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Drugs and Brugada syndrome patients: Review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org)

      Background

      Worldwide, the Brugada syndrome has been recognized as an important cause of sudden cardiac death in individuals at a relatively young age. Importantly, many drugs have been reported to induce the characteristic Brugada syndrome-linked ECG abnormalities and/or (fatal) ventricular tachyarrhythmias.

      Objective

      The purpose of this study was to review the literature on the use of drugs in Brugada syndrome patients, to make recommendations based on the literature and on expert opinion regarding drug safety, and to ensure worldwide online and up-to-date availability of this information to all physicians who treat Brugada syndrome patients.

      Methods

      We performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation to each drug, and initiated a website (www.brugadadrugs.org).

      Results

      The literature search yielded 506 reports for consideration. Drugs were categorized into one of four categories: (1) drugs to be avoided (n = 18); (2) drugs preferably avoided (n = 23); (3) antiarrhythmic drugs (n = 4); and (4) diagnostic drugs (n = 4). Level of evidence for most associations was C (only consensus opinion of experts, case studies, or standard-of-care) as there are no randomized studies and few nonrandomized studies in Brugada syndrome patients.

      Conclusion

      Many drugs have been associated with adverse events in Brugada syndrome patients. We have initiated a website (www.brugadadrugs.org) to ensure worldwide availability of information on safe drug use in Brugada syndrome patients.

      Keywords

      Abbreviations:

      ACC (American College of Cardiology), AHA (American Heart Association), ECG (electrocardiogram), ESC (European Society of Cardiology)

      Introduction

      Worldwide, the Brugada syndrome is recognized as an important cause of sudden cardiac death occurring in individuals at a relatively young age. Brugada syndrome is diagnosed in the presence of specific electrocardiographic (ECG) abnormalities (known as the type 1 Brugada syndrome ECG; Figure 1) seen in combination with an absence of gross structural abnormalities and several other criteria.
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: consensus report.
      In addition, Brugada syndrome often shows familial aggregation.
      Figure thumbnail gr1
      Figure 1Conversion of a normal ECG to a type 1 Brugada syndrome ECG during ajmaline challenge. Note the coved-type ST segments (arrows) in the right precordial ECG leads at peak ajmaline (note that V3 is placed in the third intercostal space above V1 [V1ic3], and V5 is placed in the third intercostal space above V2 [V2ic3]).
      The presence of the type 1 Brugada syndrome ECG in particular has been linked to an increased risk for ventricular tachyarrhythmias, cardiac arrest, and sudden death in patients with Brugada syndrome.
      • Gehi A.K.
      • Duong T.D.
      • Metz L.D.
      • Gomes J.A.
      • Mehta D.
      Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis.
      Importantly, many drugs have been reported to induce the type 1 Brugada syndrome ECG and/or (fatal) arrhythmias in patients with Brugada syndrome (Figure 2). Therefore, patients with Brugada syndrome should be advised not to use these drugs or to use them only under controlled conditions.
      Figure thumbnail gr2
      Figure 2Nonsustained ventricular tachycardia in a patient who was given flecainide for paroxysmal atrial fibrillation. Note the coved-type ST segments (arrow). The patient was diagnosed with Brugada syndrome during an ajmaline provocation test.
      Although the most appropriate treatment of Brugada syndrome is under discussion,
      • Paul M.
      • Gerss J.
      • Schulze-Bahr E.
      • et al.
      Role of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data.
      • Eckardt L.
      • Probst V.
      • Smits J.P.
      • et al.
      Long-term prognosis of individuals with right precordial ST-segment-elevation Brugada syndrome.
      avoidance of potentially proarrhythmic drugs and treatment of fever (which is a well-known trigger of cardiac events in Brugada syndrome)
      • Amin A.S.
      • Meregalli P.G.
      • Bardai A.
      • Wilde A.A.
      • Tan H.L.
      Fever increases the risk for cardiac arrest in the Brugada syndrome.
      • Skinner J.R.
      • Chung S.K.
      • Nel C.A.
      • et al.
      Brugada syndrome masquerading as febrile seizures.
      are generally accepted to be an important part of (prophylactic) treatment. However, some patients may (only) be appropriately treated with an implantable cardioverter-defibrillator. Some drugs may have an antiarrhythmic effect and thus may be used favorably in the acute or chronic setting.
      • Belhassen B.
      • Glick A.
      • Viskin S.
      Efficacy of quinidine in high-risk patients with Brugada syndrome.
      • Probst V.
      • Denjoy I.
      • Meregalli P.G.
      • et al.
      Clinical aspects and prognosis of Brugada syndrome in children.
      • Mizusawa Y.
      • Sakurada H.
      • Nishizaki M.
      • Hiraoka M.
      Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment.
      Because Brugada syndrome has a rather low prevalence (estimated at 1:2,000, varying in different regions around the world),
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      these and other critical characteristics of Brugada syndrome may not be common knowledge for many physicians.
      • Perez Riera A.R.
      • Filho C.F.
      • Uchida A.H.
      • et al.
      Study of the extent of the information of cardiologists from Sao Paulo city, Brazil, regarding a low-prevalence entity: Brugada syndrome.
      With the aim of aiding all physicians who treat patients with Brugada syndrome, we discussed the interaction between drugs and Brugada syndrome, performed an extensive review of the literature, formed an international expert panel to produce a consensus recommendation for each drug, and initiated a website (www.brugadadrugs.org;Figure 3) to ensure worldwide online and up-to-date availability of this knowledge base.

