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Antiarrhythmic Medications

Editor: Muhammad F. Hashmi Updated: 2/19/2023 2:13:13 PM


The antiarrhythmic medications have typically been categorized according to the Vaughan-Williams (VW) classification system. The system classifies the medications according to the main mechanism of action (although several agents retain properties from multiple classes). The VW classification breaks down into four main categories, with some references adding a fifth.[1][2][3]

Class I

  • Class Ia: Causes moderate degree blockage of fast sodium channels. Drugs include quinidine, procainamide, and disopyramide. These are the most pro-arrhythmic of the sodium channel blockers due to prolonged QTc interval; use is limited due to pro-arrhythmic potential. Quinidine is used in selected patients with Brugada syndrome as an alternative to the implantable cardioverter-defibrillator placement (ICD). Treatment with quinidine can be useful in patients with short QT syndrome and recurrent ventricular arrhythmias (VA). Therapy with quinidine may reduce the number of shocks in patients with short QT syndrome who have undergone ICD placement. Disopyramide is still used occasionally with hypertrophic obstructive cardiomyopathy (HOCM), particularly as a combination with beta-blocker or verapamil to treat symptoms such as angina or dyspnea in patients with HOCM not responding to beta-blockers or verapamil alone. Procainamide can be a valuable agent to help unmask and diagnose Brugada syndrome in patients suspected of having Brugada syndrome but without a definitive diagnosis. Procainamide is a recommended agent to restore sinus rhythm in patients with Wolff-Parkinson-White (WPW) in whom atrial fibrillation (AF) occurs without hemodynamic instability in association with a wide QRS complex or with a rapid pre-excited ventricular response. It also can be useful in an attempt to terminate ventricular tachycardia and arrhythmia.[4][5]
  • Class Ib: Causes mild degree blockage of sodium channels. Drugs include lidocaine and mexiletine. These drugs shorten the QTc interval, are used for VA only, especially post-myocardial infarction VA, and are not useful for atrial arrhythmias. In long QT syndrome, mexiletine shortens the QTc interval and has been used to reduce recurrent and ICD arrhythmias.[6]
  • Class Ic: Causes marked degree of sodium blockage and no effect on QT interval. Drugs include flecainide or propafenone. These drugs are reasonable for ongoing management in patients without structural heart disease or ischemic heart disease who have symptomatic supraventricular tachycardia (SVT) and are not candidates for or prefer not to undergo catheter ablation. These agents are also useful for pharmacological cardioversion of AF. Some patients may use the "pill in pocket" strategy. The pill in the pocket refers to a treatment strategy where the patient with paroxysmal AF does not take a regularly scheduled maintenance dose of the medication but instead carries a loading dose of the agent. Suppose the patient senses an episode of AF has started. In that case, they take a loading dose of the respective treatment medication as a one-time dose and attempt chemical cardioversion back to a more regular rhythm. Flecainide and propafenone - should not be used for patients with any "structural heart disease." The Cardiac Arrhythmia Suppression Trials (CAST I and II) showed increased mortality in patients who had a previous myocardial infarction treated with class Ic agents (flecainide, encainide, moricizine) versus placebo when trying to reduce the frequency of premature ventricular contractions (PVCs). The implications of this trial are that class Ic agents are not routinely prescribed to patients with left ventricular dysfunction. This data essentially rules out the majority of ventricular arrhythmias for treatment with class Ic agents.[7]

Class II

Beta-blockers (BB) are indicated for rate control in patients with paroxysmal, persistent, or permanent AF and atrial flutter. Oral beta-blockers are useful for ongoing management in symptomatic supraventricular tachycardia (SVT) patients. Beta-blockers are often first-line antiarrhythmic therapy because of their excellent safety profile and effectiveness in treating ventricular arrhythmias. Therapy with beta-blockers reduces adverse cardiac events for long QT syndrome and catecholaminergic polymorphic ventricular tachycardia. In patients with symptomatic  (PVCs) in an otherwise normal heart, treatment with a beta-blocker is useful to reduce recurrent arrhythmias and improve symptoms.[6][8]

Class III

Potassium channel blockers decrease potassium efflux out of the cell and prolong the QTc interval.

