Antiarrhythmic agent
Antiarrhythmic agents are medications designed to treat or prevent abnormal heart rhythms, known as arrhythmias, by modulating the heart's electrical activity to restore or maintain a normal sinus rhythm.[1] These drugs work primarily by blocking specific ion channels or receptors in cardiac cells, thereby influencing the phases of the cardiac action potential, reducing automaticity, slowing conduction, or terminating re-entrant circuits that cause irregular beats.[1] They are classified under the Vaughan-Williams system into four main classes based on their predominant mechanisms of action, with additional categories for drugs that do not fit neatly into these groups.[1] Class I agents are sodium channel blockers that depress phase 0 of the action potential, subdivided into Ia (e.g., quinidine, procainamide, which moderately prolong the QT interval), Ib (e.g., lidocaine, mexiletine, which shorten the QT interval), and Ic (e.g., flecainide, propafenone, which markedly slow conduction without affecting QT).[1] Class II agents, beta-adrenergic blockers like metoprolol and atenolol, inhibit sympathetic stimulation to reduce heart rate and automaticity, often used for rate control in supraventricular tachycardias.[1][2] Class III agents, such as amiodarone and sotalol, block potassium channels to prolong the action potential duration and refractory period, effectively terminating ventricular and atrial arrhythmias but carrying risks like QT prolongation.[1] Class IV agents, non-dihydropyridine calcium channel blockers including verapamil and diltiazem, slow conduction through the atrioventricular node to control ventricular rates in atrial fibrillation or flutter.[1][2] Indications for antiarrhythmic agents span a range of arrhythmias, including atrial fibrillation, ventricular tachycardia, supraventricular tachycardia, and premature beats, with selection depending on the arrhythmia type, underlying heart disease, and patient factors.[1][2] For instance, class Ic drugs are suitable for paroxysmal supraventricular tachycardia in structurally normal hearts, while class III agents like amiodarone are versatile for both atrial and ventricular rhythms but require monitoring due to potential toxicities.[1] Despite their efficacy, these agents carry a risk of proarrhythmia, where they may induce new or worsen existing arrhythmias, particularly in patients with structural heart disease, necessitating careful electrocardiographic monitoring and individualized therapy.[1]Introduction
Definition and Purpose
Antiarrhythmic agents are pharmacological interventions designed to prevent, treat, or terminate abnormal heart rhythms, known as arrhythmias, by modulating the electrical activity in cardiac cells through targeted effects on ion channels, receptors, or pumps.[1] These drugs address disruptions in the heart's normal sinus rhythm, which can arise from various underlying cardiac conditions, and are essential for stabilizing cardiac function in affected patients.[3] The primary purpose of antiarrhythmic agents is to suppress ectopic beats, slow conduction velocity, prolong refractoriness, or restore sinus rhythm in clinical scenarios such as atrial fibrillation, ventricular tachycardia, or supraventricular tachycardia.[1] By altering the membrane potential, action potential duration, or conduction properties in cardiac tissue, these agents help mitigate the risks associated with irregular rhythms, including hemodynamic instability and thromboembolism.[3] Their mechanisms generally involve modifying ion fluxes to restore orderly electrical propagation without inducing excessive suppression of normal cardiac activity.[4] The scope of antiarrhythmic therapy encompasses both rhythm control strategies, which aim to maintain sinus rhythm through pharmacological cardioversion or suppression of recurrences, and rate control approaches, which focus on moderating ventricular response to prevent tachycardia-related complications.[1] These interventions play a critical role in reducing arrhythmia-related morbidity and mortality, particularly in high-risk populations.[5] Antiarrhythmic agents are prescribed to millions of patients annually worldwide, reflecting the substantial burden of arrhythmias; for instance, atrial fibrillation alone affects approximately 59 million individuals globally as of 2019, many of whom require such therapy as a mainstay of management.[6] Evidence from landmark trials, such as the AFFIRM study involving over 4,000 patients with atrial fibrillation, indicates variable efficacy between rhythm and rate control strategies, with no survival advantage for rhythm control using antiarrhythmic drugs compared to rate control, though both approaches effectively manage symptoms and reduce hospitalizations in select cases.[7]Types of Arrhythmias Treated
