Tricyclic Antidepressant Overdose R. Kevin Smith, DO, and Karen O'Mara, DO Chicago, Illinois Overdose from tricyclic antidepressants (TCAs) is increasing. TCAs are well absorbed orally, highly protein bound, and high­ ly lipid soluble. Clinical features of poisoning with TCAs occur within 12 hours of ingestion, usually after a dose of 20 mg/kg or more. Clinical symptomatology involves various anticholiner­ gic, central nervous system, and cardiovascular effects. Car­ diovascular toxicity accounts for the majority of the fatalities and may include a hyperdynamic response, various arrhyth­ mias and heart blocks, or severe hypotension. Prolongation of the QRS interval of 10 msec or more implies severe toxicity. Many factors limit the usefulness of drug levels in the over­ dosed patient. Treatment revolves around good supportive care and general poisoning management. The physician should no longer use physostigmine precipitously. Sodium bicarbon­ ate is effective in treating many of the cardiovascular compli­ cations. Other cardiac drugs are used but with varying effi­ cacy. Patients with significant signs or symptoms of toxicity require monitored hospitalization until clinically free of mani­ festations for 24 to 48 hours. Overdosage with tricyclic antidepressant drugs sion, coma with respiratory arrest, convulsions, has been reported as early as 1959, one year after complex arrhythmias, and myocardial depression. their introduction to psychiatry. Because of the The purpose of this paper is to review the current complex central and peripheral toxic effects of body of knowledge on tricyclic antidepressants these drugs, the physician who treats the over­ (TCAs) and their toxicity. Increased understand­ dosed patient may find himself managing hypoten- ing of the mechanisms of toxicity, pharmacologic interactions, and clinical manifestations allows the outline of a rational mode of therapy for patients who present with TCA overdose. The need for a safe, effective pharmacologic From the Department of Emergency Medicine, Mercy Hos­ therapy for endogenous depression led to early ac­ pital and Medical Center, Abraham Lincoln School of Medi­ cine, University of Illinois College of Medicine, and the ceptance of TCAs in the United States more than Department of Emergency Medicine, University of Chicago two decades ago. The subsequent reported inci­ Hospitals and Clinics, Chicago, Illinois. Requests for re­ prints should be addressed to Dr. R. Kevin Smith, Depart­ dence of profound toxic effects from overdose ment of Emergency Medicine, Mercy Hospital and Medical with these drugs has apparently not outweighed Center, Stevenson Expressway at King Drive, Chicago, IL 60616. the benefits, as these drugs are prescribed more 0094-3509/82/080247-07$01.75 ® 1982 Appleton-Century-Crofts THE JOURNAL OF FAMILY PRACTICE, VOL. 15, NO. 2: 247-253, 1982 247 TRICYCLIC ANTIDEPRESSANT OVERDOSE than 24 million times annually in the United arrhythmic, “ quinidine-like” effect.8-9 In toxic in­ States. The current indications for use of these gestions, the list is expanded to include myocar­ drugs are endogenous depression and adjunctive dial and central nervous system depression. therapy for enuresis in children.1 The increasing incidence of overdose with these drugs correlates with prescribing practices, making them available to two high-risk populations: the accidental inges­ tion2-3 in children less than five years of age, and Effects at Therapeutic Doses the adolescent and adult suicidal ingestion groups. Sedation Tricyclics resemble phenothiazines chemically in this effect. The tertiary amines (imipramine, ami­ triptyline, and doxepin) are more sedative than are the secondary amines.4 These sedative effects may result from their potent antihistaminic properties.10 Pharmacology Tricyclic antidepressant drugs have a three-ring nucleus (hence the term tricyclic), consisting of a seven-membered central ring bounded by two ben­ zene rings. Imipramine and amitriptyline each Anticholinergic Effects contain an aminopropyl side chain with three sub­ Both central and peripheral manifestations are stitutions. These drugs are the parent tertiary seen. Tricyclics are competitive antagonists of amine compounds. Demethylation of these parent acetylcholine at the neuroreceptor site. Anticho­ drugs produces the secondary amines, desipra- linergic manifestations are common at therapeutic mine and nortriptyline, that are also pharmacolog­ doses and include dry mouth, constipation, uri­ ically active.4 Doxepin (a tertiary amine) and nary retention, and mydriasis. protriptyline differ from the other TCAs in their central ring structure. These six drugs are the most commonly prescribed in the United States and are marketed under a variety of brand names. There has