  • Amiodarone exerts sympatholytic, sodium, and calcium antagonistic properties that decrease AV and sinus node conduction. This drug is recommended in patients with AF to maintain sinus rhythm, especially in patients with left ventricular systolic dysfunction. It is also a reasonable option in pharmacological cardioversion. This agent can be used in critically ill patients without pre-excitation to attain ventricular rate control, although it is less effective than non-dihydropyridine calcium channel blockers. Amiodarone is the most common antiarrhythmic medication used for the suppression of VA. In patients with hemodynamically unstable persistent VA after defibrillation, intravenous amiodarone should be administered to achieve a stable rhythm. And it has shown effectiveness in VA suppression in patients with ischemic heart disease with ongoing beta-blockers treatment.
  • Dronedarone reduces the hospitalization rate for AF in sinus rhythm patients with a non-permanent AF history. However, the clinician should not prescribe dronedarone in patients with AF that cannot be converted into normal sinus rhythm (permanent AF). According to the FDA review, it doubles the rate of cardiovascular death, stroke, and heart failure in such patients.
  • Dofetilide is used for atrial arrhythmias only. Oral dofetilide is useful for acute pharmacological cardioversion in atrial fibrillation or atrial flutter patients.
  • Sotalol shares the effects of class II and class II, non-cardioselective beta-blocker, and potassium channel blockers. Therefore, clinicians can use it to treat both ventricular and supraventricular arrhythmias. It is not effective for converting AF to sinus rhythm but may be used to prevent recurrent AF. Sotalol also showed its efficacy in suppressing VA. 
  • Ibutilide is indicated for AF or atrial flutter only.[6][7]

Class IV

Non-dihydropyridine calcium channel blockers (diltiazem, verapamil) decrease conduction velocity and slow conduction through the AV node. They are useful for ventricular rate control in acute and chronic AF and atrial flutter. Diltiazem and verapamil are options in the acute treatment of hemodynamically stable patients with SVT,  focal, and multifocal atrial tachycardias.[7]

Other Antiarrhythmic Drugs

  • Adenosine is useful for diagnosing and terminating SVT due to either atrioventricular nodal reentrant tachycardia (AVNRT) or orthodromic atrioventricular reentrant tachycardia (AVRT). This drug may also be utilized diagnostically; adenosine helps unmask atrial flutter or atrial tachycardia (AT). Adenosine is also useful in terminating focal AT of a triggered mechanism and differentiating focal AT from AVNRT and AVRT.
  • Digoxin - Although digoxin is not usually first-line therapy for ventricular rate control in patients with AF, a combination of digoxin and beta-blocker/or non-dihydropyridine calcium channel blockers is a reasonable rate control option in patients with AF and heart failure.

In revised classification, original Vaughan Williams Classes I through IV are maintained but subcategorized these classifications due to recent developments, including the presence of Na+ current components (for Class I), advancements in autonomic (G protein-mediated) signaling (for Class II), K+ channel subclassification (for Class III), and new molecular targets related to Ca2+ homeostasis (for Class IV). Also, Class V to VII has been described.[9]

Updated Vaughan Williams Classification[10]

Class 0: HCN Channel Blockers

Ivabradine: Stable angina and chronic heart failure with heart rate ≥70 bpm

Class I: Voltage-gated Na+ Channel Blockers

Ia: Quinidine, disopyramide, procainamide- Supraventricular tachyarrhythmias, recurrent atrial fibrillation, ventricular tachycardia, ventricular fibrillation, Brugada syndrome, short Q-T syndrome(SQTS)[11]

Ib: Lidocaine, mexiletine- Ventricular tachycardia, ventricular fibrillation, especially after myocardial infarction

Ic: Encainide, flecainide, propafenone- Supraventricular and ventricular tachyarrhythmias resistant to standard treatments in the absence of structural heart disease, and premature ventricular contractions, catecholaminergic polymorphic ventricular tachycardia

Id: Ranolazine- Potential treatment option for tachyarrhythmias and ventricular tachycardia

Class II: Autonomic Inhibitors/Activators

IIa: Inhibitors: Pindolol, carvedilol, timolol, nadolol (non-selective βB); bisoprolol, atenolol, metoprolol, esmolol (selective β1 blocker)- Rate control of atrial fibrillation, atrial flutter, and ventricular tachyarrhythmias

IIb: Activators: Isoproterenol- Ventricular escape rhythm (complete AV block prior to pacemaker implantation)

IIc: Inhibitors: Atropine- Symptomatic sinus bradycardia, conduction block.

