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Foundational Sciences · Pharmacology
Antiarrhythmics (Vaughan-Williams)
A Step 1-focused walkthrough of the Vaughan-Williams antiarrhythmic classes (I–IV plus adenosine and magnesium), pairing each agent's mechanism and clinical use with its signature board toxicity — drug-induced lupus, amiodarone organ toxicity, torsades, and the CAST proarrhythmia rule.
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The Vaughan-Williams framework
Antiarrhythmics are grouped by the Vaughan-Williams (VW) system according to which phase of the cardiac action potential (AP) they target:
- Class I – Na⁺-channel blockers → slow the phase 0 upstroke in fast-response tissue (atria, ventricles, Purkinje). Subdivided IA / IB / IC by binding kinetics and effect on AP duration.
- Class II – β-blockers → ↓ sympathetic drive at the SA/AV nodes (↓ phase 4 slope; act on phase 0 of slow-response tissue).
- Class III – K⁺-channel blockers → prolong phase 3 repolarization → ↑ AP duration, ERP, and QT.
- Class IV – non-dihydropyridine Ca²⁺-channel blockers (verapamil, diltiazem) → ↓ AV-nodal conduction.
- Unclassified – adenosine, Mg²⁺, digoxin.
Big picture: Class I and III act mainly on fast-response myocardium (Na⁺-dependent phase 0), while Class II and IV act on the slow-response nodal tissue that depends on Ca²⁺ for depolarization.
Must-know points
- Class I potency of Na⁺ block: IC > IA > IB. IA also blocks K⁺ (↑ AP duration/QT); IB shortens AP duration; IC minimally changes AP duration but markedly slows conduction (↑ QRS).
- IA (quinidine, procainamide, disopyramide): atrial + ventricular arrhythmias; watch torsades, cinchonism (quinidine), drug-induced lupus (procainamide), anticholinergic + negative inotropy (disopyramide).
- IB (lidocaine, mexiletine): best for acute post-MI/ischemic ventricular arrhythmias and digoxin-induced arrhythmias; preferentially block inactivated Na⁺ channels in ischemic/depolarized tissue.
- IC (flecainide, propafenone): SVT/AF in structurally normal hearts only — contraindicated post-MI/structural disease (CAST trial → ↑ mortality).
- Class II (β-blockers): ↓ SA/AV nodal activity (↑ PR); rate control, SVT, mortality benefit post-MI/HF; overdose → glucagon; esmolol is ultra-short-acting IV.
- Class III (amiodarone, sotalol, dofetilide, ibutilide, dronedarone): ↑ AP duration/QT; sotalol / dofetilide / ibutilide → torsades; amiodarone paradoxically has low torsades risk.
- Amiodarone has class I–IV actions plus organ toxicity: pulmonary fibrosis, thyroid dysfunction, hepatotoxicity, corneal deposits, blue-gray skin — monitor PFTs / LFTs / TFTs.
- Class IV (verapamil, diltiazem): ↓ AV conduction → rate control/SVT; constipation (verapamil), bradycardia, AV block, HF; verapamil ↑ digoxin levels.
- Adenosine = drug of choice to diagnose/terminate AVNRT/SVT (very short-acting, ~15 s); Mg²⁺ = drug of choice for torsades and for digoxin-induced arrhythmias.
Drug → mechanism → use → signature toxicity
| Drug (VW class) | Mechanism | Main clinical use | Key toxicity / association |
|---|---|---|---|
| Quinidine (IA) | Na⁺ + K⁺ block; ↑ AP/QT | Atrial & ventricular arrhythmias | Cinchonism, torsades, thrombocytopenia, ↑ digoxin |
| Procainamide (IA) | Na⁺ + K⁺ block | AF, VT (incl. WPW) | Drug-induced lupus (anti-histone), agranulocytosis, torsades |
| Disopyramide (IA) | Na⁺ + K⁺ block | Ventricular arrhythmias | Anticholinergic, negative inotropy → HF |
| Lidocaine (IB) | Blocks inactivated Na⁺; ↓ AP | Acute post-MI VT, digoxin arrhythmias | CNS: perioral numbness, tremor, seizures |
| Mexiletine (IB) | Oral IB | Chronic ventricular arrhythmias | GI upset, tremor |
| Flecainide (IC) | Strong Na⁺ block; ↑ QRS | SVT/AF, structurally normal heart | Proarrhythmic — avoid post-MI (CAST) |
| Metoprolol / Esmolol (II) | β1 block → ↓ AV conduction | Rate control, SVT, post-MI | Bradycardia, AV block, bronchospasm; OD → glucagon |
| Amiodarone (III) | K⁺ block + class I/II/IV | AF, VT (broad-spectrum) | Pulmonary fibrosis, thyroid, hepatotox, corneal/skin |
| Sotalol (III) | K⁺ block + β-block | AF, VT | Torsades, bradycardia |
| Dofetilide / Ibutilide (III) | K⁺ block; ↑ QT | Convert AF / flutter | Torsades |
| Verapamil / Diltiazem (IV) | L-type Ca²⁺ block → ↓ AV | Rate control AF, SVT | Constipation, AV block, HF; verapamil ↑ digoxin |
| Adenosine (other) | ↑ K⁺ efflux, ↓ Ca²⁺ → ↓ AV | DOC dx/tx of SVT (AVNRT) | Flushing, chest pain, transient asystole, "impending doom" |
Sorting out Class I (IA vs IB vs IC)
All Class I drugs block voltage-gated Na⁺ channels, but they differ in binding kinetics and effect on AP duration:
- Class IA (quinidine, procainamide, disopyramide) — intermediate dissociation plus K⁺ block → ↑ AP duration, ERP, and QT. Broadly effective for atrial and ventricular arrhythmias but carry torsades risk.
