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Antiarrhythmic drugs
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Action potential and ion flux in myocardial contractile cells

Resting potential (approx. -90mV) relies primarily on potassium channels (inward-rectifier potassium channels), ensuring a steady potassium
efflux (iK1).

Phase 0 (depolarization): Neighboring cells stimulate voltage-gated sodium channels within the cell, causing them to open briefly. This results in
a sodium influx (iNa ), and, consequently, the membrane potential increases just beyond 0 mV (overshoot).

Phase 1 (partial repolarization): The brief influx of chloride and efflux of potassium (not shown here) causes membrane potential to decrease.

Phase 2 (plateau): The opening of voltage-gated L-type calcium channels causes an influx of calcium ions (iCa), counteracting the repolarization
and keeping the membrane potential at approximately 0mV.

Phase 3 (repolarization): Rapid repolarization occurs via the opening of outward-rectifier potassium channels, resulting in a net efflux of
potassium.

Phase 4 (resting potential): A steady efflux of potassium (ik1) occurs until the cell is stimulated again and the process begins again at phase 0.

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Antiarrhythmic drugs

Overview
Last updated: Sep 28, 2020

Clinical Sciences

Learned

Summary

Antiarrhythmic drugs are used to prevent recurrent arrhythmias and restore sinus rhythm in patients with cardiac arrhythmias. These drugs are
classified based on their electrophysiological effect on the myocardium. Antiarrhythmic drugs do not improve the survival of patients with non-
life-threatening arrhythmias and may increase mortality, particularly in patients with structural heart disease. They are associated with severe
adverse effects, primarily due to their proarrhythmic effects on the myocardium. Patients who have received an intravenous antiarrhythmic
should be monitored closely with serial ECGs. Several classes of antiarrhythmics, including beta blockers, calcium channel blockers, amiodarone,
cardiac glycosides, and lidocaine, also have other medical uses, which are discussed in their respective articles.

Overview

Classes of antiarrhythmic drugs [1][2]

Class Mechanism of action Use

Drug group Examples Adv

Class IA Fast sodium Reduce conduction Moderate blockade of Quinidine Paroxysmal

antiarrhythmics channel velocity (negative Na+ channels Procainamide supraventricular
blockers dromotropy), (intermediate Disopyramide tachycardia (PSVT):
particularly in association/dissociation) Ajmaline AVNRT and AVRT
depolarized tissue Prolong AP duration Antidromic AVRT and
(e.g., during (right shift) WPW (procainamide)
tachycardia) Slow conduction Atrial fibrillation (AFib)
velocity and atrial flutter
State- Prolong effective Ventricular
dependent: refractory period (ERP) arrhythmias
The faster the Weak blockade of the
heart rate, the K+ channel
greater the
effect.

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Classes of antiarrhythmic drugs [1][2]

Class Mechanism of action Use

Drug group Examples Adv
Decreases
Class IB Weak blockade of Na+ Lidocaine Ventricular
the slope of
antiarrhythmics channels (fast Mexiletine arrhythmias
phase 0
association/dissociation) Phenytoin (especially post-MI)
depolarization
Shorten AP duration
Stabilize
membrane Slow conduction
velocity
Categorized into 3
No effect on or slight
subgroups based
prolongation of ERP
upon their effects
Strongest effect on
on the Na+ channel
ischemic myocardium
and the action
potential (AP)
Class IC duration Strong blockade of Na+ Flecainide PSVT
antiarrhythmics channels (slow Propafenone AFib (cardioversion)
association/dissociation) Atrial flutter
→ QRS prolongation
No to minimal effect on
AP duration (no shift)

Slow conduction
velocity
Prolong ERP in AV
node and accessory
tract
ERP unaffected in
Purkinje and ventricular
tissue

