EM@3AM – Phenytoin Toxicity

Author: Erica Simon, DO, MHA (@E_M_Simon, EMS Fellow, SAUSHEC, USAF) // Edited by: Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital) and Brit Long, MD (@long_brit, EM Attending Physician, SAUSHEC, USAF)

Welcome to EM@3AM, an emdocs series designed to foster your working knowledge by providing an expedited review of clinical basics. We’ll keep it short, while you keep that EM brain sharp.


A 55-year-old male, with a history of seizure disorder (recent diagnosis: TBI following an MVC) and GERD (cimetidine), presents to the emergency department for “shaking,” and “difficulty walking.” The patient reports the onset of bilateral upper extremity tremor, and gait ataxia twelve hours prior to arrival. He notes his ataxia as progressively worsening: “I have to hold walls to get anywhere.” The male denies visual changes, slurred speech, and additional motor and sensory deficits. Review of systems is remarkable for the recent initiation of phenytoin therapy.

Triage VS: BP 123/76, HR 82, T 99.6 F oral, RR 14, SpO2 97% on room air.

Pertinent physical examination findings:
Neuro: GCS 15; DTRs (biceps and patellar 3+ bilaterally); positive Romberg
CV: Regular rate and rhythm, no murmurs, rubs, or gallops
Lungs: CTAB
Abdomen: Soft, non-distended, non-tender

What’s the next step in your evaluation and treatment?


Answer: Phenytoin Toxicity1-6

  • Therapeutic Indications: Anticonvulsant indicated for the control of generalized tonic-clonic and complex-partial seizures, and for the prevention and treatment of seizures occurring during or after neurosurgery.1,2
  • Drug Facts:
    • Mechanism of Action: Creates a voltage-dependent blockade of membrane voltage-gated sodium channels, thereby inhibiting the repetitive, high frequency firing of action potentials.1 (Primary site of action: motor cortex2).
    • Pharmacokinetics:
      • Undergoes hepatic metabolism (CYP 450): numerous drug-drug interactions.2,3
        • Examples of drugs which may increase serum phenytoin levels: acute alcohol intake, amiodarone, chloramphenicol, cimetidine, diazepam, disulfiram, estrogens, fluoxetine, phenothiazines, salicylates, sulfonamides, trazodone, etc.2
      • Exhibits significant protein binding (unbound component, “free phenytoin,” produces the pharmacological effect).2
      • Manufactured as Phenytoin Sodium Capsules (100mg phenytoin sodium; peak blood concentration: 1.5-3 hours following PO intake), and Extended Phenytoin Sodium Capsules (30 mg phenytoin sodium; peak blood concentration: 4-12 hours following PO intake), both with a recommended dosage of 300 mg QD.2
      • Average plasma half-life following ingestion: 22 hours.2
      • Therapeutic window: 10-20 mcg/mL.2
    • Clinical Manifestations of Toxicity: Variable: patients may experience nausea, vomiting, tremor, nystagmus, ataxia, dysarthria, or coma in the setting of severe toxicity.1,2
    • Evaluation and Treatment:2,3
      • Assess the ABCs and obtainVS.
      • Perform a thorough H&P (to include a medication reconciliation).
        • Neuro: nystagmus, hyper-reflexia, and cerebellar findings may be present in the setting of phenytoin toxicity.
      • Laboratory evaluation: LFTs (evaluate hepatic function2,3) and free phenytoin level.
        • If free phenytoin level is unavailable:
          • Serum phenytoin level and serum albumin level may be utilized to calculate the free phenytoin level (Sheiner-Tozer formula: less accurate than a laboratory free phenytoin level4).
      •  Treatment:
        • Supportive care.
        • Consult Toxicology:
          • Consider GI decontamination.5
          • If the airway is protected, consider MDAC in cases where serum phenytoin levels escalate/remain elevated (MDAC reduces the elimination half-life of phenytoin, however, studies have yet to demonstrate morbidity/mortality benefit).5
        • Extracorporeal Treatments in Poisoning Workgroup Recommendations (following review of 51 articles (case series, case reports, and pharmacokinetic data) involving 46 patients (low quality evidence)):6
          • Intermittent hemodialysis (first line), or hemoperfusion (second line) viewed reasonable:
            • In select cases of severe toxicity.
            • If prolonged coma is expected or present.
            • If prolonged, incapacitating ataxia is present.
  •  Pearls:
    • Overdose: adult lethal dose estimated as 2-5 g PO.2
    • Severe toxicity may manifest as QRS prolongation and dysrhythmias secondary to sodium channel blockade, but this is not considered a typical feature of phenytoin poisoning.2
    • Maintain a high index of suspicion for phenytoin toxicity in the elderly, critically ill, and in those with reduced hepatic function (decreased albumin level = increased free phenytoin).1,2

References:

  1. Davies J. Mechanism of action of antiepileptic drugs. Seizure. 1995; 4(4) 267-271.
  2. Dilantin. New York, New York: Pfizer Inc; Aug 2012: Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/084349s060lbl.pdf
  3. Imam S, Landry K, Kaul V, Gambhir H. Free phenytoin toxicity. AJEM. 2014; 32(10): 1301.e3-1301.e4.
  4. Krasowski M, Penrod L. Clinical decision support of therapeutic monitoring of phenytoins: measured versus adjusted phenytoin plasma concentration. BMC Med Inform Decis Mak. 2012; 12:7.
  5. Skinner C, Chang A, Matthews A, et al. Randomized controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels. Clin Tox (Phila). 2012; 50:764-769.
  6. Anseeuw K, Mowry J, Burdmann E, 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.

 

For Additional Reading:

Toxcard: Phenytoin Poisoning:

TOXCARD: PHENYTOIN POISONING

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