Class 2 Antiarrhythmics

Class 2 antiarrhythmics include beta-blockers, which exert their therapeutic effects by blocking epinephrine and norepinephrine from binding to the beta-adrenergic receptors in cardiac tissue. The outcome is an antiarrhythmic effect, which results from decreased sinoatrial node activity and increased atrioventricular conduction time and refractory period. Additional effects include decreased cardiac contractility, afterload, and blood pressure. Class 2 antiarrhythmics are used in the management of atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular arrhythmias. Adverse effects include bradycardia, hypotension, bronchospasm, fluid retention, and fatigue. Beta-blockers should not be used in individuals with decompensated heart failure, shock, and severe bradycardia.

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Chemistry and Pharmacodynamics

Definition

Class 2 antiarrhythmics include beta-blockers, which competitively inhibit epinephrine and norepinephrine from binding to the beta-adrenergic receptors on vascular and cardiac cells.

Chemical structure

  • Contain an aromatic or heteroaromatic ring with an amine group
  • Propranolol is the prototype drug.
  • Most clinically used beta-blockers are delivered as racemates, except timolol.
Chemical structure of propranolol

Chemical structure of propranolol

Image: “Chemical structure of propranolol” by catclock. License: Public Domain

Mechanism of action

  • Beta-blockers competitively inhibit the beta-adrenergic receptors:
    • Nonselective agents that bind to and induce antagonistic effects at both beta-1 (B1) and beta-2 (B2) receptors
    • Cardioselective agents only bind to B1 receptors.
  • Receptor locations:
    • B1: 
      • Sinoatrial (SA) node
      • Atrioventricular (AV) node
      • Atrial and ventricular muscle
      • Kidneys
    • B2:
      • Blood vessels
      • Bronchi
      • GI tract
      • Uterus
      • Liver
      • Urinary tract
  • Action on cardiac cells:
    • Block the binding of catecholamines (epinephrine) to G-protein-coupled receptors (B1 receptor) → inhibit activation of adenylyl cyclase
    • ↓ Conversion of ATP to cAMP → ↓ protein kinase A activation
    • Calcium (Ca) channels are not phosphorylated → do not open → ↓ Ca influx into the myocardial cells
    • Nodal effect:
      • ↓ SA node activity
      • ↑ AV node conduction time and refractory period
      • ↓ Slope and prolonged phase 4

Physiologic effects

  • Antiarrhythmic effects:
    • Negative chronotropic effects (HR)
    • Negative dromotropic effects:
      • Delays speed and ability to instigate an action potential
      • ↓ Conduction velocity
    • Prolonged refractory period
    • Membrane-stabilizing activity (MSA) and intrinsic sympathomimetic activity (ISA) do not have a major impact on antiarrhythmic potency.
  • B1 blockade:
    • ↓ Oxygen demand:
      • ↓ HR 
      • ↓ Contractility 
      • ↓ Afterload
      • ↓ Blood pressure
    • ↑ Oxygen supply (indirectly):
      • Prolongs diastole
      • Improves perfusion
  • B2 blockade:
    • Vasoconstriction
    • Bronchoconstriction
  • Alpha-1 (A1) blockade:
    • Seen with carvedilol
    • Further ↓ afterload due to ↓ systemic vascular resistance (SVR)
  • ECG effects: PR prolongation

Adrenergic receptor types and their properties

Table: Adrenergic receptor types and their properties
Receptor locationResponse to stimulusResponse to blockade
B1 receptors
HeartSA node↑ HR↓ HR
Atria↑ Contractility and conduction speed↓ Contractility and conduction speed
AV node and His-Purkinje fibers↑ Automaticity and conduction speed↓ Automaticity and conduction speed
Ventricles↑ Contractility, automaticity, conduction speed↓ Contractility, automaticity, conduction speed
KidneyJG cells↑ Renin release↓ Renin release
B2 receptors
Arteries
  • Carotid
  • Coronary
  • Peripheral
VasodilationVasoconstriction
LungsBronchiolar smooth muscleBronchodilationBronchoconstriction
BladderWallRelaxationContraction
LiverHepatic tissueStimulates glycogenolysis
  • ↓ Insulin secretion
  • ↓ Glycogenolysis
A1 receptors
ArteriesPeripheralVasoconstrictionVasodilation
BladderSphincterContractionRelaxation
AV: atrioventricular
SA: sinoatrial
JG: juxtaglomerular

