Antiarrhythmic Drug Classes

Class I Antiarrhythmics (Sodium Channel Blockers)

• Mechanism: Block fast sodium channels (Na+ channels) in the cardiac membrane, decreasing the slope of phase 0 depolarization and slowing conduction velocity
• Effect on action potential: Decreased rate of rise of the upstroke (dV/dt), prolonged QRS duration, increased effective refractory period (ERP)
• Subclassifications:
• Class IA (Quinidine, Procainamide, Disopyramide): Moderate Na+ channel blockade + moderate K+ channel blockade → prolonged QT interval
• Class IB (Lidocaine, Mexiletine): Weak Na+ channel blockade + K+ channel blockade → shortened action potential duration (APD), minimal QT prolongation
• Class IC (Flecainide, Propafenone): Strong Na+ channel blockade with minimal K+ channel effects → marked QRS prolongation, minimal QT change

Class II Antiarrhythmics (Beta-Blockers)

• Mechanism: Block β-adrenergic receptors, reducing catecholamine-mediated effects on cardiac tissue
• Effect on nodal tissue: Decrease automaticity in the sinoatrial (SA) and atrioventricular (AV) nodes; slow AV nodal conduction velocity and increase AV nodal refractoriness
• Effect on action potential: Predominantly affects nodal tissue; minimal effect on ventricular myocardium
• Clinical context: Particularly effective for arrhythmias triggered by sympathetic activation or those dependent on AV nodal conduction

Class III Antiarrhythmics (Potassium Channel Blockers)

• Mechanism: Block potassium channels, delaying repolarization (phase 3) and prolonging action potential duration (APD)
• Effect on cardiac tissue: Increase effective refractory period (ERP) in all cardiac tissues; prolong QT interval
• Amiodarone (special case): Unique properties—possesses properties of all four Vaughan-Williams classes (IA, II, III, IV); exhibits multiple mechanisms including Na+ channel blockade, β-blockade, K+ channel blockade, and non-competitive calcium channel antagonism
• Other agents: Sotalol (also has β-blocking properties—Class II/III), Dofetilide, Ibutilide, Dronedarone

Class IV Antiarrhythmics (Calcium Channel Blockers)

• Mechanism: Block L-type calcium channels in nodal tissue (SA and AV nodes), which depend on calcium influx for phase 0 depolarization
• Effect on nodal tissue: Slow SA node automaticity and AV nodal conduction; increase AV nodal refractoriness
• Agents: Verapamil, Diltiazem (non-dihydropyridine agents)
• Minimal ventricular effect: Limited activity on ventricular myocardium since ventricular tissue primarily uses sodium channels for depolarization

Additional Classification: Class II Agents and Digoxin

• Digoxin: Works through vagomimetic effects and AV nodal slowing; increases parasympathetic tone via vagal stimulation; increases serum potassium through Na+/K+-ATPase inhibition
• Ivabradine: Selectively inhibits the "funny current" (If) in the SA node, slowing heart rate without affecting conduction or refractoriness

• Supraventricular arrhythmias: Atrial fibrillation, atrial flutter, atrioventricular reentrant tachycardia (AVNRT), atrioventricular nodal reentrant tachycardia (AVNRT), atrial tachycardia
• Ventricular arrhythmias: Ventricular tachycardia (VT), ventricular fibrillation (VF), premature ventricular contractions (PVCs) with hemodynamic consequence
• Factors favoring antiarrhythmic use:
• Hemodynamic instability from arrhythmia
• Frequent symptomatic episodes
• Failed or contraindicated catheter ablation
• Intolerance to rate control alone
• Acute conversion need (e.g., ibutilide for pharmacologic cardioversion)

• Risk factors for arrhythmia development (leading to antiarrhythmic need):
• Structural heart disease (coronary artery disease, myocardial infarction, cardiomyopathy, valvular disease)
• Electrolyte abnormalities (hypokalemia, hypomagnesemia)
• Hyperthyroidism, stimulant use (cocaine, amphetamines, caffeine)
• Autonomic activation (stress, exercise, fever)
• Pulmonary disease, sleep apnea

• Palpitations: Most common symptom; described as racing, irregular, or pounding sensation in chest
• Syncope or presyncope: Indicating hemodynamically significant arrhythmia or rapid ventricular response
• Dyspnea: From reduced cardiac output or pulmonary edema secondary to rapid rate
• Chest discomfort: May indicate ischemia precipitated or worsened by arrhythmia
• Fatigue and exercise intolerance: Chronic effects of frequent arrhythmias

