The need for treatment of arrhythmias depends on the symptoms and the seriousness of the arrhythmia. Treatment is directed at causes. If necessary, direct antiarrhythmic therapy, including antiarrhythmic drugs, cardioversion-defibrillation, implantable cardioverter-defibrillators (ICDs), pacemakers (and a special form of pacing, cardiac resynchronization therapy), catheter ablation, surgery, or a combination, is used.
Most antiarrhythmic drugs are grouped into 4 main classes (Vaughan Williams classification) based on their dominant cellular electrophysiologic effect (see table Antiarrhythmic Drugs (Vaughan Williams Classification)).
Class I: Class I drugs are subdivided into subclasses a, b, and c. Class I drugs are sodium channel blockers (membrane-stabilizing drugs) that block fast sodium channels, slowing conduction in fast-channel tissues (working atrial and ventricular myocytes, His-Purkinje system).
Class II: Class II drugs are beta-blockers, which affect predominantly slow-channel tissues (sinoatrial [SA] and atrioventricular [AV] nodes), where they decrease rate of automaticity, slow conduction velocity, and prolong refractoriness.
Class III: Class III drugs are primarily potassium channel blockers, which prolong action potential duration and refractoriness in slow- and fast-channel tissues.
Class IV: Class IV drugs are the nondihydropyridine calcium channel blockers, which depress calcium-dependent action potentials in slow-channel tissues and thus decrease the rate of automaticity, slow conduction velocity, and prolong refractoriness.
Adenosine slows or blocks AV nodal conduction and can terminate tachyarrhythmias that rely upon AV nodal conduction for their perpetuation.
Ivabradine inhibits the SA node funny current and slows SA node rate. More inclusive updates to the Vaughan Williams classification have been proposed (1).
Antiarrhythmic Drugs (Vaughan Williams Classification)
Drug | Dosage | Target Levels | Selected Adverse Effects | Comments |
|---|---|---|---|---|
Class Ia Uses: APB and VPB suppression, SVT and VT suppression, AF or atrial flutter, and VF suppression | ||||
IV: Initially, 1.5 mg/kg over > 5 minutes followed by an infusion of 0.4 mg/kg/hour Oral immediate-release: 100 or 150 mg every 6 hours Oral controlled-release: 200 or 300 mg every 12 hours | 2–7.0 mcg/mL (5.9–20.6 mcmol/L) | Anticholinergic effects (urinary retention, glaucoma, dry mouth, blurred vision, intestinal upset), hypoglycemia, torsades de pointes VT; negative inotropic effects (which may worsen heart failure or hypotension) | Drug should be used cautiously in patients with impaired LV function. Dosage should be decreased in patients with renal insufficiency. Adverse effects may contribute to nonadherence. Infusion rate or dosage should be decreased or drug stopped if QRS interval widens (> 50% if initially < 120 millisecond or > 25% if initially > 120 millisecond) or if QTc interval is prolonged > 550 millisecond. IV form is not available in the US. | |
IV: 10–15 mg/kg bolus at 25–50 mg/minute, followed by a constant IV infusion of 1–4 mg/minute Oral: 250–625 mg (rarely, up to 1 g) every 3 or 4 hours Oral controlled-release: For patients < 55 kg, 500 mg; for patients 55–91 kg, 750 mg; or for patients > 91 kg, 1000 mg every 6 hours | 4–10 mcg/mL (17–34 mcmol/L ) | Hypotension (with IV infusion), serologic abnormalities (especially a positive ANA test) in almost 100% taking drug for > 12 months, drug-induced lupus (arthralgia, fever, pleural effusions) in 15–20%, agranulocytosis in < 1%, torsades de pointes VT | Sustained-release preparations obviate the need for frequent dosing. Infusion rate or dosage should be decreased or drug stopped if QRS interval widens (> 50% if initially < 120 millisecond or > 25% if initially >120 millisecond) or if QTc interval is prolonged > 550 millisecond. | |