Cardiac arrhythmias are broadly classified into supraventricular and ventricular types based on their origin within the heart. Supraventricular arrhythmias arise above the ventricles, typically involving the atria or atrioventricular (AV) node, and include conditions such as atrial fibrillation (AF), atrial flutter, and AV nodal reentrant tachycardia (AVNRT). These often result in rapid heart rates but are generally less life-threatening than ventricular arrhythmias unless they lead to hemodynamic instability. Ventricular arrhythmias originate in the ventricles and encompass ventricular tachycardia (VT) and ventricular fibrillation (VF), which can degenerate into life-threatening rhythms causing sudden cardiac arrest.[8][9] Antiarrhythmic agents are indicated for various therapeutic goals depending on the arrhythmia type and clinical context. For acute termination, they are used to restore sinus rhythm, such as in cardioversion of AF or termination of paroxysmal supraventricular tachycardias. In chronic management, these drugs suppress recurrent episodes, for example, preventing VT recurrence after myocardial infarction (MI) in patients with structural heart disease. Additionally, they facilitate rate control by slowing AV nodal conduction in persistent AF to reduce ventricular response rates and alleviate symptoms. The prevalence of these arrhythmias underscores their clinical significance; AF affects approximately 4.5-5% (or 10.5 million adults) of the general population in the United States as of 2024, with rates increasing markedly with age to over 20% in individuals aged 80 years and older, while ventricular arrhythmias contribute to 350,000-400,000 cases of sudden cardiac death annually in the US.[10][11][12] Prevalence is projected to continue rising, reaching 12-15 million cases in the US by 2050 due to population aging.[12] Diagnosis of arrhythmias relies on non-invasive and invasive methods to identify the rhythm disturbance and guide agent selection. Standard electrocardiography (ECG) provides initial detection of abnormal rhythms, while ambulatory Holter monitoring captures intermittent episodes over 24-48 hours, and electrophysiology studies offer detailed mapping of conduction pathways for complex cases. Agent selection is informed by the underlying mechanism, which includes reentry (circus movement in a circuit of conducting tissue), enhanced automaticity (spontaneous depolarization in pacemaker cells), and triggered activity (afterdepolarizations leading to premature beats). Antiarrhythmic drugs may serve as first-line therapy for symptomatic arrhythmias but are often used adjunctively to non-pharmacological interventions like catheter ablation or implantable devices in refractory cases.[13][14][15][16][17]Cardiac Electrophysiology
Action Potential Phases
The cardiac action potential in non-pacemaker cells, such as ventricular myocytes, is characterized by five distinct phases that govern the electrical activity of the heart, enabling coordinated contraction and relaxation.[18] These phases arise from the sequential activation and inactivation of voltage-gated ion channels, resulting in dynamic changes in membrane potential from approximately -90 mV at rest to +30 mV during peak depolarization.[19] Understanding these phases is essential for elucidating the electrophysiological basis of cardiac rhythm.[20] Phase 0 represents the rapid depolarization phase, where the membrane potential shifts abruptly from negative to positive due to a massive influx of sodium ions (Na⁺) through fast voltage-gated sodium channels (Nav1.5).[21] This upstroke is extremely fast, with a maximum velocity of up to 500 V/s in Purkinje fibers, directly determining the speed of conduction through the myocardium.[18] Phase 1 is the early repolarization or notch phase, marked by a partial return toward the resting potential. It results from the inactivation of sodium channels, coupled with efflux of potassium ions (K⁺) via the transient outward current (I_to) through channels like Kv4.3 and Kv1.4, and sometimes chloride ion (Cl⁻) influx.[21] This creates a characteristic notch in the action potential waveform, particularly prominent in epicardial cells.[20] Phase 2, the plateau phase, maintains a relatively stable depolarized state for 200-300 ms, balancing inward calcium ion (Ca²⁺) influx through L-type calcium channels (Cav1.2) with outward K⁺ efflux via delayed rectifier currents.[19] This prolonged duration allows sufficient time for calcium-mediated excitation-contraction coupling in the myocardium.