Physical examination findings

• Irregular pulse: Irregularly irregular pattern in atrial fibrillation; regular rapid rate in supraventricular tachycardia (SVT)
• Signs of hemodynamic compromise: Hypotension, cool extremities, altered mental status
• Heart murmur or gallop: If underlying structural disease present
• Cannon a waves (in JVP): Suggest AV dissociation (seen in VT or complete heart block)

Side effects and toxicity presentation

• Class IA toxicity: Cinchonism (tinnitus, visual disturbances, tremor), lupus-like syndrome (procainamide)
• Class IB toxicity: Tremor, dizziness, confusion, seizures (especially lidocaine with high levels)
• Class IC toxicity: Proarrhythmia (especially in setting of structural disease)
• Class III toxicity: QT prolongation, Torsades de Pointes
• Amiodarone toxicity: Pulmonary fibrosis, hepatotoxicity, thyroid dysfunction (hypo- and hyperthyroidism), photosensitivity, blue-gray skin discoloration, corneal deposits, peripheral neuropathy
• Digoxin toxicity: Nausea, vomiting, arrhythmias (ectopic activity), visual disturbances

Electrocardiographic Diagnosis

• 12-lead ECG: Gold standard for arrhythmia identification
• Atrial fibrillation: Absent P waves, irregular ventricular response, "irregularly irregular" rhythm
• Atrial flutter: Sawtooth F waves (flutter waves), typically regular ventricular response (often 2:1 conduction)
• Supraventricular tachycardia (SVT): Regular narrow complex tachycardia; P wave may be buried in QRS or T wave
• Ventricular tachycardia: Wide complex tachycardia (QRS >120 ms), AV dissociation, fusion or capture beats (pathognomonic)
• Wolff-Parkinson-White (WPW) syndrome: Short PR interval (<120 ms), delta wave (slurred upstroke of QRS), wide QRS complex

• Holter monitor or event monitor: For detection of paroxysmal arrhythmias
• Electrophysiologic study (EPS): When arrhythmia mechanism unclear or when considering ablation; also useful for assessing drug efficacy

Laboratory Assessment

• Serum electrolytes: Hypokalemia, hypomagnesemia increase arrhythmia risk and proarrhythmic drug effects
• Thyroid function tests: Hyperthyroidism can precipitate or worsen arrhythmias (especially atrial fibrillation)
• Digoxin level: Therapeutic range 0.5–2.0 ng/mL; levels >2 ng/mL associated with toxicity
• Drug levels: Measured for Class IA agents (quinidine, procainamide) and some Class IB agents (lidocaine); therapeutic ranges guide dosing
• Liver and renal function: Important for drug metabolism and clearance
• CBC: Baseline for agents with hematologic risk (procainamide—lupus, agranulocytosis; amiodarone—thyroid effects)

Imaging

• Echocardiography: Assess for structural heart disease (ejection fraction, wall motion abnormalities, valvular disease); important prognostic information for antiarrhythmic selection
• Chest X-ray: Evaluate for cardiomegaly, pulmonary disease; baseline for amiodarone (assess for future pulmonary toxicity)
• Cardiac MRI: When structural substrate unclear (infiltrative disease, scar)

Other Diagnostic Modalities

• Exercise stress testing: Identify exercise-induced arrhythmias; assess response to beta-blockers
• Cardiac biomarkers (troponin): If arrhythmia associated with acute ischemia

Class I Antiarrhythmics (Sodium Channel Blockers)

Class IA Agents (Quinidine, Procainamide, Disopyramide)

• Quinidine:
• Mechanism: Na+ and K+ channel blockade; also has anticholinergic properties
• Indications: Atrial fibrillation/flutter, SVT, ventricular arrhythmias
• Dosing: 200–400 mg PO three times daily (varies by formulation)
• Adverse effects: Cinchonism, GI upset (diarrhea very common), lupus-like syndrome, thrombocytopenia, hypotension
• Monitoring: QRS and QT intervals; baseline and periodic CBC, ANA

• Procainamide:
• Mechanism: Na+ and K+ channel blockade
• Indications: Similar to quinidine; also used IV for acute conversion
• Dosing: 50 mg/kg IV loading, then 1–4 mg/min infusion; or 250–500 mg PO q3–6h
• Adverse effects: Lupus-like syndrome (dose and duration dependent; ~30% of patients on chronic therapy), agranulocytosis, hepatotoxicity
• Monitoring: ANA, CBC, LFTs; QRS/QT interval

