Tricyclic Antidepressant Overdose

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Amoxapine is unique in having a fourth ring as a side structure, but retains the classic three-ring nucleus of the tricyclics. Maprotiline hydrochlo- ride, the only ...

Concepts in Emergency and Critical Care Carlotta M. Rinke, MD, Section Editor

Tricyclic Antidepressant Overdose A Review David A. Frommer, MD; Kenneth W. Kulig, MD; John A. Marx. MD: Barry Rumack, MD

Significant advances in diagnosis and management of tricyclic antidepressant overdose have occurred in recent years. This article reviews epidemiologic, pharmacologic, and therapeutic information to provide a systematic approach to these potentially life-threatening overdoses. The tricyclics are discussed as a group, with individual drugs specified when established differences exist. (JAMA 1987;257:521-526)

0 true apothecary Thy drugs are quick. Shakespeare W: Romeo and Juliet, act V, scene 3, line 119

SYNTHESIS of the forerunner of the first tricyclic antidepressant (TCA), iminodibenzyl, occurred in the late 19th century, with investigation of its derivatives beginning in the late 1940s.' Imipraznine hydrochloride, which is chemically similar to the phenothiazines, was selected for further trials in psychotic patients as a result of its . sedative-hypnotic effects. Although ineffective in treating psychoses, it was fortuitously discovered in 1957 to be quite effective in treating endogenous depression. In 1958, initial reports in the American literature demonstrated that 83% of depressed patients taking TCAs significantly improved.' By 1959, lethal overdoses were first reported. CHEMICAL STRUCTURE

The term tricyclics is derived from the three-ring chemical structure of the central portion of the molecule. Amitriptyline hydrochloride and imipramine are prototypes (Fig). Three carbon substituents are found on the terminal From the Department of Emergency Medicine, Boston City Hospital (Dr Frommer); the Clinical Toxicology Fellowship Program (Dr Kulig) and the Department of Pediatrics (Dr Rumack), University of Colorado Medical School, Denver; and the Rocky Mountain Poison and Drug Center (Drs Kulig and Rumack) and the Department of Emergency Medicine (Dr Marx), Denver General Hospital. Reprint requests to Department of Emergency Medicine, Boston City Hospital, 818 Harrison Ave, Boston, MA 02118 (Dr Frommer).


23/30, 1987—Vol 257, No. 4

nitrogen of their side chains, thus classifying them as tertiary amines within the tricyclic class. The pharmacologically active demethylated metabolites, nortriptyline hydrochloride and desipramine hydrochloride, retain two carbon substituents on the terminal nitrogen of the side chain, and are therefore secondary amines. Doxepin hydrochloride, trimipramine maleate, and protriptyline hydrochloride have minor alterations of the basic tricyclic structure, but are similar in their efficacy and toxicity. Amoxapine is unique in having a fourth ring as a side structure, but retains the classic three-ring nucleus of the tricyclics. Maprotiline hydrochloride, the only tetracyclic currently available in the United States, has a similar toxicity profile to the TCAs and will therefore be included in this discussion. EPIDEMIOLOGY

The annual incidence of TCA overdose in the United States has been estimated at 500 OW.' Tricyclics are responsible for a disproportionate share of both intensive care unit (ICU) admissions and mortality when compared with other drug ingestions, and probably represent the most common lifethreatening drug ingestion worldwide. In one series, over 50% of serious overdoses resulting in admission to an adult ICU involved TCAs. 4 A typical patient profile has been described for those TCA ingestions resulting in fatal outcomes. These patients are likely to be female, between 20 and 29 years old, single, employed,

living alone, and without prior suicide attempts or history of drug abuse.' Data on TCA mortality are difficult to interpret because published series frequently select very different types of patients, ranging from asymptomatic children at home to critically ill adults in an ICU setting. Thus, mortality figures have ranged from 0% to 15% (Table 1). In both the 1983 and 1984 annual reports of the American Association of Poison Control Centers, TCAs were the number one cause of death from drug ingestion.'• A retrospective review of coroner's records determined that over 70% of successful TCA suicides are pronounced dead without ever reaching a health care facility.' The magnitude of this problem is thus fax greater than series from poison centers or hospitals suggest. PREVENTION AND DEVELOPMENT OF NEWER CYCLIC ANTIDEPRESSANTS

Tricyclic antidepressants are effective therapy for endogenous depression and are widely prescribed. Therefore, they are frequently available to suicideprone patients. Since TCAs are also widely prescribed as treatment for childhood enuresis, accidental as well as intentional overdoses occur.' A typical therapeutic dosage of a TCA is 2 to 4 mg/kg/d, while 15 to 20 mg/kg is thought to be potentially lethal.' To place this into pediatric perspective, for a child weighing 10 kg, as few as four 50-mg tablets may be fatal. Thus, preventive measures must include limiting amounts of nonrefillable prescriptions, safe packaging, and limiting access to medication by "poisonproofing" the home. Each of these measures may lessen the number of serious Advisory Panel: Mickey Stewart Eisenberg, MD, Seattle; Joseph E. Parrillo, Jr, MD, Bethesda. Md; and Donald D. Trunkey, MD. San Francisco.

Tricyclic Antidepressants—Frommer et al


Table 1.—Incidence of Significant Clinical Fincings After Tricyclic Antidepressant Overdose in Published Case Series'

Tertiary Amines

Finding Sinus tachycardia (heart rate, X100 beats , minit


CHCH 2C1-12N(0-1,)2



Amitriptyline Hydrochloride Endep, SK-Amitriptyline Hydrochloride) Secondary Amines

ONO Desipramine Hydrochloride (Norpramin, Pertofrane)

/–"N lU N=C

OHO o•0 #01


Hypotension (systolic blood pressure.

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