23. Antiarrhythmic drugs

Page created on February 25, 2019. Last updated on January 7, 2022 at 22:01

Cardiac electrophysiology

We can divide the normal action potential into 5 phases:

  1. Upstroke phase
  2. Early-fast repolarization
  3. Plateau
  4. Repolarization
  5. Diastole

These phases can be seen on the figure below. Note that this shows the depolarization of the ventricle.


This shows the action potential of the ventricle. The phases are marked with numbers.

The cardiac pacemaker cells don’t have “normal” action potentials, so they skip phase 1 and 2. In these cells is phase 0 the rapid depolarization, phase 3 the repolarization and phase 4 the spontaneous diastolic depolarization.

Action potential of pacemaker cell

The figure above shows how the cardiac pacemaker cells in the sinus node and AV node spontaneously depolarize. The membrane slowly depolarizes by itself (phase 4) until it reaches the threshold, at which point the membrane spontaneously depolarizes (phase 0). After this will the membrane repolarize (phase 3) The period of slow depolarization on the figure is called the spontaneous diastolic depolarization (SDD). From the figure can you see that the minimal membrane potential, the lowest membrane potential reached during SDD, is around -70mV.

There are four different “phenomena” that lie in the background of arrhythmias:

  • Increased automaticity
    • Spontaneous action potentials in myocardial cells
  • Premature depolarization
  • Re-entry
  • AV block
Antiarrhythmic drugs

This type of drug is used to prevent recurrent arrhythmias and to restore sinus rhythm in people with current cardiac arrhythmias. Antiarrhythmic drugs are classically classified according to the Vaughan Williams classification. There are four drug classes in this classification:

  • Class I – Na+ channel blockers
    • Class Ia – Na+ channel blockers of intermediate strength
    • Class Ib – Weak Na+ channel blockers
    • Class Ic – Strong Na+ channel blockers
  • Class II – Beta blockers
  • Class III – K+ channel blockers
  • Class IV – Ca2+ channel blockers

Some antiarrhythmic drugs don’t fit into this classification and are mentioned outside it.

Cardiac electrophysiology is a difficult thing. By treating one problem can we produce another. While these drugs are antiarrhythmic is the reality that they only work in specific situations – antiarrhythmics that in some situations decrease arrhythmia may be pro-arrhythmic in other situations or even in the same situation. This is a severe issue and limits their clinical use.

Some classes of antiarrhythmics are more proarrhythmic than others. From most to least pro-arrhythmic, these are Ic > Ia > Ib > III > IV > II. Class IV and class II antiarrhythmics have virtually no proarrhythmic potential.

Note also that studies have shown that the use of antiarrhythmics in non-life-threatening arrhythmias does not decrease mortality and may even increase it. All antiarrhythmics are associated with severe side-effects, primarily due to their proarrhythmic effect.

Class I drugs
  • Class Ia
    • Disopyramide
    • (Quinidine)
    • (Procainamide)
  • Class Ib
    • Lidocaine
    • (Mexilitine)
  • Class Ic
    • Propafenone
    • Flecainide

These drugs are Na+ channel blockers. These channels are responsible for the phase 0 of the ventricular action potential and phase 4 of the pacemaker action potential. Blocking these channels causes the rate of depolarization during phase 0 to decrease.

Three types of class I drugs exist: Class Ia, Ib and Ic. The different types affect the action potential in different ways.

Class Ia are Na+ channels blockers of medium strength. The only important drug in this class is disopyramide, although previously quinidine and procainamide were used. They prolong the QT-interval, which increases the risk for torsade de pointes. They’re not much used.

Class Ib are Na+ channel blockers of weak strength. This class has stronger effect on ischaemic myocardium than healthy myocardium, theoretically making it a good choice for arrhythmias that occur after AMI.

Class Ic are strong Na+ channel blockers. They can be used in paroxysmal supraventricular tachycardias and atrial fibrillation.

Class II drugs
  • Metoprolol
  • Bisoprolol
  • Esmolol
  • Nebivolol

The class II drugs are beta blockers. These drugs prevent sympathetic activity-triggered arrhythmias. They have the no pro-arrhythmic effect.

For the use as antiarrhythmic are β1 selective beta blockers with no intrinsic sympathomimetic activity (ISA) preferred, like those mentioned above.


Beta blockers are widely used in cardiology. Their major antiarrhythmic use lies in preventing the occurance of sudden cardiac death due to ventricular fibrillation after myocardial infarction, but they are also used in atrial fibrillation, paroxysmal supraventricular tachycardia and premature ventricular beats.

