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Vaughan Williams Classification of Anti-arrhythmic Agents

• The Vaughan Williams (VW) scheme groups drugs by the dominant ion-channel or autonomic effect on the cardiac action potential. Many modern agents display mixed properties, and newer drugs (e.g. ivabradine) lie outside the original four classes; nevertheless the VW system remains the core framework examined in specialist curricula.

Class	Primary target	Effect on ECG	Representative drugs (RSA availability bold)	Typical indications	Key safety issues
I (Na⁺ block)	Fast Na⁺ channel	↓ Phase 0 upstroke; QRS ± QT	Ia quinidine, procainamide, disopyramide • Ib lidocaine, mexiletine • Ic flecainide, propafenone	SVT & VT (Ic in structurally normal hearts; Ib for ischaemic VT)	Pro-arrhythmia (torsades with Ia, CAST mortality with Ic in IHD)
II (β-block)	β-adrenergic receptor	↓ slope of phase 4; ↑ PR	Esmolol, atenolol, metoprolol, sotalol*	Rate control (AF), catechol-triggered VT, congenital long-QT	Bradycardia, bronchospasm, masking hypoglycaemia
III (K⁺ block)	I_Kr / I_Ks	QT prolongation; ↑ ERP	Amiodarone, dronedarone, sotalol, dofetilide, ibutilide*	Rhythm control (AF), VT suppression, WPW	Torsades (except amiodarone), extracardiac toxicity (amiodarone)
IV (Ca²⁺ block)	L-type Ca²⁺ channel	↑ PR; little QT effect	Verapamil, diltiazem	AV-node dependent SVT, rate control of AF	Hypotension, worsened HF with LVSD
V (Misc.)	–	–	Adenosine, digoxin, magnesium, ivabradine	Diagnostic or rate-slowing (adenosine), rate control & inotropy (digoxin), torsades prophylaxis (Mg²⁺)	Drug-specific (see below)

• _Sotalol combines non-selective β-blockade (Class II) with dose-dependent IKr inhibition (Class III).

Class I–Na⁺ Channel Blockers

Pharmacology

• Ia moderate Na⁺ block and I_Kr block → ↑ action potential duration (APD) & QT.
• Ib weak Na⁺ block; selective for depolarised/ischaemic tissue → ↓ APD.
• Ic strong Na⁺ block; minimal effect on repolarisation but marked QRS widening

Clinical Pearls

• Flecainide/propafenone effective “pill-in-the-pocket” cardioversion in paroxysmal AF with normal ventricles. Contra-indicated in coronary or structural heart disease (CAST).
• Lidocaine remains first-line for ischaemia-related VT/VF when amiodarone is unavailable or when ROSC is delayed; recent observational data suggest higher pre-hospital ROSC versus amiodarone.
• Procainamide IV favoured over amiodarone for stable monomorphic VT in 2022 ESC VA guideline (Class IIa)

Class II–β-Adrenergic Antagonists

• Reduce Ca²⁺ influx at the sinus and AV nodes, flatten phase 4 and prolong refractoriness, especially within ischaemic border zones.
• Robust outcome data: β-blockers reduce mortality post-MI and in heart failure, and lower sudden death risk in congenital long-QT.
• Esmolol (ultra-short acting) is useful for rapid peri-operative rate control.
• Sotalol needs in-hospital initiation (≥3 days) to monitor QTc; torsades risk rises sharply when creatinine clearance < 60 mL min⁻¹.

Class III–K⁺ Channel Blockers

Amiodarone

• Multi-channel blockade (I_Na, I_CaL, I_Kr, β-blockade) → minimal torsades risk despite marked QT.
• Extremely long half-life (15–60 days); load 5 mg kg⁻¹ over 1 h, then infusion 15 mg kg⁻¹ day⁻¹.
• Toxicities: pulmonary fibrosis, thyroid dysfunction (inhibits T4→T3 conversion), hepatotoxicity, corneal micro-deposits, photosensitivity.

Dronedarone

• Non-iodinated amiodarone analogue with shorter t½ (~24 h).
• Contra-indicated in NYHA III–IV HF or LVEF < 35 %.
• 2023 Veterans cohort: lower ventricular pro-arrhythmia and bradycardia than sotalol, with similar mortality.

Other Agents

• Dofetilide (not marketed in SA)–mandatory in-hospital loading; safe in LV dysfunction.
• Ibutilide–IV conversion of recent-onset AF/AFl; monitor for torsades.
• Bretylium is obsolete.

Class IV–Non-dihydropyridine Ca²⁺ Channel Blockers

• Slow AV nodal conduction and prolong node refractoriness.
• Useful for termination of AVNRT/AVRT and ventricular rate control in AF (when β-blockers contra-indicated).
• Avoid if LVEF < 40 % or concomitant β-blockade (heart block risk).
• Verapamil causes cerebral vasodilatation and is sometimes used in refractory cerebral vasospasm.

Class V–Miscellaneous / Unclassified

Drug	Mechanism	Typical dose	Clinical notes
Adenosine	A₁-receptor → ↑ K⁺ outflow, ↓ cAMP	6 mg rapid IV push (then 12 mg)	Diagnostic & therapeutic for AV-node dependent SVT; contra-indicated in asthma
Digoxin	Na⁺/K⁺-ATPase inhibition (↑ Ca²⁺) + vagotonic AV block	Load 10–15 µg kg⁻¹ PO/IV	Narrow therapeutic index; toxicity worsened by hypokalaemia & renal failure
Magnesium	Modulates Ca²⁺ influx, stabilises membrane	2 g IV over 5 min	First-line for torsades de points even with normal Mg²⁺
Ivabradine (Class 0)	Funny-current (I_f) inhibition	5–7.5 mg PO bd	Lowers sinus rate without BP effect; benefit in inappropriate sinus tachycardia

Guideline-directed Drug Selection (2020–2025)

• First-line rhythm control in AF (no structural heart disease): flecainide, propafenone, sotalol, dronedarone.
• Heart failure, significant LV hypertrophy or post-MI: amiodarone or dofetilide preferred; avoid Ic agents.
• Stable monomorphic VT: procainamide > amiodarone > sotalol (ESC 2022).
• Polymorphic VT / torsades: cease QT-prolonging agents, give Mg²⁺ 2 g IV, correct K⁺ > 4.5 mmol L⁻¹, institute over-drive pacing.

