Tricyclic Antidepressant Toxicity


Article Author:
Muhammad Khalid


Article Editor:
Muhammad Waseem


Editors In Chief:
Jeanie Skibiski
Kathrin Allen
Brian Cornelius


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
3/9/2019 10:12:18 PM

Introduction

Tricyclic antidepressants (TCAs) were introduced in the late 1950s for the treatment of depression. However, with the advent of selective serotonin reuptake inhibitors (SSRIs) and other new antidepressants, the use of TCAs has become limited, although it is still used to treat depression that has not responded to treatment with less toxic agents. In adults, TCAs are also used in migraine headache prophylaxis, treatment of neuralgic pain, including the pain associated with Ciguatera poisoning, and obsessive-compulsive disorder. In children, TCAs have been used to treat nocturnal enuresis. Despite the current limited use of TCAs, the curve for TCA-overdose associated hospitalization and fatality is on the rise.[1][2][3][4]

Etiology

Since TCAs are mostly used for treating patients with chronic pain and neuropsychiatric disorders, toxicity and overdoses are mostly seen in these patients, who are taking them for these debilitating disease. These drugs are commonly prescribed for these diseases, and therefore are readily available to these patients.

Epidemiology

According to the database, TCA overdose accounted for 1.12 exposures per 10,000 population in 1992. Recently, the trend for antidepressant overdose has shifted more towards SSRIs. However, the rate of hospitalization is higher in cases of TCA overdose compared to SSRI, because of the narrower therapeutic index with TCAs.

Pathophysiology

Tricyclic antidepressants impose their therapeutic effects by inhibiting presynaptic reuptake of norepinephrine and serotonin in the central nervous system (CNS). This effect in the CNS can cause seizures. TCAs are weakly basic, and an acidic environment facilitates the formation of the ionized form and potentiates this effect. In cases of toxicity, TCAs block a number of receptors including peripheral alpha-adrenergic, histaminic, muscarinic and central serotonin receptors. Blockade of alpha-adrenergic receptors can cause hypotension. Blockade of muscarinic receptors can cause signs of anticholinergic toxicity, such as tachycardia, fever, dry mouth and skin, decreased bowel sounds and altered mental status. Blockade of histamine receptors can also cause altered mental status. TCAs can cause cardiac toxicity. Blockade of fast sodium channels in myocardial cells slows the action potential and provides a membrane stabilizing effect. The characteristic QRS prolongation seen in TCA overdose occurs secondary to prolongation of phase “0” of the myocardial action potential. This effect can lead to heart block and bradycardia. QT prolongation seen in cases of TCA overdose occurs due to potassium channel blockade that may potentially cause Torsades de Pointes. TCAs can also exert a quinidine-like toxic effect on the myocardium that can cause decreased cardiac contractility and hypotension.[5][6][7]

Toxicokinetics

TCAs are rapidly absorbed in the gastrointestinal tract. However, following an overdose, owing to the inherent anticholinergic effects, TCAs may decrease the gastrointestinal motility and cause delayed absorption and toxicity. Co-ingestion of other anticholinergic medications may cause more erratic absorption. TCAs have a long elimination half-life as these drugs are largely bound to the plasma protein and highly lipid soluble. Renal excretion occurs after significant first-pass hepatic metabolism. TCAs are primarily metabolized by CYP2D6, and the enzyme inducers and inhibitors of this pathway may alter their metabolism. Toxicity may occur because of the primary compound or its metabolite. Respiratory or metabolic acidosis may reduce the unbound fraction of TCA and may potentiate the harmful effects. Signs of toxicity usually appear within 2 hours’ post-ingestion. If after 6 hours’ post-ingestion, there are no signs of toxicity seen both clinically and on the electrocardiogram, and the patient has normal bowel sounds, then most likely the patient has not taken a significant overdose and can be medically cleared for psychiatric evaluation if needed. Once significant toxicity occurs it usually lasts for 24-48 hours. However, there are case reports of significant toxicity due to Amitriptyline that lasted up to 5 days’ post-ingestion.