• Disopyramide:
• Mechanism: Na+ channel blockade + strong anticholinergic effects
• Indications: Atrial and ventricular arrhythmias; particularly useful in hypertrophic cardiomyopathy (negative inotropic and anticholinergic effects reduce LV obstruction)
• Dosing: 150–300 mg PO three times daily (immediate release) or 300 mg PO twice daily (sustained release)
• Adverse effects: Anticholinergic (urinary retention, dry mouth, constipation, blurred vision), negative inotropic effect (contraindicated in heart failure)
• Monitoring: QRS/QT interval; urinalysis for retention

Class IB Agents (Lidocaine, Mexiletine)

• Lidocaine:
• Mechanism: Weak Na+ channel blockade; shortens APD
• Indications: Acute VT/VF in setting of acute MI; rarely used for chronic suppression
• Dosing: 1.5 mg/kg IV bolus, repeat at 0.5–0.75 mg/kg up to 3 doses; then 1–4 mg/min infusion
• Adverse effects: CNS (tremor, dizziness, confusion, seizures at high levels); less cardiotoxic than Class IA
• Monitoring: Clinical seizure activity; drug level (therapeutic 1.5–5 mcg/mL); discontinue if side effects develop
• Clinical context: First-line for acute VT/VF in acute MI, but limited role in chronic therapy (poor oral bioavailability, variable metabolism)

• Mexiletine:
• Mechanism: Oral analog of lidocaine; weak Na+ channel blockade
• Indications: Chronic suppression of ventricular arrhythmias; particularly useful in long QT syndrome (paradoxically shortens QT)
• Dosing: 150–200 mg PO three times daily
• Adverse effects: GI (nausea, vomiting, diarrhea); tremor, dizziness, confusion
• Monitoring: QRS interval; drug levels (0.5–2 mcg/mL)

Class IC Agents (Flecainide, Propafenone)

• Flecainide:
• Mechanism: Potent Na+ channel blockade; minimal K+ channel effects; markedly slows conduction
• Indications: Atrial fibrillation/flutter, SVT (AVNRT, AVRT); ventricular arrhythmias ONLY in absence of structural heart disease (CAST trial)
• Dosing: 50–100 mg PO twice daily
• Adverse effects: Proarrhythmia (life-threatening, especially in structural disease—CAST trial landmark finding); dizziness, blurred vision, tremor
• Critical caveat: Contraindicated in coronary artery disease, prior MI, cardiomyopathy, or reduced ejection fraction due to unacceptable mortality risk from proarrhythmia
• Monitoring: QRS interval (should not prolong >50% from baseline); consider EPS or stress testing

• Propafenone:
• Mechanism: Potent Na+ channel blockade + weak β-blocking and Ca2+ channel blocking properties
• Indications: Similar to flecainide; AVOID in structural heart disease
• Dosing: 150–300 mg PO three times daily (or 225–425 mg PO twice daily sustained release)
• Adverse effects: Similar to flecainide; also has negative inotropic effects; may worsen heart failure
• Drug interactions: CYP2D6 inhibitor; interacts with metoprolol, other beta-blockers

Class II Antiarrhythmics (Beta-Blockers)

• Mechanism: Reduce catecholamine effects; slow AV nodal conduction
• Agents: Metoprolol, propranolol, esmolol (IV), atenolol
• Indications:
• First-line for rate control in atrial fibrillation/flutter
• SVT (especially those triggered by catecholamines)
• Post-MI ventricular arrhythmias
• Arrhythmias in hyperthyroidism
• Arrhythmias triggered by exercise or stress

• Key advantages:
• Improve survival post-MI
• Well-tolerated with long safety record
• No direct proarrhythmic effects

• Dosing examples:
• Metoprolol: 25–100 mg PO twice daily; or 5 mg IV q5min up to 15

Proarrhythmia — the class-defining hazard

• Class IC (flecainide, propafenone): potent, use-dependent Na⁺ channel blockade worsens with tachycardia, so conduction slows most where it is already slow — reentry through infarct scar becomes sustainable. This is the mechanism behind the excess mortality seen in post-MI patients in the CAST trial; contraindicated with CAD, prior MI, or reduced EF.
• Flecainide alone in atrial flutter can slow the flutter circuit enough to permit 1:1 conduction with a very rapid wide-complex response — always pair a Class IC agent with an AV nodal blocker (ACC/AHA/ACCP/HRS 2023 atrial fibrillation guideline).
• Class IA and Class III (K⁺ channel block): prolonged repolarization → early afterdepolarizations → torsades de pointes. Risk rises with hypokalemia, hypomagnesemia, bradycardia, female sex, and QT-prolonging co-medications. Dofetilide and sotalol require in-hospital ECG-monitored initiation and renal dose adjustment; sotalol also carries beta-blocker liabilities.

