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Drugs for Arrhythmias

By L. Brent Mitchell, MD, Libin Cardiovascular Institute of Alberta

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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), 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.

Digoxin and adenosine are not included in the Vaughan Williams classification. Digoxin shortens atrial and ventricular refractory periods and is vagotonic, thereby prolonging AV nodal conduction and AV nodal refractory periods. Adenosine slows or blocks AV nodal conduction and can terminate tachyarrhythmias that rely upon AV nodal conduction for their perpetuation.

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

Disopyramide

IV: Initially, 1.5 mg/kg over > 5 min followed by an infusion of 0.4 mg/kg/h

Oral immediate-release: 100 or 150 mg q 6 h

Oral controlled-release: 200 or 300 mg q 12 h

2–7.5 μg/mL

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.

If QRS interval widens (> 50% if initially < 120 msec or > 25% if initially > 120 msec) or if QTc interval is prolonged > 550 msec, infusion rate or dosage should be decreased or drug stopped.

IV form is not available in the US.

Procainamide*

IV: 10–15 mg/kg bolus at 25–50 mg/min, followed by a constant IV infusion of 1–4 mg/min

Oral: 250–625 mg (rarely, up to 1 g) q 3 or 4 h

Oral controlled-release: For patients < 55 kg, 500 mg; for patients 55–91 kg, 750 mg; or for patients > 91 kg, 1000 mg q 6 h

4–8 µg/mL

Hypotension (with IV infusion), serologic abnormalities (especially ANA) in almost 100% taking drug for > 12 mo, 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.

If QRS interval widens (> 50% if initially < 120 msec or > 25% if initially >120 msec) or if QTc interval is prolonged > 550 msec, infusion rate or dosage should be decreased or drug stopped.

Quinidine*

Oral: 200–400 mg q 4–6 h

2–6 μg/mL

Diarrhea, colic, flatulence, fever, thrombocytopenia, liver function abnormalities, torsades de pointes VT; overall adverse effect rate of 30%

If QRS interval widens (> 50% if initially < 120 msec or > 25% if initially > 120 msec) or if QTc interval is prolonged > 550 msec, dosage should be decreased or drug stopped.

Class Ib

Uses: Suppression of ventricular arrhythmias (VPB, VT, VF)

Lidocaine

IV: 100 mg over 2 min, followed by continuous infusion of 4 mg/min (2 mg/min in patients > 65) and 5 min after first dose, a 2nd 50-mg bolus

2–5 μg/L

Tremor, seizures; if administration is too rapid, drowsiness, delirium, paresthesias; possibly increased risk of bradyarrhythmias after acute MI

To reduce toxicity risk, clinicians should reduce dosage or infusion rate to 2 mg/min after 24 h.

Extensive first-pass hepatic metabolism occurs.

Mexiletine

Oral immediate-release: 100–250 mg q 8 h

Oral slow-release: 360 mg q 12 h

IV: 2 mg/kg at 25 mg/min, followed by 250-mg infusion over 1 h, 250-mg infusion over next 2 h, and maintenance infusion of 0.5 mg/min

0.5–2 μg/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

Flecainide

Oral: 100 mg q 8 or 12 h

IV: 1–2 mg/kg over 10 min

0.2–1 μg/mL

Occasionally, blurred vision and paresthesias

If QRS complex widens (> 50% if initially < 120 msec and > 25% if initially > 120 msec), dose must be decreased or drug stopped.

IV form is not available in US.

Propafenone

Oral: Initially, 150 mg tid, titrated up to 150–300 mg tid

IV: 2-mg/kg bolus, followed by 2 mg/min infusion

0.1–1.0 μg/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)

Acebutolol

Oral: 200 mg bid

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.

Atenolol

Oral: 50–100 mg once/day

Betaxolol

Oral: 20 mg once/day

Bisoprolol

Oral: 5–10 mg once/day

Carvedilol

Oral: Initially, 6.25 mg bid, followed by titration to 25 mg bid

Esmolol

IV: 50–200 μg/kg/min

Metoprolol

Oral: 50–100 mg bid

IV: 5 mg q 5 min up to 15 mg

Nadolol

Oral: 60–80 mg once/day

Propranolol

Oral: 10–30 mg tid or qid

IV: 1–3 mg (may repeat once after 5 min if needed)

Timolol

Oral:10–20 mg bid

Class III (membrane-stabilizing drugs)

Uses: Any tachyarrhythmia except torsades de pointes VT

Amiodarone

Oral: 600–1200 mg/day for 7–10 days, then 400 mg/day for 3 wk, followed by a maintenance dose (ideally, 200 mg/day)

IV: 150–450 mg over 1–6 h (depending on urgency), followed by a maintenance dose of 0.5–2.0 mg/min

1–2.5 μg/mL

Pulmonary fibrosis (in up to 5% of patients treated for > 5 yr), 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; changes 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.

By prolonging refractoriness, drug may cause homogeneous conditions of repolarization throughout the heart.

IV form can be used for conversion.

