Class III antiarrhythmic drugs are indispensable for cardiac rhythm control, yet their susceptibility to clinically used ion channel modulating drugs remains insufficiently characterized. Because Kv11.1 channels are present in neurons and glia, their pharmacological engagement may influence excitability and cell viability. Here, we investigated Sotalol, Ibutilide, and Amiodarone, three clinically used Kv11.1 active compounds with distinct lipophilicity profiles, using an integrated strategy that combines whole-cell patch-clamp electrophysiology, cell viability assays, and physiologically based pharmacokinetic (PBPK) modeling in neuron-like SH-SY5Y cells, a human model widely used for neurotoxicity and ion-channel studies. Sotalol produced minimal electrophysiological changes, whereas Ibutilide caused moderate suppression of outward K⁺ currents, and Amiodarone did not show acute effects under our patch-clamp conditions. However, Amiodarone induced pronounced morphological changes and loss of viability in vitro, while Ibutilide showed moderate cytotoxicity and Sotalol caused minimal metabolic alterations. PBPK simulations contextualized these findings, predicting extensive, time-dependent brain accumulation of Amiodarone, moderate entry of Ibutilide, and minimal penetration of Sotalol. Together, these data reveal a clear link between drug lipophilicity, brain exposure, and neuronal vulnerability. Amiodarone's high lipid solubility drives persistent intracellular retention and cytotoxic morphology, while Ibutilide primarily exerts transient electrophysiological effects. This integrated PBPK-in-vitro framework provides a mechanistic basis for differentiating CNS risk among antiarrhythmics and highlights lipophilicity and broad ion channel activity as key determinants of neuronal safety.

The saga of antiarrhythmic drug (AAD) therapy reflects a field shaped by empiricism and burdened by challenges related to safety. The Singh-Vaughan-Williams classification was a timely necessity that eventually slowed pharmacological innovation by prioritizing electrophysiologic properties over arrhythmogenic mechanisms. The present, limited pharmacological armamentarium demands efforts to reassess legacy antiarrhythmics, repurpose non-antiarrhythmic agents as upstream or downstream therapy, and develop novel compounds. Flecainide, propafenone, and dronedarone have demonstrated their reliable efficacy and safety, even in patients with structural heart disease, which should allow clinicians to reduce their reliance on amiodarone. Previous concerns regarding the proarrhythmic risk of dofetilide and ibutilide are currently managed through careful patient selection and adequate QT interval monitoring. Novel targeted AADs are advancing through the development pipeline, of which etripamil and landiolol have already been approved. Other emerging drugs, such as SK channel blockers (AP30663 and AP31969), RyR2 blockers, CaMKII inhibitors, and TASK-1 blockers (doxapram), are aligned with the new paradigm of atrial fibrillation that focuses on triggers and re-entry. Once triggered, arrhythmias are perpetuated by the underlying substrate, which could be directly targeted by antifibrotic therapy. Developing concepts such as atrial cardiomyopathy allows clinicians to characterize substrate objectively, in order to assess disease severity and individualize antiarrhythmic treatment. The future of antiarrhythmic therapy will be reshaped by artificial intelligence and digital twinning, which allow precise phenotyping and a tailored approach based on individual patient profiles, complemented by rhythm monitoring through wearables.

Ibutilide is a class III antiarrhythmic drug used intravenously for the chemical cardioversion of atrial fibrillation (AF) and atrial flutter (AFL). It mainly acts by blocking the rapid component (Ikr) of delayed rectifier K[+] channels, resulting in prolongation of action potential duration in the atrium. Ibutilide fumarate is a methanesulfonamide derivative that is structurally similar to sotalol without the β-adrenoreceptor blocking activity. The success rate of cardioversion of atrial flutter with ibutilide is in the range of 50-70%, whereas its efficacy for the conversion of atrial fibrillation is 30-50%. As compared to ibutilide monotherapy, coadministration with propafenone has a significantly higher success rate of AF termination. Ibutilide is also effective in pre-excited AF by reducing the risk of AF related ventricular tachycardia and thereby reducing the risk of sudden cardiac death. It is a safe drug to use for cardioversion in patients on chronic amiodarone therapy. The main side effect of dofetilide is torsade de pointes (tdp), which occurs in 4% patients, and monomorphic ventricular tachycardia, which occurs in 4.9% patients. Proadministration of magnesium reduces the risk of torsade de pointes. Patients should be monitored for at least 4 h for tdp. Targeting complex fractionated electrograms with the assistance of an ibutilide infusion during catheter ablation of persistent AF has shown mixed results. Conversion rate with an ibutilide infusion is only 30% in the presence of an enlarged left atrium (>5 cm) and 37.7% in the presence of mitral valve disease (MVD), whereas the conversion rate was 82.5% in the absence of MVD and 85% in the absence of both an enlarged left atrium and mitral valve disease (p = <0.001). Ibutilide can be used effectively in patients who are not a candidate for direct current cardioversion or who chose not to undergo electric cardioversion.

This review outlines the pharmacologic strategies for acute management of atrial fibrillation and atrial flutter, with a focus on rate and rhythm control. It details the efficacy, indications, and safety profiles of commonly used agents, including beta-blockers, calcium channel blockers, and antiarrhythmic drugs such as amiodarone, ibutilide, dofetilide, and flecainide. The article highlights patient-specific considerations, emerging therapies, and the need for safer, faster acting drugs as atrial fibrillation prevalence rises. Both traditional and novel approaches are discussed to guide evidence-based clinical decision-making in acute settings.

There is a dearth of systematic data on efficacy and safety of ibutilide in children and adults with CHD and also in pediatric age-group patients. To determine the efficacy and safety of ibutilide in these populations, and to characterize the determinants of its efficacy. Patients with CHD and children < 18 years old with structurally normal hearts were recruited between Jan 1, 2010 and Dec 1, 2020. Logistic regression models were used to determine the effect of covariates on odds of successful cardioversion with ibutilide. 53 patients underwent 105 chemical cardioversions (age: 27.5 ± 10.4 years [75% males], 80% atrial flutter) with ibutilide during the study period. The overall rate of successful cardioversion with ibutilide in our cohort was 70.4% (mean ibutilide dose: 1.5 ± 0.65 mg). Presentation in atrial flutter (P = 0.08) and male gender (0.07) showed a trend towards significance. Adverse effects were reported after 8 ibutilide administrations (7.6%, n = 6/8 [75%] female).