      Methods

      Literature review

      PubMed (Text: Brugada; MeSH terms: Chemicals and Drugs Category; only reports in English were considered) and expert knowledge was used to investigate drugs that have been associated with the type 1 Brugada syndrome ECG, with arrhythmias or with antiarrhythmic properties in Brugada syndrome patients. Although there is large variation in the extent to which different drugs have been associated with Brugada syndrome, we aimed to investigate the first reported drug–Brugada syndrome association for each drug but favored larger, combined clinical–experimental or otherwise important studies (e.g., those that report arrhythmias). Thus, we refer to many, but not to all, reports that describe an association between a certain drug and Brugada syndrome. Furthermore, we sought drugs with cardiac ion channel blocking effects that hypothetically have the potential to have deleterious effects in Brugada syndrome patients but that have not yet been reported to have deleterious effects. Finally, for most drugs having a clinical association with Brugada syndrome, we were able to retrieve confirmatory experimental studies showing the effects of the drug on cardiac electrophysiology.

      Recommendations

      As there are no randomized clinical trials in Brugada syndrome, the level of evidence (American College of Cardiology/American Heart Association/European Society of Cardiology [ACC/AHA/ESC] format) for most associations is C (only consensus opinion of experts, case studies, or standard of care) and for some associations is B (nonrandomized studies). To ascertain the validity of the recommendations given, we formed an international expert panel (the BrugadaDrugs.org Advisory Board) to summarize the clinical and experimental evidence and expert opinion. The classification of recommendation is expressed in a modified ACC/AHA/ESC format as follows:
      • Class I: There is evidence and/or general agreement that a given treatment is potentially proarrhythmic (or potentially antiarrhythmic) in Brugada syndrome patients.
      • Class IIa: There is conflicting evidence and/or divergence of opinion about the drug, but the weight of evidence/opinion is in favor of a potentially proarrhythmic (or potentially antiarrhythmic) effect in Brugada syndrome patients.
      • Class IIb: There is conflicting evidence and/or divergence of opinion about the drug, and the potential proarrhythmic (or potentially antiarrhythmic) effect in Brugada syndrome patients is less well established by evidence/opinion.
      • Class III: There is very little evidence and/or agreement that a drug is potentially proarrhythmic (or potentially antiarrhythmic) in Brugada syndrome patients.
      Subsequently, we have listed the drugs into four groups:
      • Drugs to be avoided by Brugada syndrome patients
      • Drugs preferably avoided by Brugada syndrome patients
      • Potential antiarrhythmic drugs in Brugada syndrome patients
      • Diagnostic drugs in Brugada syndrome
      Within these groups, we differentiated between different drug classes (e.g., antiarrhythmic drugs and psychotropic drugs).

