eMedicine Specialties > Emergency Medicine > Toxicology

Toxicity, Cyclic Antidepressants

Vivian Tsai, MD, MPH, Assistant Professor at Mount Sinai School of Medicine, Queens Hospital Center
Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn; Mark Biittner, MD, Consulting Staff, Department of Emergency Medicine, Sutter Roseville Medical Center; Daniel M Joyce, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent's and Saint Mary's Medical

Updated: Nov 3, 2009

Introduction

Background

Most of the cyclic antidepressants (CAs) contain a 3-ring molecular structure. CAs were first used in the 1950s to treat clinical depression. The first report of the adverse effects of tricyclic overdose came within 2 years of their clinical use.

Despite the increasing popularity of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of depression, CAs continue to play an important role in the treatment of enuresis, obsessive-compulsive disorder, attention deficit hyperactivity disorder, school phobia, and separation anxiety in the pediatric population. In adults, indications for CAs include depression, neuralgic pain, chronic pain, and migraine prophylaxis. Some of the more commonly prescribed CAs include amitriptyline, desipramine, imipramine, nortriptyline, doxepin, clomipramine, and protriptyline. Maprotiline, a tetracyclic compound, and amoxapine, a dibenzoxapine, are newer compounds that have a slightly different structure and toxicologic profile.

Pathophysiology

The CAs are well absorbed orally and undergo significant first-pass metabolism in the liver. They have a large volume of distribution and have long half-lives that generally exceed 24 hours. After the CAs are metabolized in the liver via glucuronic acid conjugation, they are then excreted through the kidneys.

The toxic effects of tricyclics are results of the following 4 main pharmacologic properties:

1. Inhibition of norepinephrine and serotonin reuptake at nerve terminals
2. Anticholinergic action
3. Direct alpha-adrenergic blockade
4. Membrane stabilizing effect on the myocardium by blocking the cardiac myocyte fast sodium channels

Tricyclic antidepressants (TCAs) may also penetrate into the CNS. Given the appropriate dosage, a particular CA exerts its therapeutic antidepressant effects by increasing biogenic amines such as norepinephrine and serotonin at nerve terminals. The same mechanism is thought to be responsible for seizure occurrence in CA overdose. Altered mental status is also frequently seen in CA overdose and is mainly attributed to anticholinergic and antihistaminergic properties of CAs.

The effects of CA overdose on the cardiovascular system result mainly from the impediment of the cardiac conduction system. CAs, like the class IA antiarrhythmics, decrease the sodium influx through the fast sodium channels and consequently decrease the slope of phase 0, leading to the widened QRS complex that is typically seen on ECGs of individuals with CA poisoning. An in vitro study reported that CAs also directly decrease myocardial contractility in a dose-dependent manner.¹ Profound hypotension is sometimes seen in CA overdose and is mainly due to the well-recognized anti–alpha-adrenergic effect of the CAs; however, these direct myocardial depressive effects may also contribute to the severe hypotension seen in CA toxicity.

Frequency

United States

Antidepressants were the eighth leading cause of toxic exposures in 2007 according to the American Association of Poison Control Centers' National Poison Data System Annual report. Cyclic antidepressants were associated with 80 deaths. The CA most frequently ingested is amitriptyline, followed by nortriptyline and doxepin. Amitriptyline exposure is associated with the most number of deaths among the various CAs.²

Mortality/Morbidity

Fatality before reaching a healthcare facility occurs in approximately 70% of patients attempting suicide with CAs. CA were the number one cause of fatality from drug ingestion until the last decade when they were surpassed by analgesics. Only 2-3% of CA overdose cases that reach a healthcare facility result in death.

Sex

CA toxicity occurs in both men and women. However, the incidence of CA exposure is greater in women than in men because women are at a higher risk for suicide attempts.

Age

CA toxicity occurs at all ages. Incidence of CA toxicity is most prevalent in persons aged 20-29 years. This again reflects the demographics of suicidal attempts.

