Last updated on June 15, 2019 at 12:46
We can divide the normal action potential into 5 phases:
- Upstroke phase
- Early-fast repolarization
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
- AV block
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 – strong Na+ channel blockers
- Class Ic – Na+ channel blockers of weak strength
- 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.
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
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. This drug can treat supraventricular and ventricular tachycardias. They prolong the QT-interval, which increases the risk for torsade de pointes.
Class Ib are Na+ channel blockers of weak strength. This class has stronger effect on ischaemic myocardium than healthy myocardium, making it a good choice for arrhythmias that occur after AMI. The drugs in this class are lidocaine (IV) and mexiletine (oral).
Class Ic are strong Na+ channel blockers. The important drug here is flecainide. They’re used to prevent paroxysmal atrial fibrillation.
Class II drugs
The class II drugs are beta blockers. These drugs prevent sympathetic activity-triggered arrhythmias.
For the use as antiarrhythmic are β1 selective beta blockers with no intrinsic sympathomimetic activity (ISA) preferred, like metoprolol, atenolol, esmolol, bisoprolol and nebivolol.
Beta blockers are used to prevent the occurance of sudden cardiac death due to ventricular fibrillation after myocardial infarction.
Class III drugs
The class III drugs are K+ channel blockers. The most important drugs here are amiodarone and dronedarone.
These drugs are used in supraventricular and 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.
- Corneal deposits
- Photosensitivity of the skin
- Thyroid dysfunction (as amiodarone contains iodine atoms)
- Pulmonary fibrosis
Droneradone has similar side effects, but doesn’t cause thyroid dysfunction as it doesn’t cause iodine atoms.
Amiodarone is very lipophilic, which causes it to slowly accumulate in adipose and other tissues, giving it a half-life of 1 month.
Class IV drugs
These drugs are Ca2+ channel blockers. This channel is important for the phase 0 in pacemaker cells. Verapamil and diltiazem are the important drugs here.
These drugs have no proarrhythmic effect, which makes them safer to use than other antiarrhythmics.
They’re used orally or IV in paroxysmal supraventricular tachycardia, atrial fibrillation and atrial flutter.
As stated earlier are there some drugs that can be used antiarrhythmically but aren’t included in the Vaughan Williams classification.
The most important ones are adenosine, magnesium sulphate and vernakalant.
Adenosine is used to terminate paroxysmal supraventricular tachycardias.
Magnesium sulphate is used to terminate torsade de pointes.
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.
Vernakalant blocks multiple ion channels that targets the atrial myocardium.
Adenosine can cause bronchospasm and hypotension.
When patients present with arrhythmias should elimination of provoking factors of the arrhythmia 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.
If pharmacological treatment is necessary is it important to keep the proarrhythmic effect of the drugs in mind. In order from most to least pro arrhythmic are: class Ic – Ia – Ib – III.
Lastly is it 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. So-called “benign” arrhythmias like extrasystoles or atrial fibrillation don’t need to be corrected.
3. Diuretic drugs
5. Drugs used to treat congestive heart failure