Class 5 Antiarrhythmic Drugs

Class 5 antiarrhythmic drugs are a miscellaneous group of medications that do not belong to a traditional class of antiarrhythmics. These drugs have varied mechanisms of action and uses. The medications in this class are digoxin, adenosine, Mg sulfate, and atropine. Digoxin’s antiarrhythmic effect comes from increased vagal tone and direct action on the atrioventricular node (AVN), resulting in decreased AVN conduction and sinoatrial (SA) automaticity. Digoxin can be used for atrial fibrillation (AFib), atrial flutter (AFL), and supraventricular tachycardia (SVT). Adenosine works on purinergic receptors to cause hyperpolarization, which causes decreased AVN velocity and increased refractoriness, making it a good choice for cardioversion of SVT. Magnesium’s mechanism of action is not well understood, but it does interact with multiple ion transport mechanisms and is helpful for patients with QT prolongation and torsades de pointes. Finally, atropine antagonizes muscarinic receptors and blocks vagal effects on the heart, making it useful in symptomatic and unstable bradyarrhythmias.

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Overview

Vaughan-Williams classification

This is the most commonly used classifications for antiarrhythmic drugs. There are 5 classes based on the drug class’s general effect (mechanism of action):

  • Class 1: sodium channel blockers (divided into 3 subgroups)
  • Class 2: beta-blockers
  • Class 3: potassium channel blockers
  • Class 4: calcium channel blockers (CCBs)
  • Class 5: miscellaneous agents that cannot be categorized into the above groups
    • They have no common mechanism of action.
    • Includes: 
      • Digoxin 
      • Adenosine 
      • Magnesium sulfate
      • Atropine

Digoxin

Mechanism of action

  • ↑ Vagal tone and direct action on the atrioventricular node (AVN): 
    • ↑ Refractory period → ↓ conduction velocity in the AVN
    • ↓ Sinoatrial (SA) node automaticity
    • Effect: ↓ ventricular rate in the setting of rapid supraventricular arrhythmias
  • Reversibly inhibits the Na/K-ATPase of myocytes, resulting in:
    • ↑ Intracellular Na → ↓ Na-calcium (Ca) antiporter exchange → ↓ Ca efflux 
    • ↑ intracellular Ca → ↑ Ca binding to contractile proteins → ↑ myocardial contractility 
  • May cause characteristic changes to a resting ECG (“digitalis effect”): 
    • ↑ PR interval (due to ↓ atrioventricular (AV) conduction)
    • ↓ QT interval
    • “Scooped” ST-segment depressions are the classic findings
    •  T wave flattening or inversions
Ecg typical “scooped” st-depression resulting from digoxin use

Typical “scooped” ST-segment depression resulting from digoxin use

Image: “Typical for digoxin intoxication is the oddly shaped ST-depression” by I.A.C. van der Bilt, MD. License: CC BY-NC-SA 3.0

Pharmacokinetics

  • Absorption: 
    • Routes of administration: 
      • Oral 
      • IV
    • Passive, nonsaturable absorption in the proximal small intestine
    • Food delays absorption.
  • Distribution:
    • Higher concentrations in:
      • Heart
      • Liver
      • Kidneys
      • Skeletal muscle
    • Crosses the blood-brain barrier and placenta
  • Metabolism and excretion: 
    • Minimal hepatic metabolism:
      • Approximately 16% of an absorbed dose is metabolized to active metabolites.
      • Does not interact with the cytochrome P450 system
    • Predominantly excreted in the urine (50%–70% as an unchanged drug)

Indications

  • Arrhythmia (for HR control when other therapies are ineffective or contraindicated)
    • Atrial fibrillation (AFib) or atrial flutter (AFL)
    • Supraventricular tachycardia (SVT)
  • Systolic heart failure

Adverse effects

  • Cardiac conduction abnormalities and arrhythmia
    • Paroxysmal atrial tachycardia (PAT)
    • Premature atrial or ventricular contractions
    • AV block
    • Ventricular arrhythmias
  • Other:
    • Nausea and vomiting
    • Skin rash
    • Blurred vision
    • Lethargy

Contraindications

  • Use should be avoided:
    • AV block
    • Wolff-Parkinson-White (WPW) syndrome
    • Ventricular fibrillation (V-fib)
    • Electrolyte abnormalities:
      • Hypokalemia
      • Hypomagnesemia
      • Hypercalcemia 
  • Use with caution:
    • Renal failure
    • Elderly patients 
    • Thyroid disease 
    • Acute coronary syndrome (ACS): may ↑ myocardial oxygen demand → ischemia
    • Hypertrophic cardiomyopathy (HCM) with left ventricular outflow tract obstruction
    • 2nd- or 3rd-degree heart block: unless a functioning pacemaker is placed

Drug interactions

  • ↑ AV blocking/bradycardic effect:
    • CCBs
    • Beta-blockers
    • Dronedarone
    • Lacosamide
  • ↑ Risk of toxicity due to:
    • ↑ Digoxin concentration:
      • Amiodarone
      • Quinidine
      • Spironolactone
    • Hypokalemia and/or hypomagnesemia:
      • Loop diuretics
      • Thiazide diuretics

Adenosine

Chemistry

Adenosine is a naturally occurring purine nucleoside base.

