Phenytoin

Introduction

Phenytoin is an anticonvulsant which acts through voltage gated sodium channel blockade. In poisoning it causes dose dependent cerebellar toxicity which can be prolonged.

Toxicokinetics

Phenytoin is slowly absorbed with peak concentrations between 2 and 12 hoursin therapeutic dosing and can be delayed up to 48 hours in overdose1. It has good CNS penetration and a volume of distribution of 0.6L/kg. It is extensively protein bound, largely to albumin.

It is metabolised by CYP2C9, undergoing saturable kinetics in overdose. The half-life in therapeutic doses is 24 to 30 hours, but this can double in large poisonings1. Inhibitors of CYP2C9 such as amiodarone, metronidazole, SSRIs and sulphonamides, increase phenytoin concentrations. Inducers of CYP2C9 such as alcohol, barbiturates, carbamazepine, rifampicin and theophylline decrease phenytoin concentrations.

Risk Assessment

Phenytoin in overdose causes dose-dependent cerebellar toxicity, levels should be monitored Q8H in toxicity until < 20mg/L.  

Serum phenytoin mg/L mg/LClinical effects2
10-20Therapeutic range, occasional nystagmus on horizontal gaze
20-30Spontaneous nystagmus
30-40Vertical  nystagmus, diplopia, ataxia, slurred speech, hyperreflexia
40-50Lethargy, confusion, hyperactivity, spasticity, clonus, choreoathetosis
>50Coma, seizures

Patients with low serum albumin or renal failure (which results in displacement of phenytoin from albumin) have a higher proportion of free phenytoin for any given population.1

Hypotension and cardiac arrhythmia are very uncommon in oral overdose. They are commonly observed in IV phenytoin is administered too rapidly due to the propylene glycol dilutent. Given the potential for sodium channel blockade, an ECG should be performed in all patients.  If the phenytoin level is increasing, it should be repeated.

Management

Most patients recover with supportive care.  Large ingestions have more unpredictable absorption and elimination resulting in prolonged toxicity. Decontamination and enhanced elimination measures should be considered in this group.

Resuscitation

Protect airway if coma. Treat seizures with benzodiazepines.

Decontamination

SDAC is indicated in all ingestions > 20mg/kg presenting within 4 hours.

Enhanced Elimination

MDAC should be offered to patients with significant CNS toxicity, which typically manifests with levels >40mg/L. In severe cases intubation can be considered to facilitate MDAC which will shorten the duration of toxicity.  

Phenytoin is thought to be moderately dialysable despite its high protein binding and therefore this may also be considered in severe toxicity.

Supportive Measures

Supportive measures are the mainstay of management. Ensure bed rails are up and mobility is strictly supervised if ataxic. Provide maintenance fluids and antiemetics.

Disposition

Discuss all patients with ingestions > 20mg/kg with the toxicology team. Toxicity is typically prolonged and most patients will require supportive care and observation in the Short Stay Unit. Permanent cerebellar dysfunction can occur following severe poisonings.2

References

  1. Wikitox 2.1.11.2.1 Phenytoin 

http://www.wikitox.org/doku.php?id=wikitox:2.1.11.2.1_phenytoin

  1. Craig S.  Phenytoin overdose complicated by prolonged intoxication and residual neurological deficits.  EMA2004; 16: 361-5
  1. The Extracorporeal Treatment in Phenytoin Poisoning: Systemic Review and Recommendations from the EXTRIP Workgroup.  Am J Kidney Dis2016; 67(2): 187-97