IId: Activators: Carbacholine, methacholine, digoxin- supraventricular tachyarrhythmias

IIe: Activators: Adenosine- Termination of PSVT

Class III: K+ Channel Blockers/Openers

IIIa: Voltage-dependent K+ channels

K+ channels (non-selective) blockers: Amiodarone, dronedarone- Atrial fibrillation, hemodynamically unstable ventricular tachycardia, life-threatening recurrent ventricular fibrillation

Kv11.1 (rapid K+ current) blockers: Dofetilide, almokalant, ibutilide, sematilide, sotalol- Ventricular tachycardia in patients in patients without a history of myocardial infarction or structural heart disease, WPW syndrome associated with atrial fibrillation. 

Kv1.5 (ultra-rapid K+ current) blockers: Vernakalant- pharmacological cardioversion of recent atrial fibrillation (in patients without structural heart disease /ischemic heart disease)[12] (not-FDA approved)[13]

IIIb: Metabolically dependent K+ channels blockers: Nicorandil, pinacidil- treatment of stable angina (second line), decrease in actional potential recovery time, shortens QT intervals.

Class IV: Ca2+ handling modulators

IVa: Surface membrane non-selective Ca2+ channels blockers: Bepridil, falipamil- Potential management of supraventricular tachyarrhythmias

Surface membrane L-type Ca2+ channels blockers: Verapamil, diltiazem- Supraventricular arrhythmias, Rate control of atrial fibrillation.

IVb: Intracellular Ca2+ channel blockers: Propafenone, flecainide- Catecholaminergic polymorphic ventricular tachycardia(CPVT)[14]

Class V Mechanosensitive channel blockers

Inhibitors: N-(p-amylcinnamoyl) anthranilic acid (under research- not FDA approved)

Class VI: Gap junction channel blockers

Inhibitors: carbenoxolone (under investigation- not FDA approved)

Class VII: Upstream target modulators

Omega-3 fatty acids: eicosapentaenoic acid, docosahexaenoic acid - Post–myocardial reduction of risk of cardiac death[15]

Statins- Potential for use in atrial fibrillation[16]

ACE inhibitors: captopril, enalapril, ramipril, lisinopril; ARBs: losartan, telmisartan- Potential application in atrial fibrillation due to heart failure[17]

Mechanism of Action

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Mechanism of Action

The cardiac action potential is the cycle of ion movement, which leads to successive depolarization and repolarization of the cardiac myocyte leading to muscle contraction.[18] The resting phase of the cardiac myocyte has a resting membrane potential of negative 80 to negative 90 mV at baseline. The antiarrhythmic medications essentially slow ion movement in various phases of the cardiac action potential and get broken down as follows.

  • Phase 0: "the depolarization" phase of the action potential; occurs by the rapid movement of sodium ions (Na+) into the cell along an electrochemical gradient, which leads to a membrane potential of approximately positive 30 mV.
  • Phase 1: "The notch,"; the initial or early repolarization phase of the action potential, involves the efflux of potassium (K+) ions.
  • Phase 2: "The plateau" phase - this phase is a balance of inward calcium ion movement that offsets the outward K+ movement.
  • Phase 3: "The repolarization" phase of the action potential; this phase is primarily caused by the movement of K+ ions along their electrochemical gradient out of the cell, essentially taking the positive charge of the K+ ion out of the cell. It restores the negative potential of the cardiac myocyte.
  • Phase 4: Restoration of the Na/K-ATPase, which restores the resting membrane potential of the cardiac myocyte.

Class 0 Antiarrhythmic

These are hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blockers. These agents block funny (I) current. Inhibition of I reducing sinoatrial node (SAN) phase 4 pacemaker depolarization rate, thereby reducing heart rate; potential decreased AV Nodal conduction and Purkinje cell automaticity increasing RR intervals. An example is ivabradine.[19]

Class I Antiarrhythmics

Class Ia, Ib, and Ic: Class I antiarrhythmics are fast sodium channel blockers. They are responsible for phase 0 of fast-response cardiac action potentials. The three subclasses differ in their efficacy for reducing the slope of phase 0, with Ic drugs having the greatest and Ib drugs having the smallest effect on phase 0. Sodium-channel blockade: Ic > Ia > Ib. Class Ia prolongs the action potential (AP) duration, leading to an increase in QTc interval. Class Ib decreases the duration of AP, causing a shortening of the QTc interval, and class Ic drugs do not affect AP duration; thus, no effect on the QTc interval.[20]

Class Id: Ranolazine has a distinct mechanism of action; it causes a reduction in late Na+ current (INaL) and affects AP recovery and refractoriness. As a result, there is a decreased action potential recovery time and reduced early afterdepolarization (EAD)-induced triggered activity.[21]

Class II Antiarrhythmic 

Class IIa: Beta-blockers - These agents inhibit beta-adrenergic activation of adenylate cyclase and reduce intracellular cAMP levels, resulting in decreased sinoatrial node (SAN) pacing and triggered activity.