For their side effects, see pharma 1.

Class III drugs
  • Amiodarone
  • Sotalol
  • Dronedarone

The class III drugs are K+ channel blockers. The most important drugs here are amiodarone. Amiodarone is the only used antiarrhythmic drug without a negative inotropic effect, which makes it widely used. It’s therefore the only antiarrhythmic drug (except beta blockers) which can be used in heart failure.

Like the name suggests, sotalol is also a beta blocker, but it has strong K+ channel blocking activity and is therefore classified as a class III antiarrhythmic.

Dronedarone was developed which is an amiodarone analogue without the iodine-atom, which would hopefully be equal in efficacy to amiodarone but without its side effects. However, it turned out that dronedarone is both less effective and more hepatotoxic than amiodarone, and it has therefore not replaced amiodarone.


  • Atrial fibrillation
  • Ventricular arrhythmias

Mechanism of action:

The class III drugs are K+ channel blockers. These channels are responsible for repolarization.

Amiodarone also blocks Na+ and Ca2+ channels and α and β adrenergic receptors.

Side effects:

  • QT prolongation

Amiodarone is famous for its various side-effects:

  • Corneal deposits
  • Photosensitivity of the skin with bluish discoloration
  • Thyroid dysfunction (as amiodarone contains iodine atoms)
  • Pulmonary fibrosis

For side effects of sotalol, see the side effects of beta blockers.


Amiodarone is very lipophilic, which causes it to slowly accumulate in adipose and other tissues, giving it a very long half-life of 1 month.

Class IV drugs
  • Verapamil
  • (Diltiazem)

These drugs are Ca2+ channel blockers. This channel is important for the phase 0 in pacemaker cells. Verapamil is the most important drug here.

These drugs have very little proarrhythmic effect.


  • Atrial fibrillation
  • Paroxysmal supraventricular tachycardia

For side effects, see topic 1.

Other antiarrhythmics (class V)

As stated earlier are there some drugs that can be used antiarrhythmically but aren’t included in the original Vaughan Williams classification. In newer forms of the Vaughan Williams classification, they’re called class V drugs.

The most important ones are digoxin, adenosine, magnesium sulphate and vernakalant.


Digoxin may be used for rate control in atrial fibrillation and in heart failure.

Adenosine is used to terminate paroxysmal supraventricular tachycardias.

Magnesium sulphate is used to terminate torsade de pointes. Due to its membrane-stabilizing properties, it is often used as an adjunct in other arrhythmias as well.

Vernakalant is used to convert atrial fibrillation to sinus rhythm.

Mechanism of action:

Adenosine binds to A1 adenosine receptors which cause a negative dromotropic effect.

Magnesium stabilizes the membrane potential.

Vernakalant blocks multiple ion channels in the atrial myocardium, making it atrial-specific.

Side effects:

Adenosine can cause bronchospasm and hypotension.


When patients present with arrhythmias elimination of provoking factors of the arrhythmia should be the primary objective. Myocardial hypoxia, stress, smoking, electrolyte disturbances are all factors that can provoke arrhythmias and that can be treated. Treating the provoking factor may cause the arrhythmia to fix itself or not reoccur.

It is also important to keep in mind that not all arrhythmias need medical therapy, especially if the medical therapy carries more risk than just leaving the arrhythmia. Many arrhythmias don’t need to be corrected.

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22. Diuretic drugs

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24. Drugs used to treat congestive heart failure

Parent page:
Pharmacology 1

5 thoughts on “23. Antiarrhythmic drugs”

  1. They like to ask about the side effects of amiodarone, and especially the corneal deposit, which you didn’t mention here.

  2. Hi! One small detail:
    Isn’t it better to number the phases like this:
    0. Upstroke phase
    1. Early-fast repolarization
    2. Plateau
    3. Repolarization
    4. Diastole
    Under afterdepolarization you have written that EAD happens in phase 2 which is the plateau phase, that could be confusing when it’s phase 3 in the beginning of this topic.
    Anyway, thank you so much for writing these topics!!

    1. This topic is not my proudest moment, so I plan to rewrite it before my exam. Before I do that I’ll have to finish the other topics. When I rewrite it I’ll come back to your comment.

  3. Hi! Perhaps it’d be worth to highlight “IOD” in amIODarone, to make the idoine atom in the molecule easier to remember.

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