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Antiarrhythmic agents
Drug class
Amiodarone
Skeletal formula of amiodarone, a common antiarrhythmic.
Class identifiers
Synonymsantiarrhythmics, cardiac dysrhythmia medications
UseArrhythmia, Atrial fibrillation, Ventricular tachycardia, etc.
ATC codeC01B
Biological targetCardiac ion channels
Clinical data
Drugs.comDrug Classes
External links
MeSHD000889
Legal status
In Wikidata

Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a class of drugs that are used to suppress abnormally fast rhythms (tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tachycardia.

Many attempts have been made to classify antiarrhythmic agents. Many of the antiarrhythmic agents have multiple modes of action, which makes any classification imprecise.

Action potential

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Plot of membrane potential versus time
Drugs affecting the cardiac action potential
Main article: Cardiac action potential

The cardiac myocyte has two general types of action potentials: conduction system and working myocardium. The action potential is divided into 5 phases and shown in the diagram. The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing efflux of potassium ions. The characteristic plateau ("2") results from the opening of voltage-sensitive calcium channels. Each phase utilizes different channels and it is useful to compare these phases to the most common classification system — Vaughan Williams — described below.

Vaughan Williams classification

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The Vaughan Williams classification[1] was introduced in 1970 by Miles Vaughan Williams.[2]

Vaughan Williams was a pharmacology tutor at Hertford College, Oxford. One of his students, Bramah N. Singh,[3] contributed to the development of the classification system. The system is therefore sometimes known as the Singh-Vaughan Williams classification.

The five main classes in the Vaughan Williams classification of antiarrhythmic agents are:

With regard to management of atrial fibrillation, classes I and III are used in rhythm control as medical cardioversion agents, while classes II and IV are used as rate-control agents.

Class Known as Examples Mechanism Medical uses[4]
Ia Fast sodium channel blockers Na+ channel block (intermediate association/dissociation) and K+ channel blocking effect.

Class Ia drugs prolong the action potential and has an intermediate effect on the 0 phase of depolarization.

Ib Na+ channel block (fast association/dissociation).

Class Ib drugs shorten the action potential of myocardial cell and has a weak effect on the initiation of phase 0 of depolarization

Ic Na+ channel block (slow association/dissociation).

Class Ic drugs do not affect action potential duration and have the strongest effect on the initiation phase 0 of depolarization

II Beta-blockers Beta blocker
Propranolol also has some sodium channel-blocking effect.
III Potassium channel blockers K+ channel blocker

Sotalol is also a beta blocker[5]
Amiodarone has mostly Class III activity, but also I, II, & IV activity[6]

IV Calcium channel blockers Ca2+ channel blocker
V Work by other or unknown mechanisms

Class I agents

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The class I antiarrhythmic agents interfere with the sodium channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.

Class I agents are called membrane-stabilizing agents, "stabilizing" referring to the decrease of excitogenicity of the plasma membrane which is brought about by these agents. (Also noteworthy is that a few class II agents like propranolol also have a membrane stabilizing effect.)

Class I agents are divided into three groups (Ia, Ib, and Ic) based upon their effect on the length of the action potential.[10][11]

  • Class Ia drugs lengthen the action potential (right shift)
  • Class Ib drugs shorten the action potential (left shift)
  • Class Ic drugs do not significantly affect the action potential (no shift)
  • Class Ia
    Class Ia
  • Class Ib
    Class Ib
  • Class Ic
    Class Ic

Class II agents

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Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart, which reduces intracellular cAMP levels and hence reduces Ca2+ influx. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node.

Class II agents include atenolol, esmolol, propranolol, and metoprolol.

Class III agents

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Effect of class III drugs on length of action potential

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.[12] Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory). The class III agents exhibit reverse-use dependence (their potency increases with slower heart rates, and therefore improves maintenance of sinus rhythm). Inhibiting potassium channels results in slowed atrial-ventricular myocyte repolarization. Class III agents have the potential to prolong the QT interval of the EKG, and may be proarrhythmic (more associated with development of polymorphic VT).

Class III agents include: bretylium, amiodarone, ibutilide, sotalol, dofetilide, vernakalant, and dronedarone.

Class IV agents

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Class IV agents are slow non-dihydropyridine calcium channel blockers. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.[citation needed]

Class IV agents include verapamil and diltiazem.

Class V and others

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Since the development of the original Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV. Such agents include:

History

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The initial classification system had 4 classes, although their definitions different from the modern classification. Those proposed in 1970 were:[2]

  1. Drugs with a direct membrane action: the prototype was quinidine, and lignocaine was a key example. Differing from other authors, Vaughan-Williams describe the main action as a slowing of the rising phase of the action potential.
  2. Sympatholytic drugs (drugs blocking the effects of the sympathetic nervous system): examples included bretylium and adrenergic beta-receptors blocking drugs. This is similar to the modern classification, which focuses on the latter category.
  3. Compounds that prolong the action potential: matching the modern classification, with the key drug example being amiodarone, and a surgical example being thyroidectomy. This was not a defining characteristic in an earlier review by Charlier et al. (1968),[17] but was supported by experimental data presented by Vaughan Williams (1970).[2]: 461  The figure illustrating these findings was also published in the same year by Singh and Vaughan Williams.[18]
  4. Drugs acting like diphenylhydantoin (DPH): mechanism of action unknown, but others had attributed its cardiac action to an indirect action on the brain;[19] this drug is better known as antiepileptic drug phenytoin.