Mechanism of action

Cardiac nodal cells:

  • Adenosine type 1 receptors → G-protein activation → blocks adenylyl cyclase
  • ↓ CAMP → L-type Ca channels are deactivated and K channels are activated
  • ↓ Ca influx and ↑ K efflux → hyperpolarization and action potential suppression
  • Antiarrhythmic effect:
    • ↓ AVN conduction velocity 
    • ↑ AVN refractory period
    • Reentry circuit through the AVN is interrupted. 
    • Normal sinus rhythm is restored.

Vascular smooth muscle cells:

  • Adenosine type 2 receptors → G-protein activation → adenylyl cyclase stimulation 
  • ↑ CAMP → protein kinase activation → stimulates K channels → hyperpolarization
  • Vascular smooth muscle relaxation → vasodilation

Pharmacokinetics

  • Absorption:
    • Route of administration: IV
    • Immediate onset
  • Metabolism and excretion: 
    • Half-life: < 10 seconds
    • Rapid cellular uptake by vascular endothelium and erythrocytes
    • Metabolized intracellularly to: 
      • AMP
      • Inosine → uric acid → excreted by kidneys

Indications

  • Arrhythmias:
    • Used in cardioversion of paroxysmal SVT (PSVT) to normal sinus rhythm
    • Transient AV blockade can aid in diagnosis of a tachyarrhythmia caused by AFib or AFL.
    • Not effective for converting AFib or AFL
  • Diagnostic aid in myocardial perfusion scintigraphy:
    • Causes vasodilation of the coronary arteries → ↑ blood flow in the normal arteries but not in stenotic coronary arteries 
    • ↓ Thallium-201 uptake in stenotic arteries → allows visualization of areas with insufficient blood flow
The use of adenosine in tachyarrhythmias 5 antiarrythmics

The use of adenosine in tachyarrhythmias:
A: Adenosine can be used to convert supraventricular tachycardias (SVTs), such as atrioventricular node (AVN) reentry tachycardia. Transient blockade of the AVN (noted by the long pause) terminates the reentry circuit, allowing for the resumption of normal sinus rhythm.
B: Sometimes, the underlying rhythm is not certain. Transient AVN blockade may allow for rhythm identification in these cases. This is demonstrated by the uncovering of “sawtooth” flutter waves due to atrial flutter (AFL).

Image by Lecturio.

Adverse effects

  • Common short-lived symptoms:
    • Flushing
    • Diaphoresis
    • Dizziness
    • Chest pain 
    • Nausea
    • Anxiety 
    • Feeling of impending doom 
  • Cardiovascular events:
    • Hypotension
    • Transient or new arrhythmias:
      • AFib/AFL
      • High-degree heart block
    • Cardiac arrest
    • Myocardial ischemia
    • Cerebrovascular accident
  • Pulmonary events:
    • Dyspnea 
    • Bronchospasm

Contraindications

  • Hypersensitivity to adenosine
  • Clinically active bronchospasm
  • 2nd- or 3rd-degree AV block
  • Sick sinus syndrome (SSS)
  • Symptomatic bradycardia
  • WPW with preexcitation AFib/AFL → can cause degeneration to V-fib

Drug interactions

  • ↓ Efficacy of adenosine (adenosine receptor antagonists):
    • Caffeine
    • Theophylline
  • ↑ Effect of adenosine (AVN blockade and/or adverse effects):
    • Carbamazepine
    • Dipyridamole
    • Nicotine
    • Digoxin
    • Verapamil

Magnesium (Mg) Sulfate

Mechanism of action

  • Mg plays an important role in cardiac conduction, since it affects multiple channels:
    • Na/K-ATPase (cofactor)
    • Ca channels (blocks)
    • Na channels 
    • Some K channels 
  • Effects:
    • ↓ Influx of Ca → suppresses early afterdepolarizations
    • Stabilization of the cardiac membrane
    • ↓ SA node impulse and ↑ conduction time

Pharmacokinetics

Magnesium supplementation for arrhythmias is usually administered IV as Mg sulfate.

