Class 1 Antiarrhythmic Drugs

Class 1 antiarrhythmics inhibit the fast Na channels in non-nodal myocardial tissues and are subdivided into 3 categories (A, B, and C) on the basis of their speed of dissociation from the Na channels and electrophysiologic effects. All drugs in class 1 reduce cardiac conduction velocity to some degree by slowing phase 0 depolarization. Indications vary between subgroups but generally include atrial and ventricular arrhythmias. Contraindications, adverse effects, and warnings are category- and drug-dependent factors.

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Cardiac action potential

  • The trajectory followed by the action potential depends on the membrane potential of cardiac cells, which varies between different parts of the heart.
  • Phase 4: resting potential
  • Phase 0: rapid depolarization phase that occurs because of the influx of Na ions through voltage-dependent Na channels
  • Phases 1‒3:
    • Represent repolarization
    • Prominent efflux of K
    • In Phase 2, the efflux of K is balanced by the transient influx of calcium → causes the action potential to plateau

Vaughan–Williams classification

  • The most commonly used classification for antiarrhythmic drugs
  • 5 classes based on the general effects of drugs (mechanisms of action):
    • Class 1: Na channel blockers (divided into 3 subgroups):
      • 1A: prolong the action potential
      • 1B: shorten the action potential
      • 1C: minimal effect on action potential duration
    • Class 2: beta-blockers
    • Class 3: K channel blockers
    • Class 4: calcium channel blockers
    • Class 5: drugs that cannot be categorized into the above groups

Mechanism of action of Na channel blockers

Class 1 antiarrhythmics bind to and block the fast Na channels in non-nodal tissue (e.g., myocytes of the atria and ventricles, His-Purkinje system):

  • The slope of phase 0 depends on:
    • Activation of fast Na channels 
    • Rapid entry of Na ions into the cell
  • Blocking these channels:
    • ↓ Slope of phase 0 → ↓ in the amplitude of action potential
    • ↓ Velocity of action potential transmission within the heart (↓ conduction velocity; negative dromotropy)
      • Important mechanism for suppressing tachycardias caused by abnormal conduction (e.g., reentry mechanisms)
      • Reentry mechanisms can be interrupted by ↓ abnormal conduction
  • Note: Na channel blockers generally have no direct effect on nodal tissue, at least through the blockade of fast Na channels.
cardiac action potential 1 Antiarrhythmic drugs

Diagram demonstrating a cardiac action potential and the phases of action for different antiarrhythmic drug classes:
The cycle starts with phase 4, the resting potential. Phase 0 is when rapid depolarization occurs due to an influx of Na ions into the cell and where class 1 (Na channel blockers) antiarrhythmics work.
Repolarization follows, with an efflux of K through fast K channels in phase 1, Ca influx in phase 2, and efflux of K through delayed K channels in phase 3.

Image by Lecturio. License: CC BY-NC-SA 4.0

Differences among the class 1 subgroups

  • Each subgroup varies in the extent of Na channel blockade.
  • In addition to affecting phase 0 of the action potential, Na channel blockers may also alter:
    • Action potential duration
    • Effective refractory period (ERP): the period of time when a new action potential cannot be initiated
  • The table below summarizes a few of the distinguishing differences in physiologic effects between class 1 subgroups.

Electrophysiologic effects of class 1 antiarrhythmic drugs

Table: Electrophysiologic effects of the class 1 antiarrhythmic drugs
Class 1 subgroupStrength of Na channel blockadeEffect on action potential durationEffect on ERPEffect seen on ECG
  • QT prolongation
  • QRS widening
  • QT shortening
  • ↑ PR duration
1CStrongMinimal to noneMinimal to none*
  • No QT change
  • QRS widening
*Exception: ↑ ERP in the atrioventricular node
ERP: effective refractory period


To recall all class I antiarrhythmic medications, think of ordering a burger at a restaurant: “Double Quarter Pounder with Lettuce, Mayo, Pickles, and Fries, Please!”