Sicilian gambit classification

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Another approach, known as the "Sicilian gambit", placed a greater approach on the underlying mechanism.[20][21][22]

It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in roughly the Singh-Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is, therefore, not a true classification in that it does not aggregate drugs into categories.[23]

Modernized Oxford classification by Lei, Huang, Wu, and Terrar

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Common anti-arrhythmic drugs under the modernized classification according to Lei et al. 2018

A recent publication (2018) has now emerged with a fully modernised drug classification.[24] This preserves the simplicity of the original Vaughan Williams framework while capturing subsequent discoveries of sarcolemmal, sarcoplasmic reticular and cytosolic biomolecules. The result is an expanded but pragmatic classification that encompasses approved and potential anti-arrhythmic drugs. This will aid our understanding and clinical management of cardiac arrhythmias and facilitate future therapeutic developments. It starts by considering the range of pharmacological targets, and tracks these to their particular cellular electrophysiological effects. It retains but expands the original Vaughan Williams classes I to IV, respectively covering actions on Na+ current components, autonomic signalling, K+ channel subspecies, and molecular targets related to Ca2+ homeostasis. It now introduces new classes incorporating additional targets, including:

  • Class 0: ion channels involved in automaticity
  • Class V: mechanically sensitive ion channels
  • Class VI: connexins controlling electrotonic cell coupling
  • Class VII: molecules underlying longer term signalling processes affecting structural remodeling.

It also allows for multiple drug targets/actions and adverse pro-arrhythmic effects. The new scheme will additionally aid development of novel drugs under development and is illustrated here.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Antiarrhythmic agent

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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 . These drugs work primarily by blocking specific ion channels or receptors in cardiac cells, thereby influencing the phases of the , reducing , slowing conduction, or terminating re-entrant circuits that cause irregular beats. 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. 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). 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. 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. 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. Indications for antiarrhythmic agents span a range of s, including , , , and premature beats, with selection depending on the arrhythmia type, underlying heart disease, and patient factors. For instance, class Ic drugs are suitable for in structurally normal hearts, while class III agents like are versatile for both atrial and ventricular rhythms but require monitoring due to potential toxicities. Despite their efficacy, these agents carry a risk of proarrhythmia, where they may induce new or worsen existing s, particularly in patients with structural heart disease, necessitating careful electrocardiographic monitoring and individualized therapy.

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. These drugs address disruptions in the heart's normal , which can arise from various underlying cardiac conditions, and are essential for stabilizing cardiac function in affected patients. The primary purpose of antiarrhythmic agents is to suppress ectopic beats, slow conduction velocity, prolong refractoriness, or restore in clinical scenarios such as , , or . By altering the , duration, or conduction properties in cardiac tissue, these agents help mitigate the risks associated with irregular rhythms, including hemodynamic instability and . Their mechanisms generally involve modifying ion fluxes to restore orderly electrical propagation without inducing excessive suppression of normal cardiac activity. The scope of antiarrhythmic therapy encompasses both rhythm control strategies, which aim to maintain through pharmacological or suppression of recurrences, and rate control approaches, which focus on moderating ventricular response to prevent tachycardia-related complications. These interventions play a critical role in reducing arrhythmia-related morbidity and mortality, particularly in high-risk populations. Antiarrhythmic agents are prescribed to millions of patients annually worldwide, reflecting the substantial burden of arrhythmias; for instance, alone affects approximately 59 million individuals globally as of 2019, many of whom require such therapy as a mainstay of management. Evidence from landmark trials, such as the AFFIRM study involving over 4,000 patients with , 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.

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. Antiarrhythmic agents are indicated for various therapeutic goals depending on the type and clinical context. For acute termination, they are used to restore , such as in of or termination of paroxysmal supraventricular tachycardias. In chronic management, these drugs suppress recurrent episodes, for example, preventing VT recurrence after (MI) in patients with structural heart disease. Additionally, they facilitate rate control by slowing AV nodal conduction in persistent to reduce ventricular response rates and alleviate symptoms. The prevalence of these underscores their clinical significance; affects approximately 4.5-5% (or 10.5 million adults) of the general population in the as of 2024, with rates increasing markedly with age to over 20% in individuals aged 80 years and older, while ventricular contribute to 350,000-400,000 cases of sudden cardiac death annually in the . Prevalence is projected to continue rising, reaching 12-15 million cases in the by 2050 due to population aging. Diagnosis of arrhythmias relies on non-invasive and invasive methods to identify the rhythm disturbance and guide agent selection. Standard (ECG) provides initial detection of abnormal rhythms, while ambulatory Holter monitoring captures intermittent episodes over 24-48 hours, and 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 (spontaneous 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 or implantable devices in refractory cases.

Cardiac Electrophysiology

Action Potential Phases

The 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. These phases arise from the sequential activation and inactivation of voltage-gated ion channels, resulting in dynamic changes in from approximately -90 mV at rest to +30 mV during peak . Understanding these phases is essential for elucidating the electrophysiological basis of cardiac rhythm. Phase 0 represents the rapid 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). This upstroke is extremely fast, with a maximum of up to 500 V/s in , directly determining the speed of conduction through the myocardium. Phase 1 is the early or notch phase, marked by a partial return toward the . It results from the inactivation of sodium channels, coupled with efflux of ions (K⁺) via the transient outward current (I_to) through channels like Kv4.3 and Kv1.4, and sometimes chloride ion (Cl⁻) influx. This creates a characteristic notch in the action potential waveform, particularly prominent in epicardial cells. 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. This prolonged duration allows sufficient time for calcium-mediated excitation-contraction coupling in the myocardium. Phase 3 involves rapid , where the 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). These currents restore the negative , preparing the cell for the next cycle. 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 channels (Kir2.1, I_K1). In contrast, pacemaker cells like those in the exhibit spontaneous during phase 4 via the funny current (I_f) and other mechanisms, driving without a true resting state. The action potential duration (APD), particularly in phases 2 and 3, can be approximated using the for key ions, such as for :
EK=RTFln⁡([K+]o[K+]i)E_K = \frac{RT}{F} \ln \left( \frac{[K^+]_o}{[K^+]_i} \right)
where RR is the , TT is , FF is Faraday's constant, and [K⁺]_o and [K⁺]_i are extracellular and intracellular concentrations, respectively; this equilibrium potential influences . Disruptions in these phases, such as prolongation of APD in phases 2 or 3, can promote early afterdepolarizations that trigger arrhythmias like .

