Why is phenytoin contraindicated in tricyclic antidepressant (TCA) toxicology?

Why Phenytoin is Contraindicated in TCA Toxicity

Phenytoin is contraindicated in tricyclic antidepressant (TCA) overdose because it is a Class IB antiarrhythmic that can worsen cardiac conduction abnormalities and has not demonstrated clinical benefit, while the American Heart Association explicitly recommends avoiding Class IA, IC, and Class III antiarrhythmics as they may worsen cardiac toxicity. 1

Mechanism of Harm

Sodium Channel Blockade Overlap

• TCAs act as sodium channel blockers similar to Class IA antiarrhythmics, causing slowed phase 0 depolarization of the cardiac action potential and impaired conduction through the His-Purkinje system. 1, 2
• While phenytoin is a Class IB antiarrhythmic that also blocks sodium channels, controlled animal studies demonstrated that prophylactic phenytoin did not prevent cardiac abnormalities from amitriptyline poisoning and did not allow animals to tolerate higher TCA doses before death. 3
• In rescue attempts after QRS widening or arrhythmias developed, only 2 of 12 animals showed improvement with phenytoin, and these results were neither blinded nor controlled. 3

Lack of Clinical Evidence

• The evidence for phenytoin in TCA toxicity is limited to case series, and in most human exposures where apparent efficacy was noted, the toxicity was not severe. 2
• Experimental studies suggest phenytoin does not compete directly for the same sodium channel binding site as TCAs, making its mechanism of action unclear and potentially unreliable. 2
• Deaths are unlikely after phenytoin intoxication alone when given orally, but cardiac complications including arrhythmias and hypotension can occur with parenteral administration. 4

Guideline-Recommended Alternatives

First-Line Therapy: Sodium Bicarbonate

• The American College of Cardiology recommends administering sodium bicarbonate 1-2 mEq/kg IV bolus for QRS prolongation >100 ms or cardiac arrhythmias, repeating doses as needed to maintain arterial pH 7.45-7.55. 1
• Sodium bicarbonate achieves therapeutic benefit through sodium loading and alkalinization, which overcome sodium channel blockade and improve cardiac conduction. 5
• This remains first-line therapy for ventricular arrhythmias in TCA toxicity. 1

Second-Line Therapy: Lidocaine (Not Phenytoin)

• The American College of Cardiology considers lidocaine as second-line therapy (Class IB antiarrhythmic) for wide-complex tachycardia refractory to sodium bicarbonate. 1, 6
• Lidocaine has faster sodium channel recovery times (1-2 seconds) compared to amitriptyline (13.6 seconds), and experimental models show it can directly displace slower-acting TCAs from sodium channels. 2
• There is more evidence supporting lidocaine use than phenytoin as adjunctive treatment for TCA-associated cardiotoxicity. 2

Critical Pitfalls

Contraindicated Medications

• The American Heart Association and American Academy of Pediatrics recommend never using physostigmine for anticholinergic symptoms, as it worsens cardiac toxicity. 1
• The American Heart Association advises avoiding Class IA, Class IC, and Class III antiarrhythmics as they may worsen cardiac toxicity. 1
• Never administer flumazenil even if benzodiazepine co-ingestion is suspected, as this may precipitate seizures or arrhythmias. 1

Monitoring Requirements

• Continuous ECG monitoring is necessary for QRS duration and dysrhythmias. 5
• The American Heart Association recommends obtaining an ECG during initial assessment, as QRS duration >100 msec indicates severe toxicity requiring immediate intervention. 1
• Monitor serum sodium (target <150-155 mEq/L) and pH (target 7.45-7.55) during sodium bicarbonate therapy to avoid iatrogenic harm. 1, 5

Refractory Cases

• The American Heart Association recommends considering VA-ECMO for cardiac arrest or refractory cardiogenic shock. 1, 5
• The American College of Cardiology considers intravenous lipid emulsion therapy as a last resort for life-threatening toxicity refractory to standard therapy. 1