Class II Beta Inhibit β-adrenergic activation of adenylate cyclase Metoprolol AFib (rate control)
antiarrhythmic blockers → ↓ cAMP → ↓ Ca2+ → ↓ SA and AV node activity Esmolol Atrial flutter
drugs Propranolol PSVT
Decrease slope of phase 4 in pacemaker cells Atenolol Premature ventricular
Slow conduction velocity Timolol contractions
Prolong AV node repolarization Carvedilol Ventricular
Prolong PR interval Sotalol arrhythmias
Atrial premature
beats [3]

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Classes of antiarrhythmic drugs [1][2]

Class Mechanism of action Use

Drug group Examples Adv

Class III Potassium Inhibit delayed rectifier potassium currents Amiodarone AFib (cardioversion
antiarrhythmic channel and rhythm control)
drugs blockers Prolong QT interval Dronedarone Atrial flutter
Prolong AP duration (reverse use dependence) and Sotalol Ventricular
ERP Bretylium arrhythmias (not
Ibutilide bretylium)
No effect on conduction velocity Dofetilide Sotalol
Supraventricular
arrhythmias
Ventricular
arrhythmias

Class IV Calcium Inhibit slow calcium channels Verapamil AFib (rate control)
antiarrhythmic channel Diltiazem Atrial flutter
drugs blockers Decrease slope of phase 0 and 4 → slower Nifedipine PSVT
conduction velocity → increased ERP Multifocal atrial
Prolong AV node repolarization tachycardia
Prolong PR interval Hypertension
(nifedipine)

Class V Variable See “Other antiarrhythmic drugs” below for details. Adenosine See below
antiarrhythmic mechanisms (drug)
drugs Digoxin
Magnesium
sulfate

All antiarrhythmic drugs are also potentially proarrhythmic! Intravenous administration should only be performed with continuous cardiac
monitoring!
References:[4][5][6][7][8]

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Other antiarrhythmic drugs

Adenosine (drug) [1]

Mechanism of action: activates Gi protein → inhibition of adenylate cyclase → ↓ cAMP → deactivation of L-type Ca2+ channels and
activation of K+ channels → ↓ Ca2+ and ↑ K+ efflux → hyperpolarization → transient AV node block (short acting, approx. 15 seconds) →
acute termination of supraventricular tachycardia
Indications
Diagnosis and termination of certain forms of paroxysmal supraventricular tachycardias (e.g., AVNRT and orthodromic AVRT)
Diagnosis of underlying AFib in supraventricular tachyarrhythmias

Adverse effects
Chest pain, flushing, hypotension, bronchospasm
Sense of impending doom
AV block
Asystole
Contraindications
Pre-excitation syndromes: antidromic AVRT, WPW

AV block
Asthma

Interactions: Theophylline and caffeine weaken the effects of adenosine because they are adenosine receptor antagonists.

Avoid adenosine in patients with suspected pre-excitation tachycardia (e.g., WPW), because it may exacerbate the tachycardia via accessory
pathway routes!

Digoxin
Mechanism of action: inhibits Na+/K+-ATPases → higher intracellular Na+ concentration → reduced efficacy of Na+/Ca2+ exchangers →
higher intracellular Ca2+ concentration → increased contractility, decreased heart rate
Indications
AFib
Atrial flutter
Chronic systolic heart failure

See cardiac glycosides.

Magnesium sulfate [9][1]

Mechanism of action: decreases calcium influx → prevents early afterdepolarizations (EADs)

Indications
Torsade-de-pointes
Refractory ventricular tachyarrhythmias (e.g., polymorphic VT)
Digoxin intoxication
Eclampsia
Constipation
Tocolysis
Adverse effects
Hypotension
Asystole
Drowsiness
Flush
Loss of reflexes
Respiratory depression

If-channel blocker
Drug: ivabradine
Mechanism of action: selectively inhibits If channel in the pacemaker cells of the SA node → prolongs slow depolarization (phase 4) → slows
heart rate

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Indications: symptomatic stable coronary heart disease and congestive heart failure (NYHA II-IV) in patients who cannot tolerate beta
blockers
Adverse effects
Vision changes: luminous phenomena (enhanced visual brightness)
Bradycardia
Hypertension

IVabradine slows depolarization in phase IV.