Key Ion Channels and Currents

Cardiac myocytes rely on a coordinated interplay of channels and transporters to generate and propagate potentials, which underpin myocardial excitability and contraction. These proteins facilitate the selective movement of ions such as sodium (Na⁺), calcium (Ca²⁺), and (K⁺) across the , creating transient changes in that drive the . Disruptions in these channels, whether genetic or acquired, can lead to arrhythmias by altering duration, conduction velocity, or . Antiarrhythmic agents often target these channels to restore normal , exploiting their state-dependent properties to selectively modulate activity during pathological rhythms. The voltage-gated sodium channel , encoded by , mediates the fast inward current (I_Na) responsible for phase 0 of the action potential, enabling rapid and high-speed conduction essential for synchronized contraction. Loss-of-function mutations in reduce I_Na amplitude, predisposing individuals to , characterized by risk due to conduction slowing and heterogeneous . 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 . Gain-of-function mutations in Cav1.2 can prolong the , as seen in Timothy syndrome, while loss-of-function variants contribute to or Brugada-like phenotypes. 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 by effluxing K⁺. The inward rectifier K⁺ current I_K1 (Kir2.1, KCNJ2) stabilizes the phase 4 near -90 mV and contributes to late , preventing spontaneous in working myocytes. Transient outward currents like I_to (Kv4.3/KCND3 with KChIP2) mediate early phase 1 , creating a notch that varies regionally to influence dispersion. Loss-of-function in KCNQ1 impairs I_Ks, causing type 1 (LQT1) with prolonged action potentials and risk, particularly during exercise. Additional currents include the Na⁺/Ca²⁺ exchanger (NCX1, SLC8A1), which bidirectionally transports ions to regulate calcium ; in forward mode, it extrudes Ca²⁺ while importing Na⁺, but reverse mode during contributes inward current that can trigger arrhythmias in calcium-overloaded cells. In pacemaker cells of the , the hyperpolarization-activated funny current I_f (HCN4 primarily) initiates phase 4 diastolic , setting the ; mutations in HCN4 lead to syndromes. 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 , 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 and calcium channels, allowing therapeutic selectivity.
Channel TypeCurrentPhase AffectedExample Disease
Voltage-gated Na⁺ (Nav1.5, )I_Na0 ()
L-type Ca²⁺ (Cav1.2, CACNA1C)I_Ca,L2 (plateau)Timothy syndrome (LQTS8)
Delayed rectifier K⁺ (hERG, KCNH2)I_Kr3 (repolarization)Long QT syndrome type 2
Delayed rectifier K⁺ (KCNQ1, KCNQ1/KCNE1)I_Ks3 (repolarization)Long QT syndrome type 1
Inward rectifier K⁺ (Kir2.1, KCNJ2)I_K13, 4 (resting)Andersen-Tawil syndrome
Transient outward K⁺ (Kv4.3, KCND3)I_to1 (early repolarization) (variants)
Na⁺/Ca²⁺ exchanger (NCX1, SLC8A1)I_NCX2, 3 (Ca²⁺ handling)
Hyperpolarization-activated cyclic nucleotide-gated (HCN4)I_f4 (pacemaker )

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. 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. 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. Class IA agents, including quinidine, , and , demonstrate moderate blockade with intermediate recovery kinetics (τ ≈ 1–10 seconds), which slows phase 0 and prolongs APD and the primarily through additional inhibition of the rapid delayed rectifier current (Iₖᵣ). These agents are used clinically for supraventricular tachyarrhythmias such as (AF) and , as well as certain ventricular tachycardias (VT), though their QT-prolonging effects increase the risk of , a polymorphic VT associated with sudden cardiac . Pharmacokinetically, quinidine is administered orally or intravenously and undergoes extensive hepatic via 3A4 (), with a of approximately 6–8 hours, necessitating dose adjustments in patients with hepatic impairment or inhibitors to avoid toxicity. , available intravenously or orally, is metabolized to N-acetylprocainamide (NAPA), an with class III properties, and carries a risk of in long-term use. Class IB agents, such as lidocaine and , exhibit weak 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. They are indicated for ventricular arrhythmias, especially those occurring post-myocardial infarction (MI), where they help suppress premature ventricular contractions and VT by accelerating in affected tissues. Lidocaine is given intravenously with a short of 1–2 hours due to rapid hepatic , while is used orally for chronic therapy, offering similar efficacy with better tolerability for outpatient management. Class IC agents, exemplified by and , provide strong blockade with slow recovery kinetics (τ > 10 seconds), markedly reducing conduction velocity and prolonging the without altering APD or , making them highly effective for rate-dependent arrhythmias. These agents are employed for paroxysmal supraventricular tachycardias, 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. Both are administered orally, with having a of 12–27 hours and undergoing CYP2D6-dependent , leading to variable based on genetic polymorphisms. 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 in post-MI patients with ventricular ectopy, prompting restricted use in structural heart disease. 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.
SubclassExamplesPrimary IndicationsKey Side Effects
IAQuinidine, , , supraventricular tachyarrhythmias, QT prolongation and ; cinchonism (quinidine); drug-induced (procainamide); effects (disopyramide)
IBLidocaine, Ventricular arrhythmias post-myocardial effects (e.g., seizures at high doses); minimal cardiac toxicity
IC, Paroxysmal , supraventricular tachycardia in structurally normal heartsProarrhythmia (increased mortality post-MI per CAST); QRS widening; negative inotropy