  • Onset of action: immediate
  • Duration of action: 30 minutes
  • Excretion: renal

Indications

Magnesium is used as an antiarrhythmic for:

  • QT prolongation and torsades de pointes
  • Digoxin toxicity
  • Other hypomagnesemia-induced arrhythmias 
    • SVT 
    • AFib/AFL
    • Ventricular tachycardia/V-fib

Adverse effects

  • Facial flushing
  • Hypotension
  • Diminished reflexes
  • Respiratory depression
  • Asystole

Warnings and precautions

Magnesium should be used with caution in patients with:

  • Neuromuscular disorders, especially myasthenia gravis (MG) → worsened symptoms
  • Renal impairment → hypermagnesemia

Drug interactions

  • Gabapentin: ↑ depressive effect 
  • Neuromuscular blocking agents: ↑ neuromuscular blocking effect
  • Dihydropyridine CCBs: ↑ risk of hypotension or muscle weakness

Atropine

Mechanism of action

  • Competitive antagonist of acetylcholine at muscarinic receptors → blocks vagal effect on the heart 
  • This leads to:
    • ↑ AVN conduction velocity
    • ↑ SA node automaticity
    • ↑ HR

Pharmacokinetics

  • Absorption:
    • Rapid
    • Well absorbed
    • Onset of action:
      • IV: almost immediate
      • IM: 15–30 minutes
  • Distribution:
    • Widely throughout the body
    • Crosses the blood-brain barrier
    • Protein binding: 14%–44%
  • Metabolism: hepatic via enzymatic hydrolysis
  • Excretion: urine

Indications

  • Arrhythmia: 
    • Symptomatic or unstable bradyarrhythmias
    • Not usually effective for:
      • 2nd-degree AV block, Mobitz type 2
      • 3rd-degree AV block
  • Other indications:
    • Muscarine-containing mushroom poisoning
    • Organophosphate poisoning
    • ↓ Salivation and respiratory secretions

Adverse effects

  • Anticholinergic effects:
    • Tachycardia
    • Pupil dilation and blurred vision
    • Dry mouth
    • Constipation
    • Urinary retention
    • Anhidrosis
    • Hallucinations and behavioral changes
  • Hypersensitivity, including anaphylactic reactions

Contraindications

  • Narrow-angle glaucoma: may precipitate acute glaucoma
  • MG: may precipitate a myasthenic crisis

Drug interactions

  • The following medications may enhance the anticholinergic effects of atropine:
    • Amantadine
    • Botulinum toxin
    • Glycopyrrolate
    • Mirabegron
  • Atropine may: 
    • ↓ The absorption of nitroglycerin
    • ↓ Therapeutic effect of acetylcholinesterase (AChE) inhibitors
    • ↑ Constipating and/or urinary retention side effects of:
      • Clozapine
      • Opioid agonists

References

  1. Levine, E. (2019). Classification of arrhythmic agents. Medscape. Retrieved August 12, 2021, from https://emedicine.medscape.com/article/2172024-overview
  2. Makielski, JC, & Eckhardt, LL. (2019). Cardiac excitability, mechanisms of arrhythmias, and action of antiarrhythmic drugs. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs
  3. Digoxin: Drug information. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/digoxin-drug-information
  4. Magnesium sulfate: Drug information. UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/magnesium-sulfate-drug-information
  5. Adenosine: Drug information.  UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/adenosine-drug-information
  6. Atropine: Drug information.  UpToDate. Retrieved July 22, 2021, from https://www.uptodate.com/contents/atropine-systemic-drug-information
  7. Hume, JR, & Grant, AO. (2012). Agents used in cardiac arrhythmias. In Katzung, BG, Masters, SB, & Trevor, AJ. (Eds.), Basic & clinical pharmacology (12th edition, pp. 227–250). https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf
  8. David, MNV, & Shetty, M. (2021). Digoxin. StatPearls. Retrieved August 26, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK556025/
  9. Singh, S, & McKintosh, R. (2021). Adenosine. StatPearls. Retrieved August 26, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK519049/
  10. Hicks, MA, & Tyagi, A. (2021). Magnesium sulfate. StatPearls. Retrieved August 26, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK554553/
  11. Voster, A. (2017). The pharmacology of amiodarone and digoxin as antiarrhythmic agents. Part I Anesthesia Refresher Course. University of Cape Town. http://www.anaesthesia.uct.ac.za/sites/default/files/image_tool/images/93/2017-29-Digoxin%20and%20Amiodarone%20%28A%20Vorster%29.pdf

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