Antiarrhythmic Drugs

Mechanisms of Arrhythmia

Altered automaticity (ectopic focus outpaces SA node) vs re-entry (unidirectional block + slow conduction → circulating impulse re-excites recovered tissue) — MOST clinically important tachyarrhythmias are re-entrant. Drugs break re-entry by: (1) slowing conduction further → unidirectional becomes bidirectional block, OR (2) prolonging refractoriness → circulating impulse meets still-refractory tissue and dies.

Vaughan-Williams Classification

Class I — subdivided by dissociation KINETICS (not potency)

IA (quinidine, procainamide, disopyramide): intermediate kinetics → ↓conduction(↑QRS) AND ↑repolarization(↑QT) — dual action, torsades risk from QT component.

IB (lidocaine, mexiletine): FAST dissociation → minimal effect on normal-rate AP, preferentially blocks depolarized/ischaemic tissue (“use-dependence”) → ischaemic ventricular arrhythmias specifically. Slightly SHORTENS repolarization. Low proarrhythmic risk.

IC (flecainide, propafenone): SLOW dissociation → strongest conduction slowing (marked ↑QRS), minimal repolarization effect. CAST trial: suppressed PVCs post-MI but ↑MORTALITY — successful arrhythmia suppression ≠ survival benefit. Now restricted to pts WITHOUT structural heart disease.

Class II — β-blockers

↓sympathetic drive to SA/AV nodes+ectopic foci. Effective: sinus tachycardia, AF/AFl rate control, catecholamine-triggered VA. PROVEN mortality benefit post-MI — most other classes lack this (CAST lesson).

Class III — K⁺ blockers

↑ERP without much ↓conduction (vs class I) — “cleaner” re-entry break, but QT-prolongation = core liability.

Amiodarone: has class I+II+III+IV actions SIMULTANEOUSLY despite III categorization. Long t½(weeks)→oral LOADING dose used. Toxicity: pulmonary fibrosis · corneal microdeposits(reversible) · thyroid dysfunction BOTH directions(iodine-rich, resembles T4 — hypo from iodine load, hyper from thyroiditis-like effect) · hepatotoxicity · blue-grey skin · photosensitivity. LOW torsades risk despite ↑QT — its Ca²⁺-blocking(IV) action protects against early afterdepolarizations — key exception to “QT-prolongers cause torsades.”

Sotalol: III + non-selective β-blocker(II). Effective but DOSE-DEPENDENT torsades risk (lacks amiodarone’s protective Ca²⁺-block) — careful QT monitoring at initiation.

Ibutilide, dofetilide: pure K⁺ blockers, acute pharmacological cardioversion of AF/AFl. Significant torsades risk → inpatient ECG-monitored initiation.

Class IV — non-DHP CCBs

Verapamil/diltiazem: ↓SA/AV conduction (nodal Ca²⁺-dependent upstroke, unlike Na⁺-dependent atrial/ventricular muscle). AVNRT + AF/AFl rate control. NEVER + β-blocker (heart block) · avoid in HF (negative inotropy) — same rules as Antianginals/Antihypertensives.

Outside Vaughan-Williams

Adenosine: A1 receptor→↑K⁺ conductance→hyperpolarize AV node→transient profound AV block. DOC for AVNRT termination. Ultra-short t½ (seconds, RBC/endothelial uptake) = deliberate feature. SE: transient flushing/chest discomfort/“impending doom,” self-limited.

Digoxin: AV ERP↑ (vagal+direct) → AF/AFl rate control, esp. if HF coexists (full detail: Drugs for Heart Failure).

MgSO4: specific for torsades de pointes (any cause) + digoxin-toxic ventricular arrhythmias.

Clinical Relevance

CAST trial = organizing lesson, not just an IC footnote: abolishing an arrhythmia on the monitor ≠ improving survival, since most classes achieve antiarrhythmic effect via mechanisms (↓conduction, altered refractoriness) that are THEMSELVES proarrhythmic, especially in structurally diseased hearts. Class II (β-blockers) = standing exception with real mortality benefit — why it stays first-line despite being the “weakest” antiarrhythmic on paper.

