DESCRIPTION

Tricyclic antidepressants (TCAs) are common oral medications used for the treatment of depression and several other medical disorders.

FORMS AND USES

• Pharmaceutical preparations include amitriptyline [Elavil, Etrafon (also contains perphenazine), Limbitrol (also contains chlordiazepoxide), Triavil (also contains perphenazine)], clomipramine (Anafranil), desipramine (Norpramin), doxepin (Adapin, Sinequan), dothiepin, imipramine (Tofranil), lofepramine, nortriptyline (Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil).
• TCAs are used to treat depression, enuresis, headaches, chronic pain, and neuropathies, and are occasionally used for antihistamine effects.
• Representative doses for amitriptyline, desipramine, or imipramine are 75 to 300 mg/day in divided doses for adults; 50 to 100 mg/day for adolescents; and 1.0 to 1.5 mg/kg/day for children (9-12 years old).
• Representative doses for nortriptyline are 75 to 150 mg/day for adults; 30 to 50 mg/day in divided doses for adolescents.

TOXIC DOSE

Clinically significant toxicity has occurred in children at doses as low as 100 mg. Adults begin to develop toxic effects after ingesting two to three times the daily dose.

PATHOPHYSIOLOGY

• Cyclic antidepressants block the neuronal reuptake of norepinephrine, serotonin, and dopamine.
• Toxic effects are caused by myocardial sodium channel blockade as well as anticholinergic, adrenergic, and alpha-blocking effects.

EPIDEMIOLOGY

• Poisoning is common.
• Toxic effects following exposure are typically moderate.
• Severe toxicity or death may occur in large ingestions.

CAUSES

• Poisoning is usually a suicidal ingestion.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.

DRUG AND DISEASE INTERACTIONS

A concomitant overdose with a monoamine oxidase inhibitor may produce severe toxicity such as serotonin syndrome.

PREGNANCY AND LACTATION

• Clomipramine, desipramine, doxepin, and protriptyline. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Amitriptyline, dothiepin, imipramine, and nortriptyline. US FDA Pregnancy Category D. Evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) may make use of the drug acceptable.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Other toxicologic causes of seizure include theophylline, isoniazid, and lindane.
• Other toxicologic causes of seizure that are especially associated with cardiac conduction abnormality include lidocaine, quinine, quinidine, encainide, cocaine, procainamide, and antihistamines.
• Nontoxicologic causes include status epilepticus from other causes (CNS tumor or bleed, meningitis, encephalitis, etc.).

SIGNS AND SYMPTOMS

Cardiac conduction abnormality, seizure, and CNS depression are characteristic and may be complicated by hyperthermia, acidosis, hypotension, rhabdomyolysis, and acute renal failure in serious cases.

Vital Signs

Tachycardia is common.

Cardiovascular

• Sinus tachycardia is common.
• Prolonged QRS and QT intervals and hypotension occur commonly and may deteriorate abruptly into ventricular dysrhythmia.

Pulmonary

• Respiratory depression or aspiration pneumonitis may develop.
• Adult respiratory distress syndrome has developed after severe overdose.

Renal

Acute renal failure may develop due to rhabdomyolysis.

Fluids and Electrolytes

Metabolic acidosis may develop due to seizures.

Neurologic

Altered mental status is common, ranging from drowsiness and confusion to seizures and coma.

PROCEDURES AND LABORATORY TESTS

Essential Tests

ECG with continuous cardiac monitoring is necessary.

• Sinus tachycardia is common.
• Limb lead QRS width greater than or equal to 0.1 seconds indicates toxicity.
• QRS width greater than or equal to 0.12 seconds is associated with an increased incidence of seizures; QRS width greater than or equal to 0.16 seconds is associated with an increased incidence of ventricular dysrhythmias.
• QRS complex with an R wave greater than or equal to 3 mm in lead aVR is associated with an increased risk of seizure or dysrhythmia.

Recommended Tests

• Arterial blood gases are measured because acidemia predisposes to more severe cardiac effects.
• Serum electrolytes, BUN, and creatinine levels are measured to assess other causes of hypotension, rhabdomyolysis, or dysrhythmia.
• Serum creatine kinase is assessed in patients with prolonged seizures or coma to assess rhabdomyolysis.
• Serum acetaminophen and aspirin levels in an overdose setting are used to detect occult ingestion.
• Head CT, lumbar puncture, bacterial cultures, and other tests are used to assess other causes of confusion, coma, or seizure.

Not Recommended Tests

Serum TCA levels are not clinically useful in overdose.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • Cardiovascular
  • Pulmonary
  • Renal
  • Fluids and Electrolytes
  • Neurologic
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment is focused on aggressive airway management, seizure control, support of cardiovascular function, and serum alkalinization in patients with dysrhythmia or QRS widening.
• The dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Hypotension, dysrhythmia, QRS widening, seizure, or coma are present.
• Toxic effects are not consistent with TCA poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Overdose effects are present (including persistent sinus tachycardia).
• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management in an intensive care setting is warranted for all patients with altered mental status, seizure, dysrhythmia (including persistent sinus tachycardia), or QRS widening.

