TRICYCLIC ANTIDEPRESSANTS INTOXICATION

TRICYCLIC ANTIDEPRESSANTS INTOXICATION

Amitriptilina, nortriptilina, imipramina, clomipramina, trimipramina, amoxapina, doxepina

Background: Tricyclic antidepressants (TCAs) cause the overwhelming majority of antidepressant poisoning resulting in morbidity and mortality. Of the newer generation cyclic antidepressants, only amoxapine and maprotiline have strong potential to cause serious morbidity.

Pathophysiology: Although the mechanism by which TCAs exert their therapeutic effects is unclear, they are thought to function by inhibiting the presynaptic reuptake of biogenic amines (serotonin and norepinephrine). TCAs can be divided into first- and second-generation antidepressants, with second-generation antidepressants exerting more selective effects on serotonin and dopamine reuptake.

TCAs produce a wide variety of toxic effects; the most severe toxicity occurs in the cardiovascular system, the peripheral nervous system (PNS), and the central nervous system (CNS).

Cardiovascular toxicity results from direct myocardial depression, cardiac conduction disturbances, effects on peripheral vasomotor tone, and changes in the autonomic nervous system.

TCAs bind to and inhibit the fast sodium channel, thereby slowing phase O depolarization in His-Purkinje and ventricular myocytes (quinidinelike effect). This results in slowed cardiac conduction (eg, prolonged QRS on the ECG), impaired cardiac contractility (via impaired cellular calcium entry), and possible ventricular dysrhythmias (caused by nonuniform sodium channel blockade).

TCAs block phase 3 repolarization in His-Purkinje myocytes, resulting in prolonged QTc on the ECG. Specifically, TCAs inhibit outward potassium current by blocking potassium channels in phase 3, which ultimately results in prolongation of the QT interval. Torsade de pointes is uncommon because the anticholinergic effects of these drugs produce offsetting tachycardia.

TCAs block L-type voltage-sensitive calcium channels; negative inotropic effects and conduction disturbances may, in part, be mediated by these effects.

TCAs inhibit alpha1-adrenergic receptors, resulting in peripheral vasodilation and orthostatic hypotension. These effects mediate, in part, refractory hypotension observed with severe TCA poisoning.

TCAs produce tachycardia from competitive blockade at muscarinic acetylcholine receptors.

TCAs block norepinephrine reuptake in the CNS and PNS (autonomic ganglia). Initially, this may result in hypertension and tachycardia. However, with prolonged blockade of reuptake, norepinephrine is depleted from the presynaptic nerve terminal (most norepinephrine released is from a recycled neurotransmitter), which results in refractory hypotension and bradycardia.

Neurologic toxicity results from CNS blockade of muscarinic acetylcholine, H1-histamine, and gamma-aminobutyric acid (GABA) receptors; inhibition of norepinephrine, serotonin, and dopamine reuptake; and blockade of neuronal fast sodium channels. Specifically, seizures likely are mediated by inhibition of norepinephrine reuptake, neuronal fast sodium channel blockade, and GABA and N-methyl-D-aspartate (NMDA)-glutamate receptor blockade.

TCAs are potent, competitive antagonists at central and peripheral muscarinic acetylcholine receptors; they readily produce anticholinergic stigmata, particularly central anticholinergic delirium.

CLINICAL

Symptoms typically progress rapidly. Onset of signs and symptoms often occurs within 2 hours following ingestion, and life-threatening effects almost always are evident 6 hours postingestion. Not uncommonly, patients present asymptomatically or minimally symptomatic and progress to life-threatening cardiovascular and neurologic toxicity within 1 hour.

• CNS

• Agitation, which can proceed rapidly to lethargy, stupor, and coma

• Coma, usually resolves by 24 hours

• Seizures in 10-25% of patients; can occur without preceding mental status changes; risk of status epilepticus with amoxapine and maprotiline

• Myoclonus and/or choreoathetosis in 40% of patients; should not be confused with or treated as seizures

• Cardiac

• Hypotension

• Dysrhythmias

• Conduction blocks

• Hypertension (early); caused by inhibition of norepinephrine reuptake

• Pulmonary

• Hypoventilation

• Aspiration

• Adult respiratory distress syndrome (ARDS)

• Anticholinergic

• Tachycardia

• Mydriasis

• Dry skin and/or mucous membranes

• Hyperthermia

• Decreased gastric motility and/or urinary retention

Physical: Mostly caused by anticholinergic effects

• Tachycardia

• Hyperthermia

• Agitation (early)

• CNS depression

• Mydriasis

• Dry mucous membranes

• Decreased or absent bowel sounds

Causes:

• Cardiac

• Quinidinelike effects from blockade of fast sodium channels

• Tachycardia caused by muscarinic anticholinergic effects

• Hypotension as a result of dysrhythmias, alpha-adrenergic blockade, cardiac conduction abnormalities and direct myocardial depression, autonomic neuron neurotransmitter depletion (caused by reuptake blockade), and capillary leakage

• Pulmonary - Hypoxia caused by hypoventilation, aspiration, and capillary leakage

• CNS - Signs and symptoms result from blockade of H1-histamine, muscarinic cholinergic, GABA, and NMDA-glutamate receptors, neuronal fast sodium channel blockade, and reuptake blockade of monoaminergic neurotransmitters

DIFFERENTIAL DIAGNOSIS

Delirium Tremens
Neuroleptic Malignant Syndrome
Shock, Cardiogenic
Shock, Septic
Subarachnoid Hemorrhage
Subdural Hematoma
Toxicity, Beta-blocker
Toxicity, Calcium Channel Blocker
Toxicity, Clonidine
Toxicity, Cocaine
Toxicity, Digitalis
Toxicity, Isoniazid
Toxicity, Monoamine Oxidase Inhibitor
Toxicity, Neuroleptic Agents

Lab Studies:

• A toxicology screen may be helpful if concurrent ingestion is possible or symptoms are not fully explained by TCAs. An abbreviated screen for acetaminophen and aspirin usually is sufficient.

