Class 3 Antiarrhythmic Drugs

Class 3 antiarrhythmics are drugs that block cardiac tissue K channels. The medications in this class include amiodarone, dronedarone, sotalol, ibutilide, dofetilide, and bretylium. The main mechanism of action includes blocking the cardiac K channels to prolong repolarization. However, some medications in this class also exert effects on Na channels, calcium channels, and adrenergic receptors. Indications vary among the medications, but include both atrial and ventricular arrhythmias. Because these medications prolong the QT interval, torsades de pointes is a potential complication of therapy.

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Overview

Cardiac action potential

  • The trajectory followed by the action potential will depend on the membrane potential of the cardiac cells, which varies between different parts of the heart.
  • Phase 4: resting potential
  • Phase 0: rapid depolarization phase that occurs because of the influx of Na through voltage-dependent Na channels
  • Phases 1–3:
    • Represents repolarization
    • Prominent efflux of K
    • Phase 2: efflux of K is balanced by the transient influx of calcium (Ca) → causes the action potential to plateau
The cardiac action potential

The cardiac action potential

Image: “Action Potential Heart Contraction, Illustration from Anatomy & Physiology” by OpenStax College. License: CC BY 3.0, cropped by Lecturio.

Vaughan-Williams classification

  • Most commonly used classification for antiarrhythmic drugs
  • 5 classes based on the general effect (mechanism of action) of the drug class:
    • Class 1: Na channel blockers (divided into 3 subgroups):
      • 1A: prolong the action potential
      • 1B: shorten the action potential
      • 1C: minimal effect on action potential duration
    • Class 2: beta blockers
    • Class 3: K channel blockers
    • Class 4: Ca channel blockers
    • Class 5: agents that cannot be categorized into the above groups
cardiac action potential 1 Antiarrhythmic drugs

Diagram demonstrating a cardiac action potential and the phases of action for different antiarrhythmic drug classes:
The cycle starts with phase 4, the resting potential. Phase 0 is when rapid depolarization happens due to an influx of sodium ions into the cell. Repolarization follows, with an efflux of potassium through fast potassium channels in phase 1, calcium influx in phase 2, and efflux of potassium through delayed potassium channels in phase 3. Potassium channel blockers typically affect phase 3.

Image by Lecturio. License: CC BY-NC-SA 4.0

General mechanism of action

  • Normal physiology:
    • Primary role of K is repolarization
    • Cardiac K channels open → efflux of K → repolarize the cell
  • K channel blockers: 
    • Bind to K channels → block K movement
    • This prevents the efflux of K → prolong repolarization (phase 3)
    • Results in ↑ action potential duration (APD) and ↑ effective refractory period (ERP)
    • Electroconvulsive therapy effect: ↑ QT interval
Image representing the action of 3 antiarrhythmics on phase 3 of the action potential

Image representing the action of class 3 antiarrhythmics on phase 3 of the action potential:
By blocking the potassium channels, phase 3 is prolonged, leading to an increase in the effective refractory period (ERP).

Image by Lecturio.

Medications within this drug class

Class 3 antiarrhythmics include a variety of medications that vary in K channel selectivity and other antiarrhythmic effects:

  • Amiodarone
  • Dronedarone 
  • Sotalol 
  • Ibutilide 
  • Dofetilide 
  • Bretylium 

Amiodarone

Mechanism of action

  • Multifactorial mechanism affecting:
    • K channels (class 3 effect) 
    • Na channels (class 1 effect)
    • Alpha- and beta-adrenergic receptors (class 2 effect)
    • Ca channels (class 4 effect)
  • Blocks rapid delayed rectifier channels (IKr) on:
    • Atrial tissue
    • Ventricular tissue
  • In addition to the typical effects of K blockers: 
    • ↓ Atrioventricular (AV) conduction 
    • ↓ Sinus node rate 
  • ECG:
    • ↑ PR interval
    • Slight QRS complex widening
    • ↑ QT interval

Pharmacokinetics

  • Absorption:
    • Oral: slow
    • IV: onset of action is quicker
  • Distribution:
    • Lipophilic:
      • ↑ Volume of distribution
      • Slow to reach the intended serum concentration → long loading period
    • Distributes to a wide range of tissues
    • Protein binding: > 96%
  • Metabolism:
    • Hepatic metabolism via CYP2C8 and 3A4
    • Active metabolite
    • Note: amiodarone is an inhibitor of CYP3A4: → ↑ concentration of drugs metabolized by CYP3A4
  • Excretion: 
    • Urine
    • Bile → feces 
    • Enterohepatic recirculation (drug excreted in bile reabsorbed in the intestines)