Oral: 200–400 mg every 4–6 hours | 2–5 mcg/mL (6.2–15.4 mcmol/L) | Diarrhea, colic, flatulence, fever, thrombocytopenia, liver function abnormalities, torsades de pointes VT; overall adverse effect rate of 30% | Infusion rate or dosage should be decreased or drug stopped if QRS interval widens (> 50% if initially < 120 millisecond or > 25% if initially > 120 millisecond) or if QTc interval is prolonged > 550 millisecond. | |
Class Ib Uses: Suppression of ventricular arrhythmias (VPB, VT, VF) | ||||
IV: 100 mg over 2 minutes, followed by continuous infusion of 4 mg/minute (2 mg/minute in patients > 65) and 5 minutes after the first dose, a 2nd 50-mg bolus | 1.5–5 mcg/L (6.4–-21.3 mcmol/L) | Tremor, seizures; if administration is too rapid, drowsiness, delirium, paresthesias; possibly increased risk of bradyarrhythmias after acute myocardial infarction | To reduce toxicity risk, clinicians should reduce dosage or infusion rate to 2 mg/minute after 24 hours. Extensive first-pass hepatic metabolism occurs. | |
Oral immediate-release: 100–400 mg every 8 hours, typically starting at 100 mg Oral slow-release: 360 mg every 12 hours IV: 2 mg/kg at 25 mg/minute, followed by 250-mg infusion over 1 hour, 250-mg infusion over next 2 hours, and maintenance infusion of 0.5 mg/minute | 0.5–2 mcg/mL | Nausea, vomiting, tremor, seizures | Oral slow-release and IV forms are not available in the US. | |
Class Ic Uses: APB and VPB suppression, SVT and VT suppression, AF or atrial flutter, and VF suppression | ||||
Oral: 100 mg every 8 or 12 hours IV: 1–2 mg/kg over 10 minutes | 0.2–1 mcg/mL (0.5–2.4 mcmol/L) | Occasionally, blurred vision and paresthesias | Dose should be decreased or drug stopped if QRS complex widens (> 50% if initially < 120 millisecond and > 25% if initially > 120 millisecond). IV form is not available in US. | |
Oral: Initially, 150 mg 3 times a day, titrated up to 225–300 mg 3 times a day if needed IV: 2-mg/kg bolus, followed by 2 mg/minute infusion | 0.1–1.0 mcg/mL | Beta-blocking activity, possible worsening of reactive airway disorders; occasionally GI upset | Pharmacokinetics are nonlinear; increases in dose should not exceed 50% of previous dose. Bioavailability and protein binding vary; drug has saturable first-pass metabolism. IV form is not available in the US. | |
Class II (beta-blockers) Uses: Supraventricular tachyarrhythmias (APB, ST, SVT, AF, atrial flutter) and ventricular arrhythmias (often in a supportive role) | ||||
Oral: 100–400mg twice a day | Beta-blocker levels not measured; dose adjusted to reduce heart rate by > 25% | Typically for beta-blockers, GI disturbances, insomnia, nightmares, lethargy, erectile dysfunction, possible AV block in patients with AV node dysfunction | Beta-blockers are contraindicated in patients with bronchospastic airway disorders. | |
Oral: 25–100 mg once a day | ||||
Oral: 5–20 mg once a day | ||||
Oral: 2.5–20 mg once a day | ||||
Oral: Initially, 3.125 mg twice a day, followed by titration to 25 mg twice a day | ||||
IV: 50–200 mcg/kg/minute | ||||
Oral: 25–100 mg twice a day IV: 2.5–5 mg every 5 minutes up to 15 mg | ||||
Oral: 10–240 mg once a day | ||||
Oral: 10–40 mg 3 or 4 times a day IV: 1–3 mg (may repeat once after 5 minutes if needed) | ||||
Oral:10–30 mg twice a day | ||||
Class III (membrane-stabilizing drugs) Uses: Any tachyarrhythmia except torsades de pointes VT | ||||
