Question 21

College Answer

Most answers displayed a good knowledge of the Vaughan Williams classification, classes I to 
IV and the relevant electrophysiological characteristics of the classes. 
Answers should also have included mention of other antiarrhythmics, such as digoxin, 
magnesium and adenosine. The second part of the question required comment about K ion 
blockade and its effects. It was helpful to mention prolongation of QT and risk of torsade. Most 
answers omitted reference to its being a racemic mixture, with different actions of the isomers.

Discussion

Vaughan Williams classification and electrophysiological mechanisms:

• Class I: fast sodium channel blockers:
  • Class Ia: prolong the action potential (eg. quinidine)
    • Prolongs the duration of the action potential (mainly by their potassium channel blocker effects); prolong the QT interval and QRS complex because of a longer Phase 0
  • Class Ib: shortens the action potential (eg. lignocaine)
    • No effect on the duration of Phase 0 (do not prolong the QRS); shorten the QT interval 
  • Class Ic: no effect on the action potential (eg. flecainide)
    • Prolong Phase 0 more than other subclasses; have little effect on the duration of the action potential and therefore do not prolong the QT interval
  • Non-VW agents:
    • Agents which slow AV nodal conduction (i.e. adenosine, digoxin)
    • Physiological membrane stabilisers (magnesium)
• Class II: Beta-blockers (eg. metoprolol)
  • Increase I_K1 inward rectifier potassium current and reduce other currents;
  • Lower resting membrane potential, reduce action potential duration, promote rapid repolarisation in Phase 3, decrease AV node conduction
• Class III: Potassium channel blockers (eg. sotalol and amiodarone)
  • Block Ikr, Iks and Ik1 currents which are responsible for Phase 3 of the cardiac action potential
  • Increase the duration of the refractory period and of the action potential as a whole
• Class IV: calcium channel blockers (eg. verapamil and diltiazem)
  • decrease the rate of Phase 0 rise in pacemaker cells
  • shorten repolarisation by decreasing the duration of Phase 2
  • decrease AV node conduction

Sotalol:

• Sotalol is a non-selective beta-blocker without sympathomimetic activity or membrane stabilising activity.
  • Decreases automatic of pacemakers, which decreases the heart rate
  • Decreases the velocity of AV nodal conduction, which prolongs the PR interval 
• It is also a Class III antiarrhythmic, as it blocks potassium current during cardiac myocyte repolarisation
  • Blockade of repolarising potassium currents in Phase 3 of the cardiac action potential prolongs the repolarisation, which prolongs the QT interval.
  • Risk of early afterdepolarisations increases because of the prolonged repolarisation

Gorre, Frauke, and Hans Vandekerckhove. "Beta-blockers: focus on mechanism of action Which beta-blocker, when and why?." Acta cardiologica 65.5 (2010): 565-570.

Johnsson, Gillis, and C-G. Regårdh. "Clinical pharmacokinetics of β-adrenoceptor blocking drugs." Clinical pharmacokinetics 1.4 (1976): 233-263.

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.

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.