Indications

  • Pharmacologic cardioversion and maintenance of sinus rhythm in atrial fibrillation
  • Rate control in critically ill individuals with hemodynamic compromise and atrial fibrillation or atrial flutter 
  • Other supraventricular tachycardia (SVT):
    • AV nodal reentrant tachycardia
    • AV reentrant tachycardia
    • Focal atrial tachycardia
  • Ventricular arrhythmias: 
    • Ventricular fibrillation
    • Ventricular tachycardia

Adverse effects

Adverse effects of amiodarone are seen mainly in long-term oral therapy (rather than short-term IV therapy).

Cardiovascular effects:

  • Bradycardia 
  • Atrioventricular block 
  • Sinoatrial arrest 
  • Prolonged QT and torsades de pointes (less common than other class 3 medications)
  • Hypotension:
    • Most commonly seen with IV administration
    • Related to rate of medication administration

Pulmonary toxicity:

  • Pulmonary fibrosis 
  • Eosinophilic pneumonia
  • Bronchiolitis obliterans organizing pneumonia (BOOP)
  • Alveolar hemorrhage
  • ARDS

Thyroid dysfunction: 

  • Hyperthyroidism
  • Hypothyroidism

Hepatotoxicity:

  • ↑ Transaminases
  • Hepatitis
  • Cirrhosis 
  • Intrahepatic cholestasis

Neurologic toxicity: 

  • Peripheral neuropathy and paresthesias
  • Tremor
  • Ataxia

Ocular effects:

  • Corneal microdeposits 
  • Optic neuropathy

Cutaneous reactions: 

  • Photosensitivity
  • “Blue man syndrome” (blue-gray discoloration of the skin)

Contraindications

  • Hypersensitivity to iodine 
  • Sick sinus syndrome 
  • 2nd- or 3rd-degree AV block 
  • Cardiogenic shock 
  • Wolff-Parkinson-White (WPW) syndrome

Drug interactions

  • QT prolongation:
    • QT-prolonging antiarrhythmics
    • Azithromycin and erythromycin
    • Domperidone
    • Antipsychotics (e.g., haloperidol, clozapine)
    • Citalopram
    • Ondansetron
  • ↑ Concentration of (due to interference with hepatic metabolism):
    • Statins → ↑ of rhabdomyolysis
    • Digoxin → ↑ risk of digoxin toxicity
    • Warfarin → ↑ of supratherapeutic INR
  • ↑ Bradycardia effect: 
    • Beta blockers
    • Calcium channel blockers

Dronedarone

Mechanism of action

  • Similar to amiodarone in structure (except it lacks iodine) and mechanism 
  • Multifactorial mechanism affecting:
    • K channels (class 3 effect) 
    • Na channels (class 1 effect)
    • Alpha- and beta-adrenergic receptors (class 2 effect)
    • Ca channels (class 4 effect)

Pharmacokinetics

  • Absorption: well absorbed orally  
  • Distribution: 
    • Less lipophilic than amiodarone
    • Highly protein-bound
  • Metabolism: 
    • Extensive 1st-pass metabolism
    • Hepatic metabolism via CYP3A4
    • Active metabolite 
  • Excretion: 
    • Feces
    • Urine

Indications

  • Maintenance of sinus rhythm in individuals with:
    • Paroxysmal atrial fibrillation
    • Persistent atrial fibrillation
  • Ineffective for pharmacologic cardioversion
  • Note: Unlike amiodarone, dronedarone is not used to treat ventricular tachyarrhythmias.

Adverse effects

  • Cardiovascular:
    • Prolonged QT interval
    • Bradycardia
  • Renal: ↑ serum creatinine 
  • GI:
    • Diarrhea
    • Nausea and vomiting
    • Abdominal pain
    • Dyspepsia
  • Neurologic: weakness
  • It is believed that dronedarone is less likely than amiodarone to cause:
    • Thyroid dysfunction
    • Hepatotoxicity
    • Pulmonary toxicity

Contraindications

  • Permanent atrial fibrillation
  • Symptomatic or severe heart failure (associated with ↑ mortality)
  • 2nd- or 3rd-degree heart block
  • Sick sinus syndrome
  • Concurrent QT-prolonging agents
  • Severe hepatic impairment
  • Previous amiodarone toxicity
  • Pregnancy and breastfeeding