[18] Phase 3 involves rapid repolarization, where the membrane potential returns to baseline as L-type Ca²⁺ channels inactivate and dominant outward K⁺ currents prevail, including the rapid delayed rectifier (I_Kr via Kv11.1) and slow delayed rectifier (I_Ks via Kv7.1).[21] These currents restore the negative resting potential, preparing the cell for the next cycle.[20] Phase 4 is the resting or diastolic phase in non-pacemaker cells, where the membrane potential stabilizes at about -90 mV, primarily due to high permeability to K⁺ through inward rectifier channels (Kir2.1, I_K1).[19] In contrast, pacemaker cells like those in the sinoatrial node exhibit spontaneous depolarization during phase 4 via the funny current (I_f) and other mechanisms, driving automaticity without a true resting state.[20] The action potential duration (APD), particularly in phases 2 and 3, can be approximated using the Nernst equation for key ions, such as for potassium:E_K = \frac{RT}{F} \ln \left( \frac{[K^+]_o}{[K^+]_i} \right)
where R is the gas constant, T is temperature, F is Faraday's constant, and [K⁺]_o and [K⁺]_i are extracellular and intracellular potassium concentrations, respectively; this equilibrium potential influences repolarization.[19] Disruptions in these phases, such as prolongation of APD in phases 2 or 3, can promote early afterdepolarizations that trigger arrhythmias like torsades de pointes.[20]
Key Ion Channels and Currents
Cardiac myocytes rely on a coordinated interplay of ion channels and transporters to generate and propagate action potentials, which underpin myocardial excitability and contraction. These proteins facilitate the selective movement of ions such as sodium (Na⁺), calcium (Ca²⁺), and potassium (K⁺) across the sarcolemma, creating transient changes in membrane potential that drive the cardiac cycle. Disruptions in these channels, whether genetic or acquired, can lead to arrhythmias by altering action potential duration, conduction velocity, or automaticity. Antiarrhythmic agents often target these channels to restore normal electrophysiology, exploiting their state-dependent properties to selectively modulate activity during pathological rhythms.[22][23] The voltage-gated sodium channel Nav1.5, encoded by SCN5A, mediates the fast inward current (I_Na) responsible for phase 0 of the action potential, enabling rapid depolarization and high-speed conduction essential for synchronized contraction. Loss-of-function mutations in SCN5A reduce I_Na amplitude, predisposing individuals to Brugada syndrome, characterized by ventricular fibrillation risk due to conduction slowing and heterogeneous repolarization.[22][24] L-type calcium channels, primarily Cav1.2 (encoded by CACNA1C), conduct the inward current I_Ca,L, which sustains the phase 2 plateau and triggers excitation-contraction coupling by releasing intracellular calcium stores. This current balances repolarizing forces to prolong the action potential, allowing sufficient time for mechanical systole. Gain-of-function mutations in Cav1.2 can prolong the QT interval, as seen in Timothy syndrome, while loss-of-function variants contribute to short QT syndrome or Brugada-like phenotypes.[22][23] Potassium channels dominate repolarization and resting potential maintenance. The rapid delayed rectifier current I_Kr, carried by hERG channels (KCNH2), and the slow delayed rectifier I_Ks, via KCNQ1 (often with KCNE1 accessory subunits), drive phase 3 repolarization by effluxing K⁺. The inward rectifier K⁺ current I_K1 (Kir2.1, KCNJ2) stabilizes the phase 4 resting potential near -90 mV and contributes to late repolarization, preventing spontaneous depolarization in working myocytes. Transient outward currents like I_to (Kv4.3/KCND3 with KChIP2) mediate early phase 1 repolarization, creating a notch that varies regionally to influence dispersion. Loss-of-function in KCNQ1 impairs I_Ks, causing type 1 long QT syndrome (LQT1) with prolonged action potentials and torsades de pointes risk, particularly during exercise.[22][25][23] Additional currents include the Na⁺/Ca²⁺ exchanger (NCX1, SLC8A1), which bidirectionally transports ions to regulate calcium homeostasis; in forward mode, it extrudes Ca²⁺ while importing Na⁺, but reverse mode during depolarization contributes inward current that can trigger arrhythmias in calcium-overloaded cells. In pacemaker cells of the sinoatrial node, the hyperpolarization-activated funny current I_f (HCN4 primarily) initiates phase 4 diastolic depolarization, setting the heart rate; mutations in HCN4 lead to bradycardia syndromes.[22][26] These channels serve as primary pharmacological targets for antiarrhythmics, with drugs binding to specific sites to modulate conductance. For instance, class I agents exhibit state-dependent blockade of Nav1.5, preferentially inhibiting open or inactivated states of I_Na during tachycardia, thereby slowing conduction in rapidly firing tissue without excessively affecting normal rhythms—a mechanism involving interactions like cation-π binding at key residues such as Phe1760. Similar state-specific modulation applies to potassium and calcium channels, allowing therapeutic selectivity.[27][26]| Channel Type | Current | Phase Affected | Example Disease |