      Results

      The PubMed search yielded 563 reports, including 506 written in English. The BrugadaDrugs.org Advisory Board selected approximately 15% of these reports as adding considerably to our knowledge and understanding of drug effects in Brugada syndrome. The drugs and accompanying recommendations are listed in Table 1, Table 2, Table 3, Table 4.
      Table 1Drugs to be avoided by Brugada syndrome patients
      Drug categoryDrug (generic)Recommendation
      Antiarrhythmic drugsAjmaline
      • Brugada J.
      • Brugada P.
      Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death.
      • Rolf S.
      • Bruns H.J.
      • Wichter T.
      • et al.
      The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol.
      • Wolpert C.
      • Echternach C.
      • Veltmann C.
      • et al.
      Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.
      • Bebarova M.
      • O'Hara T.
      • Geelen J.L.
      • et al.
      Subepicardial phase-0 block and discontinuous transmural conduction underlie right-precordial ST-segment elevation by a SCN5A loss-of-function mutation.
      Class I
      Flecainide
      • Krishnan S.C.
      • Josephson M.E.
      ST segment elevation induced by class IC antiarrhythmic agents: underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia.
      • Brugada R.
      • Brugada J.
      • Antzelevitch C.
      • et al.
      Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.
      • Gasparini M.
      • Priori S.G.
      • Mantica M.
      • et al.
      Flecainide test in Brugada syndrome: a reproducible but risky tool.
      • Meregalli P.G.
      • Ruijter J.M.
      • Hofman N.
      • Bezzina C.R.
      • Wilde A.A.
      • Tan H.L.
      Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome.
      • Stokoe K.S.
      • Balasubramaniam R.
      • Goddard C.A.
      • Colledge W.H.
      • Grace A.A.
      • Huang C.L.
      Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/– murine hearts.
      Class I
      Pilsicainide
      • Takenaka S.
      • Emori T.
      • Koyama S.
      • Morita H.
      • Fukushima K.
      • Ohe T.
      Asymptomatic form of Brugada syndrome.
      • Fujiki A.
      • Usui M.
      • Nagasawa H.
      • Mizumaki K.
      • Hayashi H.
      • Inoue H.
      ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome.
      • Takagi M.
      • Doi A.
      • Takeuchi K.
      • Yoshikawa J.
      Pilsicanide-induced marked T wave alternans and ventricular fibrillation in a patient with Brugada syndrome.
      • Kimura M.
      • Kobayashi T.
      • Owada S.
      • et al.
      Mechanism of ST elevation and ventricular arrhythmias in an experimental Brugada syndrome model.
      Class I
      Procainamide
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Brugada J.
      • Brugada P.
      Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death.
      • Joshi S.
      • Raiszadeh F.
      • Pierce W.
      • Steinberg J.S.
      Antiarrhythmic induced electrical storm in Brugada syndrome: a case report.
      • Villemaire C.
      • Savard P.
      • Talajic M.
      • Nattel S.
      A quantitative analysis of use-dependent ventricular conduction slowing by procainamide in anesthetized dogs.
      Class I
      Propafenone
      • Matana A.
      • Goldner V.
      • Stanic K.
      • Mavric Z.
      • Zaputovic L.
      • Matana Z.
      Unmasking effect of propafenone on the concealed form of the Brugada phenomenon.
      • Akdemir I.
      • Davutoglu V.
      • Aksoy M.
      Intermittent Brugada syndrome misdiagnosed as acute myocardial infarction and unmasked with propafenone.
      • Hasdemir C.
      • Olukman M.
      • Ulucan C.
      • Roden D.M.
      Brugada-type ECG pattern and extreme QRS complex widening with propafenone overdose.
      • Shan Q.
      • Yang B.
      • Chen M.
      • et al.
      Short-term normalization of ventricular repolarization by transcatheter ablation in a patient with suspected Brugada Syndrome.
      • Stark U.
      • Stark G.
      • Poppe H.
      • et al.
      Rate-dependent effects of detajmium and propafenone on ventricular conduction and refractoriness in isolated guinea pig hearts.
      Class IIa
      Psychotropic drugsAmitriptyline
      • Bolognesi R.
      • Tsialtas D.
      • Vasini P.
      • Conti M.
      • Manca C.
      Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose.
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Bebarta V.S.
      • Phillips S.
      • Eberhardt A.
      • Calihan K.J.
      • Waksman J.C.
      • Heard K.
      Incidence of Brugada electrocardiographic pattern and outcomes of these patients after intentional tricyclic antidepressant ingestion.
      • Nau C.
      • Seaver M.
      • Wang S.Y.
      • Wang G.K.
      Block of human heart hH1 sodium channels by amitriptyline.
      Class IIa
      Clomipramine
      • Goldgran-Toledano D.
      • Sideris G.
      • Kevorkian J.P.
      Overdose of cyclic antidepressants and the Brugada syndrome.
      • Pacher P.
      • Bagi Z.
      • Lako-Futo Z.
      • Ungvari Z.
      • Nanasi P.P.
      • Kecskemeti V.
      Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine.
      Class IIa
      Desipramine
      • Babaliaros V.C.
      • Hurst J.W.
      Tricyclic antidepressants and the Brugada syndrome: an example of Brugada waves appearing after the administration of desipramine.
      • Chow B.J.
      • Gollob M.
      • Birnie D.
      Brugada syndrome precipitated by a tricyclic antidepressant.
      • Akhtar M.
      • Goldschlager N.F.
