Antiarrhythmic agent


Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart, such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.
Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.

Vaughan Williams classification

The Vaughan Williams classification was introduced in 1970 by Miles Vaughan Williams.
Vaughan Williams was a pharmacology tutor at Hertford College, Oxford. One of his students, Bramah N. Singh, contributed to the development of the classification system. The system is therefore sometimes known as the Singh-Vaughan Williams classification.
The five main classes in the Vaughan Williams classification of antiarrhythmic agents are:
With regard to management of atrial fibrillation, classes I and III are used in rhythm control as medical cardioversion agents, while classes II and IV are used as rate-control agents.
ClassKnown asExamplesMechanismMedical uses
IaFast-channel blockers
 channel block and K+ channel blocking effect; affects QRS complexclass 1a prolong the action potential and has intermediate effect on the 0 phase of depolarization
Ib
  • Lidocaine
  • Phenytoin
  • Mexiletine
  • Tocainide
    		• Na+ channel block ; can prolong QRS complex in overdoseclass 1b shorten the action potential of myocardial cell and has weak effect on intiation of phase 0 of depolarization
    Ic
  • Encainide
  • Flecainide
  • Propafenone
  • Moricizine
    		• Na+ channel block has no effect on action potential and has the strongest effect on the initiation phase 0 of depolarization
  • Prevents paroxysmal atrial fibrillation
  • Treats recurrent tachyarrhythmias of abnormal conduction system
  • Contraindicated immediately after myocardial infarction
    • IIBeta-blockers
  • Carvedilol
  • Propranolol
  • Esmolol
  • Timolol
  • Metoprolol
  • Atenolol
  • Bisoprolol
  • Nebivolol
    		• Beta blockingPropranolol also shows some class I action
    • Decrease myocardial infarction mortality
    • Prevent recurrence of tachyarrhythmias
    • Propranolol has sodium channel-blocking effects
    IIIPotassium Channel Blockers
  • Amiodarone
  • Sotalol
  • Ibutilide
  • Dofetilide
  • Dronedarone
  • E-4031
  • Vernakalant
    		• K+ channel blockerSotalol is also a beta blocker
    Amiodarone has Class III mostly, but also I, II, & IV activity
    • In Wolff-Parkinson-White syndrome
    • ventricular tachycardias and atrial fibrillation
    • atrial flutter and atrial fibrillation
    • : prevention of paroxysmal atrial fibrillation, and haemodynamically stable ventricular tachycardia
    IVCalcium Channel Blockers
  • Verapamil
  • Diltiazem
    		• Ca2+ channel blocker
  • Prevent recurrence of paroxysmal supraventricular tachycardia
  • Reduce ventricular rate in patients with atrial fibrillation
    • V
  • Adenosine
  • Digoxin
  • Magnesium Sulfate
    		• Work by other or unknown mechanisms Used in supraventricular arrhythmias, especially in heart failure with atrial fibrillation, contraindicated in ventricular arrhythmias. Or in the case of magnesium sulfate, used in torsades de pointes.

    Class I agents

    The class I antiarrhythmic agents interfere with the sodium channel.
    Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.
    Class I agents are called membrane-stabilizing agents, "stabilizing" referring to the decrease of excitogenicity of the plasma membrane which is brought about by these agents.
    Class I agents are divided into three groups based upon their effect on the length of the action potential.
    Class II agents are conventional beta blockers. They act by blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart, which reduces intracellular cAMP levels and hence reduces Ca2+ influx. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node.
    Class II agents include atenolol, esmolol, propranolol, and metoprolol.

    Class III agents

    Class III agents predominantly block the potassium channels, thereby prolonging repolarization. Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias.. The class III agents exhibit reverse-use dependence. Inhibiting potassium channels, slowing repolarization, results in slowed atrial-ventricular myocyte repolarization. Class III agents have the potential to prolong the QT interval of the EKG, and may be proarrhythmic.
    Class III agents include: bretylium, amiodarone, ibutilide, sotalol, dofetilide, vernakalant and dronedarone.

    Class IV agents

    Class IV agents are slow non-dihydropyridine calcium channel blockers. They decrease conduction through the AV node, and shorten phase two of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.
    Class IV agents include verapamil and diltiazem.

    Class V / other agents

    Since the development of the original Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV.
    Agents include:
    The initial classification system had 4 classes, although their definitions different from the modern classification. Those proposed in 1970 were:
    1. Drugs with a direct membrane action: the prototype was quinidine, and lignocaine was a key example. Differing from other authors, Vaughan-Williams describe the main action as a slowing of the rising phase of the action potential.
    2. Sympatholytic drugs : examples included bretylium and adrenergic beta-receptors blocking drugs. This is similar to the modern classification, which focuses on the latter category.
    3. Compounds that prolong the action potential: matching the modern classification, with the key drug example being amiodarone, and a surgical example being thyroidectomy. This was not a defining characteristic in an earlier review by Charlier et al., but was supported by experimental data presented by Vaughan Williams. The figure illustrating these findings was also published in the same year by Singh and Vaughan Williams.
    4. Drugs acting like dephenylhydantoin : mechanism of action unknown, but others had attributed its cardiac action to an indirect action on the brain; this drug is better known as antiepileptic drug phenytoin.

      Sicilian gambit classification

    Another approach, known as the "Sicilian gambit", placed a greater approach on the underlying mechanism.
    It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in roughly the Singh-Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is, therefore, not a true classification in that it does not aggregate drugs into categories.

    A modernized Oxford classification by Lei, Huang, Wu and Terrar

    A recent publication has now emerged with a fully modernised drug classification. This preserves the simplicity of the original Vaughan Williams framework while capturing subsequent discoveries of sarcolemmal, sarcoplasmic reticular and cytosolic biomolecules. The result is an expanded but pragmatic classification that encompasses approved and potential anti-arrhythmic drugs. This will aid our understanding and clinical management of cardiac arrhythmias and facilitate future therapeutic developments. It starts by considering the range of pharmacological targets, and tracks these to their particular cellular electrophysiological effects. It retains but expands the original Vaughan Williams classes I to IV, respectively covering actions on Na+ current components, autonomic signalling, K+ channel subspecies, and molecular targets related to Ca2+ homeostasis. It now introduces new classes incorporating additional targets, including:
    It also allows for multiple drug targets/actions and adverse pro-arrhythmic effects. The new scheme will additionally aid development of novel drugs under development and is illustrated below.