Clinical

History

History of suicidal ideation, prior suicide attempts, circumstances around ingestion, intended CA (CA) usage, co-ingestants, time of ingestion, and dose ingested should be obtained from the patient directly and also from the patient's family.

Onset of symptoms typically occurs within 2 hours of ingestion, which corresponds to the peak CA serum level, which may range from 2-12 hours.

Determining which specific CA is involved may be helpful. Although amoxapine is associated with higher incidence of seizures, maprotiline exhibits more severe cardiac toxicity. Determine status in the following systems:

• Cardiovascular
  • Palpitation
  • Chest pain
  • Hypotension
• CNS
  • Convulsion
  • Decrease mental status
  • Respiratory depression
  • Drowsiness
  • Coma
• Peripheral autonomic system
  • Dry mouth
  • Dry skin
  • Urinary retention
  • Blurred vision

Physical

Physical findings are usually consistent with the anticholinergic toxidrome and quinidinelike cardiotoxicity.

• Tachycardia
• Hypotension and orthostasis
• Fever
• Altered mental status
• Ileus
• Absent bowel sounds
• Rigidity
• Dry skin and mucous membranes
• Mydriasis

Causes

• Unintentional ingestion (most common cause in pediatric population)
• Intentional ingestion; suicidal ideation

Differential Diagnoses

Other Problems to Be Considered

Brugada syndrome

Workup

Laboratory Studies

• Studies have shown that serum cyclic antidepressant (CA) level does not correlate well with severity of CA toxicity and is a poor predictor of clinical outcome.
• Because multisubstance ingestion is common, routine screening for other potentially treatable toxins is recommended (eg, acetaminophen). Request for the other serum toxicologic levels should be guided based on the clinical picture. For example, in patients with acidosis, assess for aspirin, ethylene glycol, and methanol.
• Assess the following:
  • Electrolyte, BUN, and creatinine levels
  • Anion gap
  • CBC count
  • Alcohol level
  • ABGs for evaluation of acidosis or hypoxia
• Point-of-care qualitative urine immunoassays are available. They detect the presence of CA in the body. Test results are positive for most TCAs in the subtherapeutic-to-toxic range, with the exception of clomipramine. False-positive results due to cross-reactivity occur in patients who are also taking cyclobenzaprine. These tests are helpful when patients' medication lists are unknown and CA toxicity is suspected based on history, clinical presentation, and ECG findings. However, in patients known to take TCAs, the urine immunoassays are of limited use because the result does not correlate with serum CA levels.³

Imaging Studies

• Chest radiography should be performed in cases of suspected aspiration or when respiratory symptoms are noted and may be used to rule out other causes of fever, tachycardia, and altered mental status.

Other Tests

Sinus tachycardia is the most common ECG finding in CA toxicity.

• Measurement of limb-leads QRS duration can be used to assess the severity of CA exposure. A QRS interval greater than 100 milliseconds is the basis for treatment with bicarbonate (alkalinization).
• Patients with a QRS interval less than 100 milliseconds are unlikely to develop seizures and arrhythmias. Patients with a QRS interval greater than 100 milliseconds have up to a 34% chance of developing seizures and up to a 14% chance of developing a life-threatening cardiac arrhythmia. With a QRS complex greater than 160 milliseconds, the chance of ventricular arrhythmias increases to 50%.
• The amplitude of the R wave in lead aVR and the ratio of the R/S waves in aVR are greater in patients who developed seizures or dysrhythmias.
• According to Liebelt et al, when the R wave in aVR equals 3 mm or more, the sensitivity and specificity for subsequent development of seizures or arrhythmias are 81% and 73%, respectively.⁴
• ECG findings that can be observed in CA toxicity include sinus tachycardia; prolongation of the PR, QRS, and QTc intervals; nonspecific ST-segment and T-wave changes; AV block; right-axis deviation of the terminal 40-millisecond vector of the QRS complex in the frontal plane; and the Brugada pattern (downsloping ST-segment elevation in leads V1-V3 in association with right bundle branch block).⁵
• A Brugada pattern was seen using ECG in 17% of patients with TCA toxicity in a retrospective study completed by Monteban-Kooistra et al.⁶ The ECG finding abnormalities resolved after administration of sodium bicarbonate.
• A study of 98 consecutive cases of CA intoxication in France found that the mortality rate was 6.7% among patients with the Brugada electrocardiographic pattern and 2.4% among patients without it. However, the result is not statistically significant (p=0.39).⁷
• Early recognition of conduction disturbances is important in suspected CA poisoning.