Agent-specific toxicities

• Quinidine: cinchonism (tinnitus, headache, visual blurring), diarrhea, thrombocytopenia; alpha-blockade causes hypotension.
• Procainamide: drug-induced lupus (higher risk in slow acetylators — check ANA), agranulocytosis; the metabolite NAPA has Class III activity and prolongs QT.
• Disopyramide: strong antimuscarinic effect (urinary retention, glaucoma exacerbation) and negative inotropy — avoid in HFrEF, exploited therapeutically in obstructive HCM.
• Lidocaine: Na⁺ channel blockade in the CNS → perioral numbness, tremor, then seizures; intravenous lipid emulsion is the accepted rescue for local anesthetic systemic toxicity.
• Amiodarone: phospholipidosis-driven pulmonary fibrosis, hepatotoxicity, corneal microdeposits, blue-gray skin discoloration, neuropathy; its iodine load causes hypothyroidism (Wolff–Chaikoff) or hyperthyroidism (Jod–Basedow). Baseline and periodic TSH, LFTs, chest imaging/PFTs, and eye exams. Inhibits CYP/P-glycoprotein — raises digoxin and potentiates warfarin.
• Dronedarone: contraindicated in decompensated or NYHA class IV heart failure and in permanent AF.
• Verapamil/diltiazem and beta blockers: additive sinus arrest and AV block; negative inotropy limits use in HFrEF. Calcium salts and glucagon are the reversal strategies in overdose.
• Digoxin: Na⁺/K⁺-ATPase inhibition → yellow-green visual halos, nausea, bidirectional VT; digoxin-specific antibody Fab fragments are the antidote.

• "Wide-complex tachycardia in WPW with atrial fibrillation": do not give AV nodal blockers (adenosine, verapamil, diltiazem, digoxin) — blocking the node shunts conduction down the accessory pathway and can precipitate VF. Procainamide (or ibutilide) is the pharmacologic choice; synchronized cardioversion if unstable. This is the single most tested antiarrhythmic contraindication.
• Torsades de pointes: the best next step is intravenous magnesium sulfate, regardless of the serum magnesium level, because Mg²⁺ suppresses the early afterdepolarization-triggered beats. Correct K⁺, stop the offending QT-prolonging drug, and overdrive pace for recurrent bradycardia-dependent episodes.
• Structural heart disease flips the answer: with CAD, prior MI, or low EF, Class IC agents are out (CAST) and amiodarone (or sotalol/dofetilide with monitoring) becomes the reasonable option — the "pill-in-the-pocket" flecainide/propafenone strategy belongs to structurally normal hearts.
• Class IB agents shorten action potential duration and preferentially bind ischemic, depolarized ventricular tissue — hence lidocaine's niche in ischemic VT and mexiletine as adjunct in long QT syndrome type 3. Class IB does not treat atrial arrhythmias.
• Buzzword map: cinchonism → quinidine; drug-induced lupus with positive antihistone antibodies → procainamide; anticholinergic side effects plus a use in obstructive HCM → disopyramide; blue-gray skin, corneal deposits, thyroid and pulmonary disease → amiodarone; yellow-green vision → digoxin.
• Amiodarone starting a new interaction: any patient on warfarin or digoxin needs dose reduction and closer monitoring; a rising INR or digoxin level shortly after "a new antiarrhythmic" is amiodarone.
• Distractor to avoid: adenosine 6 mg IV push terminates AV-node-dependent SVT but is diagnostic-only in atrial flutter and useless in VT — do not choose it for a hemodynamically unstable patient, where electrical therapy wins. Recall that the shockable rhythms are ventricular fibrillation and pulseless ventricular tachycardia (AHA ACLS), and amiodarone or lidocaine is given only as an adjunct after defibrillation, never in place of it.
• Rate control first line in AF: beta blockers or non-dihydropyridine calcium channel blockers per the ACC/AHA/ACCP/HRS atrial fibrillation guideline — avoid verapamil/diltiazem in HFrEF.