Class IIb: Nonselective beta-agonist- This agent works by activating the adrenergic system(l)-induced Gs-protein effects of increasing adenylyl kinase activity decreases RR and PR intervals. Consequently, there is a suppression of bradycardia-dependent EAD-related triggered activity. Isoproterenol exerts both chronotropic and inotropic effects, improving sinus and AV nodal function without a vasopressor effect. It is indicated for acute treatment of symptomatic sinus bradycardia or atrioventricular block.[22]

Class IIc: Muscarinic M2 receptor inhibitors (atropine)- Inhibits supraventricular (SAN, atrial, AVN) muscarinic M2 cholinergic receptors, decreasing RR and PR intervals, thus increasing SA node automaticity and AV nodal conduction.[22]

Class IId: Muscarinic M2 receptor activators (pilocarpine, carbachol, methacholine, digoxin)- These drugs activate supraventricular (SA node, atrial, AV node) muscarinic M2 cholinergic receptors, hyperpolarizing the SA node, and shortening action potential duration in atrial and AV nodal tissue. It also displays inhibitory effects on adenylyl cyclase and cAMP activation, resulting in increased RR and PR intervals, reduced SA node automaticity, and decreased AVN conduction. In addition, digoxin is also a Na/K-ATPase inhibitor. Binding with the sodium pump increases intracellular Na+ concentration, which will drive Ca2+ influx. That will lead to increase contractility of the heart and prolongation of phase 4 and phase 0 of the cardiac action potential, thus slowing down conduction through the AVN.[23]

IIe Adenosine A1 receptor activator (adenosine)- Activating adenosine A1 receptors in supraventricular tissue activates G protein-coupled inward rectifying K+ channels hyperpolarizing the SA node; inhibitory effects on adenylyl cyclase and cAMP activation; increased RR and increased PR intervals. Consequently, decreasing SA node automaticity and AV nodal conduction. In addition, decreases early after depolarization (EAD) induced and delayed after depolarization (DAD) induced triggered activity. Terminates SVT via hyperpolarization by increasing K+ efflux and inhibiting Ca2+ current.[24]

Class III antiarrhythmics (K+ channel blockers and openers)

Class III antiarrhythmics block potassium channels resulting in prolonged atrial, Purkinje, ventricular myocyte action potential recovery, increased ERP, reduced repolarization reserve, and prolonged QT intervals. Amiodarone also exerts sympatholytic, sodium, and calcium antagonistic properties that decrease conduction through the AV and sinus node. Sotalol shares class II and class III antiarrhythmic properties. 

IIIa: Nonselective potassium channel blockers (amiodarone, dronedarone): Block multiple potassium channel targets resulting in prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals. An increase in AP recovery time and the refractory period, with a decreased reentrant tendency. Note: amiodarone also delays sinus node rate and atrioventricular conduction.[25]

Rapid potassium current (I) blockers: (dofetilide, ibutilide, sotalol)- Prolonged atrial, Purkinje, and ventricular myocyte AP recovery, increased ERP, and reduced repolarization reserve; prolonged QT intervals, increase in AP recovery time and refractory period with a decreased reentrant tendency.[26]

Ultrarapid K current (I) blockers: Venrnakalent increases the refractory period and reentrant tendency. Useful for immediate conversion of atrial fibrillation without structural heart disease.[27]

IIIb:  Metabolically dependent K+ channel openers(nicorandil)- Opening ATP-sensitive K+ channels, shortening AP recovery, refractoriness, and repolarization reserve in all cardiomyocytes apart from SAN cells; shortened QT intervals. Nicorandil use during PCI could reduce the rate of ventricular arrhythmia in STEMI patients undergoing percutaneous coronary intervention.[28]

Class IV Antiarrhythmics

Class IV antiarrhythmic inhibits slow Ca2+ channels and reduces the slope of phases 0 and 4, resulting in inhibited SAN pacing, AVN conduction, prolonged ERP, and PR interval. 