      Brugada electrocardiographic pattern due to tricyclic antidepressant overdose.
      • Sudoh Y.
      • Cahoon E.E.
      • Gerner P.
      • Wang G.K.
      Tricyclic antidepressants as long-acting local anesthetics.
      Class IIa
      Lithium
      • Babaliaros V.C.
      • Hurst J.W.
      Tricyclic antidepressants and the Brugada syndrome: an example of Brugada waves appearing after the administration of desipramine.
      • Darbar D.
      • Yang T.
      • Churchwell K.
      • Wilde A.A.
      • Roden D.M.
      Unmasking of Brugada syndrome by lithium.
      Class IIa
      Loxapine
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Kinugawa T.
      • Kotake H.
      • Mashiba H.
      Inhibitory actions of amoxapine, a tricyclic antidepressant agent, on electrophysiological properties of mammalian isolated cardiac preparations.
      Class IIa
      Nortriptyline
      • Sudoh Y.
      • Cahoon E.E.
      • Gerner P.
      • Wang G.K.
      Tricyclic antidepressants as long-acting local anesthetics.
      • Tada H.
      • Sticherling C.
      • Oral H.
      • Morady F.
      Brugada syndrome mimicked by tricyclic antidepressant overdose.
      • Muir W.W.
      • Strauch S.M.
      • Schaal S.F.
      Effects of tricyclic antidepressant drugs on the electrophysiological properties of dog Purkinje fibers.
      Class IIa
      Trifluoperazine
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Klockner U.
      • Isenberg G.
      Calmodulin antagonists depress calcium and potassium currents in ventricular and vascular myocytes.
      Class IIa
      Anesthetic drugsBupivacaine
      • Phillips N.
      • Priestley M.
      • Denniss A.R.
      • Uther J.B.
      Brugada-type electrocardiographic pattern induced by epidural bupivacaine.
      • Vernooy K.
      • Delhaas T.
      • Cremer O.L.
      • et al.
      Electrocardiographic changes predicting sudden death in propofol-related infusion syndrome.
      • de La Coussaye J.E.
      • Brugada J.
      • Allessie M.A.
      Electrophysiologic and arrhythmogenic effects of bupivacaine A study with high-resolution ventricular epicardial mapping in rabbit hearts.
      • Berman M.F.
      • Lipka L.J.
      Relative sodium current block by bupivacaine and lidocaine in neonatal rat myocytes.
      Class IIa
      Propofol
      • Vernooy K.
      • Delhaas T.
      • Cremer O.L.
      • et al.
      Electrocardiographic changes predicting sudden death in propofol-related infusion syndrome.
      • Inamura M.
      • Okamoto H.
      • Kuroiwa M.
      • Hoka S.
      General anesthesia for patients with Brugada syndrome A report of six cases.
      • Saint D.A.
      The effects of propofol on macroscopic and single channel sodium currents in rat ventricular myocytes.
      • Robinson J.D.
      • Melman Y.
      • Walsh E.P.
      Cardiac conduction disturbances and ventricular tachycardia after prolonged propofol infusion in an infant.
      Class IIb
      Other substancesAcetylcholine
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Noda T.
      • Shimizu W.
      • Taguchi A.
      • et al.
      ST-segment elevation and ventricular fibrillation without coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome.
      • Montgomery P.R.
      • Dresel P.E.
      Conduction defects in experimental atrial arrhythmia.
      Class IIa
      Alcohol (toxicity)
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Shimada M.
      • Miyazaki T.
      • Miyoshi S.
      • et al.
      Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome.
      • Habuchi Y.
      • Furukawa T.
      • Tanaka H.
      • Lu L.L.
      • Morikawa J.
      • Yoshimura M.
      Ethanol inhibition of Ca2+ and Na+ currents in the guinea-pig heart.
      Class IIb
      Cocaine
      • Littmann L.
      • Monroe M.H.
      • Svenson R.H.
      Brugada-type electrocardiographic pattern induced by cocaine.
      • Ortega-Carnicer J.
      • Bertos-Polo J.
      • Gutierrez-Tirado C.
      Aborted sudden death, transient Brugada pattern, and wide QRS dysrhythmias after massive cocaine ingestion.
      • Bebarta V.S.
      • Summers S.
      Brugada electrocardiographic pattern induced by cocaine toxicity.
      • Xu Y.Q.
      • Crumb Jr., W.J.
      • Clarkson C.W.
      Cocaethylene, a metabolite of cocaine and ethanol, is a potent blocker of cardiac sodium channels.
      Class IIa
      Ergonovine
      • Noda T.
      • Shimizu W.
      • Taguchi A.
      • et al.
      ST-segment elevation and ventricular fibrillation without coronary spasm by intracoronary injection of acetylcholine and/or ergonovine maleate in patients with Brugada syndrome.
      • Muller-Schweinitzer E.
      The mechanism of ergometrine-induced coronary arterial spasm: in vitro studies on canine arteries.
      Class IIb
      Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion.
      Table 2Drugs preferably avoided by Brugada syndrome patients
      Drug categoryDrug (generic)Recommendation
      Antiarrhythmic drugsAmiodarone
      • Chalvidan T.
      • Deharo J.C.
      • Dieuzaide P.
      • Defaye P.
      • Djiane P.
      Near fatal electrical storm in a patient equipped with an implantable cardioverter defibrillator for Brugada syndrome.
      • Paul G.
      • Yusuf S.
      • Sharma S.
      Unmasking of the Brugada syndrome phenotype during the acute phase of amiodarone infusion.
      • Wu L.
      • Rajamani S.
      • Shryock J.C.
      • et al.
      Augmentation of late sodium current unmasks the proarrhythmic effects of amiodarone.
      Class IIb
      Cibenzoline
      • Tada H.
      • Nogami A.
      • Shimizu W.
