Toxicology 5: Tricyclic Antidepressants Overdose Portal
Pharmacology/Pathophysiology
Tricyclic antidepressants (TCAs) exert their effects by a variety of mechanisms. TCAs block the re-uptake of biogenic amines (such as norepinephrine), block muscarinic acetylcholine receptors, and act as H1 receptor antagonists. TCAs also exhibit a quinidine-like effect on the myocardium, resulting in a variety of arrhythmias and conduction defects.
Pharmacokinetics
Toxic plasma concentrations occur 1 hour after ingestion but may be delayed in overdoses secondary to anticholinergic effects, which decrease GI motility. Half-lives vary greatly among individuals and may be prolonged. Enterohepatic recirculation occurs; repeat dose AC may benefit the patient. TCAs have a large volume of distribution making extracorporeal removal of little value.
Range of Toxicity
Adults: Ingestion of 10 to 20 mg/kg of most TCAs constitutes a moderate to serious exposure. Ingestions > 35 mg/kg are likely to be fatal without treatment. PEDS: Doses > 3.5 mg/kg/day are associated with ECG changes. A normal dose of imipramine for treatment of enuresis is 1.5 mg/kg/day. As there is limited toxicity data in children, refer patients ingesting > 1.5 mg/kg into the ED.
Clinical Effects
- HEENT: Nystagmus, blurred vision, dry mouth, flushing, mydriasis
- CV: Widening of the QRS interval is the most commonly used marker of toxicity. A QRS interval > 0.1 second is indicative of potential toxicity. Intervals > 0.16 are likely to result in significant arrhythmias and seizures. Prolonged QT and PR intervals may also be noted. Other arrhythmias include tachycardia, supraventricular tachycardia, premature atrial and ventricular contractions, VT, VF, and asystole.
- Hypertension followed by hypotension
- RESP: ARDS, aspiration pneumonitis
- CNS: Seizures, CNS depression, drowsiness, coma, extra pyramidal effects
- GI/GU: Decreased or absent bowel sounds, urinary retention
- OTHER: Metabolic acidosis, hyper-/hypothermia
Decontamination
- Use of Syrup of Ipecac is contraindicated due to the potential for rapid loss of consciousness and seizures.
- Check ABCs; correct acidosis.
- Establish IV access immediately.
- Respiratory status. Protect the airway with a cuffed ET tube before decontamination begins.
- Perform gastric lavage with a large-bore orogastric tube
(36 to 42 French) for these patients:
- comatose
- presenting withing 4 to 6 hours of ingestion
- presenting with an unknown time of ingestion
- Administer AC with cathartic before lavage. Lavage out and administer a new dose with a cathartic. The AC dose should be 10 times the amount of the drug ingested. If this is unknown, then give 1 to 2 g/kg.
A second dose of AC with cathartic may be administered 3 to 4 hours after the first, providing the patient has active bowel sounds.
Treatment
- Supportive care
- Obtain a 12-lead ECG.
Conduction defects
A QRS interval of > 0.1 second is widely considered as a risk factor for patients to develop serious complications in CA overdoses. If this is present, alkalinize the patient. - Alkalization
- Administer sodium bicarbonate. Dose: 1 to 2 mEq/kg
bolus
The desired arterial pH to obtain is 7.45 to 7.55.
Sodium bicarbonate infusion may be needed to obtain desired pH. Dose: 1 to 2 amps/L in D5W 1/2 NS at 150 to 200 cc/hour. (Adjust rates per patient.) Bolus dosing may also be done and may be a safer method of maintaining the desired pH. - Hyperventilation has been used to rapidly raise pH, but at least in animal studies, sodium bicarbonate has been shown to be more effective.
- In animal studies, hypertonic saline (10 cc/kg of 7.5%) was found more effective than alkalization in experimental tricyclic poisoning. This treatment may be considered for critically poisoned patients not responding to standard therapy.
- Administer sodium bicarbonate. Dose: 1 to 2 mEq/kg
bolus
- Ventricular Arrhythmias
- Sodium bicarbonate is the most effective treatment
- Treat refractory arrhythmias with lidocaine as per ACLS guidelines.
- Phenytoin may be considered as a third- or fourth-line agent. Phenytoin has been shown to increase the incidence of VT. Dose: Load at 15 to 18 mg/kg infused at < 50 mg/min
- In a hemodynamically unstable patient, attempt the preceding measures along with direct current counter shock. Follow ACLS guidelines for all patients.
- Seizures
-
Diazepam is the preferred drug treatment.
Dose: Adult 5 to 10 mg IV; may repeat every 15 minutes up to 30 mg
PEDS: Child: 0.25 to 0.4 mg/kg/dose IV up to 10 mg/dose - Consider phenytoin or phenobarbital (loading dose: 10 to 20 mg/kg) as second-line agents. Animal studies indicate that phenobarbital may be slightly more efficacious than phenytoin.
- Refractory seizures may require paralyzing agents, pentobarbital, or general anesthesia.
- Use of flumazenil to reverse the effects of a benzodiazepine for patients with a concomitant TCA ingestion is contraindicated due to the potential for precipitation seizures.
- Physostigmine may be used in refractory seizures. However, because of its potential to cause severe complications in TCA ingestions, its use is not recommended without consultation with a poison center toxicologist.
-
Diazepam is the preferred drug treatment.
- Hypotension
- Trendelenburg position and IV fluids
- Norepinephrine is the preferred drug for treatment. Dose: 0.1 to 0.2 µg/kg/min initially and then titrate.
- Consider dobutamine if the cardiac output is low and
the pulmonary wedge pressure is elevated beyond 18 mm Hg.
Dopamine may increase the incidence of cardiac arrhythmias and exacerbate beta-adrenergic-mediated vasodilation, which will theoretically worsen hypotension. Dopamine is considered a third-line agent. Dose: 2 to 5 µg/kg/min initially and then titrate. - If all of the preceding measures have been tried and the patient remains hypotensive, consider the use of an intra-aortic balloon.
- Enhancing Elimination
- Forced diuresis and hemodialysis are not effective in
removing TCAs.
In the past, hemoperfusion has been used with limited success for critical cases. - Monitoring
- Check vital signs frequently.
- Monitor the patient for a minimum of 6 hours. If symptoms develop, continue monitoring until the patient is asymptomatic and arrhythmia-free for 24 hours.
- Repeat a 12-lead ECG every 2 to 3 hours or as needed per patient.
- Repeat the ABCs every 2 to 4 hours for patients undergoing alkalinization. The goal is to maintain arterial pH at 7.45 to 7.55.
- Monitoring of urine pH plays no role in management.
- Check bowel sounds to govern use of repeat dose AC.
- If respiratory complications develop, obtain chest radiograph and repeat within the following 24 hours.
- Check fluid and electrolyte status frequently.
- TCA levels are not useful in the initial management of TCA poisoning. However, they may be of benefit if the diagnosis is unclear. Serum and urine drug screens may be useful if you suspect co-ingestants.