Procedures

• GI decontamination may be helpful within the first several hours postingestion because CAs can slow gastric emptying through the anticholinergic activity.
  • Gastric lavage may be helpful in recovering and identifying the CA ingested. However, one study that compared the use of gastric lavage and activated charcoal versus charcoal alone showed no benefit in clinical outcome.⁸ Usually, lavage is recommended for patients who developed significant toxicity requiring endotracheal intubation and who presented after relatively recent ingestion (several hours).
  • Activated charcoal reduces the absorption of CAs. It may also be beneficial in cases of multisubstance ingestion. It should be administered only in patients who are able to protect the airway.
• Endotracheal intubation is indicated if the patient cannot adequately maintain a safe airway.

Treatment

Prehospital Care

Endotracheal intubation is necessary in a patient who is obtunded and unable to protect the airway. Intravenous access should be established as soon as possible. Administer intravenous fluid if the patient is hypotensive. Prompt transport of the patient to the nearest emergency department is implicit.

Evidence-based management guidelines for tricyclic antidepressant poisoning are available from the American Association of Poison Control Centers.⁹

Emergency Department Care

The greatest risk of seizures and arrhythmias occurs within the first 6-8 hours of cyclic antidepressant (CA) ingestion. The treatment of an asymptomatic patient with a history of CA ingestion is mainly supportive therapy. For all patients with possible CA toxicity, airway protection, ventilation and oxygenation, intravenous fluids, cardiac monitoring, and performing ECG are all essential measures.

Consider early gastric decontamination using charcoal if the patient presents within 2 hours of ingestion.

Once suicidal ideation is ruled out and the patient remains asymptomatic for 6-8 hours postingestion without any ECG changes, the patient may be discharged home. If suicidal ideation is present, evaluation for admission to a psychiatric facility is mandatory.

• Airway: Endotracheal intubation may be necessary in patients who present with seizures or who are in a comatose state for airway protection.
• Hyperventilation: The use of hyperventilation is controversial. It has been recommended traditionally for the resultant alkaline state hyperventilation achieves. Alkalinization is thought to increase protein binding of CA and promote CA excretion, thereby decreasing cardiotoxicity. However, a randomized controlled animal study shows that hyperventilation has little effect on reversing CA toxicity.¹⁰
• Hypotension
  • Normal saline intravenous fluids are indicated for CA-induced hypotension.
  • For hypotension refractory to intravenous saline, vasopressors with alpha-agonist effect (eg, Neo-Synephrine, norepinephrine) may be used.
• GI decontamination: Once the patient is stabilized, activated charcoal can be considered.
• Intravenous sodium bicarbonate
  • Serum alkalinization with intravenous sodium bicarbonate has been the mainstay of therapy in CA-induced cardiovascular toxicity. Prolonged QRS is most often the indication for serum alkalinization in CA toxicity. Not all physicians agree on what the duration of QRS should be in order for them to institute intravenous sodium bicarbonate therapy. However, about 88% of the poison control directors in the United States use a QRS of 100 milliseconds or greater as the cut off for intravenous sodium bicarbonate. Evidence suggests the reversal of toxic effects of CA (eg, QRS prolongation, myocardial depression) following serum alkalization and sodium loading with sodium bicarbonate.
  • Animal studies have shown hypertonic saline to be effective in reversing CA toxicity.¹⁰ However, no study adequately compared the efficacy of hypertonic saline versus sodium bicarbonate. Sodium loading may be the most important factor in the reversal of the symptoms of cyclic antidepressant toxicity.
• Hypertonic saline: The use of hypertonic saline in CA toxicity remains controversial. Though 7.5% hypertonic saline has been shown to correct hypotension and QRS widening in severe CA overdose in a swine model,¹⁰ limited evidence supports the use of hypertonic saline in CA toxicity in humans.
• Benzodiazepines: The seizures in CA toxicity are usually self-limited. The treatment of choice for prolonged or recurrent seizures in CA toxicity is a benzodiazepine. Most CA-induced seizures are usually brief and resolve prior to the administration of anticonvulsants. General anesthesia should be reserved for patients with status epilepticus who are unresponsive to the standard treatment regimen (eg, benzodiazepines, barbiturates, propofol). This may prevent hyperthermia and rhabdomyolysis.
• Hemodialysis or hemoperfusion: Because of the large volume of distribution and high protein-binding characteristics of CAs, hemodialysis has not been shown to be effective in the treatment of CA overdose.
• Physostigmine: This is a short-acting cholinesterase inhibitor used for the reversal of anticholinergic symptoms. It should not be used in treating CA toxicity because of the reported cases of physostigmine-induced seizures and asystole.