Class II Agents

Class II antiarrhythmic agents, commonly referred to as beta-adrenergic blockers, exert their effects by antagonizing beta receptors to mitigate influence on . These drugs are subdivided by receptor selectivity and additional properties: non-selective agents like 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 , offer vasodilatory benefits alongside antiarrhythmic actions. The primary mechanism involves blockade of beta-1 receptors on cardiac myocytes, which inhibits adenylate cyclase activation and reduces intracellular (cAMP) levels. This leads to diminished L-type calcium current (ICa,L) in the AV node and reduced funny current (If) in the , thereby slowing AV nodal conduction, prolonging refractoriness, decreasing sinus node , and suppressing catecholamine-induced triggered activity and ectopic beats. Clinically, these agents are indicated for ventricular rate control in and flutter, acute termination and chronic prevention of supraventricular tachycardias, and suppression of in catecholamine-sensitive scenarios, such as or post-surgical settings. They also confer cardioprotection following ; the Beta-Blocker Heart Attack Trial demonstrated that reduced total mortality by 25% over a mean follow-up of 24 months in post-MI patients without contraindications. In patients with arrhythmias, the Carvedilol or Metoprolol European Trial () reported a 17% relative reduction in all-cause mortality with compared to metoprolol tartrate. Furthermore, was associated with a 35% lower risk of atrial tachyarrhythmias and inappropriate shocks in cohorts. Pharmacokinetically, beta-blockers like metoprolol undergo extensive hepatic metabolism via cytochrome P450 2D6, while agents such as atenolol are renally excreted; and are lipophilic and hepatically cleared with variable due to first-pass effects. Intravenous formulations enable rapid acute control of tachyarrhythmias, whereas oral dosing supports long-term management, often requiring and monitoring for hepatic or renal dysfunction. Common adverse effects encompass , , , and AV nodal blockade, with non-selective agents like additionally risking and exacerbation of . Contraindications include or , second- or third-degree AV block, severe , and , necessitating cautious use in patients with supraventricular arrhythmias involving the AV node.

Class III Agents

Class III antiarrhythmic agents primarily exert their effects by blocking potassium channels, thereby prolonging the action potential duration (APD) and (ERP) during phase 3 of the . 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. Unlike other classes, these agents do not significantly alter conduction velocity but focus on delaying to prevent tachyarrhythmias. The primary targets are the rapid (IKr) and slow (IKs) components of the delayed rectifier current, with selective of IKr being common among pure class III agents. This inhibition slows potassium efflux, maintaining a more positive for longer, which is particularly effective against atrial and ventricular tachyarrhythmias. , a broad-spectrum agent, additionally blocks sodium and calcium channels and exhibits beta-adrenergic antagonism, contributing to its multifaceted antiarrhythmic profile beyond pure effects. Key agents include , , , and . Amiodarone is widely used due to its efficacy across various arrhythmias, though its non-selective actions distinguish it from more targeted options. Sotalol combines IKr blockade with non-selective beta-blockade, enhancing its utility in rate control alongside rhythm restoration. Dofetilide is a pure IKr blocker, offering specificity for (AF) conversion without significant effects on other channels. Dronedarone, structurally similar to amiodarone, provides a less toxic alternative with milder blockade and reduced tissue accumulation. 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. 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. 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. Sotalol supports maintenance of sinus rhythm post-AF, with efficacy comparable to amiodarone in some subgroups. Pharmacokinetic profiles vary significantly among class III agents, influencing dosing and monitoring. exhibits a prolonged of several weeks to months due to extensive tissue distribution and hepatic metabolism, leading to cumulative effects and risks of dysfunction (in up to 20% of patients) and pulmonary (1-2% incidence with long-term use). is primarily renally cleared, necessitating dose adjustments in impaired function to avoid QT prolongation. also relies on renal excretion, with hospitalization required for initiation to monitor for QT changes. has a shorter than (13-19 hours) and is hepatically metabolized, but it carries warnings for . A major concern with class III agents is proarrhythmia, particularly (TdP) from excessive prolongation, occurring in 1-4% of patients depending on status and drug dose. This risk is heightened with IKr blockers like and , where or hypomagnesemia exacerbates channel blockade, potentially leading to early afterdepolarizations. , despite QT prolongation, induces TdP less frequently (0.5-1%) due to its multichannel effects stabilizing the membrane.
AgentPrimary TargetsIndicationsMonitoring Needs
IKr, IKs, Na+, Ca2+, β-receptorsAF conversion/maintenance, VT/VF suppression in ICD patientsThyroid function, pulmonary imaging, liver enzymes,
IKr, β-receptorsAF/VT maintenance, supraventricular arrhythmiasRenal function, QT prolongation, electrolytes
IKr (pure)AF/ cardioversionIn-hospital initiation, , renal function, electrolytes (K+, Mg2+)
IKr, IKs, Na+, β-receptors (milder)Paroxysmal AF maintenance (non-permanent)Liver function, , avoid in