been recent approval of two other TCAs, tri- Blockage of the Amine Pump mipramine and amoxapine, and one tetracyclic One popular hypothesis for endogenous de­ antidepressant, maprotiline. Trimipramine is pression is the norepinephrine depletion hypothe­ structurally and pharmacologically similar to imip- sis. According to this hypothesis, symptoms of ramine, while amoxapine may possess a more depression are correlated with the level of norepi­ rapid action but less potent activity compared with nephrine (and serotonin) in the brain. Tricyclics the other TCAs.5 Maprotiline’s antidepressant ac­ block the reuptake of norepinephrine at the syn­ tivity is similar to the older compounds,6 but apse, allowing for a longer sojourn of this neuro­ it may possess more adverse effects, particularly transmitter. It is thought that this mechanism may seizures.7 be the means by which tricyclics influence de­ pressive symptoms.4 Recent work is emphasizing the changes in the pre- and postsynaptie receptor sensitivity as contributing to the antidepressant activity.11 Actions Four effects of therapeutic doses of tricyclics have been described: (1) sedation (phenothiazine- like effect), (2) central and peripheral anticholiner­ gic effects, (3) blockade of the presynaptic uptake Antiarrhythmic Effect of amine neurotransmitters, the perceived etiology A quinidine-like antiarrhythmic effect of tricy­ of the antidepressant action,4 and (4) the anti­ clics has been documented. In one study, imipra- 248 THE JOURNAL OF FAMILY PRACTICE, VOL. 15, NO. 2, 1982 TRICYCLIC ANTIDEPRESSANT OVERDOSE mine was shown to reduce atrial and ventricular Toxicologic Properties arrhythmias at therapeutic antidepressant levels.9 Acute tricyclic antidepressant ingestion in ex­ cess of 20 mg/kg has been associated with toxic manifestations of myocardial depression, serious arrhythmias, coma, and respiratory arrest. How­ ever, death has occurred in a child with a dose of 200 mg. The lowest known fatal dose in an adult is Pharmacokinetics reported at 500 mg, although survival is also re­ ported in an adult after an acute ingestion of 10 g.14 Tricyclic antidepressants are well absorbed oral­ Toxic sequelae are complex and relate in part to ly from the gastrointestinal tract and are rapidly the high lipid solubility of the drug and distribution distributed into tissue compartments because of into all body tissues, including the central nervous their high lipid solubility, reflected by their large system. volumes of distribution. The TCAs are highly Early toxic effects on the heart are mediated plasma protein bound (76 percent to 98 percent), through anticholinergic mechanisms and are seen with an alpha, acid glycoprotein as the major pro­ as narrow complex tachyarrhythmias. These may tein. Once a steady-state plasma drug level has be hemodynamically significant and require treat­ been established, there is a positive correlation ment. With larger doses direct myocardial de­ between drug level and clinical antidepressant pression with decreased contractility and resultant response. This varies between 50 and 170 ng/mL, hypotension are noted. His-Purkinje conduction is depending on the tricyclic.12 prolonged, and wide complex arrhythmias and Because of their high lipid solubility, tricyclics sinoatrial and atrioventricular blocks are seen. are reported to show tissue levels 10 times greater Ventricular ectopy and arrhythmias are common than plasma levels, and myocardial levels have and often refractory to treatment.15'20 been reported to be 40 to 200 times plasma levels. Toxic effects on the central nervous system can Children, with lower lipid stores, may have higher be mediated through anticholinergic mechanisms blood levels at similar milligram per kilogram and possibly through blockade of amine neurotrans­ doses, possibly enhancing toxic effects.12 mitter reuptake. Alteration in neurotransmitter The TCAs are metabolized by demethylation, ratio in the brain has been speculated as a possible oxidation and aromatic hydroxylation, and glucu- mechanism for the seizures and choreoathetosis ronidization via the hepatic microsomal enzyme commonly seen in TCA overdoses. Increased tox­ systems and are excreted in the urine. A small icity results in profound central nervous sys­ portion of the drug is excreted unchanged and is tem depression, although the mechanisms are detectable in the urine. The demethylated forms of speculative.21'23 amitriptyline, imipramine, and doxepin result in pharmacologically active metabolites. Enhancement of the hepatic microsomal en­ zymes will alter the rate of metabolism of TCAs. Substances that act in this way include barbitu­ rates, alcohol, and cigarettes and will increase the rates of metabolism of TCAs.4-12 Gastric secretion Plasma Drug