Amitriptyline toxicity

Nattel S and Mittleman M (1984) Treatment of ventricular tachyarrhythmias resulting from amitriptyline toxicity in dogs. Journal of Pharmacology and Experimental Therapeutics 231 430—435. 

A number of other reports and studies clearly confirm that marked increases occur in the levels of amitriptyline, " clomipramine, desipramine, " imipramine " and nortriptyline, " accompanied by toxicity, if fluoxetine is added without reducing the dosage of the tricyclic antidepressant. Delirium and seizures have also been described, and a death has been attributed to chronic amitriptyline toxicity caused by fluoxetine. The pharmacokinetics of fluoxetine appear not to be affected by amitriptyline. ... 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

Additional ADRs linked to diet pills include psychosis myocardial ischemia drug interactions, such as the interaction of fenfluramine with imipramine, fenfluramine with amitriptyline or desipramine, or the toxic reaction between fluoxetine and phentermine and the release of serotonin while inhibiting its reuptake, contributing to hyperserotonin reactions. When the next craze takes hold of patients and their physicians, hopefully physicians and pharmacists will take a more vocal position and recommend restraint, xmtil some proof of efficacy and lack of toxicity is shown for new faddish off-label combinations. 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Selective serotonin re-uptake inhibitors such as paroxetine tend to cause less antimuscarinic side-effects and are less toxic in overdose than the tricylic antidepressants, such as amitriptyline. However, selective serotonin re-uptake inhibitors are more likely to cause gastrointestinal disturbances, such as nausea and vomiting, than tricylic antidepressants. Selective serotonin re-uptake inhibitors and tricylic antidepressants are equally effective. 

Determination of amitriptyline plasma concentrations is not routinely recommended but maybe useful in identifying toxicity, drug interactions, or noncompliance (adjustments in dosage should be made according to clinical response not... 

Thus, the patient with a toxic TCA concentration (see the case at the start of the Metabolism section) developed excessively high amitriptyline plasma levels due to the additive effects of diminished left ventricular function leading to decreased hepatic arterial blood flow alcohol and age-related decline in liver function and, finally. 

The results for this tertiary amine tricyclic are less convincing in terms of efficacy but quite robust with regard to toxicity. The optimal range for this medication in terms of antidepressant efficacy is approximately 80 to 150 ng/mL (amitriptyline plus nortriptyline). Studies generally found a nonsignificant trend with a remission rate of 48% within versus 29% outside this range. 

A method of treating human mental disorders involving depression which comprises orally administering to a human affected by depression 5-(3-dimethylaminopropylidene) dibenzo[a,d][l,4]cycloheptadiene (amitriptyline) or its non-toxic salts in daily dosages of 25 to 250 mg of said compound. 

The tricyclics, such as clomipramine (Anafranil), amitriptyline (Elavil), and imipramine (Tofranil), have been used for several decades. I have previously described their central nervous system toxic effects in some detail (Breggin, 1983b see also Breggin, 1991b). This section will therefore be abbreviated. A list of some of the older antidepressants can be found in the appendix. 

However, the use of antidepressants in completed suicide showed an upward trend, while the use of more violent methods (gassing, hanging) fell During this time prescription of moclobemide and two SSRIs (citalopram and fluoxetine) increased, while that of tricyclics (mainly doxepin and amitriptyline) remained steady. The mean annual fatal toxicity index was highest for tricyclics, such as doxepin, trimipramine, and amitripyline, and lowest for SSRIs. 

In a controlled comparison between clomipramine and amitriptyline, the former caused adverse effects more often, especially drowsiness (3). Overdose toxicity is the same as with other tricyclic antidepressants (4) fatal interactions with monoamine oxidase (MAO) inhibitors have been reported (SEDA-18, 16 5). Altogether, toxic effects are not substantially different. 

Lofepramine is an imipramine analogue whose animal pharmacology suggests low toxicity (1). Its clinical efficacy is similar to that of imipramine and amitriptyline. Patients on lofepramine report less dryness of the mouth, fewer disturbances of accommodation, and less drowsiness, but a greater incidence of tremor (2). 

There are concerns that citalopram may be less safe in acute overdose than other SSRIs (SEDA-21,12). Among all fatal poisonings in one forensic district of Sweden, citalopram was the fourth most commonly used drug (22 of 358 cases) (29). However, when correction was made for prescription rate, citalopram was less toxic than amitriptyline, dextropropoxyphene, or nitrazepam. This study has confirmed that citalopram is less toxic than tricyclic antidepressants such as amitriptyline. However, whether it is more toxic than other SSRIs is still uncertain. 

