Antiarrhythmics

Understand the pharmacology of antiarrhythmic drugs

Antiarrhythmic drugs are typically classified using the Vaughan Williams classification system, which divides drugs into four classes based on their effect on the cardiac action potential. Many drugs will act via multiple mechanisms.

• Class I: Block voltage-gated Na channels
  • Class Ia: Intermediate dissociation
  • Class Ib: Fast dissociation
  • Class Ic: Slow dissociation
• Class II: β-Blockers
• Class III: Prolong the action potential (Usually via K⁺ channel blockade)
• Class IV: Ca²⁺ antagonists

This classification is notably incomplete, as some drugs (such as amiodarone) fit into multiple categories, and others (such as digoxin, adenosine, and magnesium) fit into none.

Class I

• Na⁺-channel blockade inhibits action potential prolongation by blocking active and refractory sodium channels in a use-dependent fashion
• This inhibits tachyarrhythmias whilst allowing normal conduction
• Extent of block depends on the heart rate, membrane potential, and the subclass of drug
• Sodium channel blockade increases pacing threshold and defibrillation energy requirement

Class Ia

• Class Ia drugs have mixed properties of Ib and Ic, and also have Class III effects
• As they prolong the AV conduction and prolong the action potential they increase both QRS duration and the QT interval
• Examples include procainamide

Pro-arrhythmic effects may result because AV nodal conduction may be increased, so despite decreased atrial activity increased ventricular conductance results in a potentially fatal shortening of diastolic time

Class Ib

• Class Ib drugs bind to open sodium channel, and will associate and dissociate from a sodium channel in the course of a normal beat
• Tachyarrhythmias are prevented because dissociation occurs too slowly for a further action potential to be generated
• Class Ib drugs will bind selectively to refractory channels, such as occurs in ischaemia
• As they have little effect on normal cardiac tissue they have little effect on the ECG
• Examples of class Ib agents include include phenytoin and lignocaine

Class Ic

• Class Ic drugs associate and dissociate slowly creating a steady-state level of block
• This causes indiscriminate blockade and general reduction in excitability
• Class Ic agents are used to suppress unidirectional or intermittent conduction pathways
• As they markedly slow conduction velocity they increase QRS duration
• Examples of Class Ic agents include flecainide

Class II

Normal β-adrenergic stimulation has a number of pro-arrhythmic effects:

• Increased pacemaker potential current
• Increased slow-inward Ca²⁺ current
• Increased repolarising K⁺ and Cl^- currents
• Increased Ca²⁺ stored in the sarcoplasmic reticulum, which may be spontaneously released causing a delayed-after-depolarisations
• Reduced serum [K⁺]*

β-blockers have an antiarrhythmic effect by antagonising these mechanisms. They are useful for treatment of arrhythmias occurring with sympathetic over-activation, such as post MI.

Class III

Blocking of outward K⁺ channels slows cardiac repolarisation, which increases the cardiac refractory period. This has a number of beneficial effects:

• Decreased automaticity
• Decreased ectopy
• Reduced defibrillation energy requirement
• Increased inotropy

Due to the prolonged repolarisation, they will also cause a long QT (though in the case of amiodarone this is not associated with an increased risk of TPD).

Class IV

Class IV drugs inhibit L-type Ca²⁺ channels, inhibiting the slow inward calcium current, which:

• Slows SA and AV nodal conduction
  AV blockade slows transmission of supra-ventricular arrhythmias.
• Reduces inotropy
• Prevents after-depolarisations
  This suppresses ectopy by reducing calcium leak from sarcoplasmic reticulum.

Alternatives to Vaughan Williams

As the Vaughan Williams classification system does not neatly divide agents, and some agents do not fit into any category, they may also be classified by their uses:

References

1. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale's Pharmacology. 6th Ed. Churchill Livingstone.
2. Brunton L, Chabner BA, Knollman B. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 12th Ed. McGraw-Hill Education - Europe. 2011.
3. Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.