Drug interactions

  • ↑ QT prolongation: 
    • Other QT-prolonging antiarrhythmics
    • Tricyclic antidepressants
    • Macrolide antibiotics
  • ↑ Serum concentration of:
    • Statins
    • Digoxin
    • Warfarin (milder than amiodarone)

Sotalol

Mechanism of action

  • Racemic mixture of d- and l-isomers
  • Dual mechanism:
    • Beta blocker (only from the l-isomer): 
      • Not cardioselective
      • No membrane-stabilizing or intrinsic sympathomimetic activity
    • IKr blocker:
      • Prolongation of both atrial and ventricular action potentials
      • Effective refractory prolongation of atrial, ventricular, and atrioventricular accessory pathways 
  • Affects tissue in:
    • Atria
    • Ventricles
    • AV node
    • Antegrade and retrograde bypass tracts (if present)
  • ECG effects:
    • ↑ QT interval (HR-rate dependent): longer with slower HRs
    • Slight ↑ PR interval

Pharmacokinetics

  • Absorption:
    • Well absorbed orally 
    • ↓ Absorption with food
  • Distribution: 
    • Hydrophilic
    • Not protein-bound
  • Metabolism: none
  • Excretion: urine

Indications

  • Atrial arrhythmias (maintenance of sinus rhythm after cardioversion):
    • Atrial fibrillation
    • Atrial flutter
  • Ventricular arrhythmias

Adverse effects

  • Cardiovascular:
    • Hypotension
    • Bradycardia
    • AV block
    • QT prolongation and torsades de pointes
  • Neurologic:
    • Dizziness
    • Fatigue
    • Asthenia (weakness/lack of energy)
    • Headache
  • Pulmonary: dyspnea
  • GI:
    • Nausea and vomiting 
    • Abdominal pain
    • Diarrhea

Contraindications

  • Sinus bradycardia
  • 2nd- or 3rd-degree AV block
  • Sick sinus syndrome
  • Prolonged QT
  • Decompensated heart failure or cardiogenic shock
  • Hypokalemia
  • Bronchospastic disease
  • Severe renal impairment

Drug interactions

  • QT prolongation:
    • QT-prolonging antiarrhythmics
    • Macrolide antibiotics
    • Citalopram
    • Antipsychotics
    • Methadone
    • Ondansetron
  • ↑  Hypotension: 
    • Antipsychotics
    • Barbiturates
    • Antihypertensives
    • Pentoxifylline
  • ↑ Bradycardia: 
    • Beta blockers
    • Alpha-2 agonists 
    • Rivastigmine
  • ↓ Serum concentration of sotalol: antacids

Ibutilide

Mechanism of action

  • IKr blocker
  • Activates slow inward Na currents
  • Affects: 
    • Atria
    • Ventricles
  • ECG:
    • ↑ QT interval (HR-dependent)
    • No change to PR or QRS

Pharmacokinetics

  • IVAbsorption:
    • Route of administration: IV 
    • Poor oral bioavailability
  • Metabolism:
    • Hepatic
    • 1 active metabolite 
  • Excretion:  
    • Urine (primary) 
    • Feces 

Indications

Ibutilide is used to pharmacologically convert AF or atrial flutter to sinus rhythm.

Adverse effects

  • Prolonged QT interval and torsades de pointes 
  • Monomorphic ventricular tachycardia
  • Supraventricular tachycardia 
  • Headache

Drug interactions

Increased QT prolongation can occur with:

  • QT-prolonging antiarrhythmics
  • Macrolide antibiotics
  • Citalopram
  • Antipsychotics
  • Methadone
  • Ondansetron

Dofetilide

Mechanism of action

  • IKr-selective
  • ECG:
    • ↑ QT interval (HR-dependent)
    • No change to PR or QRS

Pharmacokinetics

  • Absorption:
    • Well absorbed orally
    • Bioavailability: > 90% 
  • Metabolism: 
    • Hepatic metabolism via CYP3A4
    • Inactive metabolites
  • Excretion: urine

Indications

Dofetilide is used for cardioversion and maintenance of sinus rhythm in atrial fibrillation and atrial flutter.

