Phenytoin is a broad-spectrum antiepileptic drug that causes dose dependent CNS toxicity with ataxia, confusion, nystagmus, and sedation/coma in overdose.

Overdose of phenytoin is usually well tolerated and is largely managed with good supportive cares. In larger overdoses multi-dose activated charcoal may also be considered.

Phenytoin-drug cytochrome p450 interactions and genetic polymorphisms can alter phenytoin metabolism and can result in toxicity even with therapeutic dosing making chronic toxicity relative common.

Central nervous system effects:

Blockade of voltage-gated sodium channels in a use-dependent manner; meaning that in therapeutic doses, it targets inhibition to rapid repeated neuronal impulses, with minimal effect on normal neuronal transmission

Phenytoin concentrates in the tissues of the brainstem and cerebellum

Cardiovascular effects:

Class 1b antiarrhythmic, with similar cardiac effects to lignocaine. However, cardiovascular toxicity after oral ingestion is extremely rare.

Rapid intravenous administration can cause short lived effects characterised by bradycardia, hypotension and ventricular arrythmias. This is most likely caused by the preparation’s dilutant (propylene glycol). There is not targeted treatment in this context and care is supportive.

Ingested doses >20mg/kg are expected to cause cerebellar toxicity (ataxia, nystagmus, dysarthria).

At doses >100mg/kg there is increasing sedation and potentially coma.

Phenytoin, in therapeutic dosing, has slow absorption with peak concentrations occurring between 2-12 hours.

In overdose, absorption is erratic and can be delayed up to 48 hours.

Phenytoin distributes well into the CNS and has a volume of distribution of 0.6L/Kg.

Phenytoin binds extensively to plasma proteins, especially albumin. Therefore, in hypoalbuminemia and uraemia (where phenytoin is displaced from albumin) there can be a much higher proportion of unbound (free) phenytoin for any given serum concentration. Some drugs, including sulphonylureas and valproate, can also temporarily displace phenytoin from albumin, increasing free phenytoin concentrations.

Only the free drug is active, and when less protein bound, dissociates into the CNS tissues more readily.

Phenytoin is hepatically metabolism. It undergoes enterohepatic recycling and is excreted in the urine.

Cytochrome P450 2C9 and 2C19 are the primary hepatic enzymes in phenytoin metabolism (predominantly CYP2C9).

At the upper-end of therapeutic concentrations, the hepatic hydroxylation system becomes saturated and enters zero-order elimination kinetics, leading to prolonged elimination at higher concentrations.

CYP2C9 genetic polymorphisms (present in up to 35% of Caucasian males) can cause an impaired rate of metabolism and prolonged half-life even with therapeutic dosing.

Co-ingestion of a CYP450 inhibiting drugs (e.g. amiodarone, warfarin, phenobarbital) can cause impaired metabolism and increased phenytoin concentrations to toxic levels. The reverse is true of drugs that induce these enzymes, where co-ingestion will decrease the phenytoin serum concentration (e.g. alcohol, barbiturates, carbamazepine, rifampicin, theophylline).

A combination of any of these factors may be involved in any case which can potentially lead to very prolonged toxicity.

Phenytoin is excreted in the urine in both free and conjugated form. Elimination rates are highly variable and dependent on the metabolic pathways and factors discussed above.

• CNS: cerebellar toxicity, confusion, sedation, coma, seizures
• CVS: arrhythmia and conduction defects are reported by rare. Hypotension and arrythmia can complicate rapid IV infusion but this is thought to be specific to IV administration due to the propylene glycol dilutant.

• Serum phenytoin concentrations: Serum concentration correlates well with severity of toxicity (acknowledging the limitations of the measured total phenytoin)). Concentrations can help confirm the development of new ataxia is due to phenytoin in chronic toxicity as well as identify slow metabolisers and track progress in cases of significant toxicity.
  

• ECG: Phenytoin toxicity is very rarely associated with arrythmia and QT prolongation, however routine cardiac monitoring is not requested.
• Renal function/hepatic function: Uraemia, hypoalbuminemia may increase free concentration with more severe or prolonged toxicity
• Pharmacogenomic testing for CYP450 polymorphism: Not readily available and costly. Could be considered in cases of high concern for genetic polymorphism and subsequent impact upon future prescribing or drug monitoring.

The typical presentation, with sedation, gross ataxia and horizontal and vertical nystagmus, may be due to intoxication with a number of CNS active drugs including alcohol, benzodiazepines and most anticonvulsants. Non-drug causes should also be considered, in particular Wernicke's encephalopathy.

Fall prevention in the context of delirium and ataxia is key. So, ensuring that the patient has appropriate supervision, including bed rails is paramount. Assess venous thromboembolism risk and consider VTE chemoprophylaxis when sedation is present, given it may be prolonged.

Airway and breathing

In most cases airway and breathing will not be compromised. However, if there is compromise then intubate the patient to secure their airway.

Circulation

Ensure hydration is maintained by administration of appropriate crystalloid particularly in a confused patient who may not be able to regulate their own intake. If MDAC is being given, ensure adequate hydration to match any excess gastrointestinal losses.

Seizures

If seizures occur, treat along standard lines, starting with an intravenous benzodiazepine.

In acute ingestions of >20mg/kg offer SDAC to alert and cooperative patients up to 4 hours after time of ingestion. If intubated, then administer SDAC, any time after via a nasogastric tube, once placement confirmed.

Give: 50g Activated Charcoal (Child: 1g/kg, max 50g)

Multi-dose Activated Charcoal (MDAC)

Enterohepatic recycling makes phenytoin amenable to enhanced elimination via MDAC.

However, it is unclear in the evidence if this correlates with improved clinical outcomes.

Consider MDAC in acute ingestions of > 100mg/kg and in those with toxicity due to slow metabolism and static serial serum concentrations.

Give: 25g Activated Charcoal (Child: 0.5g/kg, max 50g) q4hrly

Dialysis:

Dialysis may increase phenytoin clearance, however there is no strong evidence of benefit. In particular death from phenytoin poisoning is rare. And thus, dialysis would not provide a clear mortality benefit.

Dialysis may reduce morbidity in severe phenytoin poisoning by reduction in coma duration and ICU length of stay. Discuss with a clinical toxicologist if considering.

There are no specific antidotes for phenytoin toxicity.

Admit patients following acute ingestions of >20mg/kg of phenytoin for at least 6 hours and only discharge once asymptomatic, and at their cognitive and functional baseline.

Ingestions of <20mg/kg can be discharged providing they are asymptomatic and have safe supervision.

Admit all patients with acute ingestions of > 100mg/kg for serial levels and ongoing management of their toxicity.

1. Anseeuw KMDM, Mowry JBP, Burdmann EAMDP, et al. Extracorporeal Treatment in Phenytoin Poisoning: Systematic Review and Recommendations from the EXTRIP (Extracorporeal Treatments in Poisoning) Workgroup. Am J Kidney Dis. 2016;67(2):187-197. EXTRIP
2. Skinner CG, Chang AS, Matthews AS, et al. Randomized controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels. Clinical Toxicology. 2012;50(8):764-769. PDF
3. Chan BS, Sellors K, Chiew AL, et al. Use of multi-dose activated charcoal in phenytoin toxicity secondary to genetic polymorphism. Clinical Toxicology. 2015;53(2):131-133. PDF
4. Chua HC, Venketasubramanian N, Tjia H, et al. Elimination of phenytoin in toxic overdose. Clin Neurol Neurosurg. 2000;102(1):6-8. PDF
5. Craig, Simon. “Phenytoin poisoning.” Neurocritical care 3 (2005): 161-170. PDF