References:[10][11][12][13][14][15][16][17][9]

References

1.
Craig CR, Stitzel RE. Modern Pharmacology with Clinical Applications. Little, Brown Medical Division; 1997

2.
Giardina EG, Zimetbaum PJ. Monitoring and Management of Amiodarone Side Effects. In: Post TW, ed. UpToDate. Waltham, MA:
UpToDate.https://www.uptodate.com/contents/monitoring-and-management-of-amiodarone-side-effects . Last updated February 13, 2017.
Accessed April 5, 2017.
3.
Manolis AS. Supraventricular Premature Beats. In: Post TW, ed. UpToDate. Waltham, MA:
UpToDate.https://www.uptodate.com/contents/supraventricular-premature-beats . Last updated March 14, 2016. Accessed February 19,
2017.
4.
Kaplan. USMLE Step 1 Lecture Notes 2016: Pharmacology. New York, NY: Kaplan; 2015

5.
Makielski JC. Myocardial action potential and action of antiarrhythmic drugs. In: Post TW, ed. UpToDate. Waltham, MA:
UpToDate.https://www.uptodate.com/contents/myocardial-action-potential-and-action-of-antiarrhythmic-drugs . Last updated September 4,
2013. Accessed April 7, 2017.
6.
UpToDate. Flecainide: Drug information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate.https://www.uptodate.com/contents/flecainide-
drug-information . Last updated January 1, 2017. Accessed October 10, 2017.
7.
UpToDate. Quinidine: Drug information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate.https://www.uptodate.com/contents/quinidine-
drug-information . Last updated January 1, 2017. Accessed October 10, 2017.
8.
Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017

9.
UpToDate, Lexicomp, Inc. Magnesium sulfate: Drug information. In: Post TW, ed. UpToDate. Waltham, MA:
UpToDate.https://www.uptodate.com/contents/magnesium-sulfate-drug-information . Last updated April 7, 2017. Accessed April 7, 2017.
10.
Jenkins B, McInnis M, Lewis C. Step-Up to USMLE Step 2 CK. Lippincott Williams & Wilkins; 2015

11.
Le T, Bhushan V, Bagga HS. First Aid for the USMLE Step 2 CK. McGraw-Hill Medical; 2009

12.
Kistler P. Focal atrial tachycardia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate.http://www.uptodate.com/contents/focal-atrial-
tachycardia?source=search_result&search=atrial+tachycardia&selectedTitle=1~150 . Last updated October 16, 2015. Accessed February 12,
2017.
13.
Levine E. Classifications of Antiarrhythmic Agents. In: Classifications of Antiarrhythmic Agents. New York, NY:
WebMD.http://emedicine.medscape.com/article/2172024-overview . August 6, 2014. Accessed April 7, 2017.
14.
Blomström-Lundqvist C, Scheinman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular
arrhythmias--executive summary. Circulation. 2003; 108(15): p.1871-1909. doi: 10.1161/01.CIR.0000091380.04100.84 .| Open in Read by
QxMD
15.
Drugs.com. Adenosine. https://www.drugs.com/pro/adenosine.html . Updated: January 1, 2017. Accessed: April 7, 2017.
16.
Dave J. Torsade de Pointes. In: Torsade de Pointes. New York, NY: WebMD.http://emedicine.medscape.com/article/1950863-overview .
February 1, 2017. Accessed April 7, 2017.
17.
Zimetbaum PJ. Pathophysiology of the long QT syndrome. In: Post TW, ed. UpToDate. Waltham, MA:
UpToDate.https://www.uptodate.com/contents/pathophysiology-of-the-long-qt-syndrome . Last updated February 9, 2017. Accessed April 7,

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2017.
18.
Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education; 2014

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