Question 9

Classify the anti-arrhythmic drugs using the Vaughan-Williams classification (30% of 
marks). Compare and contrast the electrophysiological effects of Class 1 anti-arrhythmic 
drugs (70% of marks).

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College Answer

Most candidates displayed a basic knowledge of the Vaughan-Williams classification and 
gave an example of each class. The remainder of the question lent itself very well to a 
tabular format. Better answers included the effect on the action potential (diagrams were 
useful here), channel dissociation kinetics (this was frequently omitted) and examples from 
each class of drug. There is an excellent table in Stoelting which answers this question 
nicely. Marks were not awarded for clinical effects.Overall, this question was generally well 
answered.

Discussion

For the first part of the question, the examiners clearly just wanted a mindless regurgitation of the Vaughan Williams classification (Miles Vaughan Williams' name was never hyphenated). 

Erh:

  • Class I: fast sodium channel blockers:
    • Class Ia: prolong the action potential (eg. quinidine)
    • Class Ib: shortens the action potential (eg. lignocaine)
    • Class Ic: no effect on the action potential (eg. flecainide)
  • Class II: Beta-blockers (eg. metoprolol)
  • Class III: Potassium channel blockers (eg. sotalol and amiodarone)
  • Class IV: calcium channel blockers (eg. verapamil and diltiazem)

Now, that "excellent table in Stoelting" which "answers this question nicely" is probably this:

Table of antiarrhythmic drug effects from Stoelting

However, the attentive reader will note that this table does not contain diagrams, mention channel dissociation kinetics or list drug examples, which the college expected from "better answers". Here, an honest attempt to incorporate everything into a ten-minute answer is offered:

  • Pharmacodynamic features of all Class I agents:
    • They bind to a site in the pore of the Nav1.5 subunit of the fast voltage-gated sodium channel
    • All prefer to bind to open or inactivated sodium channels 
    • Effects are more pronounced in ischaemic tissue
  • Subclasses of Class I agents:
    • Each class has distinct effects on the shape of the cardiac action potential:
      Effects of antiarrhythmic drugs on the cardiac action potential
  • Electrophysiological properties:
    • Class Ia agents
      • Prolongs the duration of the action potential (mainly by their potassium channel blocker effects)
      • Therefore, prolong the QT interval
      • Prolong the QRS complex because of a longer Phase 0
      • Use-dependence: block effect (and QRS prolongation) is more pronounced in tachycardia because of slow dissociation from the binding site in diastole
    • Class Ib agents
      • Have no effect on the duration of Phase 0
      • Therefore, do not prolong the QRS
      • Dissociate rapidly from the binding site, therefore free from use dependence
      • Shorten the duration of the action potential, mainly by preventing late sustained sodium current
      • Therefore, shorten the QT interval
    • Class Ic agents
      • Prolong Phase 0 more than other subclasses
      • Therefore, prolong the QRS duration
      • Dissociate slowly from the binding site, which means they are highly use-dependent (with tachycardia, QRS prolongation is greatest)
      • Have little effect on the duration of the action potential and therefore do not prolong the QT interval

References

Capucci, Alessandro, Daniela Aschieri, and Giovanni Quinto Villani. "Clinical pharmacology of antiarrhythmic drugs." Drugs & aging 13.1 (1998): 51-70.

Carmeliet, Edward, and Kanigula Mubagwa. "Antiarrhythmic drugs and cardiac ion channels: mechanisms of action." Progress in biophysics and molecular biology 70.1 (1998): 1-72.

Vaughan Williams, E. M. "Classification of antiarrhythmic drugs." Symposium on Cardiac Arrhythmias. Sweden, Astra 1970. 1970.

Williams, EM Vaughan. "A classification of antiarrhythmic actions reassessed after a decade of new drugs." The Journal of Clinical Pharmacology 24.4 (1984): 129-147.

Lei, Ming, et al. "Modernized classification of cardiac antiarrhythmic drugs." Circulation 138.17 (2018): 1879-1896.

Pott, C., et al. "Class I antiarrhythmic drugs: mechanisms, contraindications, and current indications." Herzschrittmachertherapie & Elektrophysiologie 21.4 (2010): 228-238.

Shenasa, Mohammad, Mohammad-Ali Shenasa, and Mariah Smith. "Class I Antiarrhythmic Drugs: Na+ Channel Blockers." Antiarrhythmic Drugs. Springer, Cham, 2020. 31-105.