Additional properties of beta-blockers

Some beta-blockers can exhibit the following properties and effects:

Table: Properties of beta-blockers
Beta-blocker propertyEffect
ISAPartial stimulation of B receptors → suboptimal lowering of HR (avoid post-MI)
MSADrug can ↓ cardiac conduction velocity by blocking myocyte Na+ channels
NODrug stimulates NO production → peripheral vasodilation
ISA: intrinsic sympathomimetic activity
MSA: membrane-stabilizing activity

Classification

Class 2 antiarrhythmics can be classified based on their beta-receptor selectivity:

  • Cardioselective beta-blockers (B1 receptors):
    • Acebutolol
    • Atenolol
    • Betaxolol
    • Bisoprolol
    • Esmolol
    • Metoprolol
  • Noncardioselective beta-blockers (B1 and B2 receptors):
    • Nadolol
    • Propranolol
    • Timolol
    • Carvedilol (also has A1 receptor-blocking activity)

Pharmacokinetics

Absorption

  • Most drugs are rapidly and completely absorbed from the GI tract.
  • ↓ Rate of absorption:
    • Elderly
    • Individuals with renal failure

Distribution

  • Rapid distribution within the body
  • Protein binding is variable.
  • Lipophilic agents can cross the blood-brain barrier.

Metabolism

  • Most lipophilic agents undergo significant 1st-pass hepatic metabolism:
    • Carvedilol
    • Metoprolol
    • Propranolol
  • Some drugs are converted to their active metabolites.
  • Hydrophobic compounds tend to undergo limited hepatic metabolism.

Excretion

  • Hepatic metabolism (lipophilic agents) → bile
  • Hydrophilic agents → renal excretion
  • Impaired liver and kidney function can ↓ rate of elimination

Indications

Arrhythmia

Class 2 antiarrhythmics are used in the management of:

  • Atrial fibrillation
  • Atrial flutter
  • Supraventricular tachycardias
  • Ventricular arrhythmias

Additional uses

Beta-blockers, as a class, encompass FDA approvals for treating:

  • Coronary heart disease:
    • Angina
    • Post-MI
  • Essential tremors
  • Glaucoma (timolol)
  • Heart failure with reduced ejection fraction
  • Hypertension
  • Hypertrophic subaortic stenosis
  • Migraine prophylaxis
  • Pheochromocytoma; adjunct
  • Variceal hemorrhage prophylaxis

Indications for class 2 antiarrhythmic medications

Table: Properties of beta-blockers
MedicationArrhythmiaAnginaMICHFHypertensionMSA
Atenolol*
  • Afib/flutter
  • SVT
  • V
XXX
Betaxolol*AfibXX
Bisoprolol*
  • Afib/flutter
  • V
XXX
Metoprolol*
  • Afib/flutter
  • SVT
  • V
XXXXX
Esmolol*
  • Afib/flutter
  • SVT
  • V
X
Acebutolol*VXXXX
Nadolol
  • Afib
  • SVT
  • V
XXX
Propranolol
  • Afib/flutter
  • SVT
  • V
XXXX
TimololAfibXXX
CarvedilolAfib/flutterXXXXX
* denotes cardioselective beta-blockers
MSA: membrane-stabilizing activity
Afib: atrial fibrillation
SVT: supraventricular tachycardia
V: ventricular arrhythmias
CHF: congestive heart failure

Adverse Effects and Contraindications

Adverse effects

  • Cardiovascular:
    • Bradycardia
    • Hypotension
    • Heart failure exacerbation (with initial therapy)
    • Withdrawal with discontinuation that can precipitate (from ↑ sympathetic activity):
      • MI (in individuals with coronary artery disease)
      • Ventricular tachyarrhythmias
      • Sudden cardiac death
  • CNS:
    • Fatigue
    • Depression
    • Vivid dreams
    • Sexual dysfunction
  • Respiratory: bronchoconstriction
  • Endocrine:
    • Hypoglycemia
    • Hyperglycemia (usually in individuals with noninsulin-dependent diabetes mellitus)
    • Dyslipidemia
    • Weight gain
    • Fluid retention
  • Dermatologic: potential exacerbation of psoriasis