Cardiotoxic effects are relatively uncommon with mianserin (2). In a placebo-controlled study in 50 patients with a variety of cardiac conditions who were taking anticoagulants, mianserin (up to 30 or 60 mg) had no effects on electrocardiography, blood pressure, or pulse rate after 3 weeks. In a second phase, mianserin (up to 60 mg/day) was compared with amitriptyline (up to 150 mg/day) and placebo in 18 healthy volunteers. Measurements included systolic time intervals, electrocardiography at rest and during exercise, echocardiography, and blood pressure. Amitriptyline had a negative inotropic effect mianserin increased ejection fraction. The results of both these experiments led the authors to conclude that mianserin is an antidepressant with very low cardiac toxicity. 

Kudo K, Imamura T, Jitsufuchi N, Zhang XX, Tokunaga H, Nagata T. Death attributed to the toxic interaction of triazolam, amitriptyline and other psychotropic drugs. Forensic Sci Int 1997 86(1-2) 35 11. 

If, following absorption, medications were undisturbed by the body, we would need to take only one dose for an eternal effect. Of course, this is not the case. As soon as drugs enter the bloodstream, the process of metabolism ensues. The body recognizes the drug as a foreign substance and eliminates it outright (say, via the kidneys, as in the case of lithium) or transforms it chemically, using a complex enzyme mechanism located in the liver. This chemical transformation enables the medication to be eliminated from the body. In some cases, the chemical transformation produces a new compound that may also have therapeutic effects (or, in some rare instances, a toxic effect). For example, fluoxetine (trade name Prozac) is transformed into norfluoxetine, which is also an antidepressant. A similar situation occurs with the old tricyclic antidepressants (amitriptyline—trade name Elavil—to nortriptyline the latter, in fact, is... 

FLECAINIDE TCAs Risk of arrhythmias Additive effect both drugs may be proarrhythmogenic. In addition, amitriptyline and clomipramine may inhibit CYP2D6-mediated metabolism of flecainide Monitor PR, BP, and ECG closely watch for flecainide toxicity... 

MAOIs TCAs-AMITRIPTYLINE CLOMIPRAMINE DESIPRAMINE IMIPRAMINE NORTRIPTYLINE t risk of stroke, hyperpyrexia and convulsions, t plasma concentrations of TCAs, with risk of toxic effects, t risk of serotonin syndrome and of adrenergic syndrome with older MAOIs. Clomipramine may trigger acute confusion in Parkinson s disease when used with selegiline TCAs are believed to also act by inhibiting the reuptake of serotonin and norepinephrine, increasing the risk of serotonin and adrenergic syndromes. The combination of TCAs and antidepressants can t risk of seizures Very hazardous interaction. Avoid concurrent use and consider the use of an alternative antidepressant. Be aware that seizures occur with overdose of TCAs just before cardiac arrest... 

AMITRIPTYLINE MODAFINIL Variable effect on amitriptyline Modafinil inhibits CYP2C9 and induces CYP1A2 Watch for both poor response and early features of toxicity of amitriptyline... 

TCAs DRUG DEPENDENCE THERAPIES-BUPROPION 1. t risk of seizures This risk is marked in elderly people, in patients with a history of seizures, addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin 2. t plasma concentrations of amitriptyline, clomipramine, desipramine, doxepin and imipramine, with risk of toxic effects 1. Bupropion is associated with a dose-related risk of seizures. TCAs lower the seizure threshold. Additive effects when combined 2. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 1. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis) 2. Initiate therapy of these drugs at the lowest effective dose... 

Overdose. Depression is a risk factor for both parasuicide and completed suicide, and TCAs are commonly taken by those who deliberately self-harm. Dothiepin (dosulepin) and amitriptyline are particularly toxic in overdose, being responsible for up to 300 deaths per year in the UK despite the many alternative antidepressants that are available. Lofepramine is at least 15 times less likely to cause death from overdose clomipramine and imipramine occupy intermediate positions. 

Amitriptyline Phenytoin Risk of phenytoin toxicity interaction poorly documented Inhibition of phenytoin metabolism... 

There were signs of opiate toxicity, reversible with naloxone, in an 80-year-old woman after concomitant treatment with amitriptyline and co-codamol (codeine plus paracetamol) (SEDA-18, 79). 

Maany I, Hayashida M, Pfeffer SL, Kron RE. Possible toxic interaction between disulfiram and amitriptyline. Arch Gen Psychiatry 1982 39(6) 743. ... 

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