Azimilide*

Oral: 100–200 mg once/day

200–1000 ng/mL

Torsades de pointes VT

Bretylium*

IV: Initially, 5 mg/kg, followed by 1–2 mg/min 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 q 6–8 h

0.8–2.4 μg/mL

Hypotension

Drug has class II properties.

Effects may be delayed 10–20 min.

Drug is used to treat potentially lethal refractory ventricular tachyarrhythmias (intractable VT, recurrent VF), for which it is usually effective within 30 min of injection.

Dofetilide

Oral: 500 mcg bid if CrCl is > 60 mL/min; 250 mcg bid if CrCl is 40–60 mL/min; 125 mcg bid if CrCl is 20–40 mL/min

N/A

Torsades de pointes VT

Drug is contraindicated if QTc is > 440 msec or if CrCl is < 20 mL/min.

Dronedarone

Oral: 400 mg bid

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 is a modified amiodarone molecule (including deiodination) with shorter half-life, smaller volume of distribution, fewer adverse effects, and less efficacy.

Drug should not be used in patients with history of heart failure or with permanent AF.

Ibutilide

IV: For patients 60 kg, 1 mg infusion or, for patients < 60 kg, 0.01 mg/kg over 10 min, with dose repeated after 10 min 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%).

Sotalol

Oral: 80–160 mg q 12 h

IV: 10 mg over 1–2 min

0.5–4 μg/mL

Similar to class II; possible depressed left ventricular function and torsades de pointes VT

Racemic [d-l] form has class II (beta-blocking) properties, [d] form does not. Both forms have class III activity. Only racemic sotalol is available for clinical use.

Drug should not be used in patients with renal insufficiency.

Class IV (Calcium channel blockers)

Uses: Termination of SVT and slowing of rapid AF or atrial flutter

Diltiazem

Oral slow-release (diltiazem CD): 120–360 mg once/day

IV: 5–15 mg/h for up to 24 h

0.1–0.4 μg/mL

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.

Verapamil

Oral: 40–120 mg tid or, for sustained-release form, 180 mg once/day to 240 mg bid

IV: 5–15 mg over 10 min

Oral prophylaxis: 40–120 mg tid

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 min).

Other antiarrhythmics

Adenosine

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.

Dipyridamole potentiates effects.

Digoxin

IV loading dose: 0.5 mg

Oral maintenance dose: 0.125–0.25 mg/day

0.8–1.6 μg/mL

Anorexia, nausea, vomiting, and often serious arrhythmias (VPBs, VT, APBs, atrial tachycardia, 2nd-degree or 3rd-degree AV block, combinations of these arrhythmias)

Contraindications include antegrade conduction over an accessory AV connection pathway (manifest Wolff-Parkinson-White syndrome) because if AF occurs, ventricular responses may be excessive (digoxin shortens refractory periods of the accessory connection).

*Availability uncertain.

AF = atrial fibrillation; ANA = antinuclear antibody; APB = atrial premature beat; AV = atrioventricular; CrCl =creatinine clearance; LV = left ventricular; QTc = QT interval corrected for heart rate; SVT = supraventricular tachycardia; VF = ventricular fibrillation; VPB = ventricular premature beat; VT = ventricular tachycardia.

Class I Antiarrhythmic Drugs

Sodium channel blockers (membrane-stabilizing drugs) block fast sodium channels, slowing conduction in fast-channel tissues (working atrial and ventricular myocytes, His-Purkinje system). In the 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. Because 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. Because class Ia drugs have intermediate kinetics, 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 kinetics of sodium channel blockade determine the heart rates at which their electrophysiologic effects become manifest.

The primary indications are supraventricular tachycardia (SVT) for class Ia and Ic drugs and ventricular tachycardia (VTs) for all class I drugs.

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 not generally recommended for such patients. Thus, these 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.

Class Ia drugs are used for suppression of atrial premature beats (APB), ventricular premature beats (VPB), supraventricular and ventricular tachycardias, atrial fibrillation (AF), atrial flutter, and ventricular fibrillation. The primary indications are supraventricular and ventricular tachycardias.

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 arrhythmias (ventricular premature beats, ventricular tachycardia,ventricular fibrillation).

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 atrial and ventricular premature beats, supraventricular and ventricular tachycardias, atrial fibrillation, atrial flutter, and ventricular fibrillation.

Class II Antiarrhythmic Drugs

Class II antiarrhythmic drugs are beta-blockers, which affect predominantly slow-channel tissues (SA and AV 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 SVTs, including sinus tachycardia, AV nodal reentry, AF, and atrial flutter. These drugs are also used to treat VTs to raise the threshold for ventricular fibrillation (VF) and reduce the ventricular proarrhythmic effects of beta-adrenoceptor stimulation.

Beta-blockers are generally well tolerated; adverse effects include lassitude, sleep disturbance, and GI upset. These drugs are contraindicated in patients with asthma.

Class III Antiarrhythmic Drugs

Class III drugs are membrane stabilizing drugs, primarily potassium channel blockers, which 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 SVTs and VTs. 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 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. 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 SVTs. They may also be used to slow rapid atrial fibrillation or atrial flutter. One form of VT (left septal or Belhassen VT) can be treated with verapamil.

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* This is the Professional Version. *