History and Physical

All patients with suspected TCA overdose should be immediately evaluated, and a 12 lead EKG should be obtained. The therapeutic index of TCAs is narrow and therefore an ingestion of 10-20 mg/kg is potentially life-threatening. Symptoms usually start in 30-40 minutes, and signs of toxicity are usually clinically apparent within 2 hours, but delayed toxicity may occur. History of co-ingestion or access to other medications, including acetaminophen and aspirin, is important. Close attention to the patient’s vital signs and repeated physical examination for evidence of an anticholinergic toxidrome, cardiac toxicity, and neurologic toxicity should be done and will help guide proper management.

Evaluation

Cardiovascular, anticholinergic and neurologic manifestations are common and should be looked for. Vital signs may be abnormal. The patient may not be able to protect his or her airway. Respiratory depression may occur. Sinus tachycardia is commonly present due to anticholinergic toxicity, but more dangerous tachydysrhythmias and even bradycardia with or without heart block can occur. Hypotension can occur due to dehydration, cardiac toxicity, and alpha-adrenergic blockade. The patient may often demonstrate anticholinergic toxicity, such as fever, dilated pupils, dry mouth, dry, warm skin, decreased bowel sounds and altered mental status. The patient may be agitated or seizing, or the patient may have decreased mental status, and may even become comatose. An EKG should be obtained early in the management of these patients, and any evidence of sodium and/or potassium channel blockade should be promptly addressed. Prolongation of QRS, due to sodium channel blockade of more than 100 milliseconds is predictive of seizures while QRS > 160 milliseconds is predictive of arrhythmia. An R/S ratio in AVR of 0.7 or more and an R wave in the AVR lead more than 3 mm is strongly predictive of seizures and arrhythmias. In addition to basic lab investigations, including levels of possible co-investments, such as acetaminophen and aspirin, a CT scan of the head to rule out other causes of altered mental status should be done if clinically indicated. It should be noted that TCA levels do not correlate with toxicity, but may be helpful in diagnosing an unknown overdose when the clinical symptoms and signs point to a possible TCA ingestion. Any sign of toxicity warrants admission in an intensive care setting for at least 24 hours. Asymptomatic patients should be continuously monitored for signs of toxicity, changes in vital signs and EKG for at least 6 hours.[8][9][10][11]

Treatment / Management

Proper management of airway, breathing, and circulation is critical in cases of TCA poisoning. Gastrointestinal decontamination by activated charcoal should be done only if conditions are appropriate and the airway is protected. Charcoal decontamination may be effective up to 2 hours’ post-ingestion, especially if the bowel sounds are diminished. Every effort should be made to minimize the formation of acidosis, as acidosis may increase cardiac and neurologic toxicity. Seizures usually respond to benzodiazepines, but in cases of refractory seizures, prompt administration of anticonvulsants, such as Phenobarbital or Propofol, or even general anesthesia should be considered. Sodium bicarbonate should be given to hemodynamically unstable patients, patients with seizures, and patients with QRS prolongation of more than 100 msec. Sodium bicarbonate is given as a bolus of 1 meq/kg followed by an intravenous infusion containing sodium bicarbonate. The aim of this therapy is to narrow the QRS and to keep the serum pH between 7.5 and 7.55. Patients who are hypotensive should be treated with IV fluids and sodium bicarbonate, and if their hypotension does not respond to this, alpha-adrenergic agents, such as norepinephrine should be used. Sodium Bicarbonate should be used to treat dysrhythmias associated with QRS widening. Temporary pacemakers have been used to treat refractory symptomatic bradycardias not responsive to sodium bicarbonate. Physostigmine, Type 1A, Type 1C, and Type 3 Anti-dysrhythmic agents should be strictly avoided, as should Flumazenil. Intralipid emulsion treatment should be considered in hemodynamically unstable patients with overdoses of lipophilic TCAs. Since TCA are highly protein bound with an extensive volume of distribution, enhanced elimination with dialysis and hemoperfusion is not effective.

