Therapy of arrhythmias

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Therapy of Arrhythmias

Physiological Basis

Arrhythmias arise from two main mechanisms:

Abnormal automaticity - ectopic pacemaker sites outside the SA node fire due to enhanced phase 4 depolarization. Most antiarrhythmic agents suppress this by blocking Na+ or Ca2+ channels, reducing the ratio of these ions to K+ and flattening the slope of phase 4 depolarization.
Reentry - a unidirectional block (from ischemia, scarring, or prolonged refractoriness) creates a circular conduction loop. This is the most common mechanism underlying arrhythmias including atrial flutter, AVNRT, and ventricular tachycardia.

The cardiac action potential has 5 phases targeted by drugs:

Cardiac myocyte action potential - Lippincott Pharmacology

Vaughan-Williams Classification of Antiarrhythmic Drugs

Class I - Sodium Channel Blockers

These drugs show use-dependence (state-dependence): they preferentially block cells discharging at high frequency, leaving normal rhythm largely intact. Their use has declined due to proarrhythmic risk, especially in patients with reduced LV function.

Subclass	Mechanism	Drugs	Key Uses	Major Toxicities
IA	Na+ block (intermediate kinetics) + K+ block; slows phase 0, widens AP	Quinidine, Procainamide, Disopyramide	Atrial & ventricular tachyarrhythmias, pre-excited atrial arrhythmias	QT prolongation, torsades de pointes; Quinidine: cinchonism, hemolytic anemia; Procainamide: lupus-like syndrome; Disopyramide: negative inotrope, anticholinergic
IB	Na+ block (fast kinetics); shortens phase 3, may shorten AP duration	Lidocaine, Mexiletine	Ventricular tachycardias (acute); prevention of VF post-cardioversion	Neurologic: dizziness, tremor, seizures (lidocaine IV); Mexiletine: nausea/dyspepsia
IC	Na+ block (slow kinetics); no change in AP duration	Flecainide, Propafenone	Supraventricular arrhythmias in structurally normal heart	Proarrhythmic - contraindicated post-MI and in structural heart disease (CAST trial)

Goodman & Gilman's, Katzung Pharmacology

Class II - Beta-Blockers

Block sympathetic input, slow SA node automaticity and AV nodal conduction velocity.

Drugs: Metoprolol, Esmolol (IV, short-acting - for acute/peri-operative arrhythmias), propranolol
Uses: Atrial flutter, atrial fibrillation (rate control), AVNRT, SVT, ventricular rate control
Toxicity: Bradycardia, hypotension, bronchospasm, fatigue, sexual dysfunction

Class III - Potassium Channel Blockers (Prolong AP and QT)

Drug	Key Features	Uses	Toxicity
Amiodarone	Blocks IKr, INa, ICa-L, and β-receptors (all 4 classes!)	Serious ventricular arrhythmias (VT/VF), AF, SVT	Pulmonary toxicity, hepatotoxicity, thyroid dysfunction (hypo/hyper), corneal microdeposits, photosensitivity, bradycardia; many drug interactions (CYP metabolism)
Sotalol	K+ block + β-blockade	VT, AF maintenance	Torsades de pointes, bradycardia
Dofetilide	Pure IKr block	AF cardioversion/maintenance	Torsades (must initiate inpatient with ECG monitoring); renal dose adjustment
Ibutilide	K+ channel block + activates inward current (IV only)	Cardioversion of AF/atrial flutter (acute)	Torsades
Dronedarone	Amiodarone derivative, multichannel	AF (not permanent AF) - reduces cardiovascular mortality	Less effective than amiodarone; avoid in heart failure

Class IV - Calcium Channel Blockers (Non-dihydropyridines)

Block L-type Ca2+ channels in the SA and AV nodes.

Verapamil: Slows SA automaticity and AV conduction; reduces contractility. Uses: SVT, AF/flutter rate control, AVNRT. Oral and IV.
Diltiazem: Similar to verapamil. IV form used for acute rate control.
Toxicity: Bradycardia, AV block, hypotension, negative inotropy. Do NOT combine with beta-blockers IV (risk of fatal AV block).

