Pharmacology of Phenytoin

Created on Mon, 12/07/2015 - 13:18
Last updated on Wed, 12/23/2015 - 01:05

Question 17 from the first paper of 2013 asks for an insane amount od detail about phenytoin, and particularly about the influence of its pharmacological properties on its use in the ICU. The college then go on to offer a nice tabulated answer. This answer is sufficient for the revising exam candidate, because it is brief, and because this question is unlikely to ever be repeated. Investing a vast amount of effort in the revision of this topic is therefore probably a waste for all but the most enthusiastic of trainees. If for whatever reason one requires a little more detail, one may look into the formal PI for Dilantin.  Another resource is the massive 63 page IARC monograph. Its for the person who not only wants to know the rates of phenytoin-induced adenocarcinoma in rats - but also the names of those rates.

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