IVa: Surface membrane Ca2+ channel blockers (bepridil, falipamil, fendiline)- Blockage of Ca2+ current, resulting in inhibition of SA node pacing, increased PR intervals, reduction in AV node conduction. It is useful in atrial fibrillation.[29]

L-type Ca2+ current blockers:(verapamil, diltiazem)- Blockage of Ca++ current, resulting in inhibition of SAN pacing, AVN conduction, and suppression of intracellular Ca signaling; increased PR intervals. Useful for rate control in atrial fibrillation.[30]

IVb: Intracellular Ca2+ channel blockers (propafenone, flecainide)-Reduced Ca++ release medicated from the sarcoplasmic reticulum. Useful for acute pharmacologic conversion of atrial flutter and fibrillation.[18]

IVd: Surface membrane ion exchanger inhibitor (bepridil)- no FDA-approved clinical use in arrhythmias.[31]

Class V Antiarrhythmics (mechanosensitive channel blockers)

The drug under investigation is N-(p-amylcinnamoyl)anthranilic acid, which acts on the transient receptor potential channel (TRPC3/TRPC6).[32] This class currently has no clinically approved indication in the treatment of arrhythmia.

Class VI Antiarrhythmic (gap junction channel blockers)

Drugs under investigation are carbenoxolone and rotigaptid. Action potential conduction depends on local intercellular circuit current spread affecting gap-junction conductances possessing apposed connexin (Cx) hemichannels electrically coupling the intracellular spaces of adjacent cardiomyocytes. Cx43 is present in both atrial and ventricular myocytes and the distal conduction system. Cx45 is present predominantly in the SA node, AV node, and Purkinje conducting system. Modulating gap junction conductance or expression, depending on circumstances, can enhance or reduce arrhythmogenesis. For example, carbenoxolone is a connexin blocking agent, which decreases ventricular/atrial conduction and AVN conduction. Connexin opening agent is the peptide analog rotigaptid. This class currently has no clinically approved indication in the treatment of arrhythmia.[33]

Class VII antiarrhythmic (upstream target modulators)

ACE inhibitors, Angiotensin receptor blockers(ARBs), Statins, Omega 3 fatty acids. These agents focus on tissue structure remodeling processes and, consequently, longer-term changes that contrast with the primary focus on the short-term effects of drugs on ion channels.[34] The cardiac disease alters the function of ion channels promoting cardiac rhythm disruptions, i.e., "arrhythmogenic remodeling." Arrhythmogenic remodeling has important pathophysiological implications that majorly affect cardiac morbidity and mortality. Upstream therapy with ARBs, ACE inhibitors, statins, and omega-3 fatty acids that target remodeling and arrhythmogenesis can be efficacious but need further clinical evaluation.[17][10]


Most antiarrhythmic medications may be administered intravenously and orally, depending on the acuity of the condition. Among class I antiarrhythmic agents, procainamide and lidocaine are administered intravenously since their primary use is acute treatment. Mexiletine is an oral analog of lidocaine. Quinidine is available in both intravenous and oral forms. Disopyramide is administered in capsules and controlled-release capsules. Oral administration of flecainide or propafenone is feasible and safe and effectively converts recent-onset atrial fibrillation to sinus rhythm. Adenosine should be administered via proximal IV as a rapid bolus infusion, followed by a saline flush. Digoxin administration may be via the oral or intravenous route and as an intramuscular injection. Administration of antiarrhythmic drugs like amiodarone, disopyramide, dofetilide, ibutilide, and sotalol with an established risk for TdP requires continuous cardiac monitoring.[35]

Hepatic Impairment: Hepatic impairment reduces the elimination of many antiarrhythmics, so dosage reductions are recommended, especially in patients with cirrhosis. For drugs such as carvedilol, lidocaine, propafenone, and verapamil, a decrease in systemic clearance and substantial prolongation of the elimination of half-life have been documented. Consequently, a two to three-fold dosage reduction in patients with moderate to severe liver cirrhosis is recommended. For disopyramide, sotalol, and procainamide, the renal route is the major route of elimination; consequently, those dosage reductions are probably unnecessary in patients with liver disease, given that renal function is normal.[36] Amiodarone therapy should be stopped if there is any clinical evidence of hepatic injury or clinical signs such as ascites, hepatomegaly, jaundice, or if serum aminotransferase activities are consistently elevated more than five times the upper limit of normal.[37]

Renal Impairment: The risk of digoxin toxicity is increased with impaired renal function, hypokalemia, or hypomagnesemia. Hence, digoxin should be prescribed cautiously in patients with preexisting renal disease.[38] Dose adjustment is needed for flecainide therapy if eGFR<35ml/min/1.73m.Sotalol is contraindicated in patients with creatinine clearance <40 ml/min. For dofetilide, dose adjustment based on initial creatine clearance measurement is recommended; the drug is contraindicated with creatinine clearance <20 ml/min according to Kidney Disease Improving Global Outcomes guidelines.[39]

