Antiarrhythmic drugs

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Antiarrhythmic Drugs

Cardiac Action Potential - Basis of Drug Action

Before classifying these drugs, it helps to know what they target:

Cardiac action potential phases with ion movements

Phase 0 - Fast upstroke: Na+ channels open (fast inward current)
Phase 1 - Partial repolarization: Na+ channels inactivate; transient K+ outward current
Phase 2 - Plateau: Voltage-sensitive Ca2+ channels open, balancing slow K+ leak
Phase 3 - Repolarization: Ca2+ channels close; K+ channels open (outward current)
Phase 4 - Spontaneous depolarization in pacemaker cells: gradual increase in Na+ permeability drives cell toward threshold

Lippincott Illustrated Reviews: Pharmacology

Mechanisms of Arrhythmias

Two principal mechanisms:

Abnormal automaticity - Ectopic pacemaker sites fire faster than the SA node. Most antiarrhythmics suppress this by blocking Na+ or Ca2+ channels, reducing the slope of Phase 4 depolarization and/or raising the discharge threshold.
Reentry - The most common cause. A unidirectional block (from ischemia, scarring, or prolonged refractory period) allows an impulse to travel in a circuit, re-exciting myocardium. Drugs can terminate reentry by converting the unidirectional block into a bidirectional block or by prolonging the refractory period of the circuit.

Vaughan Williams Classification

The standard classification (Vaughan Williams, 1970) groups drugs by their predominant action on the cardiac action potential. Most antiarrhythmic drugs affect more than one ion current and many exert ancillary effects on contractility or the autonomic nervous system, so this classification has real limitations in clinical practice.

Goodman & Gilman's Pharmacological Basis of Therapeutics

CLASS I - Sodium Channel Blockers

Block the fast inward Na+ current (I_Na), reducing conduction velocity in fast-response tissue and increasing QRS duration. Effect is rate-dependent (use-dependent block): more block at faster heart rates.

Sub-classified by the kinetics of Na+ channel binding/unbinding (τ_recovery):

Class IA - Intermediate kinetics, also block K+ channels

These drugs slow Phase 0 AND prolong the action potential duration (APD) by also blocking K+ channels (I_Kr), extending the refractory period. They prolong the QT interval.

Drug	Key Features	Clinical Use	Notable Toxicities
Quinidine	Oldest; also antimuscarinic	AF, VT	Cinchonism (tinnitus, headache, visual disturbances), hemolytic anemia, esophagitis, torsades de pointes
Procainamide	IV/IM available	VT, pre-excited AF	Drug-induced lupus (SLE-like syndrome), hypotension, torsades via NAPA metabolite in renal failure
Disopyramide	Strong antimuscarinic effects	AF, VT	May precipitate heart failure; anticholinergic side effects (urinary retention, dry mouth)

Class IB - Fast kinetics, shorten APD

Block Na+ channels in inactivated state with rapid recovery. They do not prolong (and may actually shorten) the APD. Preferentially affect ischemic or depolarized tissue.

Drug	Route	Key Features	Toxicities
Lidocaine	IV only (high first-pass)	Drug of choice for acute ventricular arrhythmias; CNS toxicity (tremor, seizures, confusion)	Neurological symptoms (dose-related)
Mexiletine	Oral analog of lidocaine	Chronic VT, used in channelopathies (LQT3, NaV1.5 mutations)	Nausea/vomiting, dyspepsia, neurological

Class IC - Slow kinetics, minimal effect on APD

Markedly slow Phase 0 and markedly widen QRS; slow dissociation from Na+ channel means the channel does not fully recover between beats - very rate-dependent effect.

Drug	Key Features	Clinical Use	Toxicities
Flecainide	Most potent Na+ blocker in class	Supraventricular arrhythmias (AF/flutter/SVT) in structurally normal hearts	Strongly proarrhythmic in ischemic heart disease (CAST trial)
Propafenone	Also has weak beta-blocking activity	Paroxysmal AF, SVT	Bronchospasm, liver failure, agranulocytosis

CAST Trial Warning: Class IC drugs (encainide, flecainide) significantly increased mortality in post-MI patients despite suppressing PVCs. These drugs are contraindicated in structural or ischemic heart disease.

CLASS II - Beta-Adrenergic Blockers

Antagonize catecholamine effects on the heart. Primarily act on SA and AV nodes - reduce automaticity (slow Phase 4) and slow AV nodal conduction. Also have direct membrane Na+ channel blocking effects.

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

Clinical uses:

Rate control in AF and atrial flutter
AV nodal reentry tachycardia (AVNRT)
Post-MI arrhythmia prevention
Hypertrophic obstructive cardiomyopathy
CPVT (catecholaminergic polymorphic VT) - first-line

Toxicities: Bradycardia, heart block, hypotension, worsening HF, bronchospasm, fatigue, exercise intolerance, sexual dysfunction, hyperlipidemia.

CLASS III - Potassium Channel Blockers

Block outward K+ currents (mainly I_Kr), prolonging Phase 3 repolarization and extending the effective refractory period and QT interval. Increased risk of torsades de pointes if QT prolongation is excessive.

