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236 Emerg Med J 2001;18:236–241

REVIEW Emerg Med J: first published as 10.1136/emj.18.4.236 on 1 July 2001. Downloaded from

Tricyclic overdose: a review

G W Kerr, A C McGuYe, S Wilkie

Abstract lism by hepatic enzymes the metabolites, some Overdoses of are of which have pharmacological activity them- among the commonest causes of drug poi- selves, are conjugated and excreted by the kid- soning seen in accident and emergency neys. departments. This review discusses the The ingestion of large quantities of , clinical presentation in self poisoning causes altered pharmacoki- and treatment of tricyclic overdose. netics.8 Gastrointestinal absorption may be (Emerg Med J 2001;18:236–241) delayed because of inhibition of gastric empty- ing and significant enterohepatic recirculation Keywords: ; overdose prolongs the final elimination. The amount of unbound tricyclic may also increase if the over- The first report of the adverse eVects of dose causes respiratory resulting in tricyclic overdose was in 1959 and came within an acidosis, which reduces protein binding. two years of their clinical usefulness having The toxic eVects of tricyclics are caused by been recognised.1 Now tricyclics are identified four main pharmacological properties: as one of the most frequently ingested 1 Inhibition of at substances in self poisoning along with para- nerve terminals. cetamol, and .2 They 2 Direct á block. are second only to as the commonest 3 A membrane stabilising or -like drug taken in fatal .34 There is eVect on the myocardium. also evidence that the number of deaths 4 action. relative to the number of prescriptions issued is significantly higher for tricyclics in comparison Clinical features to other antidepressants.5 The dose ingested, even if reliably confirmed, http://emj.bmj.com/ On average 268 people in Britain die each is a poor predictor of the subsequent clinical year after taking an overdose of tricyclic drugs.5 outcome. Doses of less than 20 mg/kg are unlikely to be fatal or cause severe complica- Accident and Despite the introduction of newer and safer 910 Emergency antidepressants the prescription of tricyclics is tions but individual variation in absorption, Department, Ayr still widespread as they are cheaper and many protein binding and metabolism limit any Hospital, still consider them to be the most eVective meaningful prediction. Dalmellington Road, group of antidepressants. The clinical features of tricyclic overdose can Ayr, Scotland be grouped according to their eVects on the on September 24, 2021 by guest. Protected copyright. G Kerr The commonest tricyclic taken in fatal over- dose is dothiepin,5 which, along with am- peripheral autonomic system (anticholinergic Accident and itriptyline, has been shown to have compara- eVects), the cardiovascular system and the cen- Emergency tively greater than other tricyclics.56 tral nervous system (table 1). Department, Crosshouse Hospital, ANTICHOLINERGIC EFFECTS Kilmarnock Pharmacokinetics Anticholinergic features are common and may A C McGuYe S Wilkie Tricyclics are rapidly absorbed from the aid diagnosis in certain patients. Generally and undergo first pass anticholinergic eVects do not cause serious Correspondence to: metabolism. They are highly protein bound clinical problems but cases of toxic megacolon Dr Kerr and have a large volume of distribution, result- and intestinal perforation have been de- ([email protected]) ing in a long half life of elimination that gener- scribed.11 12 Accepted for publication ally exceeds 24 hours and in the case of By impairing sweating heat dissipation is 26 September 2000 is 31 to 46 hours.7 After metabo- reduced and this can result in a fever, especially if seizures occur. Central block can Table 1 Clinical features and complications of tricyclic antidepressant overdose also alter thermoregulation.13 Cardiovascular system Central nervous system Anticholinergic eVects CARDIOVASCULAR EFFECTS Sinus Drowsiness Dry mouth Prolonged PR/QRS/QT Coma Blurred vision The commonest cardiovascular eVect is a sinus ST/T wave changes Convulsions Dilated pupils tachycardia, which is attributable to the inhibi- block Pyramidal signs tion of norepinephrine reuptake and the Vasodilatation Rigidity Absent bowel sounds Pyrexia anticholinergic action. However, the most Cardiogenic shock Respiratory depression Myoclonic twitching important toxic eVect of tricyclics is the Ventricular fibrillation/tachycardia Ophthalmoplegia slowing of depolarisation of the cardiac action Asystole potential by inhibition of the current