|---|---|---|---|
| Voltage-gated Na⁺ (Nav1.5, SCN5A) | I_Na | 0 (depolarization) | Brugada syndrome |
| L-type Ca²⁺ (Cav1.2, CACNA1C) | I_Ca,L | 2 (plateau) | Timothy syndrome (LQTS8) |
| Delayed rectifier K⁺ (hERG, KCNH2) | I_Kr | 3 (repolarization) | Long QT syndrome type 2 |
| Delayed rectifier K⁺ (KCNQ1, KCNQ1/KCNE1) | I_Ks | 3 (repolarization) | Long QT syndrome type 1 |
| Inward rectifier K⁺ (Kir2.1, KCNJ2) | I_K1 | 3, 4 (resting) | Andersen-Tawil syndrome |
| Transient outward K⁺ (Kv4.3, KCND3) | I_to | 1 (early repolarization) | Brugada syndrome (variants) |
| Na⁺/Ca²⁺ exchanger (NCX1, SLC8A1) | I_NCX | 2, 3 (Ca²⁺ handling) | Brugada syndrome |
| Hyperpolarization-activated cyclic nucleotide-gated (HCN4) | I_f | 4 (pacemaker depolarization) | Sinus bradycardia |
Vaughan Williams Classification
Class I Agents
Class I antiarrhythmic agents primarily act as blockers of the voltage-gated sodium channels (Naᵥ1.5), inhibiting the fast inward sodium current (Iₙₐ) responsible for phase 0 depolarization of the cardiac action potential, thereby reducing the maximum upstroke velocity (Vₘₐₓ) and slowing conduction velocity in a use-dependent manner that preferentially affects rapidly firing or ischemic tissues.[1] This use-dependence arises from the drugs' preferential binding to open or inactivated channel states during rapid heart rates, enhancing their antiarrhythmic efficacy while minimizing effects on normal sinus rhythm.[28] Within the Vaughan Williams classification, Class I agents are subdivided into IA, IB, and IC based on their sodium channel binding kinetics (recovery time constants, τ) and secondary effects on action potential duration (APD) and repolarization.[1] Class IA agents, including quinidine, procainamide, and disopyramide, demonstrate moderate sodium channel blockade with intermediate recovery kinetics (τ ≈ 1–10 seconds), which slows phase 0 depolarization and prolongs APD and the QT interval primarily through additional inhibition of the rapid delayed rectifier potassium current (Iₖᵣ).[28][1] These agents are used clinically for supraventricular tachyarrhythmias such as atrial fibrillation (AF) and atrial flutter, as well as certain ventricular tachycardias (VT), though their QT-prolonging effects increase the risk of torsades de pointes, a polymorphic VT associated with sudden cardiac death.[1][29] Pharmacokinetically, quinidine is administered orally or intravenously and undergoes extensive hepatic metabolism via cytochrome P450 3A4 (CYP3A4), with a half-life of approximately 6–8 hours, necessitating dose adjustments in patients with hepatic impairment or CYP3A4 inhibitors to avoid toxicity.[30] Procainamide, available intravenously or orally, is metabolized to N-acetylprocainamide (NAPA), an active metabolite with class III properties, and carries a risk of drug-induced lupus erythematosus in long-term use.[1] Class IB agents, such as lidocaine and mexiletine, exhibit weak sodium channel blockade with fast recovery kinetics (τ ≈ 0.1–1 second), preferentially binding to inactivated channels and shortening APD, particularly in ischemic or depolarized myocardium, without significant QT prolongation.[28][1] They are indicated for ventricular arrhythmias, especially those occurring post-myocardial infarction (MI), where they help suppress premature ventricular contractions and VT by accelerating repolarization in affected tissues.[1] Lidocaine is given intravenously with a short half-life of 1–2 hours due to rapid hepatic metabolism, while mexiletine is used orally for chronic therapy, offering similar efficacy with better tolerability for outpatient management.[1] Class IC agents, exemplified by flecainide and propafenone, provide strong sodium channel blockade with slow recovery kinetics (τ > 10 seconds), markedly reducing conduction velocity and prolonging the effective refractory period without altering APD or QT interval, making them highly effective for rate-dependent arrhythmias.[28][1] These agents are employed for paroxysmal supraventricular tachycardias, AF cardioversion (e.g., via "pill-in-the-pocket" strategy), and VT in patients with structurally normal hearts, but their use is contraindicated post-MI due to proarrhythmic risks.