Basic Electrophysiology Underlying Arrhythmia

A cardiac arrhythmia arises from either an abnormality of impulse generation (altered automaticity — an ectopic focus fires faster than the SA node, or the SA node itself is suppressed/escapes are needed) or an abnormality of impulse conduction (most importantly re-entry — a self-sustaining circuit forms when a region of unidirectionally blocked, slowly-conducting tissue allows an impulse to travel around a loop and re-excite tissue that has already recovered from its refractory period). Most clinically important tachyarrhythmias are re-entrant; most antiarrhythmic drug mechanisms are best understood as ways of breaking a re-entrant circuit — either by slowing conduction further (converting unidirectional to bidirectional block, extinguishing the circuit) or by prolonging refractoriness (so the circulating impulse arrives at tissue still refractory and dies out).

The Vaughan-Williams Classification

The standard framework groups antiarrhythmics by their dominant ion-channel/receptor action, even though several agents have actions spanning more than one class:

Class I — Sodium Channel Blockers, Subdivided by Kinetics

Class I is itself subdivided by how quickly the drug dissociates from the Na⁺ channel (a fast-dissociating drug barely slows normal-rate conduction; a slow-dissociating one does so markedly) — this “kinetics of association/dissociation” idea, not the raw potency of channel block, is what actually separates the subclasses and explains their differing ECG/clinical effects:

• IA (quinidine, procainamide, disopyramide): intermediate dissociation kinetics. Slows conduction (widens QRS) AND prolongs repolarization (widens QT) — a dual action that makes IA drugs simultaneously useful for both atrial and ventricular arrhythmias and prone to a specific proarrhythmic risk (torsades de pointes) from the QT-prolonging component.
• IB (lidocaine, mexiletine): fast dissociation kinetics — binds and unbinds quickly, so it has little effect on the normal action potential at normal heart rates, but preferentially blocks depolarized/ischaemic tissue (which stays in a Na⁺-channel-inactivated, drug-accessible state longer) — this “use-dependence” is why lidocaine works well for ischaemic ventricular arrhythmias specifically and is essentially inactive orally-relevant for atrial arrhythmias. Shortens (not prolongs) repolarization slightly, low proarrhythmic risk.
• IC (flecainide, propafenone): slow dissociation kinetics — the strongest conduction-slowing of the three subclasses (marked QRS widening) with minimal effect on repolarization. Highly effective at suppressing arrhythmia acutely, but the CAST trial finding (flecainide/encainide increased mortality post-MI despite successfully suppressing PVCs) is the single most important fact in this subclass — it demonstrated that successfully treating an ECG abnormality is not the same as improving survival, and IC drugs are now restricted to patients without structural heart disease.

Class II — β-Blockers

Reduce sympathetic drive to the SA and AV nodes, slow nodal conduction, and reduce automaticity in ectopic foci that depend on catecholamine stimulation — genuinely effective for sinus tachycardia, rate control in AF/AFl, and suppressing catecholamine-triggered ventricular arrhythmia (exercise-induced, post-MI). Also carry a proven mortality benefit post-MI, a property most other antiarrhythmic classes conspicuously lack (see the CAST-trial lesson above).

Class III — Potassium Channel Blockers

Prolong the action potential and the ERP without slowing conduction velocity much (in contrast to class I) — in principle a “cleaner” way to break re-entry, though the QT-prolongation this requires is itself the class’s core liability.

• Amiodarone: the most widely used and most complex antiarrhythmic in clinical use — pharmacologically it has class I, II, III, and IV actions all at once, despite being categorized under III for its dominant K⁺-channel effect. Extremely long half-life (weeks), extensive tissue accumulation (an oral loading-dose strategy is used specifically because of this), and a distinctive, high-yield toxicity profile: pulmonary fibrosis, corneal microdeposits (reversible, usually visually insignificant), thyroid dysfunction in both directions (amiodarone is iodine-rich, structurally resembles thyroxine — can cause either hypothyroidism from the iodine load or hyperthyroidism from a direct thyroiditis-like effect), hepatotoxicity, blue-grey skin discoloration, and photosensitivity. Despite this burden, amiodarone has a comparatively low torsades de pointes risk relative to other class III agents — its concurrent Ca²⁺-channel-blocking action is thought to protect against the early afterdepolarizations that actually trigger torsades, an important and specifically examined exception to the “QT-prolonging drugs cause torsades” rule.
• Sotalol: a class III agent that is also a non-selective β-blocker (combining II and III actions) — genuinely effective but carries a dose-dependent torsades de pointes risk that amiodarone’s mechanism spares it from; requires careful QT monitoring, especially at initiation.
• Ibutilide, dofetilide: pure K⁺-channel blockers used for acute pharmacological cardioversion of atrial fibrillation/flutter — significant torsades risk, requiring inpatient initiation with ECG monitoring.