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and this delays propagation of depolarisation Management

through both myocardium and conducting tis- REDUCING ABSORPTION Emerg Med J: first published as 10.1136/emj.18.4.236 on 1 July 2001. Downloaded from sue.14 This results in prolongation of the QRS The majority of papers regarding gastric lavage complex and the PR/QT intervals with a include many diVerent types of overdose predisposition to cardiac . This substances. Kulig et al showed that lavage only inhibition of sodium flux into myocardial cells improved clinical outcome in obtunded pa- can occur to such an extent that depressed tients if performed within one hour of inges- 35 contractility can result15 16 and this, coupled tion in a study of 592 poisoned patients. A with the reduction in peripheral resistance, subsequent study of over 800 patients failed to contributes to hypotension. show any improvement in outcome from 36 The overall incidence of serious cardiovas- gastric lavage and it may even move ingested 37 cular arrhythmias is low. In one series four drug into the small bowel. The consensus patients from 153 admitted to an intensive care statement of European toxicologists that gas- unit had either a nodal or ventricular arrhyth- tric lavage should only be performed within 17 one hour of the ingestion of a potentially life mia and only 3 of 225 patients admitted to 38 another developed arrhyth- threatening dose is based on such papers. 18 Where specifically tricyclic poisonings have mias. Hypotension is more common with an been examined approximately 9% of the incidence of 14% to 51% having been estimated ingested dose has been recovered39 reported.19–21 but a comparison of gastric lavage and activated charcoal versus charcoal alone 40 CENTRAL NERVOUS SYSTEM EFFECTS showednodiVerence in clinical outcome. Coma was present in 53 patients (17%) of a There is no evidence to suggest that lavage series of 31622 and the incidence is even higher should be considered outwith the one hour (52%) in the initial presentation of overdoses period in tricyclic poisoning. with a fatal outcome.23 Activated charcoal may reduce the absorp- Twenty four patients (6.2%) from a series of tion of tricyclics and the benefits of both single 41 42 388 admitted to intensive care had seizures24 and multiple doses have been described. and confirmed a previous report of seizures Although Crome et al reported that a single exacerbating hypotension.25 This is thought to dose of activated charcoal reduces absorption be caused by the metabolic acidosis associated of tricyclics, the 12 subjects were given charcoal only 30 minutes after a therapeutic with the seizures increasing the 41 of the tricyclic by decreasing the amount that is dose of . Others have also found a reduction when charcoal was given four protein bound or altering the eVect of tricyclics 43 on the cardiac membrane sodium channels. hours after a therapeutic dose. However, studies of tricyclic overdoses involving 77 and 17 patients failed to show any reduction in sys-

temic absorption after a single dose of http://emj.bmj.com/ 44 45 Investigations charcoal. It should be noted that doses of Plasma tricyclic concentrations are not widely 20 g or 10 g of charcoal were used respectively. Crome41 and Karkkainen46 both studied the available and measured levels often lack sensi- use of multiple dose activated charcoal in six tivity in detecting active metabolites. Petit et patients and reported an acceleration of al26 demonstrated an increased incidence of tricyclic elimination, but other small studies seizures, coma and in patients also involving therapeutic doses have failed to

with a total tricyclic level greater than 1000 µg/l 47 48 on September 24, 2021 by guest. Protected copyright. confirm this. Two studies reported on mul- but subsequently it has been shown that tiple dose regimens in a total of six tricyclic prolongation of the QRS duration (>0.16 sec- overdose patients and neither provides evi- onds) is a better predicator of seizures or dence to support a significant eVect on ventricular arrhythmias than the plasma drug elimination.49 50 concentration.27 The QRS duration has also