Enhancing Healthcare Team Outcomes

Tricyclic antidepressant toxicity can be life-threatening and is best managed by a multidisciplinary team that consists of an emergency department physician, nurse practitioner, poison control specialist, cardiologist and a neurologist. As with all cases of poisoning, proper management of airway, breathing, and circulation is critical in cases of TCA poisoning. Gastrointestinal decontamination by activated charcoal should be done only if conditions are appropriate and the airway is protected. Sodium bicarbonate should be given to hemodynamically unstable patients, patients with seizures, and patients with QRS prolongation of more than 100 msec. Some patients may even require temporary pacing for bradycardia. Hydration and close monitoring in an ICU setting is recommended. It is vital to make sure that the patient has no other co-ingestants in the systemic circulation.  For patients managed promptly, the outcomes are good. However, if treatment is delayed or the patient has ingested multiple other agents, the prognosis is guarded. Prior to discharge, if attempted suicide is suspected, the patient should be referred to a mental health counselor. Parents should be urged to keep all medications in a locked cabinet away from the reach of children. [12][13](Level V)

 

 


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Tricyclic Antidepressant Toxicity - Questions

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An honor student who suffers from panic attacks, especially during exams, is prescribed the tricyclic antidepressant imipramine. To keep awake, the student takes more than a handful of these pills. Of the following, what is the most likely symptom of an acute overdose?



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A patient overdoses with a tricyclic antidepressant. Her blood pressure is 80/P and pulse is 110. What medication should be used?



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Which medication is frequently given to patients who have overdosed on a tricyclic antidepressant?



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Which of the following statements about over dosage of tricyclic antidepressants is incorrect?



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A 15-year-old boy tried to commit suicide by ingesting tricyclic antidepressant (TCA) medication. What is the most common cause of death following TCA ingestion?



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Which of the following medications should be administered to a child with tricyclic antidepressant poisoning?



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What is the most common cause of death in tricyclic antidepressant poisoning?



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Which of the following would be most helpful in an amitriptyline overdose?



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A patient has been depressed and takes an overdose of a tricyclic antidepressant. She presents with hallucinations, confusion, dilated pupils, tachycardia, and hypotension. Which of the following is the antidote of choice?



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A 17-year old patient has been brought to the emergency department. She is minimally responsive and when the monitor is placed she has a very wide QRS with sinus tachycardia. What class of medications has she likely ingested?



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EMS finds an unconscious patient with an empty amitriptyline bottle. What is the best management step?



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Which of the following medications is indicated for the treatment of seizures due to tricyclic antidepressant (TCA) overdose?



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A 4-year-old female presents to the emergency room with tachycardia, lethargy, and seizures. Upon further questioning, no significant past medical history or medications are revealed. She lives at home with her mom, who takes no medications, and her grandmother, who takes "something for depression." No one has witnessed any ingestion. Which of the following is the most appropriate management?



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A 15-year-old patient takes an overdose of an unknown quantity of an unknown medication. Initially, he is drowsy, but then develops widening of the QRS, right bundle branch block, and hypotension. Select the most appropriate management.



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What is the target serum pH for the treatment of tricyclic antidepressant-induced cardiovascular toxicity?



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A young female patient is seen in the emergency department after an attempted suicide. Her family claims that she took several imipramine pills. She has been depressed for some time and wanted to end her life. Which of the following is true regarding a tricyclic antidepressant (TCA) overdose? Select all that apply.



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In a patient suffering from tricyclic antidepressant toxicity, which of the following anticholinergic features would be observed? Select all that apply.



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Tricyclic Antidepressant Toxicity - References

References

Avau B,Borra V,Vanhove AC,Vandekerckhove P,De Paepe P,De Buck E, First aid interventions by laypeople for acute oral poisoning. The Cochrane database of systematic reviews. 2018 Dec 19;     [PubMed]
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