Tricyclic antidepressant poisoning : cardiovascular toxicity.

Wolfson Unit of Clinical Pharmacology, School of Clinical and Laboratory Sciences, University of Newcastle, and National Poisons Information Service (Newcastle Centre), Newcastle upon Tyne, UK.
Toxicological Reviews 01/2005; 24(3):205-14.
Source: PubMed

ABSTRACT Tricyclic antidepressants remain a common cause of fatal drug poisoning as a result of their cardiovascular toxicity manifested by ECG abnormalities, arrhythmias and hypotension. Dosulepin and amitriptyline appear to be particularly toxic in overdose. The principal mechanism of toxicity is cardiac sodium channel blockade, which increases the duration of the cardiac action potential and refractory period and delays atrioventricular conduction. Electrocardiographic changes include prolongation of the PR, QRS and QT intervals, nonspecific ST segment and T wave changes, atrioventricular block, right axis deviation of the terminal 40 ms vector of the QRS complex in the frontal plane (T 40 ms axis) and the Brugada pattern (downsloping ST segment elevation in leads V1-V3 in association with right bundle branch block). Maximal changes in the QRS duration and the T 40 ms axis are usually present within 12 hours of ingestion but may take up to a week to resolve. Sinus tachycardia is the most common arrhythmia due to anticholinergic activity and inhibition of norepinephrine uptake by tricyclic antidepressants but bradyarrhythmias (due to atrioventricular block) and tachyarrhythmias (supraventricular and ventricular) may occur. Torsade de pointes occurs uncommonly. Hypotension results from a combination of reduced myocardial contractility and reduced systemic vascular resistance due to alpha-adrenergic blockade. Life-threatening arrhythmias and death due to tricyclic antidepressant poisoning usually occurs within 24 hours of ingestion. Rapid deterioration is common. Level of consciousness at presentation is the most sensitive clinical predictor of serious complications. Although a QRS duration >100 ms and a rightward T 40 ms axis appear to be better predictors of cardiovascular toxicity than the plasma tricyclic drug concentration, they have at best moderate sensitivity and specificity for predicting complications.

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    • "However, toxicity of amitriptyline has been observed during standard treatments, and frequently during suicidal or accidental overdosage. Tricyclic antidepressant overdosage has toxic effects over cardiovascular, autonomous nervous, and central nervous systems, and may result in cardiotoxicity, cardiac conduction delays, dysrhythmia, hypotension, altered mental status, and seizures (Thanacoody and Thomas, 2005; Kiyan et al., 2006). "
    Oxidative Stress and Diseases, 04/2012; , ISBN: 978-953-51-0552-7
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    • "The blockade of cardiac sodium channels, which increases the duration of cardiac action potential and refractory period and delays atrioventricular conduction, is the primary mechanism responsible for arrhythmias. Hypotension, which is the most common cause of death and the most difficult complication to treat, results from a combination of reduced myocardial contractility and diminished systemic vascular resistance caused by alpha-adrenergic blockade and inhibition of norepinephrine uptake (Thanacoody and Thomas, 2005; Liebelt, 2006; Benowitz, 2007). Our previous study indicated that antagonism of adenosine A 1 and A 2a receptors hinders the prolongation of QRS and develops hypotension related to amitriptyline poisoning. "
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    ABSTRACT: We investigated the contribution of endogenous adenosine to amitriptyline-induced cardiovascular toxicity in rats. A control group of rats was pretreated with intraperitoneal (i.p.) 5% dextrose and received intravenous 0.94 mg/kg/min of amitriptyline for 60 minutes. The second and third groups of rats pretreated with i.p. 10 mg/kg of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA), an adenosine deaminase inhibitor, and i.p. 1 mg/kg of S-(4-nitrobenzyl)-6-thioinosine (NBTI), a facilitated adenosine transport inhibitor, received 5% dextrose and amitriptyline infusion, respectively. Outcome parameters were mean arterial pressure (MAP), heart rate (HR), QT and QRS durations, and plasma adenosine concentrations. Plasma adenosine concentrations were increased in all groups. In the control group, amitriptyline decreased MAP and HR and prolonged QT and QRS durations after 10 minutes of infusion. In EHNA/NBTI-pretreated rats, amitriptyline prolonged QRS duration at 10 and 20 minutes. In EHNA/NBTI pretreated rats, amitriptyline-induced MAP, HR reductions, and QRS prolongations were more significant than that of dextrose-infusion-induced changes. Our results indicate that amitriptyline augmented the cardiovascular effects of endogen adenosine by increasing plasma levels of adenosine in rats.
    Drug and Chemical Toxicology 12/2011; 35(4):423-31. DOI:10.3109/01480545.2011.640682 · 1.10 Impact Factor
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    • "In accord with these findings, a decrease in QRS duration may also be explained by the enhancing effect of theophylline on cellular cAMP production. As is known, the blockage of cardiac sodium channels, which increases the duration of the cardiac action potential and the refractory period, and delays AV conduction, is the primary mechanism responsible for arrhythmias and QRS prolongation (Thanacoody and Thomas, 2005). Sodium bicarbonate reverses the membrane-depressant effects of TCA by increasing extracellular sodium concentrations and by the direct effect of pH on fast sodium channels (Liebelt and Francis, 2002). "
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    ABSTRACT: We planned this study in order to investigate the effects of theophylline on cardiovascular parameters in an anaesthetized rat model of amitriptyline toxicity. In the preliminary study, we tested theophylline as 1 mg/kg of bolus, followed by a 0.5-mg/kg infusion. Toxicity was induced by the infusion of 0.94 mg/kg/min of amitriptyline up to the point of a 40-45% inhibition of mean arterial pressure (MAP). The rats were randomized to two groups: a group of 5% dextrose bolus followed by 5% dextrose infusion, and another group with theophylline bolus followed by infusion. Amitriptyline caused a significant decrease in MAP and prolongation in QRS; however, it did not alter heart rate (HR). When compared to the dextrose group, theophylline administration increased MAP, shortened prolonged QRS duration, and increased HR (P < 0.05, respectively). There was no statistically significant difference in the results of arterial blood-gas analyses among the groups (P > 0.05). Bolus doses followed by a continuous infusion of theophylline were found to be effective in reversing the hypotension and QRS prolongation seen in amitriptyline toxicity. One of the possible explanations of this beneficial effect is nonselective adenosine antagonism of theophylline. Further studies are needed to reveal the exact mechanism of the observed effect.
    Drug and Chemical Toxicology 10/2010; 34(1):53-60. DOI:10.3109/01480545.2010.495947 · 1.10 Impact Factor
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