been associated with the probability of requir- ALKALINISATION 18 ing ventilation but it is possible for a patient The use of in tricyclic poi- with very high plasma concentrations to have a 28 soning has been shown to have beneficial normal QRS duration and the use of the QRS eVects. Brown et al51 successfully treated five duration as a reliable indicator of poisoning children with tricyclic induced arrhythmias by 29 30 severity is controversial. Decreased R-R administering boluses of sodium bicarbonate variation has been described as a method of and subsequently they confirmed this an- 31 identifying tricyclic overdose and it has been tiarrhythmic action in experimental work with suggested that a terminal R wave greater than 3 dogs. Further work with dogs has demon- mm in lead aVR is a more useful predictor of strated a reduction in QRS duration, conver- seizures or arrhythmias than QRS duration.32 sion of arrhythmias and a rise in blood pressure The most frequent acid base disturbance is following sodium bicarbonate.52 acidosis.33 This is often a mixed acidosis with In a review of 91 patients treated with both respiratory depression and myocardial sodium bicarbonate, hypotension was cor- impairment/hypotension resulting in reduced rected in 20 of 21 patients (96%) within one tissue perfusion and the production of lactate. hour and QRS prolongation was corrected in Hypokalaemia may be present and in a series 39 of 49 patients (80%).53 Similar eVects have of 295 patients 9% had a potassium concentra- been described after alkalinisation by hyper- tion less than 3.0 mmol/l.34 ventilation54 55 but the combined use of both

www.emjonline.com 238 Kerr, McGuYe, Wilkie

techniques has resulted in profound alkalosis, have failed to show any significant benefit from

which is associated with higher rates of in the prevention or management of Emerg Med J: first published as 10.1136/emj.18.4.236 on 1 July 2001. Downloaded from mortality.56 arrhythmias.63 67 The mechanism of this eVect is a subject of The use of â blockers may further reduce debate. Brown et al51 demonstrated that the myocardial contractility and although reported of amitriptyline in- as being eVective in treating arrhythmias both creased with a more alkali pH and this was in humans68 and animals,63 in all cases there 57 confirmed by a later study. This reduction in was an marked decrease in blood pressure the pharmacologically active unbound fraction associated. and a direct eVect on myocardial contractility The use of glucagon in one patient was by correcting the metabolic acidosis present, reported to increase blood pressure and reduce were thought to be the causes. It is not surpris- the QRS duration but sodium bicarbonate had ing therefore that sodium bicarbonate has a also been given shortly before the glucagon.69 therapeutic eVect in patients with an acidosis. An animal experiment with glucagon found no However, it has also been found to be eVective 58 59 beneficial eVect on blood pressure or arrhyth- in the absence of acidosis and even in a 63 mias. patient with a preceding alkalosis.60 sulphate has been used success- The administration of hypertonic sodium fully in an overdose patient with refractory chloride to rats with toxicity has 70 been shown to be as eVective as sodium bicar- ventricular fibrillation. Although an early experiment with two dogs found no benefit bonate in reversing QRS prolongation and 63 hypotension while respiratory alkalosis had lit- with magnesium, Knudsen reported that 59 magnesium sulphate converted ventricular tle eVect. McCabe et al used a large animal 71 swine model, which confirmed these findings tachycardia to sinus rhythm in 9 of 10 rats. and actually demonstrated that hypertonic Physostigmine is a short acting cholinest- saline had significantly more eVect on these erase inhibitor that was proposed in the 1970s parameters than sodium bicarbonate.61 From as a treatment for arrhythmias. Since then, these experiments it has been suggested that however, it has been described as causing asys- 72 73 increasing the extracellular sodium concentra- tole and seizures. There is no role for its use tion is the major mechanism. Other experi- in the management of tricyclic toxicity. mental work on the depolarisation of purkinje fibres has shown that the eVects of increasing HYPOTENSION the extracellular sodium concentration and of Hypotension is thought to result from a raising the pH are distinct and additive.62 combination of decreased myocardial contrac- tility and peripheral vasodilatation. In cases ANTIARRHYTHMIC TREATMENT refractory to the use of intravenous fluids the In general antiarrhythmic drugs should be

