anti arrythmics
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Vaughan Williams antiarrhythmic drug classification action potential
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Antiarrhythmic Drugs
Mechanisms of Arrhythmia (Context)
Arrhythmias arise from two main mechanisms:
- Abnormal automaticity — ectopic pacemaker activity
- Reentry — a unidirectional block allows an impulse to travel retrogradely and re-excite proximal tissue, generating a circus loop
Antiarrhythmic drugs modify impulse generation and conduction to suppress these mechanisms. A critical caveat: many are proarrhythmic themselves, particularly by prolonging the QT interval → risk of torsades de pointes (TdP).
Vaughan-Williams Classification
The dominant framework, grouping drugs by their predominant effect on the cardiac action potential. Note its limitations — many drugs span multiple classes (amiodarone acts on all four), and some drugs (adenosine, digoxin) don't fit at all.
Class I — Sodium Channel Blockers
Block fast inward Na⁺ channels → slow Phase 0 depolarization. Subclassified by kinetics of Na⁺ channel binding:
| Subclass | Kinetics | Potency | Effect on AP | Drugs |
|---|---|---|---|---|
| IA | Intermediate | Moderate | Slows Phase 0; prolongs repolarization (↑QT) | Quinidine, Procainamide, Disopyramide |
| IB | Fast | Low | Slows Phase 0; shortens Phase 3 repolarization (↓QT) | Lidocaine, Mexiletine |
| IC | Slow | High | Markedly slows Phase 0; minimal effect on repolarization | Flecainide, Propafenone |
Class IA
Quinidine
- Blocks Na⁺, IKr, IKs, Ito, and KATP channels; also α-adrenergic and anticholinergic effects
- Prolongs QT via IKr block (reverse use-dependent — more effect at slow rates → TdP risk)
- Unique use: Brugada syndrome and idiopathic VF (blocks Ito)
- Side effects: Cinchonism (tinnitus, visual disturbances, headache), hemolytic anemia, esophagitis, QT prolongation, TdP
- Hemodynamics: vasodilation via α-blockade → hypotension
Procainamide
- Similar to quinidine but less anticholinergic
- Active metabolite NAPA has Class III (K⁺ channel blocking) properties
- Key adverse effect: Lupus-like syndrome (ANA positive in 80%; symptomatic in ~30% with long-term use), also hypotension
Disopyramide
- Strongest anticholinergic effects of the class → dry mouth, urinary retention, blurred vision, constipation
- Negative inotrope — avoid in heart failure
Class IB
Lidocaine
- IV only (extensive first-pass if oral)
- Preferentially affects ischemic/depolarized tissue (use-dependent)
- Primary use: ventricular arrhythmias, especially post-MI and reperfusion
- Side effects: CNS — tremor, ataxia, paresthesias, confusion, seizures (dose-dependent)
Mexiletine
- Oral analogue of lidocaine
- Used for ventricular arrhythmias and long QT syndrome type 3
- Side effects: N/V, dyspepsia, CNS effects
Class IC
Flecainide & Propafenone
- Most potent Na⁺ channel blockers; markedly slow conduction
- Highly effective for AF/flutter rhythm control and SVT
- ⚠️ CAST trial: Flecainide/encainide increased mortality post-MI → contraindicated in structural heart disease (ischemic or LV dysfunction)
- Propafenone also has mild β-blocking and weak Ca²⁺ channel effects
- Propafenone-specific: bronchospasm, liver toxicity, agranulocytosis
Class II — Beta-Adrenergic Blockers
Block β₁ receptors → inhibit Phase 4 (pacemaker) depolarization in SA and AV nodes → ↓ heart rate, ↓ AV conduction
Key agents: Metoprolol, Atenolol, Esmolol (IV, ultra-short acting), Carvedilol, Propranolol
Uses:
- SVT, atrial flutter/AF (rate control)
- Post-MI (reduce sudden cardiac death)
- Hypertrophic cardiomyopathy, long QT syndrome
Side effects: Bradycardia, heart block, hypotension, bronchospasm (non-selective), fatigue, exercise intolerance, sexual dysfunction, hyperlipidemia
Class III — Potassium Channel Blockers
Block K⁺ channels (primarily Kv11.1 / IKr, encoded by KCNH2) → prolong Phase 2–3 repolarization → ↑ action potential duration → ↑ QT interval
⚠️ QT prolongation is both the therapeutic mechanism and the primary risk (TdP)
