Tricyclic antidepressants drug overdose

Vohra, J. D. (1974) Cardiovascular abnormalities following tricyclic antidepressant drug overdose. Drugs, 7, 323. 

Revicki DA, Palmer CS, Phillips SD, et al (1997). Acute medical costs of fluoxetine versus tricyclic antidepressants a prospective multicentre study of antidepressant drug overdoses. Pharmacoeconomics 11, 48—55. 

The cardiac toxicity of tricyclic antidepressants in overdose has been a source of continued concern. Undesirable cardiovascular effects, besides representing a major therapeutic limitation for this category of drugs, delineate an area in which tricyclic compounds with novel structures, as well as second-generation antidepressants, may have significant advantages. The cardiovascular effects of tricyclic antidepressants and the new generation of antidepressants have been reviewed (SEDA-18,16) (16). 

Marshall, J.B. and Forker, A.D., Cardiovascular effects of tricyclic antidepressant drugs therapecutic usages, overdose and management of complications. Am. Heart J., 103, 401-414, 1982. 

Gard, H., Knapp, D., Walle, T., Gaffney, T. and Hanenson, I. (1973) Qualitative and quantitative studies on the disposition of amitriptyline and other tricyclic antidepressant drugs in man as it relates to the management of the overdosed patient. Clin. Tox., 6, 571. 

Our understanding of the mechanism of antidepressant action has evolved over time. In the late 1950s, the first molecules introduced for the treatment of MDD were the so-called tricyclic antidepressants (TCAs), represented by imipramine (7). Subsequent experience with TCAs supported the role of both 5-HT and NE, although these drug molecules act on other neuronal systems as well. Despite their elfectiveness, the use of TCAs was limited due to poor tolerability and safety concerns, in particular, severe toxicity when taken in overdose. 

Tricyclic antidepressants are cardiotoxic, inducing tachycardias and an increased tendency for ventricular arrhythmias with high doses. This dose dependent cardiotoxicity gives these agents a low therapeutic index. Overdoses are characterized by cardiac conduction disturbances, hyperpyrexia, hypertension, confusion, hallucinations, seizures and coma and there is a high mortality rate in suicide attempts. Depressed patients should therefore not be given more than one week supply of these drugs. 

A number of drugs in addition to atropine and scopolamine have antimuscarinic properties. Tbese include tricyclic antidepressants, phenothiazines, and antihistamines. Physostigmine has been used in the treatment of acute toxicity produced by these compounds. However, physostigmine can produce cardiac arrhythmias and other serious toxic effects of its own, and therefore, it should be considered as an antidote only in life-threatening cases of anticholinergic drug overdose. 

Toxic effects, such as seizures and arrhythmias, of other drugs taken in overdose, especially tricyclic antidepressants, may emerge with reversal of sedative effect of benzodiazepines,... 

Boehnert, M.T. and Lovejoy, F.H. (1985) Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after and acute overdose of tricyclic antidepressants. N Engl Med 313 474 79. 

This is the most widely prescribed group of antidepressant drugs, essentially because of their safety in overdose and their relative lack of adverse effects in comparison to the tricyclic antidepressants. They are all inhibitors of reuptake of 5-HT with no significant effect on reuptake of noradrenaline (norepinephrine). The different potencies of the drugs currently available are illustrated in Table 10.5, together with details of other aspects of their pharmacology. 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

Tricyclic antidepressants (eg, amitriptyline, desipramine, doxepin, many others see Chapter 30) are among the most common prescription drugs involved in life-threatening drug overdose. Ingestion of more than 1 g of a tricyclic (or about 15-20 mg/kg) is considered potentially lethal. 

Long-term health effects from antidepressants include the increased risk of deliberate self-harm (DSH), which may occur more with the SRRIs than the tricyclic antidepressants. The self-harm may occur by overdosing with the prescribed drug, but is more frequently by other means. 

Cardiovascular toxicity is also frequently encountered in poisoning. Hypotension may be due to depression of cardiac contractility hypovolemia resulting from vomiting, diarrhea, or fluid sequestration peripheral vascular collapse due to blockade of -adrenoceptor-mediated vascular tone or cardiac arrhythmias. Hypothermia or hyperthermia due to exposure as well as the temperature-dysregulating effects of many drugs can also produce hypotension. Lethal arrhythmias such as ventricular tachycardia and fibrillation can occur with overdoses of many cardioactive drugs such as ephedrine, amphetamines, cocaine, tricyclic antidepressants, digitalis, and theophylline. 

Yuan CM, Spandorfer PR, Miller SL et al (2003) Evaluation of tricyclic antidepressant false positivity in a pediatric case of cyproheptadine (periactin) overdose. Ther Drug Monit 25 299-304... 

Tragically, while the older antidepressant drugs cannot prevent suicide and can cause it, in relatively small amounts, they can become lethal instruments in the hands of suicidal patients. As little as 1 week s supply of most tricyclics can cause death, often due to cardiac dysfunction. In combination with other drugs, their lethality increases. Thus millions of depressed, suicidal patients are given the tool with which to kill themselves. By 1981, the tricyclics were overtaking the barbiturates as the medications most frequently involved in serious overdoses ( Tricyclics, 1981). The tricyclics remain a major public health problem as agents of suicide (Henry et al., 1995). 

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