Pregnancy Considerations: In women with preexisting cardiac arrhythmias, recurrence during pregnancy is a concern. Due to the risk of teratogenicity, clinicians should choose the lowest effective dose for antiarrhythmic therapy. As of 2015, the FDA pregnancy letter category system (A, B, C, D, X) has been substituted with a new rule that provides reasoning about the potential risk and benefits for the mother and fetus. Quinidine has been used successfully for maternal and fetal ventricular and supraventricular arrhythmias due to the ease of placental transfer. Reports show that procainamide use in pregnancy results in no apparent complications to the fetus.

Given the potential increased risk for preterm labor and limited data regarding the drug's safety in pregnancy, disopyramide should be avoided. Intravenous lidocaine during pregnancy is efficacious without evident fetal complications. Further, it is typically utilized as an anesthetic during the peripartum. Lidocaine is a suitable option for intravenous treatment of ventricular arrhythmias. Mexiletine use may be safe in pregnancy, but it should be used cautiously, given the lack of data. Clinical experience with propafenone is limited to flecainide; hence flecainide use is favored over propafenone during pregnancy in patients without structural heart disease. 

Beta-blockers are used commonly in pregnancy for managing hypertension and tachycardia. The concern associated with β-blocker is reduced birth weight. Specifically, atenolol has an increased risk of reduced birth weight. All β-blockers are former FDA category C, excluding atenolol (category D) and pindolol (category B). The most commonly reported adverse event with amiodarone is fetal hypothyroidism. However, most hypothyroidism is temporary and resolves after replacement therapy. There are reports of symptomatic fetal bradycardia and rare congenital abnormalities associated with amiodarone. Hence, amiodarone should be administered when treatment for life-threatening arrhythmias is needed and other therapies are ineffective or contraindicated. As usual, clinicians must consider the amiodarone benefits against the risks ( category D).[40] 

Breastfeeding Considerations: Clinicians should discuss the risk vs. benefit with the patient to make a shared decision regarding particular drugs during pregnancy and lactation. According to the American College of Obstetricians & Gynecologists (ACOG) guidelines, antiarrhythmic drugs such as lidocaine, procainamide, adenosine, digoxin, verapamil, diltiazem, atenolol, and esmolol are probably compatible with breastfeeding. Amiodarone and sotalol may be unsafe during breastfeeding.[41]

Adverse Effects

Antiarrhythmic medications have several areas of concern. First and foremost, most agents also have some degree of pro-arrhythmic potential. Practically speaking, while trying to suppress arrhythmias with the medications, the medications themselves can lead to other (potentially more dangerous) arrhythmias.[42] For example, the class Ia sodium channel blockers (quinidine, procainamide, and disopyramide) effectively prolong the QTc interval and thus increase the risk of ventricular tachycardia (torsades de pointes).[43]

Other side effects of class Ia antiarrhythmics are more drug-specific. Procainamide may induce lupus erythematosus, reversible after discontinuation of the offending drug. An adverse effect caused by treatment with quinine is called cinchonism and includes nausea, dizziness, headache, tinnitus, and visual changes. Disopyramide has an anticholinergic effect and accounts for many adverse side effects, such as flushed and dry skin, thirst, hyperthermia, mydriasis, confusion, agitation, and urinary retention. Due to arrhythmogenic effects, class Iantiarrhythmics are contraindicated in post-myocardial infarction patients.

Therapy with beta-blockers may have cardiovascular side effects such as bradycardia and AV block. Beta-blockers noncardiac side effects include exacerbation of asthma and COPD, lethargy, and dyslipidemia. All K+ channel blockers share this potential side effect. The reason for this is straightforward if one compares the action potential phases to the ECG. The T wave on the ECG represents ventricular repolarization. Phase 3 of the action potential represents repolarization. If a K+ channel blocker is given, this prolongs phase 3 of the action potential due to the slow efflux of K+ ions. If the repolarization phase of the action potential is prolonged, the T-wave on the corresponding ECG also gets prolonged, which creates a prolonged QTc interval. Drodenadrone is not for use in a patient with severe heart failure or decompensated heart failure, or cases of permanent atrial fibrillation, according to pulled safety data from eight clinical trials.[44] Amiodarone side effects are wide-ranging and include corneal microdeposits of amiodarone, hypothyroidism, hyperthyroidism, pulmonary fibrosis, elevated liver function tests, nausea, and myopathy.[25]

