on ICU management
Chemical properties
  • 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
Chemical relatives
  • A derivative of hydantoin
  • Other relatives are danrolene and fosphenytoin
  • Cross-hypersensitivity may occur
Administration
  • IV or PO/NG
  • Conveniently available as an oral suspension for NG administration
Absoption
  • 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.
Distribution
  • Volume of distribution: 0.5-1.0L/kg
  • Susceptible to removal by plasmapheresis and haemoperfusion
Protein binding
  • 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)
Metabolism/elimination
  • 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
Half life
  • mean plasma half-life is 22 hours
  • Optimal for once daily dosing
Mechanism of action
  • "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
Indications
  • Control of generalised tonic-clonic seizures
  • Prevention of post-TBI seizures
  • Cheap and familiar
Contraindications
  • Levitiracetam is an (expensive) alternative
Adverse effects
  • 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
Interactions
  • 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)
Acute overdose
  • 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