      • et al.
      ST segment and T wave alternans in a patient with Brugada syndrome.
      • Sarkozy A.
      • Caenepeel A.
      • Geelen P.
      • Peytchev P.
      • de Z.M.
      • Brugada P.
      Cibenzoline induced Brugada ECG pattern.
      • Niwa R.
      • Honjo H.
      • Kodama I.
      • Maruyama K.
      • Toyama J.
      Na+ channel blocking effects of cibenzoline on guinea-pig ventricular cells.
      Class IIb
      Disopyramide
      • Sugao M.
      • Fujiki A.
      • Nishida K.
      • et al.
      Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Chinushi M.
      • Aizawa Y.
      • Ogawa Y.
      • Shiba M.
      • Takahashi K.
      Discrepant drug action of disopyramide on ECG abnormalities and induction of ventricular arrhythmias in a patient with Brugada syndrome.
      • Shimizu W.
      • Antzelevitch C.
      • Suyama K.
      • et al.
      Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome.
      • Grant A.O.
      • Chandra R.
      • Keller C.
      • Carboni M.
      • Starmer C.F.
      Block of wild-type and inactivation-deficient cardiac sodium channels IFM/QQQ stably expressed in mammalian cells.
      Class IIb
      Lidocaine
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Barajas-Martinez H.M.
      • Hu D.
      • Cordeiro J.M.
      • et al.
      Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel.
      Lidocaine use for local anesthesia seems to be safe if the amount administered is low and if it is combined with adrenaline, which results in a local effect only.
      Class IIb
      Propranolol
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Kasanuki H.
      • Ohnishi S.
      • Ohtuka M.
      • et al.
      Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease.
      • Shimada M.
      • Miyazaki T.
      • Miyoshi S.
      • et al.
      Sustained monomorphic ventricular tachycardia in a patient with Brugada syndrome.
      • Aouate P.
      • Clerc J.
      • Viard P.
      • Seoud J.
      Propranolol intoxication revealing a Brugada syndrome.
      • Shimada M.
      • Nakamura Y.
      • Iwanaga S.
      • et al.
      Nonischemic ST-segment elevation induced by negative inotropic agents.
      Class IIb
      Verapamil
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Chinushi M.
      • Tagawa M.
      • Nakamura Y.
      • Aizawa Y.
      Shortening of the ventricular fibrillatory intervals after administration of verapamil in a patient with Brugada syndrome and vasospastic angina.
      • Fish J.M.
      • Antzelevitch C.
      Cellular Mechanism and arrhythmogenic ootential of T-wave alternans in the Brugada syndrome.
      Class IIb
      Psychotropic drugsCarbamazepine
      • Megarbane B.
      • Leprince P.
      • Deye N.
      • et al.
      Extracorporeal life support in a case of acute carbamazepine poisoning with life-threatening refractory myocardial failure.
      • Brau M.E.
      • Dreimann M.
      • Olschewski A.
      • Vogel W.
      • Hempelmann G.
      Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na(+) currents in rat sensory neurons.
      Class IIb
      Cyamemazine
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Crumb W.
      • Llorca P.M.
      • Lancon C.
      • Thomas G.P.
      • Garay R.P.
      • Hameg A.
      Effects of cyamemazine on hERG, INa, ICa, Ito, Isus and IK1 channel currents, and on the QTc interval in guinea pigs.
      Class IIb
      Doxepin
      • Bebarta V.S.
      • Phillips S.
      • Eberhardt A.
      • Calihan K.J.
      • Waksman J.C.
      • Heard K.
      Incidence of Brugada electrocardiographic pattern and outcomes of these patients after intentional tricyclic antidepressant ingestion.
      • Muir W.W.
      • Strauch S.M.
      • Schaal S.F.
      Effects of tricyclic antidepressant drugs on the electrophysiological properties of drug Purkinje fibers.
      Class IIb
      Fluoxetine
      • Rouleau F.
      • Asfar P.
      • Boulet S.
      • et al.
      Transient ST segment elevation in right precordial leads induced by psychotropic drugs: relationship to the Brugada syndrome.
      • Pacher P.
      • Bagi Z.
      • Lako-Futo Z.
      • Ungvari Z.
      • Nanasi P.P.
      • Kecskemeti V.
      Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine.
      Class IIb
      Imipramine
      • Robert E.
      • Bruelle P.
      • de La Coussaye J.E.
      • et al.
      Electrophysiologic and proarrhythmogenic effects of therapeutic and toxic doses of imipramine: a study with high resolution ventricular epicardial mapping in rabbit hearts.
      Class IIb
      Maprotiline
      • Bolognesi R.
      • Tsialtas D.
      • Vasini P.
      • Conti M.
      • Manca C.
      Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose.
      • Igawa O.
      • Kotake H.
      • Kurata Y.
      • et al.
      Electrophysiological effects of maprotiline, a tetracyclic antidepressant agent, on isolated cardiac preparations.
      Class IIb
      Perphenazine
      • Bolognesi R.
      • Tsialtas D.
      • Vasini P.
      • Conti M.
      • Manca C.
      Abnormal ventricular repolarization mimicking myocardial infarction after heterocyclic antidepressant overdose.
      • Bebarova M.
      • Matejovic P.
      • Pasek M.
      • et al.
      Effect of antipsychotic drug perphenazine on fast sodium current and transient outward potassium current in rat ventricular myocytes.
      Class IIb
      Phenytoin
      • Al Aloul B.
      • Adabag A.S.
      • Houghland M.A.
      • Tholakanahalli V.
      Brugada pattern electrocardiogram associated with supratherapeutic phenytoin levels and the risk of sudden death.