avoided and the correction of hypotension, use of inotropic agents may be required. In http://emj.bmj.com/ theory pure á agents should be used to hypoxia and acidosis will reduce the cardio- 74 toxic eVects of tricyclics. Where antiarrhythmic avoid unopposed â stimulation. agents are used it is important to avoid certain Norepinephrine has been found to be more drugs that exacerbate the cardiac eVects of tri- eVective than in the management of cyclics. Class 1a (quinidine, , dis- hypotension, possibly as the eVect of dopamine opyramide) and class 1c drugs such as flecain- partially depends on the release of endogenous ide, prolong depolarisation in a similar fashion norepinephrine stores that are depleted in to tricyclics. Likewise class 3 drugs (, tricyclic overdose because of reuptake inhibi- on September 24, 2021 by guest. Protected copyright. ) also prolong the QT interval and tion.75 A study with amitriptyline poisoned rats may predispose to arrhythmias. has suggested that the use of epinephrine is less Lignocaine () has been reported as likely to cause arrhythmias in comparison with being eVective in the treatment of frequent norepinephrine.76 Its use may be preferable ventricular ectopics in 13 overdose patients but because this and further experiments have in some patients the ectopics persisted for up demonstrated an additional benefit from the to 72 hours.21 Experiments with four dogs combined use of sodium bicarbonate and failed to show any significant eVect on the epinephrine.77 treatment of arrhythmias63 and other research Extracorporal circulation has been used in with rats found that lignocaine only success- patients who have not improved with the use of fully treated one case from ten with tricyclic inotropes78 79 and experimental work in pigs induced ventricular arrhythmias.64 has demonstrated increased survival with this Phenytoin is a class 1b agent, which, unlike technique.80 1a and 1c drugs, can increase the rate of phase 0 depolarisation. Boehnert described the suc- cessful treatment of ventricular arrhythmias in CARDIAC ARREST three patients with the use of phenytoin.65 Where patients have a cardiac arrest after When phenytoin was used in a study of 10 ingestion of tricyclics recovery is possible even patients it was found to correct conduction after prolonged . Patients have defects in five patients within 46 minutes and recovered after three and five hours of external in the remaining five within 14 hours.66 cardiac massage.81–83 This may be attributable However, these patients were stable with no to metabolism and redistribution of the tricy- arrhythmias and phenytoin did not change clic during this time with a subsequent reduc- their clinical outcome. Animal experiments tion of its eVect on the myocardium.

