Antiarrhythmic drug classification

Antiarrhythmic drug classification

Click on the play button for the audio commentary.

The popular Vaughan Williams classification was published in 1975 [1]. It is still being used by most of us. The Sicilian Gambit published in 1991 [2] has not been so popular because of its complexity.

Vaughan Williams classification is approximately as follows:

 Class I: Sodium channel blockers

◦a: Moderate Na channel block. e.g. Quinidine, Disopyramide

◦b: Weak Na channel block. e.g. Lignocaine, Mexiletine

◦c: Marked Na channel block. e.g. Flecainide, Propafenone

 Class II: Beta blockers

 Class III: Potassium channel blockers: Amiodarone, Sotalol, Ibutilide

 Class IV: Calcium channel blockers

In 2018, an extended update (Modernized Classification of Cardiac Antiarrhythmic Drugs) was published by Ming Lei et al [3]. This classification has classes I to VII of which class VII is a group of upstream is a group of upstream target modulators and not direct anti arrhythmic drugs. The whole classification is quite extensive. It is approximately like this:

 Class 0: HCN channel blockers: e.g. Ivabradine

 Class I: Voltage gated sodium channel blockers

◦a: Nav 1.5 open state, intermediate dissociation. e.g. Quinidine, Disopyramide

◦b: Nav 1.5 open state, rapid dissociation. e.g. Lignocaine, Mexiletine

◦c: Nav 1.5 inactivated state, slow dissociation. e.g. Flecainide, Propafenone

◦d: Nav 1.5 late current. e.g. Ranolazine

 Class II: Autonomic inhibitors and activators

◦a: Nonselective β inhibitor: Carvedilol, Propranolol; Selective β1 inhibitor: Metoprolol

◦b: Nonselective β activator: Isoproterenol

◦c: Muscarinic M2 inhibitor: Atropine, Hyoscine, Scopolamine

◦d: Muscarinic M2 activator: Pilocarpine, Digoxin

◦e: Adenosine A1 activator: Adenosine, ATP

Class III: Voltage dependent potassium channel openers and blockers 

  IIIa: Nonselective potassium channel blocker: Amiodarone, Dronedarone

        HERG blocker (I_Kr): Dofetilide, Ibutilide, Sotalol

        I_Ks blocker: No clinically approved drugs in use

        I_Kur blocker: Vernakalant

        I_to1 blocker: Tedisamil (Under regulatory review for AF conversion)

  IIIb: I_KATP opener: Nicorandil, Pinacidil

  IIIc: I_KACh blocker: BMS 914392 (Under regulatory review for AF Rx)

Class IV: Calcium handling modulators

  IVa: Surface membrane Ca²⁺ channel blocker

         Non selective: Bepridil

          I_CaL blocker: Verapamil, Diltiazem

          I_CaT blocker: No clinically approved drugs in use 

  IVb: Intracellular Ca²⁺ channel blocker:

           SR RyR2- Ca²⁺ channel blocker: Flecainide, Propafenone (Overlaps Ic)

           IP3R- Ca²⁺ channel blocker: No clinically approved drugs in use

  IVc:  Sarcoplasmic reticular Ca²⁺-ATPase activator: No approved drugs

  IVd: Surface membrane ion exchange inhibitor: No approved drugs

  IVe: Phosphokinase and phosphorylase inhibitors: No approved drugs

Class V: Mechanosensitive channel blockers

           TRPC3/TRPC6 blocker: N-(p-amylcinnamoyl)anthranilic acid- on trial

Class VI: Gap junction channel blockers

           Cx (Cx40, Cx43, Cx45) blocker: Carbenoxolone – under investigation

Class VII: Upstream target modulators

           ACEI, ARB, Omega-3 fatty acids, Statins

This classification is also a bit too extensive and difficult for routine clinical use. Moreover this includes several subclasses in which no drug is available. Hence this is a futuristic classification hoping that drugs in those groups will become available later. Group VII contains drugs with upstream action and are not direct antiarrhythmic agents. If these redundant groups are removed, this classification can become much simpler. Of course, an updated classification is needed as several new drugs with different mechanisms of action have been introduced after the original classification in 1975. It may also be noted that some drugs like Flecainide comes in two groups. That problem was there earlier also as Amiodarone had all the classes of actions and Sotalol was both a beta blocker and a class III agent.

References

1. E M Vaughan Williams. Classification of antidysrhythmic drugs. Pharmacol Ther B. 1975;1(1):115-38. 
2. Task Force of the Working Group on Arrhythmias, the European Society of Cardiology. The Sicilian Gambit: a new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms.Circulation. 1991; 84:1831–1851.
3. Ming Lei, Lin Wu, Derek A Terrar, Christopher L-H Huang. Modernized Classification of Cardiac Antiarrhythmic Drugs. Circulation. 2018 Oct 23;138(17):1879-1896.