  • Disopyramide
  • Quinidine
  • Procainamide
  • Lidocaine
  • Mexiletine
  • Phenytoin
  • Flecainide
  • Propafenone

Class 1A


  • Medications:
    • Disopyramide
    • Quinidine
    • Procainamide
  • Mnemonic for class 1A agents: “Double Quarter Pounder”

Mechanism of action

  • Na channel effects:
    • Intermediate speed of binding and dissociation from voltage-gated Na channels
    • Slows the upstroke of action potential and conduction
  • K channel effects:
    • Blocks K channels → ↓ K efflux → slows repolarization
    • Leads to ↑ ERP and action potential duration → QT prolongation
  • Other effects:
    • Anticholinergic activity → can ↑ sinoatrial rate and atrioventricular conduction
    • ↓ Myocardial contractility
  • Affects the following myocardial tissues:
    • Atria
    • Ventricular
    • Purkinje
Effect of 1A antiarrhythmics on cardiac action potential

Effect of group 1A antiarrhythmics on the cardiac action potential:
Notice the delayed phase 0 upstroke, as well as increased effective refractory period and action potential duration

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Absorption:
    • Oral, IV, and IM routes
    • Rapid and significant absorption
  • Distribution:
    • Protein binding:
      • ↑ For quinidine
      • ↓ For procainamide
    • Widely distributed
  • Metabolism:
    • Disopyramide and quinidine: hepatic metabolism by cytochrome P450
    • Procainamide: hepatic metabolism to an active metabolite (N-acetylprocainamide, implicated in torsades de pointes)
  • Excretion: predominantly renal


Due to severe side effects, such as their proarrhythmic effect, class 1A medications are usually reserved for life-threatening arrhythmias such as:

  • Ventricular arrhythmias
  • Atrial arrhythmias
  • Specific indications:
    • Wolff-Parkinson-White syndrome (procainamide)
    • Brugada syndrome (quinidine)

Adverse effects


  • Proarrhythmic
  • QT prolongation → torsades de pointes
  • Widening of the QRS complex
  • Hyperkalemia exacerbates cardiac toxicity.
  • ↑ Atrioventricular node conduction:
    • ↑ Ventricular rate in individuals with uncontrolled atrial fibrillation
    • Treatment with beta-blockers, digoxin, or calcium channel blockers is required.
  • Hypotension
  • Negative inotropes → may exacerbate heart failure
  • ↓ Presynaptic acetylcholine release at the neuromuscular junction → prolonged activity of neuromuscular blocking agents
  • Use has been associated with ↑ mortality


  • Anticholinergic side effects:
    • Xerostomia
    • Urinary retention
    • Blurred vision
    • Avoid in acute angle-closure glaucoma.
  • Numerous drug interactions


  • Drug with the highest proarrhythmic effect in its class
  • GI upset
  • Cinchonism: tinnitus, hearing loss, headache, and delirium
  • Avoid in glucose-6-phosphate-dehydrogenase (G6PD) deficiency.
  • Avoid with monoamine oxidase inhibitors (MAOIs).


  • Agranulocytosis and pancytopenia due to bone marrow suppression
  • Reversible drug-induced lupus
  • Vasculitis


  • 2nd- and 3rd-degree heart block
  • Cardiogenic shock
  • Congenital long QT syndrome
  • Myasthenia gravis: exacerbation due to anticholinergic effects
  • Avoid with fluoroquinolone antibiotics because of the risk of QT prolongation.

Class 1B


  • Medications:
    • Lidocaine
    • Mexiletine
    • Phenytoin
  • Mnemonic used for class 1B agents: “Lettuce, Mayo, Pickles”

Mechanism of action

  • Rapid binding and dissociation from voltage-gated Na channels → weakest effect on phase 0
  • ↓ ADP
  • Normal or ↓ ERP
  • Affects the following myocardial tissues:
    • Ventricular
    • Purkinje
    • Less effect on atrial tissue
    • Strongest binding in ischemic and depolarized tissues
Effect of 1B antiarrhythmics on cardiac action potential

Effect of Group 1B antiarrhythmics on the cardiac action potential. Notice the decrease in action potential duration

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Absorption:
    • Lidocaine:
      • IV only
      • Immediate and complete absorption
    • Mexiletine:
      • Oral
      • Well absorbed
    • Phenytoin:
      • Oral, IM, and IV administration
      • Poor water solubility
  • Distribution:
    • Lidocaine:
      • Plasma protein binding is dependent on drug concentration.
      • Crosses the blood-brain and placental barriers by passive diffusion
    • Mexiletine: plasma protein binding: 50%‒60%
    • Phenytoin:
      • Extensively bound to plasma proteins
      • Prone to competitive displacement
  • Metabolism:
    • Metabolized by the cytochrome P450 system
    • Lidocaine: high 1st-pass metabolism
    • Mexiletine: low 1st-pass metabolism 
  • Excretion: Metabolites and unchanged drugs are renally excreted.