Consultations

• Poison control center
• Toxicologist
• Cardiologist for pacemaker placement and arrhythmia management, when indicated
• ICU admission for patients with cardiovascular and/or neurologic manifestations of CA toxicity

Medication

Treatment of cyclic antidepressant (CA) toxicity focuses on airway management, dysrhythmias, seizures, and hypotension. Sodium bicarbonate, benzodiazepines, and norepinephrine are the DOCs for these complications.

GI decontaminant

This agent prevents further absorption of drug and other co-ingestants from the GI tract.

Activated charcoal (Liqui-Char)

Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. May be administered with or without cathartic (eg, Sorbitol 70%), except in young pediatric patients, where electrolyte imbalance may be of concern. Does not dissolve in water.
For maximum effect, administer within 30 min of ingesting poison.

Dosing

Adult

1 g/kg PO initial (if the ingestion occurred 1-2 h before presentation)

Pediatric

1-2 g/kg PO; not to exceed 15-30 g

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix charcoal with sherbet, milk, or ice cream (decreases adsorptive properties)

Contraindications

Documented hypersensitivity; poisoning or overdose of mineral acids and alkalies; unprotected airway with absent gag reflex

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check for presence of bowel sounds before repeat administration to minimize risk of charcoal ileus; not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black

Cardiovascular agents

Sodium bicarbonate is indicated for QRS intervals greater than 100 milliseconds, seizures, acidosis (pH level <7), hypotension, cardiac arrest, or dysrhythmia. Antidysrhythmic agents may be helpful. However, avoid certain drugs that exacerbate the cardiac effects of CAs, such as quinidine and procainamide (class IA), flecainide (class IC), and bretylium and amiodarone (class III). Vasopressors are used for the treatment of hypotension not corrected by intravenous fluids.

Sodium bicarbonate (Neut)

First-line therapy for QRS interval >100 milliseconds or if dysrhythmias are present. Correction of acidosis promotes protein binding of CA and improves myocardial contractility. Doses or IV drip may be administered with a pH goal of 7.5-7.55. Monitor and replace potassium as needed to prevent hypokalemia.

Dosing

Adult

1-2 mEq/kg bolus IV; IV drip of 3 amps of sodium bicarbonate in 1 L of D5W to maintain a pH of 7.45-7.55

Pediatric

Administer as in adults

Interactions

Urinary alkalinization, induced by increased sodium bicarbonate concentrations, may cause decreased levels of lithium, tetracyclines, chlorpropamide, methotrexate, and salicylates; increases levels of amphetamines, pseudoephedrine, flecainide, anorexiants, mecamylamine, ephedrine, quinidine, and quinine

Contraindications

Alkalosis; hypernatremia; hypocalcemia; severe pulmonary edema; unknown abdominal pain

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Should only be used to treat documented metabolic acidosis and hyperkalemia-induced cardiac arrest; can cause alkalosis, decreased plasma potassium, hypocalcemia, and hypernatremia; may cause sodium retention if renal function is impaired; caution in conditions with electrolyte imbalances, such as CHF, cirrhosis, edema, corticosteroid use, or renal failure; when administering, avoid extravasation because can cause tissue necrosis

Lidocaine (Xylocaine)

Class IB antiarrhythmic that increases electrical stimulation threshold of ventricle, suppressing automaticity of conduction through tissue. Second DOC for CA dysrhythmias.

