Antidepressants, Tricyclic
Tricyclic antidepressants taken in overdose by suicidal patients are a substantial cause of poisoning hospitalizations and deaths. Currently available tricyclic antidepressants are described in Table II–7. Amitriptyline also is marketed in combination with chlordiazepoxide (Limbitrol) or perphenazine (Etrafon or Triavil). Cyclobenzaprine (Flexeril), a centrally acting muscle relaxant (See Skeletal Muscle Relaxants), is structurally related to the tricyclic antidepressants but exhibits minimal cardiotoxic and variable CNS effects. Newer, noncyclic antidepressants are discussed in Antidepressants, General (Noncyclic). Monoamine oxidase inhibitors are discussed in Monoamine Oxidase Inhibitors.
Mechanism of toxicity. Tricyclic antidepressant toxicity affects primarily the cardiovascular and central nervous systems.
Cardiovascular effects. Several mechanisms contribute to cardiovascular toxicity:
Anticholinergic effects and inhibition of neuronal reuptake of catecholamines result in tachycardia and mild hypertension.
Peripheral alpha-adrenergic blockade causes vasodilation and contributes to hypotension.
Membrane-depressant (quinidine-like) effects cause myocardial depression and cardiac conduction disturbances by inhibition of the fast sodium channel that initiates the cardiac cell action potential. Metabolic or respiratory acidosis may contribute to cardiotoxicity by further inhibiting the fast sodium channel.
Central nervous system effects. These effects result in part from anticholinergic toxicity (eg, sedation and coma), but seizures are probably a result of inhibition of reuptake of norepinephrine or serotonin in the brain or other central effects.
Pharmacokinetics. Anticholinergic effects of these drugs may retard gastric emptying, resulting in slow or erratic absorption. Most of these drugs are extensively bound to body tissues and plasma proteins, resulting in very large volumes of distribution and long elimination half-lives (see Tables II–7 and II–61). Tricyclic antidepressants are metabolized primarily by the liver, with only a small fraction excreted unchanged in the urine. Active metabolites may contribute to toxicity; several drugs are metabolized to other well-known tricyclic antidepressants (eg, amitriptyline to nortriptyline, imipramine to desipramine).
Toxic dose. Most of the tricyclic antidepressants have a narrow therapeutic index, so that doses of less than 10 times the therapeutic daily dose may produce severe intoxication. In general, ingestion of 10–20 mg/kg is potentially life-threatening.
Clinical presentation. Tricyclic antidepressant poisoning may produce any of three major toxic syndromes: anticholinergic effects, cardiovascular effects, and seizures. Depending on the dose and the drug, patients may experience some or all of these toxic effects. Symptoms usually begin within 30–40 minutes of ingestion but may be delayed owing to slow and erratic gut absorption. Patients who are awake initially may abruptly lose consciousness or develop seizures without warning.
Anticholinergic
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