Miscellaneous (Unclassified) Agents

Drug	Mechanism	Use	Notes
Adenosine	Activates inward K+ rectifier (IK), causing brief complete AV block	Drug of choice for acute PSVT (AVNRT/AVRT)	IV bolus only; duration 10-15 seconds; side effects: flushing, chest tightness, transient dyspnea. Blocked by theophylline; enhanced by dipyridamole
Digoxin	Na+/K+-ATPase inhibitor; indirect vagotonic effect on AV node	AF/flutter rate control, SVT	Narrow therapeutic index; toxicity: AV block, bradycardia, GI symptoms, visual disturbances (yellow-green halos); levels elevated by quinidine, amiodarone
Magnesium sulfate	Multiple ion channel effects	Torsades de pointes (first-line), digoxin toxicity arrhythmias	IV infusion
Atropine	Muscarinic antagonist	Symptomatic bradycardia, AV block	Increases SA node rate
Epinephrine	α/β-adrenergic agonist	VF not responding to defibrillation (ACLS)	Used in cardiac arrest

Drug Therapy by Arrhythmia Type

Therapeutic indications for common arrhythmias

Therapeutic indications for commonly encountered arrhythmias - Lippincott Pharmacology

Atrial Fibrillation / Flutter

Rate control: Beta-blockers (metoprolol), CCBs (verapamil, diltiazem), or digoxin
Rhythm control / cardioversion: Amiodarone, dofetilide, flecainide/propafenone (only if no structural heart disease), ibutilide (IV, acute)
Anticoagulation: Long-term oral anticoagulant therapy (warfarin or DOACs) is mandatory to reduce stroke risk

Supraventricular Tachycardias (AVNRT, AVRT)

Acute: Vagal maneuvers first; then IV adenosine (drug of choice for acute termination); IV verapamil or diltiazem as alternatives
Chronic prevention: Beta-blockers, verapamil, or catheter ablation (preferred for recurrent cases)

Ventricular Tachycardia (acute)

Hemodynamically unstable: Immediate DC cardioversion
Hemodynamically stable: IV amiodarone (preferred) or IV lidocaine

Ventricular Fibrillation

Electrical defibrillation is first-line and most important
IV amiodarone or lidocaine if refractory to defibrillation
Epinephrine during ACLS

Torsades de Pointes

IV magnesium sulfate (first-line)
Correct electrolyte abnormalities (K+, Mg2+)
Stop any QT-prolonging drug
Overdrive pacing if refractory

Bradyarrhythmias / AV Block

Acute: IV atropine, temporary pacing
Definitive: Permanent pacemaker implantation

Non-Pharmacological Therapy

Modality	Description	Indications
Electrical cardioversion (DC)	Synchronized shock timed to QRS	Hemodynamically unstable AF/flutter, VT with pulse
Defibrillation	Unsynchronized shock	VF, pulseless VT
Catheter ablation (RFA/cryoablation)	Destroys arrhythmia focus or pathway via catheter	AVNRT, AVRT (WPW), AF (pulmonary vein isolation), typical atrial flutter (CTI), VT
Implantable Cardioverter-Defibrillator (ICD)	Detects VT/VF and delivers a shock	Secondary prevention after VT/VF arrest; primary prevention in HF (EF ≤35%)
Permanent pacemaker	Electrical pacing of bradycardia	SSS, high-degree AV block, chronotropic incompetence
Vagal maneuvers	Carotid massage, Valsalva	Acute SVT (first-line before adenosine)

Proarrhythmic Risk - Important Principles

All antiarrhythmic drugs carry the risk of causing arrhythmias (proarrhythmia):

Class IA, III drugs prolong QT and can precipitate torsades de pointes
Class IC drugs are strongly contraindicated in ischemic heart disease (CAST study showed increased mortality)
Amiodarone has the lowest risk of torsades despite QT prolongation
Hypokalemia, hypomagnesemia, and bradycardia potentiate drug-induced torsades

As a result, antiarrhythmic drug prescribing requires:

Confirming a definitive arrhythmia diagnosis
Excluding or correcting precipitating factors
Establishing that benefit outweighs proarrhythmic risk
Monitoring ECG (QT interval, PR, QRS width)

Goodman & Gilman's Pharmacological Basis of Therapeutics; Katzung Basic & Clinical Pharmacology, 16th ed.; Lippincott Illustrated Reviews: Pharmacology; Braunwald's Heart Disease

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