  • Ventricular arrhythmias
  • Lidocaine and mexiletine are useful in treating hemodynamically stable ventricular tachycardia.
  • Phenytoin:
    • Useful for reversal of digitalis-induced arrhythmias
    • Rarely used as an antiarrhythmic
    • More commonly used as an anticonvulsant

Adverse effects

  • CNS effects:
    • Lidocaine:
      • Tremors
      • Dysarthria
      • Insomnia or drowsiness
      • Confusion
      • Seizures
    • Mexiletine:
      • Tremors
      • Dysphoria
      • Ataxia
      • Nystagmus
  • Cardiac effects:
    • Hypotension
    • Sinus slowing and bradycardia
    • Asystole
    • May precipitate arrhythmias
    • Hyperkalemia increases toxicity.
  • Phenytoin:
    • Gingival hyperplasia
    • Nystagmus
    • Ataxia
    • Nausea


  • 2nd- and 3rd-degree heart block
  • Wolff-Parkinson-White syndrome
  • Severe hepatic dysfunction (leads to restricted metabolism → ↑ toxicity)

Class 1C


  • Medications:
    • Flecainide
    • Propafenone
  • Mnemonic used for class 1C agents: “Fries, Please!”

Mechanism of action

  • Na channel effects:
    • Slows the speed of binding and dissociation from voltage-gated Na channels → ↑ effect
    • Prolongs the upstroke of the action potential (has the greatest ↓ in the slope of phase 0)
    • No (or minimal) impact on action potential duration and ERP, no effect on QT interval (exception: ↑ ERP in atrioventricular node)
  • Other effects:
    • ↓ Myocardial contractility
    • Propafenone is also used as a:
      • Beta-blocker
      • Calcium channel blocker
  • The following myocardial tissues are affected:
    • Atria
    • Ventricles
    • Purkinje fibres
Effect of 1C antiarrhythmics on cardiac action potential

Effect of group 1C antiarrhythmics on the cardiac action potential:
Notice that this group has the greatest effect on phase 0, while the action potential duration remains about the same.

Image by Lecturio. License: CC BY-NC-SA 4.0


  • Absorption:
    • Administered orally
    • Well absorbed
    • Flecainide: ↓ absorption when taken with milk
  • Distribution:
    • Flecainide: 40% protein bound
    • Propafenone: 95% protein bound
  • Metabolism:
    • Hepatic: cytochrome P450 system
    • Propafenone:
      • 2 active metabolites
      • 2 genetically distinct metabolic groups of individuals: poor and extensive metabolizers
  • Excretion: urine and feces


  • Paroxysmal atrial fibrillation/flutter
  • Prevention of paroxysmal supraventricular tachycardia
  • Prevention of ventricular arrhythmias
  • Propafenone: treatment of life-threatening ventricular arrhythmias

Adverse effects


  • Proarrhythmic effects:
    • Premature ventricular contractions
    • Ventricular tachycardia/fibrillation
    • Disturbances in K and magnesium levels can cause arrhythmias.
  • ↑ Risk of death in individuals with MI
  • May aggravate or precipitate heart failure


  • Headache
  • Dizziness
  • Dyspnea
  • Tremors


  • Metallic taste
  • Dizziness
  • Bradycardia
  • Bronchospasm possible in individuals with asthma due to beta-blockade


  • 2nd- and 3rd-degree heart block
  • Brugada syndrome
  • Structural heart disease: ↑ mortality in individuals with heart failure and MI
  • To be used with caution in individuals with hepatic and renal impairment → ↓ elimination

Comparison of Antiarrhythmic Drug Classes

Table: Comparison of antiarrhythmic drug classes 1‒4
ClassMechanism of actionEffectsArrhythmia indications
  • Block fast Na channels
  • ↓ Na entry into myocardial cells
  • Affect depolarization
  • ↓ Phase 0 slope
  • ↓ Conduction velocity in non-nodal tissues
  • Atrial and ventricular
  • WPW syndrome
1CMostly atrial
  • Block beta receptors
  • ↓ Ca influx into myocardial cells
  • Affect refractory period
  • ↓ Phase 4 slope
  • ↑ Phase 4 duration
  • ↓ Conduction velocity in nodal and non-nodal tissues
Atrial and ventricular
  • Block K channels
  • ↓ K efflux from myocardial cells
  • Affect repolarization
  • ↑ Phase 3 duration
  • Most drugs ↓ impulse transmission in non-nodal tissues
  • Amiodarone and sotalol ↓ nodal conduction
Atrial and ventricular
  • Block Ca channels
  • ↓ Ca influx into myocardial cells
  • Affect phase 2 in non-nodal tissues
  • ↓ Phase 0 slope in nodal tissues
  • ↓ Conduction velocity in nodal tissues
Ca: calcium
WPW: Wolff-Parkinson-White


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