Class IV Agents

Class IV antiarrhythmic agents consist primarily of non-dihydropyridine , such as verapamil and , which act as antagonists of L-type calcium channels (Ca_v1.2). These drugs selectively inhibit the slow inward calcium current (I_Ca,L) responsible for phase 0 depolarization in the sinoatrial (SA) and atrioventricular (AV) nodes, where action potentials depend on calcium influx rather than sodium. By depressing this current, they prolong the on the electrocardiogram, slow conduction through the AV node, and reduce in nodal tissues, while exerting minimal effects on the fast sodium-dependent phase 0 in ventricular myocardium. This nodal selectivity makes them effective for managing supraventricular arrhythmias without significantly altering ventricular excitability. Clinically, verapamil and are used for ventricular rate control in (AF) and , as well as for terminating or preventing atrioventricular nodal reentrant (AVNRT). Intravenous administration is preferred for acute settings, with verapamil demonstrating an onset of action within 2-3 minutes, leading to rapid slowing of AV nodal conduction. Oral formulations are employed for chronic therapy to maintain rate control. However, these agents are contraindicated in patients with Wolff-Parkinson-White (WPW) syndrome and AF, as blocking the AV node can enhance conduction through the accessory pathway, potentially accelerating ventricular rates and risking . Pharmacokinetically, both drugs undergo extensive hepatic metabolism via 3A4 (), resulting in variable (20-35% for verapamil and 40% for diltiazem after first-pass effect) and half-lives of 3-7 hours for verapamil and 3-6 hours for diltiazem. Their inhibition of can lead to significant drug interactions, increasing levels of substrates like , statins, or other antiarrhythmics, necessitating dose adjustments. Monitoring focuses on hemodynamic parameters such as and rather than plasma levels. Common adverse effects include due to and negative inotropy, from excessive nodal suppression, and (particularly with verapamil, affecting over 20% of patients). and are also frequent, while occurs more with . These agents are generally avoided in systolic , as their negative inotropic effects can worsen . Evidence from the Danish Verapamil Trials (DAVIT I and II) supports their role in post-myocardial (MI) patients without , demonstrating a significant reduction in the combined endpoint of death or first reinfarction (from 21.6% to 18.0% in DAVIT II) with oral verapamil, though overall mortality remained neutral (13.8% vs. 11.1%). Subgroup analyses indicated benefits in preventing major events like reinfarction or death in those with preserved left ventricular function, but harm in patients with , reinforcing cautious use.

Class V and Other Agents

Class V antiarrhythmic agents encompass a heterogeneous group of drugs that do not align with the blockade (Class I), beta-adrenergic antagonism (Class II), prolongation (Class III), or blockade (Class IV) mechanisms of the Vaughan Williams . These agents primarily target non-voltage-gated ion channels, receptors, or enzymes, offering niche roles in acute termination, rate control, or adjunctive therapy for specific arrhythmias. Adenosine, a prototypical Class V agent, acts as an ultra-short-acting atrioventricular (AV) nodal blocker by activating adenosine A1 receptors on atrial myocytes and AV nodal cells, which increases potassium conductance through G-protein-coupled inwardly rectifying potassium (GIRK) channels, leading to transient hyperpolarization and suppression of AV nodal conduction. Administered as a rapid intravenous bolus of 6 to 12 mg, adenosine effectively terminates (PSVT), particularly those involving reentry circuits dependent on the AV node, such as (AVNRT) or orthodromic AV reentrant tachycardia (AVRT), with success rates exceeding 90% in AV node-dependent cases. It also aids in acute diagnosis by transiently unmasking underlying or . However, its is under 10 seconds, limiting use to acute settings, and it is contraindicated in patients with or Wolff-Parkinson-White syndrome due to risks of precipitating with rapid ventricular response. Digoxin, another key Class V agent, exerts its antiarrhythmic effects indirectly by inhibiting the Na+/K+- pump, which elevates intracellular sodium and subsequently calcium levels while enhancing through parasympathetic activation of muscarinic M2 receptors, thereby slowing sinoatrial (SA) node firing and prolonging AV nodal refractoriness. It is primarily used for ventricular rate control in (AF), especially in patients with concomitant (HF) or when beta-blockers are contraindicated, with typical oral loading doses of 0.5 to 1 mg followed by maintenance of 0.125 to 0.25 mg daily. The Investigation Group (DIG) trial demonstrated that reduces HF hospitalizations by approximately 28% without affecting overall mortality in patients with systolic HF, including those with AF, supporting its role as a second-line adjunctive in about 20-30% of chronic AF cases where rate control is needed. Nonetheless, carries a narrow (0.5-2 ng/mL), with toxicity risks including , visual disturbances, and proarrhythmic effects exacerbated by renal impairment, , or drug interactions. Among other miscellaneous agents, selectively inhibits the hyperpolarization-activated cyclic nucleotide-gated (HCN) "funny" current (If) in the SA node, reducing spontaneous depolarization and without affecting contractility or , making it useful for rate control in chronic stable or HF with and elevated s (≥70 bpm) despite beta-blocker therapy. serves as an acute intervention for , a polymorphic associated with QT prolongation, by stabilizing cardiac membranes and suppressing early afterdepolarizations, with an initial 2 g intravenous dose effectively terminating episodes in most cases regardless of serum magnesium levels. Omega-3 polyunsaturated fatty acids, such as (EPA) and (DHA), exhibit mild antiarrhythmic properties through membrane stabilization, reduction of , and modulation of ion channels, potentially lowering the risk of sudden cardiac death post-myocardial infarction or postoperative , though evidence from meta-analyses shows inconsistent benefits for arrhythmia prevention and no primary antiarrhythmic indication. These agents are generally avoided or used cautiously in structural heart disease due to limited efficacy data and potential proarrhythmic risks in such populations.