Dosing

Adult

1-1.5 mg/kg IV bolus, may repeat up to total of 3 mg/kg; maintenance drip of 1-4 mg/min by mixing 2 g in 250 mL of D5W

Pediatric

20-50 mcg/kg IV bolus; 1 mcg/kg/min

Interactions

Coadministration with cimetidine or beta-blockers, increases toxicity; coadministration with procainamide and tocainide may result in additive cardiodepressant action; may increase effects of succinylcholine

Contraindications

Documented hypersensitivity; Adams-Stokes syndrome, Wolff-Parkinson-White syndrome; severe SA, AV, or IV block if artificial pacemaker not in place

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Use a solution without preservatives; caution in heart failure, hepatic disease, hypoxia, hypovolemia or shock, respiratory-depression, and bradycardia; reduce dose by 50% in acute hepatic failure patients; may increase risk of CNS and cardiac adverse effects in elderly patients; high plasma concentrations can cause seizures, heart block, and AV conduction abnormalities

Norepinephrine (Levophed)

Stimulates beta1- and alpha-adrenergic receptors, which, in turn, increases cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases. DOC to treat hypotension refractory to fluid resuscitation in CA toxicity. Dopamine is second-line and less effective.

Dosing

Adult

2-4 mcg/min IV; titrate to desired response; 8-30 mcg/min usual range

Pediatric

0.05-0.1 mcg/kg/min IV; not to exceed 2 mcg/kg/min

Interactions

Enhances pressor response of norepinephrine by blocking the reflex bradycardia caused by norepinephrine

Contraindications

Documented hypersensitivity; peripheral or mesenteric vascular thrombosis because ischemia may be increased and area of infarct extended

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Correct blood-volume depletion, if possible, before therapy; extravasation may cause severe tissue necrosis and, thus, should be administered into a large vein; caution in occlusive vascular disease

Anticonvulsants

Benzodiazepines are preferred for treatment of seizures. Do not use barbiturates in patients with hypotension. Do not use phenytoin in patients with dysrhythmias.

Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life (longer than diazepam).
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation.
Monitoring patient's blood pressure after administering dose is important. Adjust prn.

Dosing

Adult

2-4 mg/dose IV over 2-5 min; may repeat in 10-15 min, usual maximal dose 8 mg

Pediatric

0.05-0.1 mg/kg/dose IV over 2-5 min; not to exceed 4 mg/dose; may repeat dose of 0.05 mg/kg in 10-15 min prn

Interactions

Toxicity in CNS increases when used concurrently with alcohol, phenothiazines, barbiturates, and MAOIs

Contraindications

Documented hypersensitivity; preexisting CNS depression; hypotension; narrow-angle glaucoma; pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic impairment, myasthenia gravis, organic brain syndrome, or Parkinson disease; may cause respiratory depression

Diazepam (Valium)

Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA. Shorter acting than lorazepam.

Dosing

Adult

0.02-0.05 mg/kg IV at 2 mg/min; not to exceed 5-10 mg

Pediatric

0.05-0.1 mg/kg IV at 1 mg/min

Interactions

Toxicity in CNS increases with coadministration of phenothiazines, barbiturates, alcohols, and MAOIs

Contraindications

Documented hypersensitivity; narrow-angle glaucoma

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution with other CNS depressants, low albumin levels, or hepatic disease (may increase toxicity); may cause respiratory depression

Midazolam (Versed)

Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before initiating procedure or repeating dose.

