Diagnosis and Discussion - Case 1126

Final Diagnosis

Tricyclic Antidepressant Overdose

Discussion

Amitriptyline is a tricyclic antidepressant (TCA). TCAs are given their name due to their chemical structure, which is a central three ring structure with an attached side chain (1). TCAs are used for the treatment of depression, anxiety, and neuralgia. They are now a second line medication for treatment of depression due to the selective serotonin/serotonin and norepinephrine reuptake inhibitors (SSRI/SNRIs) (1). The mechanism of action of TCAs is inhibition of serotonin, norepinephrine, and dopamine reuptake at the presynaptic terminals. TCAs also are antagonists to central and peripheral muscarinic acetylcholine receptors, peripheral alpha-1 adrenergic receptors, histamine (H1) receptors, and central nervous system gamma-aminobutyric acid (GABA) A receptors (2). The absorption, distribution, metabolism, and excretion of TCAs are well known. After oral administration, TCAs are rapidly absorbed in the small intestine, enter the portal circulation and experience first pass metabolism in the liver (2). Then, the TCAs will enter the systemic circulation where they have a high volume of distribution (Vd). This high Vd is due to their lipophilic properties and significant protein binding (2).  The metabolism and elimination of TCAs mainly occurs in the liver, where the hepatic CYP isoenzymes demethylate the side chain component and hydroxylate the central ring structure of the TCA (2). Of note, the demethylated metabolite of amitriptyline is nortriptyline. The elimination half-life for most of the TCAs is around 24 hours (2).

TCAs remain one of the commonly encountered drugs associated with emergency department visits (3). A TCA overdose commonly presents with signs and symptoms attributed through the receptors the drug acts on, which were discussed previously. The TCA toxidrome profile is largely anticholinergic in nature manifesting as mydriasis, urinary retention, flushed skin, and dry mucous membranes. Neurologic manifestations include agitation, coma, and seizures. In addition, TCAs also block cardiac fast sodium channels, which can lead to fatal arrythmias and characteristic electrocardiogram changes. These characteristics changes are conduction abnormalities shown by QRS duration greater than 100 milliseconds and/or a QTc greater than 470 milliseconds (1). Other cardiovascular manifestations such as tachycardia and hypotension are common. TCA overdose in the emergency department is treated by management of the patient’s airway, breathing and circulation. Interventions may include intubation, mechanical ventilation, and fluid resuscitation. When the patient presents to the emergency department within 2 hours of ingestion, activated charcoal may be given, if there is no gastrointestinal complication such as an ileus or bowel obstruction (1).  Electrocardiogram abnormalities are treated based on the duration of the QRS. If the QRS is greater than 100 milliseconds, a challenge of intravenous sodium bicarbonate is given and the QRS is assessed for shortening. If the QRS narrows, sodium bicarbonate is administered as a continuous infusion. CNS manifestations tend to resolve with supportive treatment, otherwise seizures are treated with benzodiazepines (1).

When there is a suspected TCA overdose, some hospitals utilize serum immunoassays. Some limitations of serum immunoassays include the inability to quantify specific TCAs and high false positive results (3). The false positive results are typically caused by drugs with a similar structure that can cross-react and produce these results. Some examples of these drugs are carbamazepine, cyclobenzaprine, and quetiapine (5). It should be noted that these cross reactants are manufacturer dependent for immunoassay kits.

The quantitative TCA level in serum/plasma in the emergency setting was previously performed to guide clinical management and provide risk stratification for patients. However, serum levels may not accurately risk stratify patients or determine resuscitation adequacy (4). There are limitations to the outdated quantitative TCA serum/plasma level in the emergency setting. One is that quantitative levels are usually not available to be ordered on a “stat” basis. The volume of distribution (Vd) of TCAs also limits the utility of the quantitative serum/plasma level. This high Vd limits the correlation between blood and the target tissues (2). Given these limitations, recent guidelines no longer recommend quantitative levels for emergency TCA overdose management. According to the 2011 Guidelines in Emergency Medicine Network (GEMNet), the ECG is preferable to serum drug level for the prediction of complications following TCA overdose (6). This guideline was created based on the limitations previously discussed as well as the ease of use of ECGs. Serum drug levels also are more invasive, have a longer turnaround time and are less widely available in the emergency department (6). In this case, serum drug levels were not ordered, and the patient recovered after supportive care and without need for serum alkalinization.

References

  1. LoVecchio F. Cyclic Antidepressants. In: Tintinalli JE, Ma O, Yealy DM, Meckler GD, Stapczynski J, Cline DM, Thomas SH. eds. Tintinalli's Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw Hill; 2020.
  2. Langman, L. Clinical Toxicology. In: Rifai, N, Horvath A, Wittwer C. eds. Tietz textbook of clinical chemistry and molecular diagnostics, 7e. Elsevier Saunders; 2018.
  3. Poklis JL, Wolf CE, Goldstein A, Wolfe ML, Poklis A. Detection and quantification of tricyclic antidepressants and other psychoactive drugs in urine by HPLC/MS/MS for pain management compliance testing. J Clin Lab Anal. 2012 Jul;26(4):286-94. doi: 10.1002/jcla.21519. PMID: 22811363; PMCID: PMC3969737.
  4. Glauser J. Tricyclic antidepressant poisoning. Cleve Clin J Med. 2000 Oct;67(10):704-6, 709-13, 717-9. doi: 10.3949/ccjm.67.10.704. PMID: 11060957.
  5. Alec Saitman, Hyung-Doo Park, Robert L. Fitzgerald, False-Positive Interferences of Common Urine Drug Screen Immunoassays: A Review, Journal of Analytical Toxicology, Volume 38, Issue 7, September 2014, Pages 387-396, https://doi.org/10.1093/jat/bku075
  6. Body R, Bartram T, Azam F, Mackway-Jones K. Guidelines in Emergency Medicine Network (GEMNet): guideline for the management of tricyclic antidepressant overdose. Emerg Med J. 2011 Apr;28(4):347-68. doi: 10.1136/emj.2010.091553. PMID: 21436332.