Overview
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
- Class 1: Na channel blockers (divided into 3 subgroups):
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.
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.
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
| Class 1 subgroup | Strength of Na channel blockade | Effect on action potential duration | Effect on ERP | Effect seen on ECG |
|---|---|---|---|---|
| 1A | Intermediate | ↑ | ↑ |
|
| 1B | Weak | ↓ | ↓ |
|
| 1C | Strong | Minimal to none | Minimal to none* |
|
ERP: effective refractory period
Mnemonic
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
Overview
- 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 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
Pharmacokinetics
- Absorption:
- Oral, IV, and IM routes
- Rapid and significant absorption
- Distribution:
- Protein binding:
- ↑ For quinidine
- ↓ For procainamide
- Widely distributed
- Protein binding:
- 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
Indications
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
General:
- 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
Disopyramide:
- Anticholinergic side effects:
- Xerostomia
- Urinary retention
- Blurred vision
- Avoid in acute angle-closure glaucoma.
- Numerous drug interactions
Quinidine:
- 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).
Procainamide:
- Agranulocytosis and pancytopenia due to bone marrow suppression
- Reversible drug-induced lupus
- Vasculitis
Contraindications
- 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
Overview
- 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 Group 1B antiarrhythmics on the cardiac action potential. Notice the decrease in action potential duration
Image by Lecturio. License: CC BY-NC-SA 4.0Pharmacokinetics
- Absorption:
- Lidocaine:
- IV only
- Immediate and complete absorption
- Mexiletine:
- Oral
- Well absorbed
- Phenytoin:
- Oral, IM, and IV administration
- Poor water solubility
- Lidocaine:
- 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
- Lidocaine:
- 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.
Indications
- 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
- Lidocaine:
- Cardiac effects:
- Hypotension
- Sinus slowing and bradycardia
- Asystole
- May precipitate arrhythmias
- Hyperkalemia increases toxicity.
- Phenytoin:
- Gingival hyperplasia
- Nystagmus
- Ataxia
- Nausea
Contraindications
- 2nd- and 3rd-degree heart block
- Wolff-Parkinson-White syndrome
- Severe hepatic dysfunction (leads to restricted metabolism → ↑ toxicity)
Class 1C
Overview
- 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 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.
Pharmacokinetics
- 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
Indications
- Paroxysmal atrial fibrillation/flutter
- Prevention of paroxysmal supraventricular tachycardia
- Prevention of ventricular arrhythmias
- Propafenone: treatment of life-threatening ventricular arrhythmias
Adverse effects
General:
- 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
Flecainide:
- Headache
- Dizziness
- Dyspnea
- Tremors
Propafenone:
- Metallic taste
- Dizziness
- Bradycardia
- Bronchospasm possible in individuals with asthma due to beta-blockade
Contraindications
- 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
| Class | Mechanism of action | Effects | Arrhythmia indications | |
|---|---|---|---|---|
| 1 | 1A |
|
|
|
| 1B | Ventricular | |||
| 1C | Mostly atrial | |||
| 2 |
|
| Atrial and ventricular | |
| 3 |
|
| Atrial and ventricular | |
| 4 |
|
| Atrial | |
WPW: Wolff-Parkinson-White
References
- Kumar, K., Zimetbaum, P. (2021). Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Clinical trials. In Knight, B. (Ed.), UpToDate. Retrieved June 19, 2021, from https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials
- Makielski, J., Eckhardt, L. (2021). Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs. In Levy, S. (Ed.), UpToDate. Retrieved June 19, 2021, from https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs
- Kumar, K. (2021). Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations. In Zimetbaum, P, Knight, B. (Ed.), UpToDate. Retrieved June 19, 2021, from https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-recommendations
- Giardina, E.G. (2021). Major side effects of class I antiarrhythmic drugs. In Zimetbaum, P. (Ed.), UpToDate. Retrieved June 19, 2021, from https://www.uptodate.com/contents/major-side-effects-of-class-i-antiarrhythmic-drugs
- Wyse, D.G., Waldo, A.L., DiMarco, J.P., et al. (2002). A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med; 347, 1825. https://pubmed.ncbi.nlm.nih.gov/12466506/
- Falk, R.H. (2001). Atrial fibrillation. N Engl J Med; 344, 1067. https://pubmed.ncbi.nlm.nih.gov/11287978/
- Dan, G.A., Martinez-Rubio, A., Agewall, S., et al. (2018). Antiarrhythmic drugs-clinical use and clinical decision making: a consensus document from the European Heart Rhythm Association (EHRA) and European Society of Cardiology (ESC) Working Group on Cardiovascular Pharmacology, endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS) and International Society of Cardiovascular Pharmacotherapy (ISCP). Europace; 20, 731. https://pubmed.ncbi.nlm.nih.gov/29438514/
- Mitchell, L.B. (2021). Drugs for arrhythmias. MSD Manual Professional Version. Retrieved July 11, 2021, from https://www.msdmanuals.com/professional/cardiovascular-disorders/arrhythmias-and-conduction-disorders/drugs-for-arrhythmias#v21365769
- King, S., et al. (2021). Antiarrhythmic medications. StatPearls. Retrieved July 11, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK482322/