• Quantitative screening or tricyclic serum concentrations rarely are worthwhile in the acute setting; they do not always correlate with the severity of ingestion and are not available in a timely manner. Severity of toxicity correlates more closely with the ECG. ECG can be used to predict the likelihood of subsequent serious cardiac (eg, ventricular arrhythmia) and neurologic (eg, seizure) toxicity and can be used in conjunction with physical findings to guide therapy. On the ECG, a QRS duration greater than 100 milliseconds is associated with a significant incidence of seizures, and a QRS duration greater than 160 milliseconds is associated with high incidence of ventricular arrhythmias. On the ECG, an R-wave greater than 3 mm on an aVR is one of the earliest signs of cardiac conduction disturbances from a TCA. Prospective data suggest that the typical period of QRS prolongation after severe tricyclic antidepressant ingestion is 12-18 hours but may be as long 3 days.

• Electrolytes should be used to screen for anion gap acidosis that exists with other ingestions and to look for metabolic disturbances that can alter mental status, cause seizures, or change the ECG.

• Serum pH

• Attempt to maintain an alkaline environment (pH = 7.45-7.55).

• Acidemia allows a greater degree of fast sodium channel binding by the TCA and produces a wider QRS on the ECG.

Imaging Studies:

• Obtain a chest radiograph after intubation or if evidence of hypoxia, aspiration, or ARDS is present.

Other Tests:

• ECG

• ECG is the single most important test for diagnosis and prognostication.

• In one study, a QRS greater than 100 milliseconds predicted seizures in 34% of patients, and a QRS greater than 160 milliseconds predicted ventricular arrhythmias in 50% of patients.

• A terminal R wave in aVR greater than 3 mm showed an 81% sensitivity and 73% specificity for seizures or arrhythmias.

• An R/S ratio of greater than 0.7 in aVR also is associated with major complications.

• Rightward deviation of QRS vector (a negative deflection in lead 1 and a positive final deflection in lead aVR) is associated with TCA toxicity.

• Case reports have described ECGs in TCA toxicity mimicking acute myocardial infarction and the Brugada syndrome.

Procedures:

• Gastric lavage

• No clear consensus on the usefulness of gastric lavage exists; however, it generally is recommended for more than a trivial TCA ingestion or minimal symptomatology within 1.5-2 hours postingestion.

• If patient exhibits declining mental status, perform intubation first. Administer activated charcoal to all patients. Orogastric lavage may be helpful if initiated within 60 minutes of ingestion in a patient who is obtunded or deteriorating rapidly while in the emergency department. Always follow orogastric lavage with activated charcoal. Orogastric lavage is acceptable therapy but not absolutely required for obtunded patients.

• Endotracheal intubation

• Aggressively manage airway for patients who present agitated or with a decreased level of consciousness. For these patients, endotracheal intubation may be required before gastric lavage or activated charcoal to prevent aspiration.

• The patient should be hyperventilated after intubation. Check proper placement with a chest x-ray. The target PaCO₂ is 30 mm Hg by ABG following intubation.

• A central venous line may be helpful in administering medication and monitoring fluid status.

• Hemodialysis

• Hemodialysis and hemoperfusion are not effective and not recommended for TCA poisoning.

• The poor efficacy of hemodialysis probably is because only a small amount of free TCA is present in the serum. TCA is highly bound to serum proteins and tissues, with a large volume of distribution.

• Only anecdotal evidence supports the efficacy of an intraaortic balloon pump (IABP) for intractable hypotension.

TREATMENT:

Prehospital Care: Rapidly transport all patients with suggested TCA ingestion to the hospital because rapid, cataclysmic, clinical deterioration may occur shortly after overdose.

• Dysrhythmias

• Sodium bicarbonate is the first-line therapy if TCA ingestion is known or strongly suspected. 1-2 mEq/kg IV bolus, followed by an IV drip of 1000 cc of D5W to which 100-150 mEq of sodium bicarbonate has been added; initiate drip rate at 3 times maintenance IVF rate and titrate drip rate to urinary pH (target >8).

• Procainamide, quinidine, beta-blockers, and calcium channel blockers are contraindicated.

• Hypotension
• Hypotension is treated with sodium bicarbonate and intravenous fluids.
• A less well studied alternative is hypertonic saline. Hypertonic saline has been shown to reverse cyclic antidepressant cardiotoxicity and may be especially useful as an alternative to sodium bicarbonate in the hypotensive patient.
• Vasopressors are recommended for refractory hypotension. Norepinephrine 0.05-0.15 mcg/kg/min IV infusion; titrate to effect

• A few case reports have described efficacy with glucagon for hypotension not responsive to usual measures.

Consultations:

• Consider consulting a regional poison control center or medical toxicologist.

• Patients with abnormal vital signs or mental status changes will need intensive care unit (ICU) care, which may require the consultation of an intensivist.

Complications:

• CNS sequelae

• Seizures

Prognosis:

• Prognosis generally is favorable without long-term CNS or cardiovascular sequelae. Most fatalities occur within the first 24 hours; survival beyond this time suggests a favorable prognosis unless severe hypoxia was present before initial treatment.

• A small subset may have prolonged neurologic sequelae after status seizures or persistent hypotension.

• Patients who remain asymptomatic following 6 hours of emergency department observation are unlikely to develop toxicity