Amitriptyline overdose

Siddiqui JH, Vakassi MM, Ghani MF. Cardiac effects of amitriptyline overdose. Curr Ther Res Clin Exp 1977 22 321. 

In 7 fatalities attributed to amitriptyline overdose, postmortem concentrations, pg/ml or pg/g (mean), were ... 

Rudorfer MV, Robins E Amitriptyline overdose clinical effects on tricyclic antidepressant plasma levels. J Clin Psychiatry 43 457M60,1982... 

Potkin SG, Shen Y, Pardes H, et al Haloperidol concentrations elevated in Chinese patients. Psychiatric Research 12 167-172,1984 Raskin A, Thomas H, Crook MA Antidepressants in black and white inpatients differential response to a controlled trial of chlorpromazine and imipramine. Arch Gen Psychiatry 32 643-649,1975 Rudorfer MJ, Robbins ELI Amitriptyline overdose clinical effects on tricyclic antidepressant plasma levels. J Clin Psychiatry 43 457-460, 1982... 

Cyclobenzaprine, a tricyclic amine structurally very similar to amitriptyline (see Figure 34-10), is used as a centrally acting skeletal muscle relaxant. Like amitriptyline, cyclobenzaprine causes sedation, produces central and peripheral muscarinic blockade, and potentiates adrenergic actions. In overdose, cyclobenzaprine may cause a typical anticholinergic toxidrome and cardiac arrhythmias, hypotension, and coma. However, cyclobenzaprine overdose is not as frequent nor as lethal as amitriptyline overdose. 

Rudorfer, M. V., Robins, E. (1982). Amitriptyline overdose Clinical effects on tricyclic antidepressant plasma levels. Journal of Clinical Psychiatry, 43, 457 60... 

Palaniswamy C, Selvaraj DR, Chugh T, Singh T, Khalique O, Tsai F, Sandhu RH. Brugada electrocardiographic pattern induced by amitriptyline overdose. Am J Ther 2010 17(5) 529-32. 

Amitriptyline is considered a classic TCA and was launched soon after imipramine in 1961. It is widely prescrihed and most commonly descrihed side effects in the pharmacological literature are apphcahle to most of the remaining TCAs. Amitriptyline overdose is considered to he particularly dangerous. Nortriptyline is the demethylated metabolite and also rndividtrally available (Kg. 18.18). 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Despite limited success with amitriptyline in some anorexia patients, using this class of antidepressants can be problematic in AN patients and therefore cannot be routinely recommended. TCAs slow gastrointestinal function and can therefore worsen the constipation and bloating that commonly plague AN patients during refeeding. In addition, TCAs can increase the likelihood of seizure or cardiac arrhythmia in patients already at risk due to electrolyte disturbances. Moreover, they are often lethal after overdose. 

When treating insomnia without depression, doxepin and amitriptyline (both tricyclic antidepressants) can be administered in low doses (25-100 mg) at bedtime. These antidepressants, however, do have troublesome anticholinergic side effects (dry mouth, constipation, blurred vision, dizziness) and adverse effects on the heart, and they can be lethal if taken in overdose. Because of their effect on heart function, these antidepressants should be avoided in patients with heart problems and administered cautiously, if at all, to those who are already receiving one of any number of newer antidepressants that inhibit the metabolism of the 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. 

Two studies found maprotiline to be clearly superior to placebo and two other studies found trends in the same direction ( p < 0.001, combined data) (Table 7-5) (105, 106, 107 and 108). More than 1,600 patients were randomly assigned to either maprotiline or a standard HCA 660 on maprotiline did well, and 247 showed minimal improvement, no change, or worsened. For the HCAs (usually imipramine or amitriptyline), 640 patients did well, and 255 showed minimal improvement, no change, or worsened. In summary, 73% did well with maprotiline, and 72% did well with a standard antidepressant. Combining these data with the Mantel-Haenszel test indicated no difference in efficacy (Table 7-6). Maprotiline has a dose-dependent risk of seizures. As with TCAs and amoxapine, overdoses of maprotiline can be lethal. %... 

Those who fail to respond to an SSRI may respond to a TCA, and vice versa. Thus, these two broad-spectrum classes can be used in a sequential strategy to adequately treat the majority of cases. However, many physicians try another newer antidepressant (e.g, venlafaxine, bupropion, nefazodone) in such patients because of the safety and tolerability problems associated with TCAs. Of note, the tolerability profile of secondary amine TCAs such as desipramine is as favorable as any of the newer antidepressants and probably better than nefazodone. Nevertheless, the secondary amine TCAs have a therapeutic index as narrow as tertiary amine TCAs (e.g., amitriptyline, imipramine) in terms of lethality in overdoses resulting from cardiotoxicity. 

The ratio of parent drug to desmethylated metabolite at steady-state has been reported to range from 0.47 to 0.70 for imipramine desipramine and from 0.83 to 1.16 for amitriptyline nortriptyline. These typical ratios can be used to help distinguish between an acute overdose (increased ratios) versus a steady-state situation (normal ratios). 

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. 

Tricyclics and the second- and third-generation agents differ mainly in the degree of sedation they produce (greatest with amitriptyline, doxepin, trazodone, and mirtazapine) and their antimuscarinic effects (greatest with amitriptyline and doxepin Table 30-3). SSRIs are generally free of sedative effects and remarkably safe in overdose. Combined with the ease of once-a-day dosing, these qualities may explain why they have become the most widely prescribed antidepressants. 

The barbiturates and meprobamate have been entirely superseded by the benzodiazepines and because of their low benefit-to-risk ratio (dependence producing, lethality in overdose, potent sedative effects) they should never be used as anxiolytics. Despite their popularity as short-term sedatives, antihistamines are ineffective anxiolytics, while the use of sedative antidepressants such as amitriptyline should be limited to the treatment of patients with symptoms of both anxiety and depression due to their limited efficacy and the poor patient compliance associated with their adverse effects. However, patients with panic disorder do appear to show a beneficial response to antidepressants (see Chapter 6). A similar argument... 

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. 

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. 

Nine patients took overdoses of fluoxetine in amounts up to 3000 mg (37 times the recommended dose) (3). One, who also took several other drugs, including amitriptyline, died, but the other eight all recovered with relatively minor symptoms in most cases. Four patients had suspected seizures during studies (3) and one who took a 3000 mg overdose had unequivocal convulsions but recovered. 

One of the putative benefits of mianserin is its alleged safety in overdose, which may be related to a reduced risk of cardiovascular adverse effects and convulsions. Data from the UK Committee on Safety of Medicines suggest that mianserin accounts for 11% of reported convulsions and 5.8% of use, putting it intermediate between amitriptyline and maprotiline (15). On the other hand, in the London Poisons Unit survey, involving 84 patients who took mianserin alone (up to 1000 mg), there were no deaths and no patients with convulsions, although this could represent a frequency of up to 3.6% (12). 

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... 

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. 

Note. When SSRIs are compared with TCAs for patients who discontinue therapy (a surrogate endpoint for tolerability), most meta-analyses show a slight benefit in favour of SSRIs. Comparisons which exclude TCAs with the most prominent anti-muscarinic effects (amitriptyline and imipramine) show either marginal benefits in favour of SSRIs or no difference between the groups. It is noteworthy that despite their pronounced adverse effects, amitriptyline and imipramine tend to be selected as standard TCAs against which SSRIs are compared. Lofepramine, the second most prescribed TCA in the UK and the one TCA which causes little sedation, has few antimuscarinic effects and is as safe as SSRIs in overdose is it under-represented in meta-analyses... 

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