Contraindications

  • Decompensated heart failure
  • Cardiogenic shock
  • Hypotension
  • Severe bradycardia
  • 2nd- or 3rd-degree AV block
  • Sick-sinus syndrome (unless a pacemaker is present)
  • Severe reactive airway disease
  • Pulmonary hypertension (esmolol)

Drug interactions

  • Enhance bradycardia:
    • Ca-channel blockers
    • Amiodarone
    • A2 agonists
    • Digoxin
  • Enhanced hypoglycemia:
    • Sulfonylureas
    • Insulin
  • Excessive vasoconstriction: ergot alkaloids

Comparison of Antiarrhythmic Drug Classes

The following table compares antiarrhythmic classes 1‒4. Class 5 is not included due to the varied mechanisms of action and effects.

Table: Comparison of antiarrhythmic drug classes 1‒4
ClassMechanism of actionEffectsArrhythmia indications
11A
  • Block fast Na channels
  • ↓ Na entry into myocardial cells
  • Affects depolarization
  • ↓ Phase 0 slope
  • ↓ Conduction velocity in nonnodal tissue
  • Atrial and ventricular
  • WPW
1BVentricular
1CMostly atrial
2
  • Block beta receptors
  • ↓ Ca influx into myocardial cells
  • Affects refractory period
  • ↓ Phase 4 slope
  • ↑ Phase 4 duration
  • ↓ Conduction velocity in nodal and nonnodal tissue
Atrial and ventricular
3
  • Block K channels
  • ↓ K efflux from myocardial cells
  • Affects repolarization
  • ↑ Phase 3 duration
  • Most drugs ↓ impulse transmission in nonnodal tissue
  • Amiodarone and sotalol also ↓ nodal conduction
Atrial and ventricular
4
  • Block Ca channels
  • ↓ Ca influx into myocardial cells
  • Affects phase 2 in nonnodal tissue
  • ↓ Phase 0 slope in nodal tissue
  • ↓ Conduction velocity in nodal tissue
Atrial
AV: atrioventricular
Ca: calcium
SA: sinoatrial
WPW: Wolff-Parkinson-White syndrome

References

  1. Hall, J.E., Guyton, A.C. (2016). The Autonomic Nervous System and the Adrenal Medulla. Guyton and Hall Textbook of Medical Physiology, 13e. Philadelphia, PA: Elsevier.
  2. Opie, L.H. (2013). β-blocking agents. Drugs for the Heart, 8e. Philadelphia, PA: Elsevier Saunders.
  3. Pencina, M.J., Navar, A.M., Wojdyla, D., et al. (2019). Quantifying Importance of Major Risk Factors for Coronary Heart Disease. Circulation; 139, 1603–1611. https://doi.org/10.1161/CIRCULATIONAHA.117.031855.
  4. Benjamin, E.J., Muntner, P., Alonso, A., Bittencourt, M.S., et al. (2019). Heart disease and stroke statistics—2019 update: A report from the American Heart Association. Circulation; 139:e56–e528. https://doi.org/10.1161/CIR.0000000000000659.
  5. Lipton, R.B., Stewart, W.F., Diamond, S., et al. (2001). Prevalence and burden of migraine in the United States: Data from the American Migraine Study II. Headache; 41, 646–657. https://doi.org/10.1046/j.1526-4610.2001.041007646.x.
  6. Jackson, J.L., Kuriyama, A., Kuwatsuka, Y., et al. (2019). Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis. PLoS One; 14, e0212785. https://doi.org/10.1371/journal.pone.0212785.
  7. De Leo, S., Lee, S.Y., Braverman, L.E. (2016). Hyperthyroidism. The Lancet; 388, 906–918. http://dx.doi.org/10.1016/S0140-6736(16)00278-6.
  8. Podrid, P. (2020). Major side effects of beta blockers. In Levy, S. (Ed.) UpToDate. Retrieved June 13, 2021, from https://www.uptodate.com/contents/major-side-effects-of-beta-blockers.
  9. Kannam, J., Gersh, B. (2021). Beta blockers in the management of chronic coronary syndrome. Verheugt, F. UpToDate. Retrieved June 13, 2021, from https://www.uptodate.com/contents/beta-blockers-in-the-management-of-chronic-coronary-syndrome.

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