1–2.5 mcg/mL (1.5–-3.9 mcmol/L) | Pulmonary toxicity, including acute or subacute pneumonitis, which may progress to pulmonary fibrosis (in up to 5% of patients treated for > 5 years), which may be fatal; QTc prolongation; torsades de pointes VT (rare); bradycardia; gray or blue discoloration of sun-exposed skin; sun sensitivity; hepatic abnormalities; peripheral neuropathy; corneal microdeposits (in almost all treated patients), usually without serious visual effects and reversed by stopping the drug; increase or decrease in thyroid function; serum creatinine increased up to 10% without change in GFR; slow clearance possibly prolonging adverse effects | Drug has noncompetitive beta-blocking, calcium channel blocking, and sodium channel blocking effects, with a long delay in onset of action. Although drug prolongs refractoriness, it does so more homogeneously than other QT prolonging drugs, so torsades de pointe VT is less common IV form can be used for conversion. | ||
Azimilide* | Oral: 100–200 mg once a day | 200–1000 ng/mL | Torsades de pointes VT | — |
IV: Initially, 5 mg/kg, followed by 1–2 mg/minute as a constant infusion IM: Initially, 5–10 mg/kg, which may be repeated to a total dose of 30 mg/kg IM maintenance dose of 5 mg/kg every 6–8 hours | 0.8–2.4 mcg/mL | Hypotension | Drug has class II properties. Effects may be delayed 10–20 minutes. Drug is used to treat potentially lethal refractory ventricular tachyarrhythmias (intractable VT, recurrent VF), for which it is usually effective within 30 minutes of injection. | |
Oral: 500 mcg twice a day if creatinine clearance (CrCl) is > 60 mL/minute; 250 mcg twice a day if CrCl is 40–60 mL/minute; 125 mcg twice a day if CrCl is 20–40 mL/minute | N/A | Torsades de pointes VT | Drug is contraindicated if QTc is > 440 millisecond or if CrCl is < 20 mL/minute. | |
Oral: 400 mg twice a day | N/A | QTc prolongation, torsades de pointes VT (rare), bradycardia, GI upset, possible hepatotoxicity (rare), serum creatinine increased up to 20% without change in GFR | Drug should not be used in patients with history of heart failure or with permanent AF. | |
IV: For patients ≥ 60 kg, 1 mg infusion or, for patients < 60 kg, 0.01 mg/kg over 10 minutes, with dose repeated after 10 minutes if the first infusion is unsuccessful | N/A | Torsades de pointes VT (in 2%) | Drug is used to terminate AF (success rate, about 40%) and atrial flutter (success rate, about 65%). | |
Oral: 80–160 mg every 12 hours IV: 10 mg over 1–2 minutes | 0.5–4 mcg/mL | Similar to class II; possible depressed left ventricular function and torsades de pointes VT | Drug should not be used in patients with renal insufficiency. | |
Vernakalant | 3 mg/kg IV over 10 minutes (maximum 339 mg) If conversion to sinus rhythm does not occur, follow up with 2nd infusion of 2 mg/kg over 10 minutes (maximum 226 mg) | N/A | Hypotension (especially in patients with heart failure) Bradyarrhythmias (especially with concomitant beta-blockade) | Drug is used to terminate recent-onset AF (success rate about 50%). Drug is not available in the United States. |
Class IV (Calcium channel blockers) Uses: Termination of SVT and slowing of rapid AF or atrial flutter | ||||
IV: 5–15 mg/hour for up to 24 hours | 0.1–0.4 mcg/mL (0.24–-1 mcmol/L) | Possible precipitation of VF in patients with VT, negative inotropy | IV form is most commonly used to slow ventricular response rate to AF or atrial flutter. | |
Oral: 40–120 mg 3 times a day or, for sustained-release form, 180 mg once a day to 240 mg twice a day IV: 5–15 mg over 10 minutes Oral prophylaxis: 40–120 mg 3 times a day | N/A | Possible precipitation of VF in patients with VT, negative inotropy | IV form is used to terminate narrow-complex tachycardias involving the AV node (success rate, almost 100% with 5–10 mg IV over 10 minutes). | |
Other antiarrhythmics | ||||