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CNS COMPLICATIONS art Wilkie undertook literature searchs, edited and wrote further drafts. Gary Kerr, Crawford McGuYe and Stewart Wilkie Seizures are usually self limiting but where edited and wrote the final draft. Gary Kerr will act as guarantor. Emerg Med J: first published as 10.1136/emj.18.4.236 on 1 July 2001. Downloaded from treatment is necessary benzodiazepines are the Funding: none. treatment of choice.9 Although some recom- mend the use of phenytoin its eYcacy has Conflicts of interest: none. never been proven67 and in a rat model was found to be of no benefit.84 Patients with Appendix: management plan for decreased conscious level and respiratory treatment of tricyclic overdose depression may require intubation. 1 Assess and treat ABCs as appropriate. 2 Examine for clinical features Check urea and electrolytes—look for low potassium DRUG ELIMINATION Check arterial blood gases—look for acidosis Tricyclic specific antibody fragments have Perform electrocardiograph—look for QRS>0.16 been developed and their eVectiveness at seconds reversing cardiovascular toxicity in animals has 3 Consider gastric lavage only if within one hour of a 85 86 potentially fatal overdose. been demonstrated by several studies. 4 Give 50 grams of charcoal if within one hour of However, experimental work has shown that ingestion. extremely large amounts are required and at 5 Give sodium bicarbonate (50 ml of 8.4%) if: present the use of Fab fragments is limited by a pH <7.1 cost and the possibility of renal toxic eVects. A b RS >0.16 seconds c Arrhythmias case report of their clinical use indicates an d Hypotension improvement in QRS and QT intervals but 6 Arrhythmias: Avoid antiarrhythmics 87 sodium bicarbonate had also been given. Correct hypoxia, hypotension, acidosis, hypokalaemia Tricyclics have a very large volume of distri- Give sodium bicarbonate. bution and this restricts the role of methods 7 Hypotension: Give intravenous fluids designed to increase drug clearance from the Consider 8 Cardiac arrest: Prolonged resuscitation may be intravascular space. The treatment of eight successful patients with resin haemoperfusion removed 9 Monitoring: Patients who display signs of toxicity no more than 3.1% of the estimated ingested should be monitored for a minimum of 12 hours. dose88 and others have also described how only small amounts of tricyclic are extracted by 1 Lancaster NP, Foster AR. Suicidal attempt by 89 overdose. BMJ 1959; 1:338–9. haemoperfusion. Other techniques such as 2 Buckley NA, Whyte IM, Dawson AH, et al. Self-poisoning forced , peritoneal dialysis and haemo- in Newcastle,1987–1992. Med J Aust 1995;164:190–3. 90 3 Obafunwa JO, Busuttil A. Deaths from substance overdose dialysis do not seem to be any better. in the Lothian and Borders region of Scotland (1983– 1991). Hum Exp Toxicol 1994;13:401–6. 4 Coleridge J, Cameron PA, Drummer OH, et al. Survey of MONITORING drug related deaths in Victoria. Med J Aust 1992;157:459– 62. Several reports have found that all major com- 5 Henry JA, Alexander CA, Sener EK. Relative mortality from plications will be apparent within six hours of overdose of antidepressants. BMJ 1995;310:221–4. 23 91 92 6 Buckley NA, Dawson AH, Whyte IM, et al. Greater toxicity http://emj.bmj.com/ ingestion and that the incidence of late in overdose of dothiepin than of other tricyclic antidepres- complications is extremely low.93 94 It has been sants. Lancet 1994;343:159–62. 7 Hollister L. Antidepressants. In: Katzung BG, ed. Basic and shown that arrhythmias do not occur after clinical . 3rd ed. Connecticut: Appleton and cardiovascular toxicity has resolved.93 95 There Lange, 1987:327–35. 8 Jarvis MR. Clinical pharmacokinetics of tricyclic antide- have been reports of ventricular arrhythmias pressant overdose. Psychopharmacol Bull 1991;27:541–50. and fatalities occurring up to five days after 9 Crome P. Poisoning due to tricyclic antidepressant over- dose. Clinical presentation and treatment. Med Toxicol ingestion but these events were in patients who 1986;1:261–85. 96 97 10 Spiker D, Biggs J. Tricyclic antidepressants (prolonged displayed continuing signs of toxicity. on September 24, 2021 by guest. Protected copyright. plasma levels after overdose). JAMA 1976;236:1711–12. Patients should have cardiac monitoring 11 McMahon AJ. Amitriptyline overdose complicated by intes- until the electrocardiogram has been normal tinal pseudo-obstruction and caecal perforation. Postgrad 98 Med J 1989;65:948–9. for 12 to 24 hours. 12 Ross JP, Small TR, Lepage PA. Imipramine overdose com- plicated by toxic megacolon. Am Surg 1998;64:242–4. 13 Hantson P, Benaissa M, Clemessy J, et al. complicating tricyclic antidepressant overdose. Intensive Conclusion Care Med 1996;22:453–55. It has been reported that the advice from the 14 Brennan FJ. Electrophysiological eVects of imipramine and on normal and depressed cardiac purkinje fibers. British centres concerning the man- Am J Cardiol 1980;46:599–606 agement of tricyclic overdose is not uniform.99 15 Marshall JB, Forker AD. Cardiovascular eVects of tricyclic antidepressant drugs: therapeutic usage, overdose, and DiVerences in the management strategies of management of complications. Am Heart J 1982;103:401. the poisons centres reflect the quality of the 16 Taylor DJE, Braithwaite RA. Cardiac eVects of tricyclic antidepressant : a preliminary study of evidence available. There are limited data and nortriptyline. Br Heart J 1978;40:1005. much of the evidence quoted is derived from 17 Thorstrand C. Clinical features in poisonings by tricyclic antidepressants with special reference to the ECG. Acta animal studies, case reports or small series of Med Scand 1976;199:337–44. healthy subjects. The quality of this infor- 18 Hulten BA, Heath A. Clinical aspects of tricyclic poisoning. Acta Med Scand 1983; 213:275–8. mation results in variable interpretations and 19 Frommer DA, Kulig KW, Marx JA, et al. Tricyclic seems to cause some ambiguity in the advice antidepressant overdose. JAMA 1987;257:521–6. 20 Shannon M, Merola J, Lovejoy FH. Hypotension in severe given. In the absence of further evidence a tricyclic antidepressant overdose. Am J Emerg Med 1988;6: consensus approach to the management of tri- 439–42. 21 Langou RA, Van Dyke C, Tahan SR, et al. Cardiovascular cyclic overdose with national guidelines could manifestations of tricyclic antidepressant overdose. Am avoid when medical staV seek advice Heart J 1980;100:458–64. 22 Starkey IR, Lawson AAH. Poisoning with tricyclic and from the poisons centres. related antidepressants—a ten year review. QJMed1980; 49:33–49. Contributors 23 Callaham M, Kassel D. Epidemiology of fatal tricyclic anti- Gary Kerr initiated the review, performed the original literature poisoning: implications for management. Ann search and wrote the first draft. Crawford McGuYe and Stew- Emerg Med 1985;14:1–9.

