Tricyclic Antidepressants

GENERAL PRINCIPLES

• TCAs have fallen out of favor as first-line treatment for major depressive disorder due to their significant toxicity in overdose.

• TCAs are still prescribed for depression as second-line agents and are also utilized for migraine prophylaxis, neuropathic pain, sleep, and pruritus.

• A number of other medications are structurally homologous to the TCAs and have similar effects in overdose: diphenhydramine and other first-generation antihistamines, cyclobenzaprine (does not cause cardiac toxicity or seizure in overdose), carbamazepine (cerebellar dysfunction also present in overdose).

Pathophysiology

TCAs antagonize a wide variety of receptors, ion channels, and pumps in overdose. Their actions on these molecular targets predict their clinical effects.

• Serotonin and norepinephrine reuptake pumps: may contribute to the development of serotonin syndrome

• Cardiac sodium channel: QRS prolongation, ventricular dysrhythmias, cardiogenic shock

• IKr potassium channel: QT interval prolongation

• Muscarinic acetylcholine receptor: antimuscarinic toxidrome

• H1 histamine receptor: somnolence

• Alpha-1 adrenoceptor: peripheral vasodilation, hypotension, tachycardia

• GABA-A receptor: seizures

DIAGNOSIS

Clinical Presentation

• Onset of toxicity is rapid—patients typically become ill within 1-4 hours of ingestion, and onset of toxicity after 6 hours is very rare. Recovery is also typically rapid (usually within 24 hours unless hypoxic end-organ injury has occurred).

• Tachycardia is invariably present unless there are co-ingestants that depress the heart rate, or the patient is moribund.

• Physical examination will demonstrate evidence of the antimuscarinic toxidrome: delirium, mydriasis (may be absent early in the clinical course), dry mucous membranes, anhidrosis, absent bowel sounds, and urinary retention.

• Seizures are common in severe poisoning.

• Hypotension, dysrhythmias, shock, and cardiac arrest may occur.

Diagnostic Testing

LABORATORIES

• Serum TCA concentrations have no role in the management of acute TCA poisoning because they are not predictive of severity of illness.

• Obtain serial blood gases and electrolytes in patients treated with sodium bicarbonate (see below).

ELECTROCARDIOGRAPHY

• Electrocardiography is an essential tool in the risk-stratification of patients with TCA poisoning.

î A QRS interval of lt;100 ms suggests that the patient is not at risk of seizures or ventricular dysrhythmias.

î A QRS interval #8805;100 ms—or, in patients with preexisting QRS prolongation due to conduction system disease, a significant increase in the QRS duration—indicates risk of seizures and/or dysrhythmias. ¹⁶

î An RSR' pattern in aVR also predicts significant toxicity. ¹⁷

TREATMENT

• The mainstay of treatment is sodium bicarbonate.

î Sodium bicarbonate is indicated in patients with QRS gt; 100, seizures, dysrhythmias, or shock.

î Sodium bicarbonate provides a sodium load to overwhelm cardiac sodium channel blockade, and also provides alkalinization, which may reduce TCA binding to cardiac sodium channels.

î Sodium bicarbonate should be administered as a bolus or series of boluses of 1-2 mEq/kg, titrated rapidly to effect, followed by an infusion at twice the maintenance rate.

#9632; The goal is to narrow the QRS to lt;100 ms (or to the patient's baseline) and reverse shock.

#9632; Avoid severe alkalemia (pH gt; 7.55); if alkalemia becomes problematic and further treatment is required, hypertonic saline may be used.

• Treat seizures with benzodiazepines or other directly GABAergic agents.

• Patients with shock or dysrhythmias that do not immediately improve with sodium bicarbonate may benefit from additional interventions:

î Norepinephrine and vasopressin may be used for hypotension that is unresponsive to sodium bicarbonate.

î Lidocaine may be used for refractory shock or dysrhythmias at usual cardiac doses; this is thought to displace the TCA from the cardiac sodium channel.

î Intravenous lipid emulsion (bolus of 1.5 cc/kg, max 100 cc, followed by infusion of 0.25 cc/kg/min ?20 minutes) may also be considered in patients with refractory shock or dysrhythmias.

• Intubation and mechanical ventilation is frequently necessary in critically ill TCA-poisoned patients with profound encephalopathy or repeated seizures.

• VA ECMO may be considered as a last resort for patients with refractory cardiovascular collapse.