Tricyclic Antidepressants: An Overview for EMS (Part 1 of 3)

Author: Robert S. Cole, CCEMT-P

DISCLAIMER: Medicine is a constantly changing science and not all therapies are clearly established. New research changes drug and treatment therapies daily. The author, and publisher of this article have used their best efforts to provide information that is up-to-date and accurate and is generally accepted within medical standards at the time of publication. However, as medical science is constantly changing and human error is always possible, the authors, editors, and publisher or any other party involved with the publication of this article do not warrant the information in this article is accurate or complete, nor are they responsible for omissions or errors in the article or for the results of using this information. The reader should confirm the information in this article from other sources prior to use. In particular, all drug doses, indications, and contraindications should be confirmed in the package insert.

1 - Introduction:

Tricyclic Antidepressants (TCAs) have the distinction of being one of the most successful, and more lethal, antidepressants ever created. Toxic ingestions of TCAs are considered to be one of the more complex toxicological emergencies involving prescription drugs.

This article will review the incidence of TCA overdoses, the mechanisms that TCA’s cause morbidity and mortality, and treatment strategies.

2 - Incidence and epidemiology:

First used clinically in the 1950’s for depression, TCAs are a direct evolution from an even more hazardous antidepressant class, Monoamine Oxidase Inhibitors (MAOIs). With a comparatively safer profile, TCAs became the drug of choice for depression well into the 80’s. The advent of other antidepressant medications have limited its role to the moderately and severely depressed who are refractory to other therapies. While Imipramine was the first TCA synthesized, Amitriptyline (Elavil®) is perhaps the best known TCA. It also has approximately twice the mortality in an overdose setting as other TCAs of the same generation.

The spread of significantly safer, although arguably less effective, anti-depressant medications such as Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Serotonin Reuptake Enhancers (SSREs) have resulted in a significant decrease of use (and overdose) of TCAs. Use of benzodiazepines’ for depressive based anxiety have also spread. In fact, admissions to Drug Abuse Warning Network (DAWN) emergency departments related to TCAs have decreased over 40% since 1995. By comparison, Mono Amine Oxidase Inhibitors (MAOI’s) dropped over 90%, Phenothiazine Anti-psychotics by 86%, for the same period. Overdoses for SSRIs increased 30%, barbiturates increased 44% and benzodiazepines increased 38% for a similar period.

The incidence of pediatric overdoses involving TCA’s remain a significant cause of death. Most pediatric overdoses are unintentional, with a majority less than 6 years of age. While a child’s lower body weight translates to higher risk of toxicity, a 2001 study in Academic Emergency Medicine ( McFee, et al) showed that the majority of unintentional pediatric cases involved levels less than the therapeutic dose range of 2-5 mg/kg, and were predominately asymptomatic. This has not translated into guidelines for a “safe overdose” criteria in pediatrics because of the incidence of non-accidental overdoses (abuse and neglect).

Considering these statistics, it would seem that TCA overdoses are becoming a rarity. A resurgence of TCAs for other illnesses however, such as Neuropathic pain, various other chronic pain disorders, ADD, sleep disorders, and even bedwetting keeps this drug class very relevant to emergency medical professionals. Fortunately, patients with these other conditions have a comparatively lower risk of suicide.

Mortality from TCA overdose tends to be about 1-2%, the majority of fatalities resulting from cardiovascular collapse. The low threshold for toxicity and the potential for severe multi-system involvement make TCAs among the most serious agents for EMS personnel to manage.

3 - Basic Pharmacodynamics

Types of Tricyclics There are two general classes of TCAs. The tertiary amines and the secondary amines. The tertiary amines (Amitriptyline, Imipramine, Trimipramine and Doxepin), which have proportionally more effect in boosting serotonin than nor-epinephrine, produce more sedation, anticholinergic effects and orthostatic hypotension. Amitriptyline and doxepin are especially sedating.

Secondary amines (Nortriptyline, Desipramine, and Protriptyline) tend more toward enhancement of nor-epinephrine levels and hence toward irritability, over stimulation and disturbance of sleep.

The tertiary amines are more useful where depression is accompanied by sleep disturbance, agitation and restlessness; and the secondary amines may be preferable where the depressed patient is fatigued, withdrawn, apathetic and inert. There are other drugs, such as Amoxapine, a tricyclic dibenzoxazepine, and Maprotiline, a tetracyclic, which are different structurally but have a similar pharmacologic profile to TCAs.

How they work

There are three major neurotransmitters in the brain that have been shown to effect mental health, nor-epinephrine (also referred to as nor-adrenalin) , serotonin (5-hydroxy tryptamine. 5HT) , and dopamine. The stimulation, inhibition, and blocking of the re- uptake of these neuron-transmitters and their components are the foundation of most modern antidepressants today. TCAs affect all three, but predominantly exert influence over serotonin and nor-epinephrine.

TCAs inhibits the re-uptake of nor-epinephrine at the noradrenergic nerve endings and the re-uptake of serotonin at the serotoninergic nerve endings in the central nervous system. This results in an increased availability of serotonin and nor-epinephrine in the brain. It is this action that is suspected to be responsible for its antidepressant properties.

TCAs other effects

In addition, TCAs affect a number of other body systems that are of specific importance in an overdose situation. TCAs inhibit α1 adrenergic effects, H1 effects, and anti- cholinergic effects. More on TCAs toxic effects will be discussed later. TCAs also effect sodium flow in the myocardium, widen the QT interval, and there for are mutually contraindicated with other drugs that also widen the QT interval, such as Procainamide, Bretylium, and Amiodarone.

Absorption, Distribution, and Elimination

TCAs are rapidly absorbed across the GI track, and are very lipid soluble, resulting in a rapid and wide distribution through out the body. TCA’s do undergo first pass metabolism in the liver prior to distribution, however some studies suggest that up to 30% of the TCA lost in first pass metabolism is recirculated into the GI tract from the bile, to be reabsorbed.

Once absorbed, TCA’s are bound in the serum to protein, until they are off loaded at the target tissue. Of course, TCAs easily cross the blood brain barrier. In fact, TCA’s have a strong affinity for both the brain and myocardium, with tissue levels 40 times greater in the brain and 5 times greater in the myocardium than elsewhere.

The patients PH level also has an effect on the distribution of the TCA. Simply put, the more acidotic the patients serum is, the more TCA is bound up in the tissues. Even with out acidosis, the levels of TCAs in target tissue are far greater than that of “free” (serum protein bound) TCAs in found in plasma, indicating strong “bond” in these tissues.

This results lower correlation between plasma TCA serum lab values and TCAs actively bound in tissue doing damage (placing even more importance on getting a accurate estimate of TCA ingested). This also explains why strategies used in other toxic ingestions that increase elimination without addressing this bond (such as dialysis) are ineffective.

TCA’s are eventually metabolized in the liver, and excreted in the renal system. It is this renal elimination that is a key component of the treatment of the TCA overdose. Most TCA’s will take up to 36 hours to clear the body, unless other measures (such as bicarbonate therapy) is instituted.