Antiarrhythmic Drugs — Pharmacology

Definition & Mechanism of Arrhythmias

Arrhythmias arise from two fundamental mechanisms:

Abnormal automaticity — ectopic pacemaker cells depolarize spontaneously outside the SA node
Re-entry — a unidirectional block creates a short-circuit pathway that re-excites cardiac muscle

Antiarrhythmic drugs suppress arrhythmias by modulating ion channel flow or altering autonomic function.

Vaughan–Williams Classification

The Singh–Vaughan–Williams classification groups drugs by their predominant effect on the cardiac action potential across four classes.

Class I — Sodium Channel Blockers

Block fast Na⁺ channels → slow Phase 0 depolarization → reduce conduction velocity

Class IA — Quinidine, Procainamide, Disopyramide

Block open and inactivated Na⁺ channels (intermediate dissociation)
Also block K⁺ channels → prolonged Phase 3 repolarization → ↑ effective refractory period (ERP) → QT prolongation
Quinidine: additional α-blocking + anticholinergic actions; causes cinchonism (tinnitus, blurred vision, headache)
Procainamide: IV only; causes lupus-like syndrome, hypotension; metabolized to NAPA (active Class III metabolite)
Disopyramide: strongest anticholinergic (dry mouth, urinary retention); negative inotrope

Uses: Atrial + ventricular tachyarrhythmias, AF rhythm control

Class IB — Lidocaine, Mexiletine

Preferentially bind inactivated Na⁺ channels (fast dissociation)
Shorten Phase 3 repolarization → shorter action potential duration
Most effective in ischemic tissue (depolarized cells accumulate drug)
Lidocaine: IV only; CNS toxicity (tremor, seizures, confusion)
Mexiletine: oral analog of lidocaine

Uses: Ventricular arrhythmias (VT, VF), especially post-MI

Class IC — Flecainide, Propafenone

Markedly slow Phase 0 (slow dissociation); pronounced effect at normal heart rates
Minimal effect on repolarization
CAST trial warning: Increased mortality in post-MI patients with structural heart disease

Uses: AF/flutter without structural heart disease ("pill-in-the-pocket" for AF)

$Class IA antiarrhythmic drug action on cardiac action potential — showing slowed Phase 0 and prolonged refractory period$

Class IA drugs: block open/inactivated Na⁺ channels, slow Phase 0, prolong ERP — Lippincott Pharmacology

Class II — β-Adrenergic Blockers

Drugs: Atenolol, Metoprolol, Esmolol (IV, ultra-short)

Block β₁ receptors → inhibit Phase 4 spontaneous depolarization in SA and AV nodes
↓ heart rate, ↓ AV conduction velocity, ↑ PR interval
Uses: Rate control in AF/flutter, SVT, post-MI arrhythmias
Adverse effects: Bradycardia, heart block, bronchospasm, worsening HF

Class III — Potassium Channel Blockers

Block K⁺ channels → prolong Phase 3 repolarization → ↑ action potential duration → ↑ ERP → QT prolongation

Drug	Key Features
Amiodarone	Class I+II+III+IV actions; longest half-life (~40–55 days); pulmonary fibrosis, thyroid toxicity, hepatotoxicity, corneal deposits, photosensitivity; drug of choice for VT/VF
Sotalol	Also has Class II (β-blocking) activity; risk of torsades de pointes
Dofetilide	Pure K⁺ blocker; AF/flutter; QT monitoring mandatory
Ibutilide	IV; acute cardioversion of AF/flutter

Uses: Ventricular arrhythmias, AF rate/rhythm control

Class IV — Calcium Channel Blockers

Drugs: Verapamil, Diltiazem (non-dihydropyridines)

Block L-type Ca²⁺ channels → slowed Phase 0 and Phase 4 in SA/AV nodes (Ca²⁺-dependent tissue)
↓ AV conduction → prolongs PR interval
Uses: SVT termination, rate control in AF/flutter
Adverse effects: Bradycardia, AV block, hypotension, negative inotropy

Miscellaneous (Unclassified) Antiarrhythmics

Drug	Mechanism	Key Use
Adenosine	Activates K⁺ channels → hyperpolarizes AV node; t½ ~10–15 sec	Drug of choice for acute SVT
Digoxin	Inhibits Na⁺/K⁺-ATPase → ↑ vagal tone → slows AV conduction	Rate control in AF (overcome by sympathetics)
Magnesium sulfate	Slows SA node + AV conduction; membrane stabilizer	Drug of choice for torsades de pointes + digoxin toxicity

Key Proarrhythmic Risks (Important!)

All antiarrhythmics can be proarrhythmic — they can cause the very arrhythmias they treat
QT prolongation → torsades de pointes (TdP): Class IA, IC, III drugs; also macrolide antibiotics + antipsychotics
CAST trial: Class IC drugs ↑ mortality post-MI → avoid in structural heart disease
Risk ↑ with hypokalemia, hypomagnesemia, or drug combinations inhibiting metabolism

Sources: Lippincott Illustrated Reviews: Pharmacology; Goodman & Gilman's Pharmacological Basis of Therapeutics; Harrison's Principles of Internal Medicine 22E

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