Verapamil may cause unwanted effects such as AV block, bradycardia, and constipation. The most frequently reported diltiazem side effects are headaches, dizziness, and edema. Calcium channel blockers (CCBs) like verapamil and diltiazem have common adverse drug reactions, i.e., peripheral edema. A prescribing cascade happens when the edema is misinterpreted as a new medical condition, and a diuretic is t prescribed to manage the peripheral edema.[45]

Minor adenosine adverse effects include flushing, a sense of impending doom, and sweating, which are usually transient due to the drug's short half-life. More severe side effects include hypotension, chest pain, AV block, and asystole. The adverse effect of bronchospasm makes it contraindicated in asthmatic patients. Clinicians should avoid adenosine in patients with SVT involving accessory pathways (WPW, antidromic AVRT) due to the risk of tachycardia exacerbation.[46]

Atrial tachycardia with AV block is arrhythmia specific for digoxin toxicity. Digoxin toxicity is characterized by nausea, vomiting, abdominal pain, fatigue, confusion, and color vision alterations.[23]

A recent meta-analysis reported that ivabradine therapy was associated with an increased incidence of atrial fibrillation, and the effect was more observed in the patients with LVEF >40%.[47] Moreover, visual disturbances and asymptomatic bradycardia has been observed in another meta-analysis.[48]


All major contraindications are according to the manufacturer's labeling.

Amiodarone, one of the most commonly used antiarrhythmic drugs, has boxed warnings for pulmonary, hepatic, and cardiac toxicity. Amiodarone is contraindicated in cardiogenic shock, sick sinus syndrome, second or third-degree atrioventricular block, and known hypersensitivity to the amiodarone or iodine. Ivabradine is contraindicated in severe hepatic impairment, significant bradycardia, sick sinus syndrome, sinoatrial block, and acute decompensated heart failure. Lidocaine is contraindicated in patients with a history of hypersensitivity amide-type anesthetics. Procainamide is contraindicated in complete heart block, idiosyncratic hypersensitivity, and established diagnosis of systemic lupus erythematosus. Quinidine is contraindicated in patients with a history of immune thrombocytopenia in patients in the complete AV block whose cardiac rhythm is dependent upon a pacemaker.

Similarly, mexiletine is contraindicated in patients with cardiogenic shock or second or third-degree AV block without a functioning pacemaker. Propafenone has a boxed warning for proarrhythmic in patients with structural heart disease. Propafenone is also contraindicated in cardiogenic shock, sick sinus node syndrome/AV block without an artificial pacemaker, and Brugada syndrome. In the CAST trial patients with asymptomatic non-life-threatening ventricular arrhythmias who had a MI more than six days but lesser than two years previously, increased mortality was observed in subjects treated with encainide or flecainide.

Non-selective beta-blockers are contraindicated in bronchial asthma, sinus bradycardia, and greater than first-degree AV block, cardiogenic shock, and acute decompensated heart failure.[49] In addition, there is a risk of exacerbation of ischemic heart disease following abrupt withdrawal of beta-blockers. IV metoprolol is contraindicated in patients with bradycardia, decompensated cardiac failure, and second and third-degree heart block. Esmolol is contraindicated in patients with severe sinus bradycardia, decompensated heart failure, cardiogenic shock, second or third-degree AV block, and hypersensitivity reactions. Ranolazine is contraindicated in patients on inhibitors/inducers of CYP3A4 and liver cirrhosis. In addition, higher doses may be associated with renal dysfunction, QTc prolongation, and syncope.[50]


All antiarrhythmic drugs are also potentially pro-arrhythmic; hence, intravenous administration should be done only under cardiac monitoring. Each agent in the Vaughn-Williams classification includes distinctive side effect profiles that require individual consideration. For example, procainamide may induce a lupus-like syndrome, while quinidine is known to produce cinchonism. The benefit of the classification is in the primary mechanism of action and the broad, predictable side effects brought about by the primary mechanism. An example would include the class III K+ channel blockers or "repolarization" blockers producing a prolonged phase 3 of the action potential and, by definition, also leading to a prolonged QT interval on the corresponding EKG. It is important to note that, Bazett's formula for QTc calculation leads to an overestimation of the QTc during atrial fibrillation, consequently reducing antiarrhythmic doses and drug efficacy.[51]

