Group III antiarrhythmics

Generic and Brand Names

• Amiodarone — Cordarone, Pacerone

• Dronedarone — Multaq

• Sotalol — Betapace, Sorine

• Ibutilide — Corvert

• Dofetilide — Tikosyn

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Class

• Vaughan Williams Class III antiarrhythmics

• Primary action: Potassium channel blockade → prolongation of repolarization and refractory period

• Many agents also have additional actions from other classes (multi-channel effects)

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Mechanism of Action

• Block potassium efflux during phase 3 of cardiac action potential → prolong action potential duration and refractory period in atrial and ventricular myocardium

• Slow heart rate and conduction in the AV node (varies by agent)

• Additional actions:

  • Amiodarone: Also blocks sodium channels (Class I), beta-adrenergic receptors (Class II), and calcium channels (Class IV)

  • Sotalol: Non-selective beta-blocker activity (Class II) plus potassium channel block

  • Dronedarone: Similar to amiodarone but without iodine moiety (less thyroid/lung toxicity, less potent)

  • Ibutilide: Also promotes slow inward sodium current during repolarization

  • Dofetilide: Pure potassium channel blocker (IKr inhibition)

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Indications

• Amiodarone:

  • Ventricular arrhythmias (life-threatening)

  • Atrial fibrillation/flutter (conversion and maintenance of sinus rhythm)

  • Supraventricular tachycardia (off-label)

• Dronedarone:

  • Maintenance of sinus rhythm in paroxysmal/persistent AF in patients without severe heart failure

• Sotalol:

  • Ventricular arrhythmias

  • Maintenance of sinus rhythm in AF/flutter

• Ibutilide:

  • Acute conversion of AF/flutter to sinus rhythm

• Dofetilide:

  • Conversion and maintenance of sinus rhythm in AF/flutter

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Dosage and Administration

• Amiodarone:

  • IV: Loading 150 mg over 10 min, then infusion (1 mg/min for 6 h, then 0.5 mg/min)

  • Oral: Loading total ~10 g over 1–2 weeks, then maintenance 100–400 mg daily

• Dronedarone: 400 mg orally twice daily with meals

• Sotalol: 80–160 mg orally twice daily; adjust for renal function

• Ibutilide: IV 1 mg over 10 min; may repeat once after 10 min if arrhythmia persists

• Dofetilide: Dose individualized based on renal function and QT interval; hospitalization required for initiation

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Monitoring

• ECG: QT interval, QRS duration, heart rate

• Blood pressure

• Renal function (sotalol, dofetilide)

• Electrolytes (K⁺, Mg²⁺) before and during therapy

• Amiodarone: Baseline and periodic thyroid, liver, lung function tests, eye exams

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Contraindications

• Marked bradycardia, AV block without pacemaker

• Prolonged QT interval or history of torsades de pointes

• Cardiogenic shock

• Severe asthma (sotalol)

• Severe hepatic impairment (amiodarone, dronedarone)

• Severe renal impairment (sotalol, dofetilide)

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Precautions

• Risk of torsades de pointes (all agents, esp. ibutilide, dofetilide, sotalol)

• Correct electrolyte disturbances before initiation

• Amiodarone: Long half-life (up to 60 days); multiple organ toxicities possible

• Dronedarone: Avoid in permanent AF and in NYHA class III–IV heart failure (increased mortality)

• Sotalol: Requires inpatient initiation in high-risk patients; renal dosing essential

• Dofetilide: Hospital initiation with continuous ECG for at least 3 days

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Adverse Effects

Common to Class III

• Bradycardia, hypotension, QT prolongation, risk of torsades de pointes

Amiodarone-specific

• Pulmonary fibrosis, thyroid dysfunction (hypo/hyperthyroidism), hepatotoxicity, corneal deposits, skin photosensitivity/blue-grey discoloration, neuropathy

Dronedarone-specific

• GI upset, increased creatinine, rash; lower risk of thyroid/pulmonary toxicity than amiodarone

Sotalol-specific

• Beta-blocker effects (fatigue, bronchospasm, depression)

Ibutilide-specific

• High torsades risk within first hours post-infusion

Dofetilide-specific

• High torsades risk during initiation; dizziness, headache

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Drug Interactions

• Other QT-prolonging drugs: Additive torsades risk (macrolides, fluoroquinolones, certain antipsychotics)

• Amiodarone: Potent CYP inhibitor — increases levels of warfarin, digoxin, statins, cyclosporine, phenytoin

• Sotalol: Additive bradycardia with beta-blockers, non-DHP calcium channel blockers

• Dofetilide: Contraindicated with verapamil, cimetidine, HCTZ, trimethoprim (increased dofetilide levels)

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Overdose

• Manifestations: Severe bradycardia, hypotension, ventricular arrhythmias, cardiac arrest

• Management: Supportive care, temporary pacing, vasopressors; magnesium for torsades; lipid emulsion therapy in severe amiodarone toxicity (case reports)

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Patient Counselling

• Report symptoms of bradycardia, dizziness, fainting, SOB

• Avoid grapefruit juice (amiodarone, dronedarone)

• Amiodarone: Avoid excessive sun exposure; inform about potential long-term toxicities and need for regular monitoring

• Sotalol/dofetilide: Stress importance of adherence and hospital monitoring during initiation

• Ibutilide: Explain hospital monitoring requirement for several hours after infusion

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Comparison Table — Class III Antiarrhythmics

Feature	Amiodarone	Dronedarone	Sotalol	Ibutilide	Dofetilide
Primary Use	Broad-spectrum arrhythmias (AF, VT, VF)	Maintenance of sinus rhythm in AF/flutter	VT, maintenance in AF/flutter	Acute AF/flutter conversion	AF/flutter conversion & maintenance
Onset (Oral)	Slow (days–weeks)	Moderate	Moderate	Immediate (IV)	Moderate
Half-life	Very long (up to 60 days)	~24 hours	12 hours	6 hours	10 hours
Torsades Risk	Low–moderate	Moderate	High	High	High
Organ Toxicities	Pulmonary, thyroid, liver, eye, skin	GI, renal creatinine ↑	Beta-blocker side effects	Acute arrhythmia risk	Acute arrhythmia risk
Initiation Setting	Outpatient (with caution)	Outpatient	Often inpatient	Inpatient	Inpatient mandatory
Extra Actions	Na⁺ block, β-block, Ca²⁺ block	Na⁺, β-block, Ca²⁺ mild	β-block	Na⁺ slow inward current	Pure K⁺ block