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 antidepressant overdose: a review G W Kerr, A C McGuYe, S Wilkie Abstract lism by hepatic enzymes the metabolites, some Overdoses of tricyclic antidepressants 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 tricyclics pharmacokinetics, 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: tricyclic antidepressant; 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 depression 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 norepinephrine reuptake at substances in self poisoning along with para- nerve terminals. cetamol, benzodiazepines and alcohol.2 They 2 Direct á adrenergic block. are second only to analgesics as the commonest 3 A membrane stabilising or quinidine-like drug taken in fatal drug overdose.34 There is eVect on the myocardium. also evidence that the number of deaths 4 Anticholinergic 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 toxicity 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 gastrointestinal tract 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 amitriptyline is 31 to 46 hours.7 After metabo- reduced and this can result in a fever, especially if seizures occur. Central cholinergic 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 tachycardia 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- Heart block Pyramidal signs Urinary retention tion of norepinephrine reuptake and the Vasodilatation Rigidity Absent bowel sounds Hypotension Delirium 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 sodium current www.emjonline.com Tricyclic antidepressant overdose 237 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 arrhythmias. 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 intensive care unit 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 bioavailability 41 of the tricyclic by decreasing the amount that is dose of nortriptyline. 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 cardiac arrest 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 sodium bicarbonate 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