DECONTAMINATION

Out of Hospital

Emesis should not be induced; coma or seizure may develop abruptly.

In the Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) is administered without a cathartic if a substantial ingestion has occurred within the previous few hours.
• Due to anticholinergic effects, a second dose of activated charcoal (0.5-1.0 g/kg) may be worthwhile 2 to 4 hours after the first dose, but evidence does not support the use of further doses.

ANTIDOTES

There is no specific antidote for TCA poisoning.

ADJUNCTIVE TREATMENT

Recommended

Hypotension

• The patient should receive 10 to 20 ml/kg of 0.9% saline intravenously and be placed in the Trendelenburg position; further fluid therapy is guided by central pressure monitoring to avoid volume overload.
• If hypotension is unresponsive, a vasopressor is administered. The dose of dopamine is 2 to 5 µg/kg/min intravenously titrated to effect up to 20 µg/kg/min; rates above this are unlikely to provide further benefit. If hypotension continues to be unresponsive, norepinephrine may be added at 0.1 to 0.2 µg/kg/min and titrated to effect. Caution: A high rate of infusion may cause tissue ischemia.

Dysrhythmia or Conduction Abnormality

• Procainamide, quinidine, or other class IA antidysrhythmic agents should be avoided.
• Seizures must be controlled concurrently.
• If QRS widening or dysrhythmia develops, sodium bicarbonate is administered, 1 to 2 mEq/kg as an intravenous bolus, repeated as needed to the narrow QRS interval, but arterial pH should not exceed 7.55.
• Simultaneous hyperventilation and bicarbonate therapy must be administered with caution because the combination may cause severe alkalemia and clinical deterioration.
• Lidocaine may be added if sodium bicarbonate alone is not effective.
  • Adult dosage is 50 to 100 mg by intravenous bolus, followed by an infusion of 2 to 4 mg/min, titrated to effect.
  • Pediatric dosage is 1 mg/kg bolus up to 100 mg followed by infusion of 20 to 50 µg/kg/min, titrated to effect.
  • The bolus dose may be repeated in 10 to 15 minutes.

Seizure

• A benzodiazepine is administered for initial control.
  • Diazepam. Adult dose is 5 to 10 mg initially, repeated every 10 minutes or longer if needed; pediatric dose is 0.2 to 0.5 mg/kg, repeated every 10 minutes or longer if needed; airway should be monitored.
  • Lorazepam. Adult dose is 2 to 4 mg by intravenous push over 2 to 5 minutes, repeated every 10 minutes or longer if needed; pediatric dose is 0.1 mg/kg by intravenous push over 2 to 5 minutes, not to exceed 4 mg per dose, and repeated every 10 minutes or longer if needed; airway should be monitored.
• If seizures persist or recur, another anticonvulsant such as phenobarbital or phenytoin should be added.

Not Recommended

• Continuous infusion of sodium bicarbonate is discouraged.
• The use of flumazenil in patients with ECG evidence of TCA overdose is contraindicated.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In the Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Recommended
  • Hypotension
  • Not Recommended

PATIENT MONITORING

All patients should receive continuous respiratory and cardiac monitoring until discharge.

EXPECTED COURSE AND PROGNOSIS

• Most adverse effects develop early.
• Patients who survive this early period without sequelae usually recover completely.
• Possible complications include permanent neurologic injury from sustained hypotension, seizures, or hypoxia.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Patients who do not develop seizure, QRS widening, hypotension, or dysrhythmia (other than mild transient sinus tachycardia) during 6 hours of observation may be discharged after gastrointestinal decontamination and psychiatric evaluation, if needed.
  • ECG criteria are less well defined in children, and most children should be admitted after significant TCA ingestion.
• From hospital. Patients may be discharged from the hospital after clinical effects have resolved and the ECG has been normal for 24 hours.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Patients with TCA overdose generally do not have an overt anticholinergic syndrome.

TREATMENT

• Patients may deteriorate abruptly.
• Aggressive airway management and careful monitoring are critical.

Poisoning by psychotropic agents: antidepressants.

See Also: SECTION II, Hypotension, Neuroleptic Malignant Syndrome and Serotonin Syndrome, Seizure, and Ventricular Dysrhythmia; SECTION III, Sodium Bicarbonate chapters.

RECOMMENDED READING

Boehnert MT, Lovejoy FH. Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985;313:474-479.

Callaham M, Kassel D. Epidemiology of fatal tricyclic antidepressant ingestion: implications for management. Ann Emerg Med 1985;14:1-9.

Author: Katherine M. Hurlbut

Reviewer: Richard C. Dart