6 mg rapid IV bolus, repeated twice at 12 mg if needed; flush bolus with additional 20 mL saline | N/A | Transient dyspnea, chest discomfort, and flushing (in 30–60%), transient bronchospasm | Drug slows or blocks AV nodal conduction. Duration of action is extremely short. Contraindications include asthma and high-grade heart block. | |
IV loading dose: 0.5 mg Oral maintenance dose: 0.125–0.25 mg once a day | 0.8–1.6 mcg/mL (1–-2 mcmol/L) | Anorexia, nausea, vomiting, and often serious arrhythmias (VPBs, VT, APBs, atrial tachycardia, 2nd-degree or 3rd-degree AV block, combinations of these arrhythmias) | ||
* Availability uncertain. | ||||
AF = atrial fibrillation; ANA = antinuclear antibody; APB = atrial premature beat; AV = atrioventricular; CrCl = creatinine clearance; GFR = glomerular filtration rate; GI = gastrointestinal; LV = left ventricular; QTc = QT interval corrected for heart rate; SVT = supraventricular tachycardia; VF = ventricular fibrillation; VPB = ventricular premature beat; VT = ventricular tachycardia. | ||||
Antiarrhythmic drug reference
1. Lei M, Wu L, Terrar DA, Huang CLH: Modernized classification of cardiac antiarrhythmic drugs. Circulation 138(17):1879–1896, 2018. doi: 10.1161/CIRCULATIONAHA.118.035455
Class I Antiarrhythmic Drugs
Class I antiarrhythmic drugs are
Sodium channel blockers (membrane-stabilizing drugs), which block fast sodium channels, slowing conduction in fast-channel tissues (working atrial and ventricular myocytes, His-Purkinje system)
In the electrocardiogram (ECG), this effect may be reflected as widening of the P wave, widening of the QRS complex, prolongation of the PR interval, or a combination.
Class I drugs are subdivided based on the kinetics of the sodium channel effects:
Class Ib drugs have fast kinetics.
Class Ic drugs have slow kinetics.
Class Ia drugs have intermediate kinetics.
The kinetics of sodium channel blockade determine the heart rates at which their electrophysiologic effects become manifest. Because class Ib drugs have fast kinetics, they express their electrophysiologic effects only at fast heart rates. Thus, an ECG obtained during normal rhythm at normal rates usually shows no evidence of fast-channel tissue conduction slowing. Class Ib drugs are not very potent antiarrhythmics and have minimal effects on atrial tissue.
Class Ic drugs have slow kinetics, so they express their electrophysiologic effects at all heart rates. Thus, an ECG obtained during normal rhythm at normal heart rates usually shows fast-channel tissue conduction slowing. Class Ic drugs are more potent antiarrhythmics.
Class Ia drugs have intermediate kinetics, so their fast-channel tissue conduction slowing effects may or may not be evident on an ECG obtained during normal rhythm at normal rates. Class Ia drugs also block repolarizing potassium channels, prolonging the refractory periods of fast-channel tissues. On the ECG, this effect is reflected as QT-interval prolongation even at normal rates. Class Ib drugs and class Ic drugs do not block potassium channels directly.
The primary indications for all class I drugs are ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation) and for class Ia and Ic drugs, supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardias).
Adverse effects of class I drugs include proarrhythmia, a drug-related arrhythmia worse than the arrhythmia being treated, which is the most worrisome adverse effect. All class I drugs may worsen VTs. Class I drugs also tend to depress ventricular contractility. Because these adverse effects are more likely to occur in patients with a structural heart disorder, class I drugs are usually used only in patients who do not have a structural heart disorder or in patients who have a structural heart disorder but who have no other therapeutic alternatives. There are other adverse effects of class I drugs that are specific to the subclass or individual drug.