      • Xu Y.Q.
      • Pickoff A.S.
      • Clarkson C.W.
      Evidence for developmental changes in sodium channel inactivation gating and sodium channel block by phenytoin in rat cardiac myocytes.
      Class IIb
      Thioridazine
      • Copetti R.
      • Proclemer A.
      • Pillinini P.P.
      Brugada-like ECG abnormalities during thioridazine overdose.
      Class IIb
      Antianginal drugsDiltiazem
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Itoh E.
      • Suzuki K.
      • Tanabe Y.
      A case of vasospastic angina presenting Brugada-type ECG abnormalities.
      • Sasaki T.
      • Niwano S.
      • Kitano Y.
      • Izumi T.
      Two cases of Brugada syndrome associated with spontaneous clinical episodes of coronary vasospasm.
      • Miyazaki K.
      • Adaniya H.
      • Sawanobori T.
      • Hiraoka M.
      Electrophysiological effects of clentiazem, a new Ca2+ antagonist, on rabbit hearts.
      Class III
      Nicorandil
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Robert E.
      • Aya A.G.
      • de La Coussaye J.E.
      • et al.
      Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts.
      Class III
      Nifedipine
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Hussain M.
      • Orchard C.H.
      Sarcoplasmic reticulum Ca2+ content, L-type Ca2+ current and the Ca2+ transient in rat myocytes during beta-adrenergic stimulation.
      Class III
      Nitroglycerine
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Matsuo K.
      • Shimizu W.
      • Kurita T.
      • Inagaki M.
      • Aihara N.
      • Kamakura S.
      Dynamic changes of 12-lead electrocardiograms in a patient with Brugada syndrome.
      • Korth M.
      Influence of glyceryl trinitrate on force of contraction and action potential of guinea-pig myocardium.
      Class III
      Sorbidnitrate
      • Antzelevitch C.
      • Brugada P.
      • Borggrefe M.
      • et al.
      Brugada syndrome: report of the second consensus conference.
      • Chinushi M.
      • Tagawa M.
      • Nakamura Y.
      • Aizawa Y.
      Shortening of the ventricular fibrillatory intervals after administration of verapamil in a patient with Brugada syndrome and vasospastic angina.
      • Atanassova R.
      • Spassov G.
      • Balansky R.
      • Boev K.
      Effects of isosorbide-5-mononitrate and isosorbide-2-mononitrate on the contractile and electrical activity and on the content of cyclic nucleotides in isolated heart muscles of the guinea-pig and dog.
      Class III
      Other substancesDimenhydrinate
      • Pastor A.
      • Nunez A.
      • Cantale C.
      • Cosio F.G.
      Asymptomatic Brugada syndrome case unmasked during dimenhydrinate infusion.
      • Lopez-Barbeito B.
      • Lluis M.
      • Delgado V.
      • et al.
      Diphenhydramine overdose and Brugada sign.
      • Kuo C.C.
      • Huang R.C.
      • Lou B.S.
      Inhibition of Na(+) current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels.
      Class IIb
      Edrophonium
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Kasanuki H.
      • Ohnishi S.
      • Ohtuka M.
      • et al.
      Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease.
      Class IIb
      Indapamide
      • Mok N.S.
      • Tong C.K.
      • Yuen H.C.
      Concomitant-acquired Long QT and Brugada syndromes associated with indapamide-induced hypokalemia and hyponatremia.
      Class IIb
      Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion; Class III: very little evidence.
      low asterisk Lidocaine use for local anesthesia seems to be safe if the amount administered is low and if it is combined with adrenaline, which results in a local effect only.
      Table 3Potential antiarrhythmic drugs in Brugada syndrome patients
      Drug categoryDrug (generic)Recommendation
      Antiarrhythmic drugsIsoproterenol/isoprenaline
      • Ohgo T.
      • Okamura H.
      • Noda T.
      • et al.
      Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation.
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Watanabe A.
      • Kusano K.F.
      • Morita H.
      • et al.
      Low-dose isoproterenol for repetitive ventricular arrhythmia in patients with Brugada syndrome.
      • Ganesan A.N.
      • Maack C.
      • Johns D.C.
      • Sidor A.
      • O'Rourke B.
      Beta-adrenergic stimulation of L-type Ca2+ channels in cardiac myocytes requires the distal carboxyl terminus of alpha1C but not serine 1928.
      In adults, an isoproterenol regimen of 0.003 ± 0.003 μg/kg/min has been used by Ohgo et al15 and 0.01–0.02 μg/kg/min has been used by Kasanuki et al.18
      Class I
      Orciprenaline
      • Kyriazis K.
      • Bahlmann E.
      • van der S.H.
      • Kuck K.H.
      Electrical storm in Brugada syndrome successfully treated with orciprenaline; effect of low-dose quinidine on the electrocardiogram.
      Class IIa
      Quinidine
      • Belhassen B.
      • Glick A.
      • Viskin S.
      Efficacy of quinidine in high-risk patients with Brugada syndrome.
      • Probst V.
      • Denjoy I.
      • Meregalli P.G.
      • et al.
      Clinical aspects and prognosis of Brugada syndrome in children.
      • Mizusawa Y.
      • Sakurada H.
      • Nishizaki M.
      • Hiraoka M.
      Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment.
      • Ohgo T.
      • Okamura H.
      • Noda T.
      • et al.
      Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation.
      • Alings M.
      • Dekker L.
      • Sadee A.
      • Wilde A.
      Quinidine induced electrocardiographic normalization in two patients with Brugada syndrome.