Adverse effects

  • Cardiovascular:
    • Prolonged QT interval and torsades de pointes 
    • Ventricular fibrillation and/or tachycardia
    • Bradycardia 
  • CNS:
    • Dizziness 
    • Headache
    • Migraine 
    • Insomnia
  • GI:
    • Nausea
    • Abdominal pain
    • Diarrhea

Contraindications

  • Congenital or acquired prolonged QT syndromes
  • Severe renal impairment

Drug interactions

  • Avoid medications that prolong QT interval.
  • Drugs that inhibit CYP3A4 → ↑ serum dofetilide:
    • Ketoconazole
    • Erythromycin
    • Verapamil
    • Metformin

Bretylium

Mechanism of action

  • IKr blocker affecting:
    • Purkinje fibers
    • Ventricular tissue
  • Blocks release of norepinephrine from nerve terminals → ↓ sympathetic activity

Pharmacokinetics

  • Route of administration: 
    • IV
    • IM
  • Distribution: not protein-bound
  • Metabolism: not metabolized
  • Excretion: urine

Indications

Bretylium is used for ventricular arrhythmias:

  • Prophylaxis or treatment
  • Consider if arrhythmia is resistant to conventional therapies

Adverse effects

  • Cardiovascular:
    • Hypotension
    • Bradycardia
    • Dizziness
  • GI:
    • Nausea
    • Vomiting 

Contraindications

  • Digoxin toxicity (digitalis-induced arrhythmia)
  • Renal impairment

Comparison of Antiarrhythmic Drug Classes

The following table compares antiarrhythmic classes 1–4. Class 5 is not included owing to the varied mechanisms of action and effects.

Table: Comparison of antiarrhythmic drug classes 1–4
ClassMechanism of actionEffectsArrhythmia indications
11A
  • Block fast Na channels
  • ↓ Na entry into myocardial cells
  • Affects depolarization
  • ↓ Phase 0 slope
  • ↓ Conduction velocity in nonnodal tissue
  • Atrial and ventricular
  • WPW syndrome
1BVentricular
1CMostly atrial
2
  • Block beta receptors
  • ↓ Ca influx into myocardial cells
  • Affects refractory period
  • ↓ Phase 4 slope
  • ↑ Phase 4 duration
  • ↓ Conduction velocity in nodal and nonnodal tissue
Atrial and ventricular
3
  • Block K channels
  • ↓ K efflux out of myocardial cells
  • Affects repolarization
  • ↑ Phase 3 duration
  • Most ↓ impulse transmission in nonnodal tissue
  • Amiodarone and sotalol also ↓ nodal conduction
Atrial and ventricular
4
  • Block Ca channels
  • ↓ Ca influx into myocardial cells
  • Affects phase 2 in nonnodal tissue
  • ↓ Phase 0 slope in nodal tissue
  • ↓ Conduction velocity in nodal tissue
Atrial

References

  1. Roden, D. M. (2016). Pharmacogenetics of potassium channel blockers. Card Electrophysiol Clin 8:385–393. Retrieved September 23, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893809/
  2. Kumar, K., Zimetbaum, P. J. (2020). Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: clinical trials. UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials
  3. Makielski, J. C., Eckhardt, L. L. L. (2019). Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs. UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs
  4. Giardina, E. G., Passman, R. (2021). Amiodarone: Adverse effects, potential toxicities, and approach to monitoring. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring
  5. Giardina, E. G., Passman, R. (2021). Amiodarone: Clinical uses. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/amiodarone-clinical-uses
  6. Passman, R., Giardina, E. G. (2020). Clinical uses of dronedarone. UpToDate. Retrieved September 21, 2021, from https://www.uptodate.com/contents/clinical-uses-of-dronedarone
  7. Giardin, E. G., Passman, R. (2020). Clinical uses of sotalol. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/clinical-uses-of-sotalol
  8. Giardina, E.G. (2020). Therapeutic use of ibutilide. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/therapeutic-use-of-ibutilide
  9. Woosley, R. L., Passman, R., Giardina, E. G. (2021). Clinical use of dofetilide. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/clinical-use-of-dofetilide
  10. Somberg, J., Molnar, J. (2020). What is new in pharmacologic therapy for cardiac resuscitation? Cardiology Research 11:141–144. Retrieved September 22, 2021, from https://cardiologyres.org/index.php/Cardiologyres/article/view/1058/1056
  11. Hume, J. R., Grant, A. O. (2012). Agents used in cardiac arrhythmias. In Katzung, B. G., Masters, S. B., and Trevor, A. J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, pp. 227–250. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

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