Class Ia antiarrhythmic drugs
Class Ia drugs have kinetics that are intermediate between the fast kinetics of class Ib and the slow kinetics of class Ic. Their fast-channel tissue conduction slowing effects may or may not be evident on an ECG obtained during normal rhythm at normal rates. Class Ia drugs block repolarizing potassium channels, prolonging the refractory periods of fast-channel tissues. On the ECG, this effect is reflected as QT-interval prolongation even at normal rates.
The primary indications for class Ia drugs are
Supraventricular tachyarrhythmias (atrial fibrillation, atrial flutter, atrial tachycardia)
Ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation)
Class Ia drugs also are used for suppression of atrial or ventricular premature beats.
Class Ia drugs may cause torsades de pointes ventricular tachycardia. Class Ia drugs may organize and slow atrial tachyarrhythmias enough to permit 1:1 AV conduction with marked acceleration of the ventricular response rate.
Class Ib antiarrhythmic drugs
Class Ib drugs have fast kinetics; they express their electrophysiologic effects only at fast heart rates. Thus, an ECG obtained during normal rhythm at normal rates usually shows no evidence of fast-channel tissue conduction slowing. Class Ib drugs are not very potent antiarrhythmics and have minimal effects on atrial tissue. Class Ib drugs do not block potassium channels directly.
Class Ib drugs are used for the suppression of ventricular tachyarrhythmias (ventricular tachycardia, ventricular fibrillation) and ventricular premature beats.
Class Ic antiarrhythmic drugs
Class Ic drugs have slow kinetics; they express their electrophysiologic effects at all heart rates. Thus, an ECG obtained during normal rhythm at normal heart rates usually shows fast-channel tissue conduction slowing. Class Ic drugs are more potent antiarrhythmics than either class Ia or class Ib drugs. Class Ic drugs do not block potassium channels directly.
Class Ic drugs may organize and slow atrial tachyarrhythmias enough to permit 1:1 AV conduction with marked acceleration of the ventricular response rate.
Class Ic drugs are used for suppression of
Class II Antiarrhythmic Drugs
Class II antiarrhythmic drugs are the
Beta-blockers
Beta-blockers affect predominantly slow-channel tissues (sinoatrial and atrioventricular nodes), where they decrease rate of automaticity, slow conduction velocity, and prolong refractoriness. Thus, heart rate is slowed, the PR interval is lengthened, and the AV node transmits rapid atrial depolarizations at a lower frequency.
Class II drugs are used primarily to treat supraventricular tachycardias, including sinus tachycardia, and to slow the ventricular response rates to atrial fibrillation or atrial flutter. These drugs are also used to treat ventricular tachycardia to raise the threshold for ventricular fibrillation and reduce the ventricular proarrhythmic effects of beta-adrenoceptor stimulation.
Beta-blockers are generally well tolerated; adverse effects include lassitude, sleep disturbance, and gastrointestinal upset. These drugs are contraindicated in patients with asthma.
Class III Antiarrhythmic Drugs
Class III drugs are
Membrane-stabilizing drugs, primarily potassium channel blockers
Class III drugs prolong action potential duration and refractoriness in slow- and fast-channel tissues. Thus, the capacity of all cardiac tissues to transmit impulses at high frequencies is reduced, but conduction velocity is not significantly affected. Because the action potential is prolonged, rate of automaticity is reduced. The predominant effect on the ECG is QT-interval prolongation.
These drugs are used to treat supraventricular and ventricular tachyarrhythmias. Class III drugs have a risk of ventricular proarrhythmia, particularly torsades de pointes VT, and are not used in patients with torsades de pointes VT.
Class IV Antiarrhythmic Drugs
Class IV drugs are
Nondihydropyridine calcium channel blockers
These drugs depress calcium-dependent action potentials in slow-channel tissues and thus decrease the rate of automaticity, slow conduction velocity, and prolong refractoriness. Heart rate is slowed, the PR interval is lengthened, and the AV node transmits rapid atrial depolarizations at a lower frequency. These drugs are used primarily to treat supraventricular tachycardias. They may also be used to slow the ventricular response rate to atrial fibrillation or atrial flutter