Class IV — Non-Dihydropyridine Calcium Channel Blockers

Verapamil and diltiazem slow conduction through the SA and AV nodes (nodal tissue’s action potential upstroke is Ca²⁺-dependent, unlike atrial/ventricular muscle’s Na⁺-dependent upstroke, which is why class IV agents act selectively on nodal tissue rather than on the whole heart). Effective for AV-nodal re-entrant tachycardia and ventricular rate control in AF/AFl. Never combine with a β-blocker (additive AV nodal depression → heart block) and avoid in heart failure (negative inotropy) — both restrictions echo the identical cautions already established for these same drugs in Antianginal Drugs and Antihypertensives.

Drugs Outside the Vaughan-Williams Scheme

• Adenosine: activates A1 receptors on the AV node → opens K⁺ channels, hyperpolarizes, transiently and profoundly slows/blocks AV conduction. Drug of choice for terminating AV-nodal re-entrant PSVT — its extremely short half-life (seconds, due to near-instant uptake by erythrocytes/endothelium) is a deliberate advantage, not a limitation: a single rapid IV bolus produces a brief, self-limiting AV block just long enough to interrupt the re-entrant circuit, after which normal conduction resumes on its own. Causes a characteristic transient flushing/chest discomfort/sense of impending doom that resolves within the same short window.
• Digoxin: AV-nodal ERP prolongation (vagal + direct) is useful for rate control in AF/AFl, particularly when heart failure coexists — covered fully in Drugs for Heart Failure.
• Magnesium sulfate: specific and effective for torsades de pointes regardless of which drug caused it, and for digoxin-toxicity-related ventricular arrhythmias — a mechanistically distinct rescue therapy worth knowing outside the four-class scheme entirely.

Clinical Relevance

The CAST trial is the organizing lesson for this entire topic, not just a footnote on class IC: an antiarrhythmic that successfully abolishes an arrhythmia on the monitor is not automatically a drug that helps the patient survive longer, because most Vaughan-Williams classes achieve their antiarrhythmic effect by mechanisms (slowed conduction, altered refractoriness) that are themselves capable of creating new, sometimes fatal, arrhythmias (proarrhythmia) — especially in structurally diseased hearts. Class II (β-blockers) is the standing exception with genuine mortality benefit, which is precisely why it remains first-line for so many indications despite being, in a narrow sense, the “weakest” antiarrhythmic on the list.

Diagram 1 — Re-entry Circuit Mechanism

What to draw: A loop of cardiac tissue with a region of unidirectional block (impulse cannot pass forward through it but can eventually pass backward once the rest of the loop has repolarized), showing an impulse travelling around the loop, re-exciting tissue that has already recovered, and perpetuating itself.

Labelling requirements: explicitly mark the unidirectionally blocked segment and the direction of circulating conduction — a re-entry diagram that doesn’t show why the block is one-directional (an area of slowed conduction/prolonged refractoriness relative to its neighbours) reduces the concept to “the impulse goes in a circle,” which misses the actual mechanism drugs are designed to interrupt.

Common exam-marking mistakes:

• Describing re-entry as simply “abnormal impulse generation” — it is a conduction abnormality, mechanistically distinct from an ectopic focus firing spontaneously, and the distinction determines which drug class is rational to reach for.
• Missing that antiarrhythmics break the circuit in one of two ways — either slowing conduction further until the block becomes bidirectional, or prolonging refractoriness until the circulating impulse meets tissue still refractory — both are valid mechanisms and different drug classes use different ones.

Note on the Vaughan-Williams Classification

Not rendered as a diagram — this is a classification of four drug classes by mechanism, which the table in notes.md already communicates directly (class, ion channel, effect on the action potential) without needing a flowchart to restate the same four rows.

Common exam-marking mistakes:

• Treating amiodarone as a “pure” class III agent — it has class I, II, III, and IV actions simultaneously, and its comparatively low torsades risk (versus other class III drugs) is specifically attributed to its class IV (Ca²⁺-blocking) component protecting against early afterdepolarizations.
• Assuming all Na⁺-channel blockers (class I) behave alike — the IA/IB/IC subdivision by association-dissociation kinetics, not raw channel-blocking potency, is what determines whether a drug widens the QRS, the QT, both, or neither, and which arrhythmias it is actually useful for.

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