Drug	Additional Actions	Clinical Use	Important Toxicities
Amiodarone	Blocks Na+, Ca2+, K+ channels AND has alpha/beta-blocking properties; Class I+II+III+IV	AF (rate + rhythm control), VT, VF prevention; "the dirty drug"	Pulmonary toxicity (pneumonitis/fibrosis), hepatotoxicity, hypo/hyperthyroidism, corneal deposits, blue-gray skin discoloration, peripheral neuropathy, bradycardia
Dronedarone	Amiodarone analog without iodine	AF (rhythm control)	Increased mortality in severe HF; less thyroid/lung toxicity than amiodarone
Sotalol	Also non-selective beta-blocker	VT, AF	Torsades de pointes (dose-dependent QT prolongation); bradycardia
Dofetilide	Pure I_Kr blocker	AF cardioversion and maintenance	Torsades de pointes (requires in-hospital initiation)
Ibutilide	IV only; also activates inward Na+ current	AF/flutter cardioversion	Torsades de pointes

Amiodarone is the most widely used antiarrhythmic overall because of its broad effectiveness, but its adverse effect profile is extensive and long-term use requires monitoring of thyroid, liver, lungs, and eyes.

CLASS IV - Calcium Channel Blockers (Non-dihydropyridines)

Block L-type Ca2+ channels in the SA and AV nodes (which are Ca2+-dependent, "slow-response" tissue). They slow AV conduction and reduce automaticity.

Drug	Route	Key Uses	Toxicities
Verapamil	PO/IV	AVNRT, rate control in AF/flutter	Bradycardia, heart block, negative inotropy (avoid in HFrEF), constipation, gingival hyperplasia
Diltiazem	PO/IV	Rate control in AF/flutter, AVNRT	Bradycardia, heart block, peripheral edema, hypotension

Avoid verapamil/diltiazem in WPW (Wolff-Parkinson-White) with AF - they may accelerate conduction down the accessory pathway, triggering VF.

Other Antiarrhythmic Agents

Adenosine

Naturally occurring nucleoside; at high doses decreases conduction velocity, prolongs refractory period, and decreases automaticity in the AV node
Drug of choice for terminating acute SVT (AVNRT, AVRT)
Extremely short duration (~10-15 seconds) due to rapid uptake by erythrocytes and endothelial cells
Given as rapid IV bolus (6 mg, then 12 mg)
Side effects: flushing, chest pain/pressure, transient dyspnea, hypotension (all brief)
Contraindicated in asthma; can be used safely in WPW

Digoxin

Inhibits Na+/K+-ATPase; indirect vagotonic effect via increased vagal tone
Shortens atrial refractory period; prolongs AV nodal conduction and refractoriness
Rate control in AF/flutter (but sympathetic stimulation easily overcomes it)
Therapeutic trough: 1.0-2.0 ng/mL for AF; 0.5-0.9 ng/mL for HFrEF
Toxicity at >2.0 ng/mL: bradycardia, AV block, ectopic ventricular beats, VT/VF; GI symptoms; yellow/blurred vision; confusion
Risk increased by hypokalemia, hypomagnesemia, renal impairment

Magnesium Sulfate (IV)

Slows SA node impulse formation; prolongs conduction along myocardial tissue
Drug of choice for torsades de pointes (regardless of magnesium level)
Also used for digoxin-induced arrhythmias

Ranolazine

Primarily antianginal; antiarrhythmic properties similar to amiodarone
Main effect: shortens repolarization, decreases APD (via late Na+ current block)
Can suppress arrhythmias associated with the long QT syndrome

Therapeutic Indications by Arrhythmia

Lippincott Illustrated Reviews: Pharmacology

Arrhythmia	First-Line / Commonly Used
Acute SVT (AVNRT)	Adenosine IV; verapamil/diltiazem; metoprolol
Atrial flutter	Rate control: metoprolol, verapamil; Rhythm: amiodarone, dofetilide
Atrial fibrillation (rate control)	Metoprolol, diltiazem, verapamil, digoxin
Atrial fibrillation (rhythm control)	Amiodarone, flecainide (no structural disease), propafenone, dofetilide, sotalol
Acute VT (hemodynamically stable)	Amiodarone IV, lidocaine IV
VT post-MI prevention	Amiodarone, beta-blockers, ICD
VF (refractory to defibrillation)	Amiodarone IV, lidocaine, epinephrine
Torsades de pointes	IV Magnesium sulfate; correct electrolytes; temporary pacing
WPW with AF	Procainamide IV; avoid AV nodal blockers
CPVT	Beta-blockers (nadolol, propranolol); flecainide

Key Points on Proarrhythmia

All antiarrhythmic drugs can cause the very arrhythmias they are meant to treat - this is the fundamental paradox of antiarrhythmic therapy:

QT prolongation (class IA, III) raises risk of torsades de pointes - a polymorphic VT that can degenerate to VF
Class IC drugs are strongly proarrhythmic in ischemic/structural heart disease (CAST trial)
Amiodarone is the least proarrhythmic of the QT-prolonging drugs, despite its other toxicities
Risk is amplified by: hypokalemia, hypomagnesemia, bradycardia, female sex, drug-drug interactions (inhibited metabolism)

Sources:

Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 34
Katzung's Basic and Clinical Pharmacology, 16th Edition
Lippincott Illustrated Reviews: Pharmacology, Chapter 11

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