| Drug | Key Features |
|---|---|
| Amiodarone | Acts on all 4 classes; most effective AAD overall; extensive toxicity with long-term use |
| Sotalol | Also a potent β-blocker (Class II + III); prominent QT prolongation |
| Dofetilide | Pure IKr blocker; QT prolongation greatest at slow rates (reverse use-dependence); used for AF/flutter |
| Ibutilide | IV only; used solely for acute cardioversion of AF/flutter |
| Dronedarone | Amiodarone analogue without iodine; milder multi-channel effects; less toxicity but contraindicated in permanent AF or decompensated HF |
Amiodarone (Special Focus)
Properties of all four Vaughan-Williams classes:
- Na⁺ channel block (Class I)
- β-blockade (Class II)
- K⁺ channel block — prolongs action potential (Class III, dominant)
- Ca²⁺ channel block (Class IV)
Uses: AF (cardioversion and maintenance), VT/VF, hemodynamically unstable VT
Toxicity (long-term): The most extensive toxicity profile of any AAD:
- Pulmonary toxicity (pneumonitis/fibrosis) — most serious
- Thyroid dysfunction (hypo- or hyperthyroidism — contains 37% iodine by weight)
- Hepatotoxicity
- Corneal microdeposits (nearly universal; rarely affects vision)
- Photosensitivity, blue-grey skin discoloration
- Peripheral neuropathy
- Half-life of 40–55 days → interactions persist long after stopping
Class IV — Calcium Channel Blockers (Non-dihydropyridines)
Block L-type Ca²⁺ channels in SA and AV nodes → ↓ automaticity and AV conduction
Agents: Verapamil, Diltiazem
Uses: SVT (rate control), AF/flutter (rate control), AVNRT
Side effects: Bradycardia, AV block, hypotension, constipation (verapamil)
⚠️ Avoid in WPW — blocking the AV node can accelerate conduction down the accessory pathway
Drugs Outside the Vaughan-Williams Schema
Adenosine
- IV, ultra-short acting (half-life ~10 seconds)
- Activates K⁺ channels in AV node → transient complete AV block
- Drug of choice for terminating AVNRT and diagnosing SVT
- Causes transient flushing, dyspnea, chest tightness — reassure patient
Digoxin
- Inhibits Na⁺/K⁺-ATPase → increases intracellular Ca²⁺ → positive inotropy
- Increases vagal tone → slows AV node conduction (rate control in AF)
- Narrow therapeutic index; toxicity: arrhythmias, N/V, visual changes (xanthopsia)
- Levels increased by hypokalemia, hypomagnesemia
Ranolazine
- Blocks late Na⁺ current (INa-late) → shortens action potential (similar to IB)
- Also K⁺ channel effects
- Used for refractory atrial and ventricular arrhythmias, often in combination
- Well tolerated (dizziness, constipation); avoid strong CYP3A inhibitors/inducers
Clinical Selection Pearls
| Situation | Preferred Agent(s) | Avoid |
|---|---|---|
| Post-MI VT/VF prevention | β-blockers (metoprolol) | Flecainide, Class IA |
| AF rhythm control, structurally normal heart | Flecainide, Propafenone, Sotalol | — |
| AF rhythm control + HF | Amiodarone, Dofetilide | Flecainide, Propafenone, Dronedarone |
| Acute SVT (AVNRT) termination | Adenosine | — |
| SVT/AF rate control | β-blockers, Verapamil, Diltiazem | — |
| VT in ischemic cardiomyopathy | Amiodarone, Sotalol | Class IC agents |
| Brugada syndrome | Quinidine | Na⁺ channel blockers (Class I generally) |
| Long QT type 3 | Mexiletine, Ranolazine | Class IA, III (further QT prolongation) |
| Hemodynamically unstable VT (acute) | Amiodarone IV, Lidocaine IV | — |
| Acute AF cardioversion | Ibutilide IV | — |
Proarrhythmic Risk Summary
All antiarrhythmic drugs carry proarrhythmic potential. The major mechanisms:
- QT prolongation → TdP: Class IA (quinidine, disopyramide), Class III (sotalol, dofetilide, ibutilide), amiodarone (less than others despite QT prolongation)
- Increased mortality in structural heart disease: Class IC (CAST trial)
- Reverse use-dependence: K⁺ channel blockers are most dangerous at slow heart rates (sotalol, dofetilide)
Sources: Lippincott Illustrated Reviews: Pharmacology; Harrison's Principles of Internal Medicine, 22e (2025); Braunwald's Heart Disease, 10e; Goldman-Cecil Medicine
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