The following are key points to remember from this American Heart Association Scientific Statement on drug-induced arrhythmias:

1. Bradycardia:
   • Sinus node automaticity is suppressed by drugs that inhibit sympathetic nervous system activity (beta-blockers) or stimulate the parasympathetic nervous system (neostigmine, pyridostigmine). Sinus node and atrioventricular (AV) node action potentials depend on sodium and calcium currents. Clonidine stimulates central α-receptors and reduces norepinephrine release. Ivabradine inhibits the hyperpolarization–activated cyclic nucleotide–gated funny channels (I_f) in the sinus node.
   • Death resulting from drug-induced bradycardia is rare; torsades de pointes can occur in the setting of QT prolongation and bradycardia.
   • Atropine can be used acutely in most patients. Patients who have undergone heart transplantation without evidence for autonomic re-innervation should not receive atropine because it can cause paradoxical heart block or even sinus arrest.
   • Treatment for overdose of sinus or AV node blocking agents includes: gastric lavage, activated charcoal, glucagon, and insulin with concomitant intravenous (IV) dextrose. IV calcium may be used for patients with calcium channel blocker overdose.
2. Atrial Fibrillation (AF) and Atrial Flutter (AFL):
   • Cardiovascular medications, alcohol, stimulants, anticancer drugs, and immuno-modulators may trigger AF/AFL.
   • Flecainide and propafenone slow atrial conduction, which can result in a 1-1 AV conduction; AV node blocking agents should be co-prescribed.
   • Alcohol promotes sympathetic nervous system stimulation, shortens atrial effective refractory period, increases interatrial electromechanical delays, and acts via vagal pathways.
   • Bisphosphonates induce AF through an unknown mechanism; these drugs release inflammatory cytokines and shorten atrial action potential and effective refractory period.
   • The anticancer medication trastuzumab increases inflammation, oxidative stress, and reactive oxygen species, causing ion channel dysfunction and remodeling, which is the proposed mechanism for AF induction.
3. Supraventricular Tachycardia:
   • Multifocal atrial tachycardia (AT) occurs in patients with pulmonary or structural heart disease, theophylline use, or hypomagnesemia. Drugs that can induce AT include beta agonists and phosphodiesterase inhibitors.
   • Digoxin toxicity can cause paroxysmal AT with AV block. Risk factors for digoxin-induced AT include serum digoxin concentrations ≥2 ng/ml, kidney disease, hypomagnesemia, and drug interactions (e.g., amiodarone, verapamil, quinidine).
   • Treatment of drug-induced focal AT includes rate-controlling medications, antiarrhythmic drugs (e.g., flecainide, propafenone, sotalol, amiodarone, ibutilide), overdrive pacing, catheter ablation, or synchronized direct current cardioversion if unstable.
   • Some ATs may be suppressed by adenosine. Treatment of multifocal AT should include treatment of underlying conditions and magnesium supplementation.
   • Drugs that may cause or exacerbate AV nodal reentrant tachycardia include amphetamines, antipsychotics, bronchodilators, corticosteroids, loop diuretics, and stimulants.
4. Drug-induced Ventricular Arrhythmias:
   • The following drug classes may cause monomorphic ventricular tachycardia: anesthetics, antiarrhythmics, anticancer drugs, anticonvulsants, antidepressants, anti-manic medications, antiplatelet, antipsychotic, beta agonists, ergot derivatives, herbs, cocaine, inotropes, phosphodiesterase inhibitors, sympathomimetics, and vasodilators.
   • Mechanisms include myocardial sodium channel activation or inhibition, intracellular calcium overload, stimulation of beta-2 receptors, and induction of coronary ischemia. Sodium channel blockade is important in the presence of scar. Intracellular calcium overload occurs in patients with digoxin and theophylline toxicity.
   • Serum digoxin concentrations should be maintained at <2 ng/ml, and serum theophylline concentration <20 mg/ml.
   • Most common genetic mutations in Brugada syndrome involve loss of function of myocyte sodium channels (SCN5A mutation). Common drugs associated with Brugada syndrome are: antiarrhythmic drugs, tricyclic antidepressants, anesthetics/analgesics including propofol, as well as alcohol, cocaine, and lithium.
5. Torsades de Pointes (TdP):
   • Drugs cause TdP through inhibition of the rapid components of the delayed rectifier potassium current (I_Kr).
   • Arizona Center for Education and Research on Therapeutics maintains an up-to-date list of QT prolonging drugs.
   • Chloroquine, hydroxychloroquine, and azithromycin are known to cause TdP, alone or in combination. Additionally, drugs used for the management of coronavirus disease 2019 (lopinavir/ritonavir) may lengthen QT interval. Typical and atypical antipsychotic agents and fluoroquinolone and macrolide antibiotics have been associated with increased risk of sudden cardiac death potentially caused by TdP.
   • Risk factors for drug-induced TdP and sudden death are: QTc >500 milliseconds, QTc lengthening >60 milliseconds from pretreatment value, female sex, age >65 years, bradycardia, acute myocardial infarction, hypokalemia, hypomagnesemia, hypocalcemia, heart failure with reduced ejection fraction, concomitant administration of ≥2 QT prolonging drugs, history of drug-induced TdP, drug-drug interactions, rapid IV administration, and inadequate dose adjustment of really or hepatically cleared QT prolonging drugs.
   • Nearly 30% of patients with drug-induced QT propagation carry mutations for one of the five major QT syndrome genes. However, general genetic screening for prediction of drug-induced TdP is not currently recommended.
6. TdP Mitigation Strategies:
   • Maintenance of potassium >4 mEq/L and magnesium >2 mg/dl.
   • Twelve-lead electrocardiogram (ECG) every 3-6 months.
   • For patients taking methadone, baseline ECG should be repeated within 30 days in those with risk factors, then annually. ECG should be performed daily when methadone dose is >120 mg daily.
   • Clinical decision support tools providing computer-based QT interval and drug-drug interaction alerts can minimize the prescribing of QT-prolonging drugs and reduce the risk of QT pronation.
   • For patients with recurrent TdP associated with bradycardia refractory to IV magnesium, overdrive pacing or isoproterenol should be considered.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardio-Oncology, Invasive Cardiovascular Angiography and Intervention, Prevention, Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Heart Transplant

Keywords: Anti-Arrhythmia Agents, Arrhythmias, Cardiac, Atrial Fibrillation, Atrial Flutter, Atrioventricular Block, Bradycardia, Brugada Syndrome, Cardiotoxicity, Coronavirus, Death, Sudden, Cardiac, Digoxin, Electrocardiography, Heart Transplantation, Neoplasms, Risk Factors, Secondary Prevention, Tachycardia, Supraventricular, Tachycardia, Ventricular, Torsades de Pointes

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