      • Yan G.X.
      • Antzelevitch C.
      Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation.
      Aim for quinidine plasma levels of 1–3 μg/mL or 3.5–11 μmol/L.
      Class I
      Other substancesCilostazol
      • Tsuchiya T.
      • Ashikaga K.
      • Honda T.
      • Arita M.
      Prevention of ventricular fibrillation by cilostazol, an oral phosphodiesterase inhibitor, in a patient with Brugada syndrome.
      • Abud A.
      • Bagattin D.
      • Goyeneche R.
      • Becker C.
      Failure of cilostazol in the prevention of ventricular fibrillation in a patient with Brugada syndrome.
      • Matsui K.
      • Kiyosue T.
      • Wang J.C.
      • Dohi K.
      • Arita M.
      Effects of pimobendan on the L-type Ca2+ current and developed tension in guinea-pig ventricular myocytes and papillary muscle: comparison with IBMX, milrinone, and cilostazol.
      Class IIb
      Recommendation: Class I: convincing evidence/opinion; Class IIa: evidence/opinion less clear; Class IIb: conflicting evidence/opinion.
      low asterisk In adults, an isoproterenol regimen of 0.003 ± 0.003 μg/kg/min has been used by Ohgo et al
      • Ohgo T.
      • Okamura H.
      • Noda T.
      • et al.
      Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation.
      and 0.01–0.02 μg/kg/min has been used by Kasanuki et al.
      • Kasanuki H.
      • Ohnishi S.
      • Ohtuka M.
      • et al.
      Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease.
      Aim for quinidine plasma levels of 1–3 μg/mL or 3.5–11 μmol/L.
      Table 4Diagnostic drugs in Brugada syndrome
      Drug categoryDrug (generic)Use
      Antiarrhythmic drugsAjmaline
      • Brugada J.
      • Brugada P.
      Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death.
      • Rolf S.
      • Bruns H.J.
      • Wichter T.
      • et al.
      The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol.
      • Wolpert C.
      • Echternach C.
      • Veltmann C.
      • et al.
      Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.
      • Bebarova M.
      • O'Hara T.
      • Geelen J.L.
      • et al.
      Subepicardial phase-0 block and discontinuous transmural conduction underlie right-precordial ST-segment elevation by a SCN5A loss-of-function mutation.
      Maximal dose 1 mg/kg
      Flecainide
      • Krishnan S.C.
      • Josephson M.E.
      ST segment elevation induced by class IC antiarrhythmic agents: underlying electrophysiologic mechanisms and insights into drug-induced proarrhythmia.
      • Brugada R.
      • Brugada J.
      • Antzelevitch C.
      • et al.
      Sodium channel blockers identify risk for sudden death in patients with ST-segment elevation and right bundle branch block but structurally normal hearts.
      • Gasparini M.
      • Priori S.G.
      • Mantica M.
      • et al.
      Flecainide test in Brugada syndrome: a reproducible but risky tool.
      • Meregalli P.G.
      • Ruijter J.M.
      • Hofman N.
      • Bezzina C.R.
      • Wilde A.A.
      • Tan H.L.
      Diagnostic value of flecainide testing in unmasking SCN5A-related Brugada syndrome.
      • Stokoe K.S.
      • Balasubramaniam R.
      • Goddard C.A.
      • Colledge W.H.
      • Grace A.A.
      • Huang C.L.
      Effects of flecainide and quinidine on arrhythmogenic properties of Scn5a+/– murine hearts.
      Wolpert et al28 reported that flecainide has 32% lower sensitivity than ajmaline in uncovering a type 1 Brugada ECG.
      Maximal dose 2 mg/kg
      Pilsicainid
      • Takenaka S.
      • Emori T.
      • Koyama S.
      • Morita H.
      • Fukushima K.
      • Ohe T.
      Asymptomatic form of Brugada syndrome.
      • Fujiki A.
      • Usui M.
      • Nagasawa H.
      • Mizumaki K.
      • Hayashi H.
      • Inoue H.
      ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs: insight into the mechanism of Brugada syndrome.
      • Takagi M.
      • Doi A.
      • Takeuchi K.
      • Yoshikawa J.
      Pilsicanide-induced marked T wave alternans and ventricular fibrillation in a patient with Brugada syndrome.
      • Kimura M.
      • Kobayashi T.
      • Owada S.
      • et al.
      Mechanism of ST elevation and ventricular arrhythmias in an experimental Brugada syndrome model.
      Maximal dose 1 mg/kg
      Procainamide
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Brugada J.
      • Brugada P.
      Further characterization of the syndrome of right bundle branch block, ST segment elevation, and sudden cardiac death.
      • Joshi S.
      • Raiszadeh F.
      • Pierce W.
      • Steinberg J.S.
      Antiarrhythmic induced electrical storm in Brugada syndrome: a case report.
      • Villemaire C.
      • Savard P.
      • Talajic M.
      • Nattel S.
      A quantitative analysis of use-dependent ventricular conduction slowing by procainamide in anesthetized dogs.
      In the first consensus report (Wilde et al2), the sensitivity of procainamide was considered relatively low.
      Maximal dose 10 mg/kg
      low asterisk Wolpert et al
      • Wolpert C.
      • Echternach C.
      • Veltmann C.
      • et al.
      Intravenous drug challenge using flecainide and ajmaline in patients with Brugada syndrome.
      reported that flecainide has 32% lower sensitivity than ajmaline in uncovering a type 1 Brugada ECG.
      In the first consensus report (Wilde et al
      • Wilde A.A.
      • Antzelevitch C.
      • Borggrefe M.
      • et al.
      Proposed diagnostic criteria for the Brugada syndrome: consensus report.
      ), the sensitivity of procainamide was considered relatively low.