- Class IB (lidocaine, mexiletine) — fast on-off kinetics; bind inactivated channels, so they act selectively on rapidly firing or ischemic/depolarized myocardium and shorten AP duration. IV lidocaine is a go-to for post-MI/ischemic VT and digoxin-induced ventricular arrhythmias.
- Class IC (flecainide, propafenone) — slow dissociation → the strongest Na⁺ block, markedly slowing conduction (↑ QRS) with little change in AP duration. Reserved for SVT/AF in structurally normal hearts; the CAST trial demonstrated ↑ mortality when used post-MI.
Memory hook: IB shortens · IC unchanged · IA prolongs AP duration; Na⁺-block potency IC > IA > IB.
Vignette → drug
Match the presentation to the offending/indicated agent:
- Long-term AF therapy → exertional dyspnea, dry cough, restrictive PFTs, reticular opacities on CXR → Amiodarone (pulmonary fibrosis; also suspect thyroid dysfunction and blue-gray skin).
- New antiarrhythmic → fever, arthralgias, malar rash, positive anti-histone antibodies → Procainamide (drug-induced lupus).
- Antiarrhythmic → tinnitus, headache, blurred vision, dizziness → Quinidine (cinchonism).
- Recent MI with sustained monomorphic VT; IV agent that targets ischemic tissue and shortens AP duration → Lidocaine.
- Narrow-complex regular tachycardia ~180 bpm; a rapid IV push causes flushing, chest tightness, a sense of impending doom, and a brief sinus pause, then conversion to sinus → Adenosine (AVNRT).
- Antiarrhythmic causing dry mouth, constipation, urinary retention, and worsening heart failure → Disopyramide (anticholinergic + negative inotropy).
Classic mnemonics
Class I sodium-channel blockers, in order IA → IB → IC:
*"Double Quarter Pounder, Lettuce Mayo Tomato, Fries Please"*
- IA — DQP: Disopyramide, Quinidine, Procainamide
- IB — LMT: Lidocaine, Mexiletine, Tocainide → *"IB is Best post-MI"*
- IC — FP: Flecainide, Propafenone
Class III members = "AIDS": Amiodarone, Ibutilide, Dofetilide, Sotalol.
Torsades-prone (↑ QT): Class IA quinidine + Class III sotalol, dofetilide, ibutilide — amiodarone is the QT-prolonging exception that rarely triggers torsades.
Beyond the four classes
- Adenosine — activates cardiac K⁺ (GIRK) efflux and ↓ Ca²⁺ influx → transiently hyperpolarizes AV-nodal cells and blocks conduction. Drug of choice to diagnose and terminate AV-nodal reentrant (paroxysmal) SVT; ultra-short acting (~15 s). Effects are blocked by caffeine/theophylline (adenosine-receptor antagonists) and potentiated by dipyridamole. Adverse: flushing, chest burning, hypotension, transient sinus pause/AV block, bronchospasm, sense of impending doom.
- Magnesium — drug of choice for torsades de pointes and for digoxin-induced arrhythmias (note: digoxin-specific antibody fragments are the definitive antidote for severe/life-threatening digoxin toxicity).
Safety point: the AV-nodal blockers — β-blockers, verapamil/diltiazem, digoxin, and adenosine — are contraindicated in pre-excited atrial fibrillation (WPW), because blocking the AV node diverts conduction down the accessory pathway → risk of ventricular fibrillation.
QT prolongation & proarrhythmia
- QT-prolonging / torsades-prone: Class IA (quinidine) and Class III (sotalol, dofetilide, ibutilide). Correct hypokalemia/hypomagnesemia and avoid stacking QT-prolonging drugs.
- Amiodarone prolongs QT but rarely causes torsades — a classic board exception.
- Class IC (flecainide, propafenone) are proarrhythmic through slowed conduction/reentry → avoid in ischemic or structural heart disease (CAST trial → ↑ mortality).
- Treat torsades with IV magnesium (plus correcting electrolytes; overdrive pacing or isoproterenol if refractory).
- Procainamide is metabolized to NAPA (N-acetylprocainamide), which has Class III activity — adding QT prolongation on top of its Class IA effect.
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