Dosing

Adult

Loading dose: 0.2 mg/kg IV
Continuous infusion: 0.1-0.4 mg/kg/h IV
Intubation and pressor support will be necessary
Alternatively: 10-15 mg IM; when other access impossible

Pediatric

Loading dose: 0.15 mg/kg IV
Maintenance dose: Infuse 1 mcg/kg/min
Titrate dose upward q5min until clinical seizure activity is controlled

Interactions

Sedative effects may be antagonized by theophyllines; narcotics and erythromycin may accentuate sedative effects because of decreased clearance

Contraindications

Documented hypersensitivity; preexisting hypotension; narrow-angle glaucoma; sensitivity to propylene glycol (diluent)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, pulmonary disease, renal impairment, and hepatic failure; may cause respiratory depression

Phenobarbital (Barbita, Luminal)

Used for seizures not responding to benzodiazepines. Significant respiratory depression; patient may require endotracheal intubation.

Dosing

Adult

Load 15-20 mg/kg IV at 25-30 mg/min; not to exceed 300-800 mg

Pediatric

Administer as in adults

Interactions

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients stabilized on anticoagulants may require dosage adjustments if added to or withdrawn from their regimen); coadministration with alcohol may produce additive CNS effects and fatality; chloramphenicol, valproic acid, and MAOIs may increase phenobarbital toxicity; rifampin may decrease phenobarbital effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraceptive methods to prevent unwanted pregnancy); menstrual irregularities may also occur

Contraindications

Documented hypersensitivity; severe respiratory disease; marked impairment of liver function; nephritic patients

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause respiratory depression; in prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis and myxedema

Miscellaneous

Magnesium sulfate has been successfully used in an overdose with refractory ventricular fibrillation.¹² Animal studies have shown that magnesium sulphate converted ventricular tachycardia to sinus rhythm in 9 of 10 rats.¹³

Magnesium sulfate

Given parenterally, magnesium decreases acetylcholine in motor nerve terminals and acts on myocardium by slowing rate of S-A node impulse formation and prolonging conduction time. May be helpful in treating ventricular fibrillation in TCA toxicity, but further study is needed.

Dosing

Adult

For life-threatening arrhythmia, 1-2 g IV (8-16 mEq) in 100 mL D5W, administered over 5-60 min followed by an infusion of 0.5-1 g/h

Pediatric

20-100 mg/kg/dose IV q4-6h prn; in severe cases, doses as high as 200 mg/kg/dose have been used

Interactions

Aminoglycosides increase magnesium sulfate's neuromuscular blockade; CNS depressants increased CNS depression; neuromuscular antagonists, betamethasone (pulmonary edema), ritodrine increased cardiotoxicity

Contraindications

Heart block; serious renal impairment; myocardial damage; hepatitis; Addison disease

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Use with caution in patients with impaired renal function; use with caution in digitalized patients (may lead to heart block); monitor serum magnesium level, respiratory rate, deep tendon reflex, renal function when magnesium sulfate is administered parenterally; use with extreme caution in patients with myasthenia gravis or other neuromuscular disease

Follow-up

Further Inpatient Care

• Level of conscious and ECG changes at presentation are the most sensitive clinical predictors of serious complications.
• Cyclic antidepressant (CA) toxicity typically lasts 24-48 hours following a significant overdose. However, studies have reported prolonged CA toxicity as long as 4-5 days.¹⁴ Amitriptyline is the drug most commonly implicated in these cases.
• Consider ICU admission for any ECG changes.
• Admission to a monitored bed is appropriate for patients exhibiting only anticholinergic symptoms and no cardiac manifestations.