Alternative Classification Systems

Sicilian Gambit Classification

The Sicilian Gambit Classification represents a mechanism-oriented framework for antiarrhythmic agents, introduced in by the of the on Arrhythmias of the . Unlike traditional systems, it emphasizes the underlying arrhythmogenic mechanisms—such as reentry, abnormal , and triggered activity—and identifies "vulnerable parameters" within these mechanisms that drugs can target to disrupt the . This approach uses a multidimensional "" model to map clinical arrhythmias, cellular electrophysiologic effects, and molecular targets, facilitating a more integrated understanding of drug actions. Key components include initial analysis of the arrhythmia's site and mechanism, followed by selection of agents that exploit specific vulnerabilities. For reentry, common in conditions like (AF), vulnerable parameters include conduction velocity, refractoriness, and excitable gap size; drugs may target these by blocking sodium (INa) or calcium (ICa) currents to slow conduction or by prolonging duration via (IK) channel blockade, such as the rapid delayed rectifier (IKr). In abnormal , the focus is on suppressing phase 4 through modulation of pacemaker currents. Non-pharmacologic factors, like ischemia, are also considered as they alter channel function and vulnerability. Examples include using IKr blockers like for reentrant termination in AF, or addressing atrial-specific targets like the ultra-rapid delayed rectifier (IKur) or gap junctions for more selective therapy in reentrant AF circuits. This classification offers advantages over the Vaughan Williams system by accommodating multi-target agents, such as , which simultaneously affects sodium, , and beta-adrenergic pathways, enabling broader mechanistic coverage without rigid class assignments. It promotes tailored therapy based on individual profiles, potentially improving efficacy in complex cases and inspiring into novel targets. Despite its conceptual strengths, the Sicilian Gambit has faced criticisms for its complexity, requiring in-depth knowledge of that hinders practical clinical application and memorization. It has not achieved widespread adoption among clinicians and educators, remaining more influential in than routine practice. Post-2000 refinements have incorporated to enhance mechanism-based targeting, such as using genetic variants (e.g., mutations in ) to predict state-specific drug-channel interactions for personalized therapy, though no major overhaul of the core framework has occurred by 2025.

Modernized Oxford Classification

The Modernized Oxford Classification of cardiac antiarrhythmic drugs was proposed in 2018 by Ming Lei, Lin Wu, Derek A. Terrar, and Christopher L.-H. Huang from the , building upon the foundational Vaughan Williams system by integrating contemporary insights into cellular signaling pathways. This framework expands the traditional ion channel-focused categories to encompass G-protein coupled receptor signaling, second messenger systems such as (), and calcium (Ca²⁺) handling mechanisms, thereby providing a more holistic view of drug actions on . The classification retains and refines Classes I–IV while introducing additional categories: Class 0 for modulators of automaticity (e.g., targeting hyperpolarization-activated cyclic nucleotide-gated [HCN] channels and the funny current I_f); Class I for blockers of membrane excitability via sodium (Na⁺) channels (subdivided into Ia–Id based on state-dependent blockade, including late Na⁺ current I_NaL); Class II for modulators (e.g., β-adrenergic blockers or activators influencing G-protein signaling and cAMP levels, as well as muscarinic receptor agents); Class III for modulators via (K⁺) channels (e.g., blockers of rapid delayed rectifier current I_Kr or slow delayed rectifier I_Ks); Class IV for intracellular Ca²⁺ handling (e.g., L-type Ca²⁺ channel blockers for I_CaL, [RyR2] stabilizers, Na⁺/Ca²⁺ exchanger inhibitors, and Ca²⁺/calmodulin-dependent protein kinase II [CaMKII] modulators); Class V for (e.g., transient receptor potential canonical [TRPC] channels); Class VI for modulators (e.g., channel blockers affecting electrical coupling); and Class VII for upstream targets of structural remodeling (e.g., antifibrotic agents). These classes emphasize interconnected pathways, such as how β-adrenergic stimulation elevates cAMP to enhance Ca²⁺ influx and , or how CaMKII activation disrupts function leading to arrhythmogenic Ca²⁺ leaks. A key innovation of this system is its ability to accommodate drugs with multifaceted effects, such as , which exhibits Class III K⁺ blockade alongside Na⁺, Ca²⁺, and autonomic influences, thereby overcoming the oversimplifications of single-class assignments in the Vaughan Williams scheme. It also incorporates emerging targets like CaMKII inhibitors to address signaling cascades implicated in arrhythmogenesis, extending beyond isolated modulation to include proarrhythmic risks and hybrid therapeutic strategies. Clinically, the classification guides research and development of hybrid therapies targeting Ca²⁺ dysregulation in (HF)-associated arrhythmias, where RyR2 leaks and CaMKII hyperactivity contribute to triggered activity and ventricular tachyarrhythmias; for instance, RyR2 stabilizers like (also a Class I agent) demonstrate efficacy in conditions like , which shares mechanisms with HF. The framework addresses gaps in prior systems by incorporating effects on non-myocyte cells, such as fibroblasts involved in , through Class VII agents that mitigate remodeling and arrhythmic substrates in diseased hearts. Its evidence base stems from the 2018 foundational review, with subsequent adoption evidenced by inclusion in the 2025 European Heart Rhythm Association (EHRA) Clinical Consensus Statement and endorsements in journals like Heart Rhythm and Europace, where it complements rather than fully supplants the Vaughan Williams classification in global guidelines as of 2025.