      Discussion

      In this study, we reviewed the literature on drug use in Brugada syndrome patients and made recommendations about their safety that were based on the literature and expert opinion. We also initiated a website (www.brugadadrugs.org) where these drugs and the recommendations can be accessed by all physicians who treat patients with Brugada syndrome and by other individuals with a possible interest (e.g., patients). On this website, we provide more detailed information on the drugs used in Brugada syndrome than is reviewed in this article. In addition, the website is updated frequently (drugs added or removed, recommendations changed) according to the latest evidence.
      Patients with Brugada syndrome should be advised not to take the drugs from the “avoid” and “preferably avoid” lists or to use these drugs only after extensive consideration and/or under controlled conditions. We advise patients to give a list of these drugs to all of their health care providers (including their general practitioner, dentist and pharmacist). In many patients with Brugada syndrome, avoidance of these drugs (and treatment of fever)
      • Amin A.S.
      • Meregalli P.G.
      • Bardai A.
      • Wilde A.A.
      • Tan H.L.
      Fever increases the risk for cardiac arrest in the Brugada syndrome.
      • Skinner J.R.
      • Chung S.K.
      • Nel C.A.
      • et al.
      Brugada syndrome masquerading as febrile seizures.
      probably is appropriate and safe treatment. Some Brugada syndrome patients seem to perform well on quinidine.
      • Belhassen B.
      • Glick A.
      • Viskin S.
      Efficacy of quinidine in high-risk patients with Brugada syndrome.
      • Probst V.
      • Denjoy I.
      • Meregalli P.G.
      • et al.
      Clinical aspects and prognosis of Brugada syndrome in children.
      • Mizusawa Y.
      • Sakurada H.
      • Nishizaki M.
      • Hiraoka M.
      Effects of low-dose quinidine on ventricular tachyarrhythmias in patients with Brugada syndrome: low-dose quinidine therapy as an adjunctive treatment.
      Recently, a prospective registry has started investigating the use of empiric quinidine therapy for treatment of asymptomatic Brugada syndrome patients (ClinicalTrials.gov identifier NCT00789165).
      • Viskin S.
      • Wilde A.A.
      • Tan H.L.
      • Antzelevitch C.
      • Shimizu W.
      • Belhassen B.
      Empiric quinidine therapy for asymptomatic Brugada syndrome: time for a prospective registry.
      Furthermore, the QUIDAM study (HydroQuinidine to Decrease Arrhythmic events in Brugada syndrome patients, ClinicalTrials.gov identifier NCT00927732), a French national double-blinded randomized study, is currently investigating the role of quinidine therapy in improving the outcome of high-risk Brugada syndrome patients. Reports have postulated an antiarrhythmic effect of other drugs (amrinone,
      • Marquez M.F.
      • Salica G.
      • Hermosillo A.G.
      • et al.
      Ionic basis of pharmacological therapy in Brugada syndrome.
      bepridil,
      • Sugao M.
      • Fujiki A.
      • Nishida K.
      • et al.
      Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.
      • Ohgo T.
      • Okamura H.
      • Noda T.
      • et al.
      Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation.
      clarithromycin,
      • Marquez M.F.
      • Salica G.
      • Hermosillo A.G.
      • et al.
      Ionic basis of pharmacological therapy in Brugada syndrome.
      denopamine,
      • Ohgo T.
      • Okamura H.
      • Noda T.
      • et al.
      Acute and chronic management in patients with Brugada syndrome associated with electrical storm of ventricular fibrillation.
      dimethyl lithospermate B,
      • Fish J.M.
      • Welchons D.R.
      • Kim Y.S.
      • Lee S.H.
      • Ho W.K.
      • Antzelevitch C.
      Dimethyl lithospermate B, an extract of Danshen, suppresses arrhythmogenesis associated with the Brugada syndrome.
      mexiletine,
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      • Kasanuki H.
      • Ohnishi S.
      • Ohtuka M.
      • et al.
      Idiopathic ventricular fibrillation induced with vagal activity in patients without obvious heart disease.
      milrinone,
      • Marquez M.F.
      • Salica G.
      • Hermosillo A.G.
      • et al.
      Ionic basis of pharmacological therapy in Brugada syndrome.
      phentolamine,
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      prazosin,
      • Miyazaki T.
      • Mitamura H.
      • Miyoshi S.
      • Soejima K.
      • Aizawa Y.
      • Ogawa S.
      Autonomic and antiarrhythmic drug modulation of ST segment elevation in patients with Brugada syndrome.
      sotalol,
      • Bertaglia E.
      • Michieletto M.
      • Spedicato L.
      • Pascotto P.
      Right bundle branch block, intermittent ST segment elevation and inducible ventricular tachycardia in an asymptomatic patient: an unusual presentation of the Brugada syndrome?.
      • Glatter K.A.
      • Wang Q.
      • Keating M.
      • Chen S.
      • Chiamvimonvat N.
      • Scheinman M.M.
      Effectiveness of sotalol treatment in symptomatic Brugada syndrome.
      tedisamil
      • Marquez M.F.
      • Salica G.
      • Hermosillo A.G.
      • et al.
      Ionic basis of pharmacological therapy in Brugada syndrome.
      • Perez Riera A.R.
      • Zhang L.
      • Uchida A.H.
      • Schapachnik E.
      • Dubner S.
      • Ferreira C.
      The management of Brugada syndrome patients.
      and 4-aminopyridine
      • Marquez M.F.
      • Salica G.
      • Hermosillo A.G.
      • et al.
      Ionic basis of pharmacological therapy in Brugada syndrome.
      ) in Brugada syndrome. We consider the evidence on use of these drugs as antiarrhythmic treatment in Brugada syndrome patients currently to be too low.
      In Brugada syndrome patients, an important issue regarding ventricular tachyarrhythmias is that they can present as an epileptic seizure and that the cerebral hypoperfusion may create a clinical picture easily confused with a postictal phase. Therefore, in patients with seizures, both epilepsy and arrhythmia syndromes such as Brugada syndrome
      • Skinner J.R.
      • Chung S.K.
      • Nel C.A.
      • et al.
      Brugada syndrome masquerading as febrile seizures.
      (or, e.g., long QT syndrome)
      • Johnson J.N.
      • Hofman N.
      • Haglund C.M.
      • Cascino G.D.
      • Wilde A.A.
      • Ackerman M.J.
      Identification of a possible pathogenic link between congenital long QT syndrome and epilepsy.
      are part of the differential diagnosis. Many antiepileptic drugs, such as carbamazepine and phenytoin, act through cerebral ion channel blockade but also will result in cardiac ion channel blockade.
      • Bahls F.H.
      • Ozuna J.
      • Ritchie D.E.
      Interactions between calcium channel blockers and the anticonvulsants carbamazepine and phenytoin.
      • Cave G.
      • Sleigh J.W.
      ECG features of sodium channel blockade in rodent phenytoin toxicity and effect of hypertonic saline.
      • Segal M.M.
      • Douglas A.F.
      Late sodium channel openings underlying epileptiform activity are preferentially diminished by the anticonvulsant phenytoin.
      The latter may have a deleterious (and possibly fatal) effect in patients with an arrhythmia syndrome such as Brugada syndrome. Therefore, it is important to exclude arrhythmia syndromes such as Brugada syndrome in patients suspected of epilepsy before a possible harmful treatment is started.
      We hope that the website will helpful to physicians who are in need of this information, and we welcome your suggestions and/or documentation on the safe or unsafe use of drugs in Brugada syndrome patients. We hope that use of the information provided on our website will prevent Brugada syndrome patients from suffering a cardiac arrest or sudden cardiac death initiated by drugs that should be avoided.

      Limitations

      The principal limitation of the association between certain drugs, Brugada syndrome, and arrhythmias is the limited number of case reports and experimental studies suggesting an effect in Brugada syndrome. Furthermore, Brugada syndrome patients may show conflicting results and large variability in their response to certain drugs. This response may also vary in different conditions (e.g., with or without fever, drug in therapeutic range, overdose, or in combination with other drugs). Therefore, clinical decision making should be based on more than the presence or absence of a (single) association in another patient. In additionally, it remains important for health care providers to recognize the active substances in medicines containing a combination of drugs and to be aware of the drug category (e.g., many tricyclic antidepressants are potentially proarrhythmic in Brugada syndrome patients).

      Acknowledgments

      We gratefully acknowledge CardioNetworks (a nonprofit organization based in The Netherlands that was founded in 2007 with the aim of providing unbiased and up-to-date medical knowledge to the global community) and particularly its chair Jonas S.S.G. de Jong, MD, for hosting the website. The inspiration for the website comes from www.qtdrugs.org, which contains lists of drugs associated with the long QT syndrome.

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