• Tricyclic antidepressants (TCA) are a class of medications traditionally used to treat depression
    • Currently being more widely prescribed for pain syndromes, peripheral neuropathy, migraine prophylaxis, panic and phobic disorders, and obsessive-compulsive disorder
  • TCA toxicity may be fatal
    • Mortality rate of ~15% (though has been lower in recent years)
    • Overdoses are on the rise given expanding use of TCAs beyond depression


  • Rapidly absorbed in the gastrointestinal tract and reach peak concentrations in the serum at 2-6 hours
  • Half-lives of TCAs have a wide range depending on the mediation ingested, anywhere from 7-58 hours
  • Note: Half-life does not dictate duration of toxicity. Duration of action and half-life are not the same


  • TCAs act on a number of different receptors leading to toxicity
  • Inhibition of the presynaptic reuptake of serotonin and norepinephrine aid in the treatment of depression
  • Cardiac Action Potential (

    Block cardiac fast acting sodium channels leading to cardiovascular effects

    • Prevents rapid ventricular depolarization during phase 0 of the ventricular action potential (Figure 1)
    • Effect on the EKG
    • Prolonged Ventricular Depolarization: QRS > 100ms
    • Rightward Deviation of the terminal 40msec QRS complex
      • Deep S wave in I and aVL
      • Large R wave in aVR (>3mm) with R:S ration >0.7 (Niemann 1986)
  • Antagonism of muscarinic acetylcholine receptors
  • Antagonism of peripheral alpha-1 adrenergic receptors
    • Peripheral vasodilation
    • Can cause marked hypotension
  • Antagonism of H1 receptors
    • Similar effects of anticholinergic activity
    • Can also see delirium and confusion
  • Antagonism of CNS gamma-aminobutyric acid (GABA) receptor
    • Potential cause of seizure activity

Physical Exam

  • Anticholinergic Toxidrome may be present
    • Physical exam findings include: mydriasis, dry and hot skin, urinary and bowel retention, hyperthermia, xerostomia, tachycardia and AMS (disorientation, confusion)
  • Pulmonary: Coarse breath sounds in the setting of ARDS
  • Cardiovascular
    • Hypotension secondary to direct myocardial depression from blockade of fast-acting sodium channels AND antagonism of peripheral alpha-1 receptors (eg vasodilation)
    • Tachycardia: initially sinus tachycardia and in cases of severe overdose  patients develop wide-complex tachycardia as a result of QRS prolongation and/or refractory hypotension
  • Abdomen: hypoactive or absent bowel sounds, suprapubic fullness secondary to urinary retention
  • Neuro: Initially altered mental status including delirium and agitation followed by lethargy and stupor, seizure activity, myoclonus, dystonia, akathisia, rigidity, myoclonus
  • Skin: dry, flushed, hot skin
  • Psych: hallucinations, picking at objects that are not there


  • EKG
    • Sinus tachycardia
    • Intraventricular conduction delay
      • Prolonged QRS >100ms
      • Rightward shift of the T40-msec QRS axis
    • Wide Complex Tachycardia (non-VT)
    • Note: The EKG should be reviewed in any patient with an anticholinergic toxidrome and, a QRS > 100 msec should preclude the use of physostigmine 

TCA Toxicity (LITFL) – Broad QRS, Sinus Tachycardia, Terminal R Wave in aVR

TCA Toxicity (LITFL) – Broad QRS

TCA Toxicity – Wide QRS/Sine Wave

  • Labs
    • Blood gas: pH status while giving sodium bicarbonate, lactate as a marker of hypoperfusion
    • Check for concomitant ingestions: salicylate and acetaminophen levels
    • Basic metabolic panel: evaluate electrolytes, renal function
    • Hepatic panel: evaluate liver function
    • Obtaining a TCA concentration is not necessary as they are delayed and, patients aren’t treated based on concentration but rather on effect of the drug.

ED Management

  • Supportive Care
    • Assess airway, breathing and circulation
    • Large bore IV X 2, supplemental O2 if needed and continuous cardiac monitoring
    • Intravenous crystalloid fluids
    • Always consider co-ingestants
    • Avoid physostigmine (Pentel 1980)
      • Despite the presence of an anticholinergic toxidrome, physostigmine should not be given to these patients
      • Small case series showed worse outcomes in TCA toxic patients treated with physostimine
    • Contact your local poison control center for expert consultation
  • Directed Management
    • Sodium Bicarbonate (NaHCO3)
      • Bolus 1-2mEq/kg with additional boluses every 3-5 minutes until the QRS narrows to <100ms and hypotension improves
      • Aim for a pH below 7.55
      • If patient is intubated, can use mechanical ventilation to control pH
      • Effects of NaHCO3
        • Increases the sodium gradient across the cardiac fast acting sodium channels which overwhelms blockade by the TCA  allowing for return of the rapid rise of phase 0 of the ventricular action potential
        • Raises serum pH which removes the TCA from the binding site on the sodium channel as the majority of drug binding to sodium channels occurs in the ionized state
      • Alternative to NaHCO3 – 3% hypertonic saline
        • 1 liter of 3% saline has 513 mEq of Na = 51.3 in 100mL. Equivalent sodium content as 50mL of 8.4% sodium bicarbonate (1 ampule)
        • Dose: 100mL bolus of 3% hypertonic saline, repeat 100mL boluses until QRS narrows
    • Gastrointestinal Decontamination
      • Activated charcoal for awake and alert patients following commands
      • Orogastric lavage for intubated patients
        • Benefit not proven in a controlled trial
        • Delayed gastric emptying from anticholinergic properties may increase benefit of lavage
  • Management of Hypotension (Niemann 1986)
    • Perform POCUS Cardiac Assessment
    • Good Ejection Fraction
      • Indicates vasodilation as source of hypotension
      • 1st Line Pressor: Norepinephrine
    • Poor Ejection Fraction
      • Cardiac +/- peripheral vasodilation as source of hypotension
      • Epinephrine – provides inotropy + vasopressor effects
      •  Dobutamine
        • Inodilator – increases contractility while causing vasodilation
        • Can consider as adjunct to inopressor if cardiac output

Take Home Points

  • TCA toxicity can be fatal. Prompt recognition and treatment can significantly reduce mortality
  • EKG findings can be pathognomonic and include QRS widening (> 100 msec) and rightward deviation of the terminal 40ms
  • Do not administer physostigmine in an anticholinergic toxidrome until an EKG has been reviewed and the QRS is determined to be < 100 msec
  • First line treatment is NaHCO3 1-2 mEq/kg
  • In patients with significant hypotension, beside echocardiogram to evaluate for cardiac contractility can help guide pressor and inotrope treatment

Read More

EMCrit: TCA Overdose

LITFL: Toxicology Conundrum 022


Boehnert MT, Lovejoy FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after ran acute overdose of tricyclic antidepressant. N Engl J Med 1985; 313:474. PMID: 4022081

Jancin, B. Tricyclic Antidepressant Overdoses are on the Rise. ACEP News, Clinical and Practice Management. December 2007.

Liebelt EL. Chapter 73: Cyclic antidepressants. In: Goldfrank’s Toxicologic Emergencies, 9th ed, Nelson LS (Ed), McGraw-Hill, New York 2011.

Niemann JT et al. Electrocardiographic criteria for tricyclic antidepressant cardiotoxicity. Am J Cardiol. 1986;57:1154–1159. PMID: 3706169