History and Development

Early Discoveries and Agents

The discovery of antiarrhythmic agents began in the late with the identification of from the foxglove plant (). In 1785, British physician published An Account of the Foxglove and Some of Its Medical Uses, based on systematic observations of over 200 patients, describing its ability to treat dropsy ( associated with ) by slowing the heart rate, particularly in cases of (then termed "irregular pulse"). This effect stemmed from digitalis's enhancement of , which prolongs atrioventricular nodal conduction and reduces ventricular response rates in without restoring . Although initially used empirically for symptomatic relief, digitalis laid the foundation for rate control strategies in supraventricular arrhythmias and remained a cornerstone therapy for over a century. By the early , quinidine emerged as the first specific agent for rhythm restoration. Derived from the bark of the tree, quinidine was isolated in the but gained recognition as an antiarrhythmic in the 1910s following reports of its efficacy in converting to . Pioneering clinical studies by R.L. Levy in demonstrated quinidine's ability to restore normal cardiac mechanism in patients with auricular (, marking it as the inaugural for . These observations, based on electrocardiographic monitoring, highlighted quinidine's role in suppressing ectopic atrial activity, though its use was tempered by risks of and . The mid-20th century saw the introduction of synthetic agents that expanded treatment options for ventricular arrhythmias. Lidocaine, initially developed as a in 1943, was repurposed in the late 1950s for acute (VT) following observations of its efficacy in suppressing arrhythmias during . Similarly, , approved by the in 1950, served as an oral analog to and was employed as a class IA for both supraventricular and ventricular tachyarrhythmias. In the , beta-blockers gained prominence for arrhythmia prevention; pronethalol, the first beta-adrenergic , was tested in 1962, followed by in 1965, which proved effective in controlling post- arrhythmias by reducing sympathetic drive and automaticity. Prior to formal classifications in the , antiarrhythmic agents were selected empirically based on clinical observation and electrocardiographic responses rather than mechanistic understanding, often grouping drugs by their effects on or without regard to specificity. This era's approach was challenged by emerging evidence of proarrhythmic risks, as precursor studies to the Cardiac Arrhythmia Suppression Trial () in the 1980s revealed that agents like encainide and , while suppressing asymptomatic ventricular ectopy post-infarction, increased mortality due to induced . Key milestones in mechanistic insight arose from early laboratories in the , where researchers like George Mines conducted experimental studies on reentrant circuits in isolated heart preparations, elucidating circus movement as a basis for and fibrillation. These foundational investigations bridged empirical with cellular , paving the way for targeted drug development.

Evolution of Classification Systems

The Vaughan Williams classification system for antiarrhythmic agents was introduced in 1970 by pharmacologist Miles Vaughan Williams, marking a foundational shift toward organizing drugs based on their effects on cardiac cellular electrophysiology, particularly ion channels such as sodium (Na⁺), beta-adrenergic receptors, potassium (K⁺), and calcium (Ca²⁺). This framework divided agents into four main classes (I–IV) with subclasses for class I, emphasizing mechanisms like sodium channel blockade to guide clinical use amid growing recognition of arrhythmia complexities. Its simplicity facilitated widespread adoption, influencing drug development and therapy selection for decades. In the 1980s and , the system's limitations became evident following major clinical trials, notably the Cardiac Arrhythmia Suppression Trial () in 1989–1991, which demonstrated increased mortality with class I sodium channel blockers like and encainide in post-myocardial infarction patients, prompting a reevaluation of mechanism-based classifications. As a response, the Sicilian Gambit was proposed in 1991 by a from the , shifting focus from rigid classes to specific arrhythmogenic mechanisms and vulnerable parameters to better account for multifactorial drug actions and proarrhythmic risks. This approach highlighted the need for more nuanced systems, especially after trials like underscored that suppressing arrhythmias did not always improve outcomes. By the 2000s, critiques intensified regarding the Vaughan Williams system's oversimplification, particularly for agents like , often termed a "" due to its broad, non-specific effects across multiple channels and signaling pathways, which defied neat categorization. Concurrently, advances in revealed inherited channelopathies, such as (LQTS), as key drivers, emphasizing genetic mutations in channels (e.g., KCNQ1 for LQT1) and prompting classifications to incorporate molecular underpinnings for targeted therapies. These insights, drawn from studies linking genetic variants to arrhythmogenic substrates, influenced a move toward hybrid models integrating electrophysiological, genetic, and clinical factors. In the , the Modernized Classification emerged in as a refinement, building on Vaughan Williams by incorporating intracellular signaling pathways and multi-target actions while preserving its core structure for practicality; it addressed gaps like amiodarone's and supported evaluation of emerging agents. Guidelines from the (AHA) and (ESC), such as the 2014 AHA/ACC/HRS atrial fibrillation update and 2016 ESC ventricular arrhythmias guidelines, began adopting hybrid approaches that blended Vaughan Williams with mechanism-oriented elements from the Sicilian , reflecting trial data like the ANDROMEDA study (2008), which demonstrated increased mortality with in patients with severe , in contrast to amiodarone's established relative safety in similar contexts from other studies. This evolution underscored a trend toward flexible, evidence-driven systems. From 2020 to , no entirely new dominant classification has supplanted Vaughan Williams, but updates emphasize precision medicine, with gene-specific therapies for channelopathies like LQTS gaining traction—such as KCNE1-targeted interventions for LQT5 or modifiers for LQT3—tailored via genomic profiling to minimize off-target effects. Recent refinements, including a updated version of the Modernized scheme published in 2025, derive a more focused and simpler scheme for clinical use and received global endorsement as the new standard in antiarrhythmic drug clinical guidelines by the European Heart Rhythm Association (EHRA) in their Clinical Consensus Statement (Europace, March 2025), informed by ongoing trials and pharmacogenomic data. This period reflects a broader shift toward personalized antiarrhythmic strategies, driven by high-impact studies on inherited arrhythmias.