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24 Taboulet P, Michard F, Muszynski J, et al. Cardiovascular 57 Levitt MA, Sullivan JB, Owens SM, et al. Amitriptyline repercussions of seizures during cyclic antidepressant plasma protein binding: eVect of plasma pH and relevance poisoning. J Toxicol Clin Toxicol 1995;33:205–11. to clinical overdose. Am J Emerg Med 1986;4:121–5. Emerg Med J: first published as 10.1136/emj.18.4.236 on 1 July 2001. Downloaded from 25 Lipper B, Bell A, Gaynor B. Recurrent hypotension 58 Brown TCK. Sodium bicarbonate and tricyclic antidepres- immediately after seizures in nortriptyline overdose. Am J sant poisoning. Lancet 1977;1:375. Emerg Med 1994;12:452–3. 59 Pentel P, Benowitz N. EYcacy and of 26 Petit JM, Spiker DG, Ruwitch JF, et al. Tricyclic antidepres- sodium bicarbonate in the treatment of desipramine toxic- sant plasma levels and adverse eVects after overdose. Clin ity of rats. J Pharmacol Exp Ther 1984;230:12–19. Pharmacol Ther 1977;21:47–51. 60 Molloy DW, Penner SB, Rabson J, et al. Use of sodium 27 Boehnert MT, Lovejoy FH. Value of the QRS duration ver- bicarbonate to treat tricyclic antidepressant-induced ar- sus the serum drug level in predicting seizures and rhythmias in a patient with alkalosis. Can Med Assoc J ventricular arrhythmias after an acute overdose of tricyclic 1984;130:1457–9. antidepressants. N Engl J Med 1985;313:474–9. 61 McCabe JL, Cobaugh, Menegazzi JJ, et al. Experimental tri- 28 Marshall JB. Tricyclic overdose. JAMA 1980;244:1900. cyclic antidepressant toxicity: a randomised, controlled 29 Foulke GE, Albertson TE. QRS interval in tricyclic antide- comparison of hypertonic saline solution, sodium bicarbo- pressant overdosage inaccuracy as a toxicity indicator in nate and hyperventilation. Ann Emerg Med 1998;32:329– emergency settings. Ann Emerg Med 1987;16:160–3. 33. 30 Buckley NA, O’Connell DL, Whyte IM, et al. Interrater 62 Sasyniuk BI, Jhamandas V. 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