[1] Both are administered orally, with flecainide having a half-life of 12–27 hours and propafenone undergoing CYP2D6-dependent metabolism, leading to variable pharmacokinetics based on genetic polymorphisms.[1] Key evidence from clinical trials underscores the benefits and hazards of Class I agents; for instance, the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that flecainide and encainide (Class IC) increased arrhythmic death and total mortality by 2.7- to 3.6-fold compared to placebo in post-MI patients with asymptomatic ventricular ectopy, prompting restricted use in structural heart disease.[31] Overall, while Class I agents remain first-line for certain rhythm control in low-risk patients, their proarrhythmic potential—exacerbated by sodium channel slowing that can facilitate reentry—necessitates careful patient selection and ECG monitoring.[1][31]| Subclass | Examples | Primary Indications | Key Side Effects |
|---|---|---|---|
| IA | Quinidine, procainamide, disopyramide | Atrial fibrillation, supraventricular tachyarrhythmias, ventricular tachycardia | QT prolongation and torsades de pointes; cinchonism (quinidine); drug-induced lupus (procainamide); anticholinergic effects (disopyramide)[1] |
| IB | Lidocaine, mexiletine | Ventricular arrhythmias post-myocardial infarction | Central nervous system effects (e.g., seizures at high doses); minimal cardiac toxicity[1] |
| IC | Flecainide, propafenone | Paroxysmal atrial fibrillation, supraventricular tachycardia in structurally normal hearts | Proarrhythmia (increased mortality post-MI per CAST); QRS widening; negative inotropy[31][1] |
Class II Agents
Class II antiarrhythmic agents, commonly referred to as beta-adrenergic blockers, exert their effects by antagonizing beta receptors to mitigate sympathetic nervous system influence on cardiac electrophysiology. These drugs are subdivided by receptor selectivity and additional properties: non-selective agents like propranolol block both beta-1 and beta-2 receptors; beta-1 selective agents such as metoprolol and atenolol primarily target cardiac beta-1 receptors; and agents with combined alpha- and beta-blockade, exemplified by carvedilol, offer vasodilatory benefits alongside antiarrhythmic actions.[1] The primary mechanism involves blockade of beta-1 receptors on cardiac myocytes, which inhibits adenylate cyclase activation and reduces intracellular cyclic adenosine monophosphate (cAMP) levels. This leads to diminished L-type calcium current (ICa,L) in the AV node and reduced funny current (If) in the sinoatrial node, thereby slowing AV nodal conduction, prolonging refractoriness, decreasing sinus node automaticity, and suppressing catecholamine-induced triggered activity and ectopic beats.[1][32] Clinically, these agents are indicated for ventricular rate control in atrial fibrillation and flutter, acute termination and chronic prevention of supraventricular tachycardias, and suppression of ventricular tachycardia in catecholamine-sensitive scenarios, such as long QT syndrome or post-surgical settings. They also confer cardioprotection following myocardial infarction; the Beta-Blocker Heart Attack Trial demonstrated that propranolol reduced total mortality by 25% over a mean follow-up of 24 months in post-MI patients without contraindications. In heart failure patients with arrhythmias, the Carvedilol or Metoprolol European Trial (COMET) reported a 17% relative reduction in all-cause mortality with carvedilol compared to metoprolol tartrate. Furthermore, carvedilol was associated with a 35% lower risk of atrial tachyarrhythmias and inappropriate implantable cardioverter-defibrillator shocks in heart failure cohorts.[1][33][34][35] Pharmacokinetically, beta-blockers like metoprolol undergo extensive hepatic metabolism via cytochrome P450 2D6, while agents such as atenolol are renally excreted; propranolol and carvedilol are lipophilic and hepatically cleared with variable bioavailability due to first-pass effects. Intravenous formulations enable rapid acute control of tachyarrhythmias, whereas oral dosing supports long-term management, often requiring titration and monitoring for hepatic or renal dysfunction.[1] Common adverse effects encompass bradycardia, hypotension, fatigue, and AV nodal blockade, with non-selective agents like propranolol additionally risking bronchospasm and exacerbation of reactive airway disease. Contraindications include asthma or chronic obstructive pulmonary disease, second- or third-degree AV block, severe bradycardia, and acute decompensated heart failure, necessitating cautious use in patients with supraventricular arrhythmias involving the AV node.[1]Class III Agents