During the administration of beta-blockers, an electrocardiogram and heart rate monitoring are more useful than TDM.[52] Amiodarone is an excellent antiarrhythmic agent, but long-term use correlates with corneal opacities, thyroid problems, and lung infiltrates. Consequently, amiodarone is not the preferred geriatric population rather than young adults. Digoxin has a narrow therapeutic index. The therapeutic serum digoxin levels range is 0.5 to 2 ng/mL. Serum concentrations of cardiac glycosides require monitoring closely to avoid digitalis toxicity. Amiodarone, verapamil, quinidine, and diltiazem increase the serum levels of digoxin and can lead to toxicity. The recommendation is to reduce the digoxin dose by 25% to 50%, closely monitoring digoxin levels weekly for several weeks. Periodic electrolyte evaluation is a recommendation. Hypokalemia may make the patient more susceptible to digitalis toxicity. Healthcare professionals can reduce the morbidity of antiarrhythmic drugs with knowledge of the adverse drug reactions,pro-arrhythmic effects of specific antiarrhythmic drugs, and therapeutic drug monitoring.[53][54]


In the case of overdose with antiarrhythmic drugs, clinicians should establish and maintain a patent airway, breathing, and circulatory support. In addition, vasopressor support is required for severe hypotension. Selected overdose management is described below.

Digoxin toxicity presents nausea, vomiting, neurological symptoms, and fatal arrhythmias. For digoxin toxicity, lidocaine can be administered for ventricular tachyarrhythmias and atropine for bradyarrhythmia. In addition, digoxin-specific antibody fragments are effective in severe toxicity.[55] Therapeutic and the excess dosage of dofetilide can lead to TdP, which is managed by reducing the dose or discontinuing drug administration. If the arrhythmia is not resolved, guidelines recommend management with activated charcoal if ingestion is within 15 minutes, followed by administering  IV magnesium and addressing the electrolyte imbalance. However, if the arrhythmia is ongoing, isoproterenol/dopamine is given as a bridge to pacing.[56] 

In the case of beta-blocker poisoning, catecholamines, high-dose insulin euglycaemic treatment, and vasopressors are administered. Glucagon has been associated with improvements in hemodynamics.[57]  IV Calcium, dopamine, and norepinephrine are used for CCB overdose. High-dose insulin is associated with lower mortality in calcium channel blocker poisoning. Extracorporeal life support is used for patients with severe shock or cardiac arrest.[58] The case report suggests lipid emulsion therapy has successfully been used to treat amiodarone and flecainide overdose. However, further research is still required.[59]

Enhancing Healthcare Team Outcomes

The cardiologist, specifically an electrophysiologist, is generally responsible for starting the patient on antiarrhythmic medication. Still, the primary care provider (clinicians, including MDs, DOs, NPs, and PAs), nurse, and pharmacist must monitor the patient. These medications are not benign, and all healthcare workers who look after patients on antiarrhythmic agents should be very familiar with the different antiarrhythmic agents. Cardiology specialty nurses are beneficial in monitoring since they have the training to recognize adverse events, understand treatment goals, and inform the specialist or other clinicians of any concerns. The pharmacist can also be a board-certified cardiology specialist and assist in agent selection, ongoing monitoring, checking for drug interactions, and maintaining communication with the prescriber. All interprofessional team members must report any changes in patient status to the rest of the team; this can include changes in the patient's condition, potential drug interactions or adverse effects, and signs of therapeutic failure. In such instances, any team member must promptly document their findings in the patient's medical record and notify other team members; in this way, appropriate corrective measures can be implemented, and all team members will have access to the same patient data. These examples of interprofessional team dynamics can drive positive outcomes for patients. [Level 5]

Each agent in the revised Vaughn-Williams classification includes distinctive side effect profiles that require individual monitoring. If there is a doubt about the medication, the clinician should seek a cardiology consult. Nurses and allied health professionals have a substantial role in managing arrhythmias such as atrial fibrillation. The European Society of Cardiology guidelines (2016) for managing atrial fibrillation suggest collaborative care in managing atrial fibrillation.[60] ESC guidelines also recommend following a patient-centered, interprofessional team approach to optimize treatment outcomes. [Level 1]


(Click Image to Enlarge)
Illustration of Anti-arrhythmic drugs with respect to cardiac action potential.
Illustration of Anti-arrhythmic drugs with respect to cardiac action potential.
Contributed by Amandeep Goyal, MD



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