Drug-induced Brugada Syndrome

Yee Guan Yap; Elijah R. Behr; A. John Camm


Europace. 2009;11(8):989-994. 

In This Article

Tricyclic Antidepressants

Tricyclic antidepressants exhibit a dose-related risk of sudden cardiac death, with a relative risk (RR) of 2.5 at maximal doses of amitriptyline compared with control subjects.[27] At or just above therapeutic levels, TCAs also have a quinidine-like antiarrhythmic action, with effects on repolarization. Hence, fatalities due to TCA overdose may be a result of QT prolongation and torsades de pointes.[28] The most common adverse cardiovascular effects of TCAs, however, are slowing of intraventricular conduction, manifested by prolongation of the PR and QRS intervals QT prolongation, torsades de pointes, and postural hypotension.[27,28] In addition, there have been reports of patients exhibiting transient Brugada type 1 ECG in the right precordial leads and marked QRS widening following therapeutic dosing and overdose of amitriptyline.[29,30] In two cases of overdose, nortriptyline has been reported to induce the type 1 ECG pattern associated with ventricular fibrillation and cardiac arrest.[31,32] In a series of 95 cases of cyclic antidepressant overdoses,[33] 10 (10.5%) presented with the Brugada ECG, 1 of whom died of recurrent ventricular fibrillation compared with 1 death among those without the Brugada ECG.

In a recently published series, however, 65 young patients without a history of cardiovascular disease who had taken intentional overdoses of either amitriptyline or clomipramine, 15% exhibited the type 1 Brugada pattern.[34] Although ventricular arrhythmia or cardiac arrest was not reported in this series, a case of cardiac arrest associated with a type 1 pattern following high-dose amitriptyline intoxication has been described elsewhere.[35]

In another series of 402 patients, the incidence of a type 1 Brugada ECG pattern was reported to be only 2.3%.[36] Interestingly, these patients had an increased incidence of non-cardiac adverse outcomes including seizures (RR: 4; 95% CI: 1.5–10.8) and hypotension (RR: 3.9; 95% CI: 2.1–7.4). A widened QRS interval was also present (RR: 4.8; 95% CI: 1.8–12.9) but there were no deaths or ventricular arrhythmias. Thus, TCA-induced Brugada syndrome (type 1 ECG and sudden death or arrhythmias) appears rare.

The primary mechanism of these ECG changes is likely to be sodium channel antagonism. TCAs cause a decrease in the maximum rate of rise (Vmax) of phase 0 of the action potential in canine Purkinje fibres. This confirms that these drugs possess effects similar to Class I antiarrhythmics.[37] Amitriptyline, however, not only acts in this manner[38] but also reduces Ito activation.[39]

The type 1 Brugada ECG has also been reported following ingestion of TCAs at therapeutic levels in patients who had normal ECG when medication exposure was removed: for example, nortriptyline[40] and desipramine.[41,42] In both desipramine-related cases, the Brugada ECG pattern manifested itself after the dosage was increased. One patient developed recurrent but successfully resuscitated ventricular fibrillation and was subsequently found to have the His558Arg SCN5A polymorphism.[42] Its relevance in this context is unclear, although polymorphisms have been identified in other drug-associated ventricular arrhythmias. Thus, it is possible that TCA-induced Brugada syndrome is related to the genetic susceptibility of an individual.

Rare reports of similar cardiotoxicity with other psychotropic medications have also been described but their true significance is unclear: maprotiline (heterocyclic antidepressant), fluoxetine (selective serotonin reuptake inhibitor), and trifluoperazine (phenothiazine).[29,30] Nonetheless, fluoxetine, similar to amitriptyline, depresses sodium and calcium channel activation in cardiac myocytes and induces significant shortening of the action potential duration (APD) in guinea pig, rabbit, and canine ventricular myocytes.[43] Similarly, phenothiazines decrease the Vmax and amplitude of phase 2.[44,45] The shortened APD may therefore induce an intramyocardial electrical gradient, the Brugada ECG pattern, and possibly the substrate for re-entry.


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