Mechanism of Action

Action Potentials and Ion Concentrations in Neuronal and Cardiac Tissues

Action Potential in Neuronal Tissue

• Depolarisation: Opening of sodium channels allows sodium ions to enter the neuron, causing the membrane potential to become more positive.
• Repolarisation: The positive membrane potential stimulates the opening of potassium channels, allowing potassium to leave the neuron, resulting in a small overshoot before returning to resting potential.

Figure 2: Action Potential in Cardiac Myocytes

• Phase 0: Voltage-gated Na⁺ channels open, and Na⁺ enters the cell.
• Phase 1: Initial rapid repolarisation as Na⁺ channels close.
• Phase 2: Slower, prolonged opening of voltage-gated Ca²⁺ channels.
• Phase 3: Closure of Ca²⁺ channels and K⁺ efflux.
• Phase 4: Cell membrane becomes permeable to K⁺ ions but remains relatively impermeable to other ions.

Normal Membrane Potentials

Steady State Distribution of Ions in the Intraand Extracellular Compartments of Cardiac Myocytes

Ion	Extracellular Concentration (mmol/L)	Intracellular Concentration (mmol/L)
Na⁺	135-145	10
K⁺	3.5-5.0	155
Cl⁻	95-110	20-30
Ca²⁺	2	10⁻⁴

Diagram of the Membrane Potential for Pacemaker Tissue

• Pre-Potential: The pre/pacemaker potential triggers the next impulse. At the peak of each impulse, K⁺ efflux causes repolarisation. As K⁺ efflux slows, the membrane begins to depolarise, forming the first part of the prepotential.
• Calcium Channels: Initially, T-type (transient) calcium channels open, completing the pre-potential. This is followed by the opening of L-type (long-lasting) calcium channels, producing the impulse.

Potassium and Sodium Movement

Phases of Cardiac Action Potential

1. Phase 0 (Depolarization)

   • Ionic Movement: Rapid influx of Na⁺ ions through voltage-gated Na⁺ channels (I_Na).
   • Voltage Change: Rapid rise in membrane potential from -90 mV to approximately +20 mV.

2. Phase 1 (Initial Repolarization)

   • Ionic Movement: Transient outward K⁺ current (I_to) briefly flows out of the cell.
   • Voltage Change: Slight decrease in membrane potential following the peak of depolarization.

3. Phase 2 (Plateau Phase)

   • Ionic Movement: Slow influx of Ca²⁺ ions through voltage-gated Ca²⁺ channels (I_CaL) balanced by K⁺ efflux (I_Kr, I_Ks).
   • Voltage Change: Membrane potential remains relatively stable, forming a plateau.

4. Phase 3 (Repolarization)

   • Ionic Movement: Continued efflux of K⁺ ions through delayed rectifier K⁺ channels (I_Kr, I_Ks).
   • Voltage Change: Gradual return of the membrane potential towards the resting level.

5. Phase 4 (Resting Membrane Potential)

   • Ionic Movement: Maintenance of the resting membrane potential primarily by K⁺ currents.
   • Voltage Change: Membrane potential stabilizes at around -90 mV.

Ionic Currents

• I_Na (Sodium Current): Responsible for the rapid depolarization during phase 0.
• I_to (Transient Outward Potassium Current): Contributes to the initial repolarization in phase 1.
• I_CaL (L-type Calcium Current): Maintains the plateau phase during phase 2 by allowing a slow influx of Ca²⁺.
• I_Kr, I_Ks (Delayed Rectifier Potassium Currents): Facilitate repolarization during phase 3 by allowing K⁺ efflux.

Drugs Targeting Site

Links

• Arrythmias
• Cardiac physiology
• Inotropes
• Anti-Hypertensive agents

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References:

1. Hindricks G, Potpara T, Dagres N, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation. Eur Heart J. 2020;41:373-498. escardio.org
2. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for ventricular arrhythmias and prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126. pubmed.ncbi.nlm.nih.gov
3. King GS, Goyal A, Grigorova Y, et al. Antiarrhythmic Medications. StatPearls (updated Feb 2024). ncbi.nlm.nih.gov
4. Pundi KN, Kabadi AM, Blomström-Lundqvist C, et al. Dronedarone versus sotalol in antiarrhythmic drug-naïve veterans with atrial fibrillation. Circulation Arrhythm Electrophysiol. 2023;16:e011893. pubmed.ncbi.nlm.nih.gov
5. American College of Cardiology/American Heart Association/Heart Rhythm Society. 2023 ACC/AHA/ACCP/HRS Guideline for the diagnosis and management of atrial fibrillation. Circulation. 2024;149:e936-e995. pubmed.ncbi.nlm.nih.gov
6. FRCA Mind Maps. (2024). Retrieved June 5, 2024, from https://www.frcamindmaps.org/
7. Anesthesia Considerations. (2024). Retrieved June 5, 2024, from https://www.anesthesiaconsiderations.com/
8. ICU One Pager. (2024). Retrieved June 5, 2024, from https://onepagericu.com/

Summaries:
Anti-arrythmatics

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© 2025 Francois Uys. All Rights Reserved.

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