Clinical Use and Considerations

Selection and Guidelines

The selection of antiarrhythmic agents is guided by evidence-based recommendations from major societies, tailored to the type of , risk profile, and comorbidities. For (AF), the 2023 ACC/AHA/ACCP/HRS guideline (as of 2025) recommends rhythm control with class Ic agents (e.g., or ) or class III agents (e.g., or ) in patients without structural heart disease, prioritizing these for maintaining in low-risk individuals. For ventricular arrhythmias, the 2022 ESC guideline (as of 2025) positions and as first-line options for reducing recurrent episodes and preventing sudden cardiac death in patients with implantable cardioverter-defibrillators (ICDs), emphasizing their role in symptomatic sustained . Selection criteria emphasize patient-specific factors to minimize proarrhythmic risks. In the presence of structural heart disease, particularly post-myocardial , class Ic agents are contraindicated due to increased mortality demonstrated in the Cardiac Arrhythmia Suppression Trial (CAST), which showed a 2.64-fold higher risk of arrhythmic death with encainide or compared to in 1,498 patients with asymptomatic ventricular ectopy. For congestive heart failure (CHF), is preferred over other agents like or class Ic drugs, as it effectively suppresses ventricular arrhythmias without worsening left ventricular function and has a neutral effect on mortality in this population. Renal function influences dosing for agents like , a class III primarily excreted renally; initial doses are reduced based on clearance (e.g., 250 mcg twice daily for CrCl 40-60 mL/min versus 500 mcg for >60 mL/min), with hepatic impairment requiring no adjustment but close monitoring. Treatment algorithms adopt a stepwise approach, starting with rate control before escalating to rhythm control. In AF, beta-blockers (e.g., metoprolol) or non-dihydropyridine (e.g., ) are first-line for ventricular rate control, with class III agents added for rhythm maintenance if symptoms persist; this sequence improves exercise tolerance and reduces hospitalization rates. For ventricular tachycardia in ICD patients, antiarrhythmic therapy synergizes with device programming by reducing shock burden; combined with beta-blockers decreases the risk of ICD shocks by approximately 73% (from 38.5% to 10.3% at 1 year) compared to beta-blockers alone, allowing longer detection intervals to avoid inappropriate therapies. Ongoing monitoring ensures efficacy and safety during therapy. Electrocardiographic (ECG) assessment of the is essential for class III agents to detect prolongation exceeding 500 ms, which signals risk, with serial ECGs recommended at initiation and every 3 months thereafter. Holter monitoring evaluates suppression over 24-48 hours, correlating symptoms like with rhythm disturbances to guide dose adjustments. Drug interactions, particularly cytochrome P450 inhibition by (e.g., elevating levels of or statins via and ), necessitate dose reductions of coadministered agents and to prevent toxicity. In special populations, selections prioritize fetal and pediatric safety. Lidocaine, a class Ib agent, is considered safe in (FDA category B) for acute ventricular arrhythmias, crossing the but without teratogenic effects in documented cases, making it preferable over agents like . For , sotalol dosing is weight-based at 0.5-1.5 mg/kg every 6-8 hours intravenously for acute use or 3-4 mg/kg/day orally, titrated under ECG monitoring to avoid QT prolongation in children with supraventricular or ventricular arrhythmias. As of 2025, guidelines increasingly integrate data, with the CABANA trial demonstrating ablation's non-inferiority to antiarrhythmic drugs for preventing composite cardiovascular events (death, , or ) in AF patients, particularly those with fewer than three nonmodifiable risk factors (adjusted 0.59), supporting its use as a first-line alternative in eligible low-risk cases.

Adverse Effects and Contraindications

Antiarrhythmic agents carry significant risks of proarrhythmia, where the drugs paradoxically induce or worsen arrhythmias. Class III agents, such as , are associated with due to prolongation, with an estimated risk of 2-5% in clinical use, particularly in patients with predisposing factors like female sex or imbalances. Class I agents can facilitate reentrant arrhythmias in hearts with , as evidenced by the Cardiac Arrhythmia Suppression Trial (CAST), which showed a 7.7% rate of arrhythmic death or in patients treated with class Ic agents (encainide or ) compared to 3% in the group, leading to a 2.5-fold increase in mortality post-myocardial . Organ-specific toxicities are prominent with certain agents. Amiodarone frequently causes pulmonary fibrosis, with an incidence of 5-15% in long-term users, and thyroid dysfunction (hypo- or ) in up to 20% of patients, necessitating routine (TSH) monitoring every 6 months. Quinidine is linked to cinchonism, manifesting as , , , and visual disturbances, alongside gastrointestinal upset such as . Other notable adverse effects include hemodynamic and conduction disturbances. Beta-blockers can precipitate and , exacerbating symptoms in susceptible patients. like verapamil may cause and atrioventricular (AV) block. Digoxin toxicity is associated with , especially in overdose, alongside gastrointestinal and visual symptoms. Contraindications are critical to prevent harm. Class Ic agents are contraindicated in due to proarrhythmic risks demonstrated in . is contraindicated in or hypomagnesemia, which heighten QT prolongation and torsades risk. All antiarrhythmic agents are generally contraindicated in sick sinus syndrome without a pacemaker, as they may worsen or . Risk mitigation involves correcting electrolytes (e.g., and magnesium levels) prior to initiation and monitoring drug levels, such as maintaining at 4-10 mcg/mL to avoid toxicity. Withdrawal syndromes are rare with these agents. The Suppression of Paroxysmal Atrial Tachyarrhythmias (SOPAT) trial reported low proarrhythmia incidence (less than 2%) with , supporting careful patient selection.

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