Class III antiarrhythmic agents primarily exert their effects by blocking potassium channels, thereby prolonging the action potential duration (APD) and effective refractory period (ERP) during phase 3 of the cardiac action potential repolarization.[1] This mechanism suppresses re-entrant arrhythmias by extending the time required for ventricular or atrial tissue to recover excitability, reducing the likelihood of premature impulses initiating new arrhythmic cycles.[28] Unlike other classes, these agents do not significantly alter conduction velocity but focus on delaying repolarization to prevent tachyarrhythmias.[36] The primary targets are the rapid (IKr) and slow (IKs) components of the delayed rectifier potassium current, with selective blockade of IKr being common among pure class III agents.[37] This inhibition slows potassium efflux, maintaining a more positive membrane potential for longer, which is particularly effective against atrial and ventricular tachyarrhythmias.[1] Amiodarone, a broad-spectrum agent, additionally blocks sodium and calcium channels and exhibits beta-adrenergic antagonism, contributing to its multifaceted antiarrhythmic profile beyond pure potassium channel effects.[38] Key agents include amiodarone, sotalol, dofetilide, and dronedarone. Amiodarone is widely used due to its efficacy across various arrhythmias, though its non-selective actions distinguish it from more targeted options.[39] Sotalol combines IKr blockade with non-selective beta-blockade, enhancing its utility in rate control alongside rhythm restoration.[1] Dofetilide is a pure IKr blocker, offering specificity for atrial fibrillation (AF) conversion without significant effects on other channels.[36] Dronedarone, structurally similar to amiodarone, provides a less toxic alternative with milder potassium channel blockade and reduced tissue accumulation.[1] In clinical practice, these agents are employed for rhythm control in AF and suppression of ventricular tachycardia (VT) or ventricular fibrillation (VF), particularly in patients with implantable cardioverter-defibrillators (ICDs). Amiodarone facilitates AF conversion to sinus rhythm in 34-50% of cases long-term and suppresses recurrent VT/VF episodes, reducing ICD shocks by up to 50% in high-risk patients.[40][41] The AFFIRM trial demonstrated that rhythm control strategies incorporating amiodarone, such as for AF maintenance, offered no survival benefit over rate control but effectively restored sinus rhythm in selected populations.[42] Dofetilide is indicated for acute AF cardioversion, achieving success in approximately 70% of cases within 24-48 hours, while dronedarone reduces AF recurrence by 25% compared to placebo in paroxysmal AF.[36][1] Sotalol supports maintenance of sinus rhythm post-AF, with efficacy comparable to amiodarone in some subgroups.[43] Pharmacokinetic profiles vary significantly among class III agents, influencing dosing and monitoring. Amiodarone exhibits a prolonged half-life of several weeks to months due to extensive tissue distribution and hepatic metabolism, leading to cumulative effects and risks of thyroid dysfunction (in up to 20% of patients) and pulmonary toxicity (1-2% incidence with long-term use).[38][44] Sotalol is primarily renally cleared, necessitating dose adjustments in impaired kidney function to avoid QT prolongation.[1] Dofetilide also relies on renal excretion, with hospitalization required for initiation to monitor for QT changes.[36] Dronedarone has a shorter half-life than amiodarone (13-19 hours) and is hepatically metabolized, but it carries warnings for liver injury.[1] A major concern with class III agents is proarrhythmia, particularly torsades de pointes (TdP) from excessive QT interval prolongation, occurring in 1-4% of patients depending on electrolyte status and drug dose.[45] This risk is heightened with IKr blockers like dofetilide and sotalol, where hypokalemia or hypomagnesemia exacerbates channel blockade, potentially leading to early afterdepolarizations.[46] Amiodarone, despite QT prolongation, induces TdP less frequently (0.5-1%) due to its multichannel effects stabilizing the membrane.[45]| Agent | Primary Targets | Indications | Monitoring Needs |
|---|---|---|---|
| Amiodarone | IKr, IKs, Na+, Ca2+, β-receptors | AF conversion/maintenance, VT/VF suppression in ICD patients | Thyroid function, pulmonary imaging, liver enzymes, QT interval[38] |
| Sotalol | IKr, β-receptors | AF/VT maintenance, supraventricular arrhythmias | Renal function, QT prolongation, electrolytes[1] |
| Dofetilide | IKr (pure) | AF/atrial flutter cardioversion | In-hospital initiation, QT interval, renal function, electrolytes (K+, Mg2+)[36] |
| Dronedarone | IKr, IKs, Na+, β-receptors (milder) | Paroxysmal AF maintenance (non-permanent) | Liver function, QT interval, avoid in heart failure[1] |