Antiarrhythmic Drugs and the Vaughan-Williams Classification

Introduction & cardiac electrophysiology

• An arrhythmia (dysrhythmia) is an abnormality of the rate, rhythm, or site of origin of the cardiac impulse, or of impulse conduction. Antiarrhythmic drugs prevent or terminate these irregularities — but only a minority of arrhythmias actually need drug treatment.
• Arrhythmias are the most important cause of sudden cardiac death (ventricular fibrillation is the single commonest mechanism); they occur in >80% of acute-MI patients. Central paradox: every antiarrhythmic can also cause arrhythmias (proarrhythmia) — so precise diagnosis, removal of precipitants, and risk minimisation are essential.
• The cardiac action potential (fast-response fibre) has five phases: Phase 0 upstroke — inward Na⁺ via Na_V1.5 (SCN5A; dV/dt_max sets conduction velocity); Phase 1 early repolarisation notch (I_TO); Phase 2 plateau — inward L-type Ca²⁺ (Ca_V1.2) balanced by outward K⁺; Phase 3 repolarisation — delayed-rectifier K⁺ (I_Kr, I_Ks, atrial I_Kur); Phase 4 diastole — stable in working myocytes (I_K1), spontaneous depolarisation in pacemakers.
• Resting potential (≈ −80 to −90 mV) is a K⁺-permeable membrane tracking E_K (Nernst); [K⁺]_o is the major determinant — hyperkalaemia depolarises and slows conduction, hypokalaemia prolongs APD and risks torsades. The commonest way drugs prolong the AP and provoke arrhythmias is block of I_Kr (KCNH2/HERG), whose pore is unusually drug-susceptible.
• Pacemaker & conduction: spontaneous phase-4 depolarisation is driven by the "funny" current I_f (HCN4); SA and AV nodes are slow-response (Ca²⁺-dependent) tissue with slow upstroke → slow conduction (AV-nodal delay = the PR interval). ECG correlates: P = atrial depolarisation, PR = AV conduction, QRS = ventricular depolarisation, QT = ventricular APD (QTc = QT/√RR, Bazett).
• Genetic channelopathies refine drug targeting: LQT-1 (KCNQ1, ↓I_Ks — β-blockers), LQT-2 (KCNH2, ↓I_Kr), LQT-3 (SCN5A, ↑late-Na⁺ — mexiletine/flecainide); CPVT (leaky RyR2 — β-blockers, then flecainide); Brugada (↓SCN5A — quinidine can be life-saving).