Complications

• Seizures
• Dysrhythmias

Miscellaneous

Medicolegal Pitfalls

• The use of physostigmine in cyclic antidepressant (CA) poisoning has been associated with complete heart block, asystole, and hypotension.
• Ipecac syrup is not recommended as the procedure in GI decontamination because of the possibility that patients experience sudden neurologic deterioration (eg, lethargy, seizures) and aspirate.
• The use of type IA and IC antidysrhythmics or other sodium channel blockade agents may exacerbate toxic effects of CAs on the myocardium.
• The use of flumazenil for reversal of benzodiazepines overdose with concomitant CAs exposure can precipitate seizures.

Special Concerns

• ECG is a highly sensitive tool and can be used to rule out CA toxicity. However, it is not specific enough to be used alone to diagnose CA overdose. Widening of QRS complex can be used as a rough guide in determining the prognosis of TCA poisoning (eg, seizures, dysrhythmias). However, characteristic ECG changes in addition to clinical presentation (anticholinergic toxidrome, seizures, hypotension, tachycardia) seen with CAs can be an adjunction in diagnosing CA toxicity.
• Lidocaine, when used to treat ventricular arrhythmia, should be administered with caution to avoid precipitating seizures.
• Ventricular bradyarrhythmias, due to depressed atrioventricular conduction and automaticity, can be treated by placement of a temporary pacemaker; alternatively, consider the use of a chronotropic agent.
• CA exposure in children is common. The potentially lethal dose (with desipramine, imipramine, or amitriptyline) is as low as 15 mg/kg. Toddlers can exceed this threshold with only 1-2 pills and should be evaluated in the emergency department.¹⁵

References

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Keywords

tricyclic antidepressants, TCAs, CAs, cyclic antidepressant toxicity, cyclic antidepressant overdose, Brugada syndrome, cyclic antidepressants, cyclic antidepressant poisoning, tricyclic antidepressant poisoning, tricyclic antidepressant overdose, cyclic antidepressant overdose, TCA overdose, CA overdose, amitriptyline, doxepin, nortriptyline, TCA poisoning, CA poisoning

Contributor Information and Disclosures

Author

Vivian Tsai, MD, MPH, Assistant Professor at Mount Sinai School of Medicine, Queens Hospital Center
Vivian Tsai, MD, MPH is a member of the following medical societies: Alpha Omega Alpha and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Mark A Silverberg, MD, FACEP, MMB, Assistant Professor, Assistant Residency Director, Department of Emergency Medicine, State University of New York Downstate College of Medicine; Consulting Staff, Department of Emergency Medicine, Staten Island University Hospital, Kings County Hospital, University Hospital, State University of New York Downstate at Brooklyn
Mark A Silverberg, MD, FACEP, MMB is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, Council of Emergency Medicine Residency Directors, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Mark Biittner, MD, Consulting Staff, Department of Emergency Medicine, Sutter Roseville Medical Center
Mark Biittner, MD is a member of the following medical societies: American College of Emergency Physicians
Disclosure: Nothing to disclose.

Daniel M Joyce, MD, Consulting Staff, Department of Emergency Medicine, Saint Vincent's and Saint Mary's Medical
Daniel M Joyce, MD is a member of the following medical societies: American College of Emergency Physicians and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT, Associate Clinical Professor; Medical and Managing Director, South Texas Poison Center, Department of Surgery/Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio
Miguel C Fernández, MD, FAAEM, FACEP, FACMT, FACCT is a member of the following medical societies: American Academy of Emergency Medicine, American College of Clinical Toxicologists, American College of Emergency Physicians, American College of Medical Toxicology, American College of Occupational and Environmental Medicine, Society for Academic Emergency Medicine, and Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart & St. Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System Pharmacists
Disclosure: Nothing to disclose.

Managing Editor

John G Benitez, MD, MPH, FACMT, FACPM, FAAEM, Associate Professor, Department of Medicine, Clinical Pharmacology Division, Vanderbilt University; Managing Director, Tennessee Poison Center
John G Benitez, MD, MPH, FACMT, FACPM, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Preventive Medicine, Society for Academic Emergency Medicine, Undersea and Hyperbaric Medical Society, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Asim Tarabar, MD, Assistant Professor, Director, Medical Toxicology, Department of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Disclosure: Nothing to disclose.

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