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Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)

Class 1 antiarrhythmics inhibit the fast Na channels Channels The Cell: Cell Membrane in non-nodal myocardial tissues and are subdivided into 3 categories (A, B, and C) on the basis of their speed of dissociation Dissociation Defense Mechanisms from the Na channels Channels The Cell: Cell Membrane and electrophysiologic effects. All drugs in class 1 reduce cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) conduction velocity to some degree by slowing phase 0 depolarization Depolarization Membrane Potential. Indications vary between subgroups but generally include atrial and ventricular arrhythmias. Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation, adverse effects, and warnings are category- and drug-dependent factors.

Last updated: 14 Mar, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential

  • The trajectory followed by the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential depends on the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential of cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) cells, which varies between different parts of the heart.
  • Phase 4: resting potential
  • Phase 0: rapid depolarization Depolarization Membrane Potential phase that occurs because of the influx of Na ions through voltage-dependent Na channels Channels The Cell: Cell Membrane
  • Phases 1‒3:
    • Represent repolarization Repolarization Membrane Potential
    • Prominent efflux of K
    • In Phase 2 Phase 2 Skin: Structure and Functions, the efflux of K is balanced by the transient influx of calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes → causes the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential to plateau Plateau Cardiac Physiology

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 Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential
      • 1B: shorten the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential
      • 1C: minimal effect on action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration
    • Class 2: beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers)
    • Class 3: K channel blockers K Channel Blockers Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers)
    • Class 4: calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (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 BIND Hyperbilirubinemia of the Newborn to and block the fast Na channels Channels The Cell: Cell Membrane in non-nodal tissue (e.g., myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology of the atria and ventricles, His-Purkinje system):

  • The slope of phase 0 depends on:
  • Blocking these channels Channels The Cell: Cell Membrane:
    • ↓ Slope of phase 0 → ↓ in the amplitude of action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential
    • ↓ Velocity of action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential transmission within the heart (↓ conduction velocity; negative dromotropy Dromotropy Dromotropy is the modulation of conduction velocity through the AV node Cardiac Physiology)
      • 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 Channels The Cell: Cell Membrane.
Cardiac action potential 1 antiarrhythmic drugs

Diagram demonstrating a cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential and the phases of action for different antiarrhythmic drug classes:
The cycle Cycle The type of signal that ends the inspiratory phase delivered by the ventilator Invasive Mechanical Ventilation starts with phase 4, the resting potential. Phase 0 is when rapid depolarization Depolarization Membrane Potential occurs due to an influx of Na ions into the cell and where class 1 (Na channel blockers) antiarrhythmics work.
Repolarization Repolarization Membrane Potential follows, with an efflux of K through fast K channels Channels The Cell: Cell Membrane in phase 1 Phase 1 Skin: Structure and Functions, Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) influx in phase 2 Phase 2 Skin: Structure and Functions, and efflux of K through delayed K channels Channels The Cell: Cell Membrane in phase 3 Phase 3 Skin: Structure and Functions.

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 Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential, Na channel blockers may also alter:
    • Action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration
    • Effective refractory period (ERP): the period of time when a new action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane 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 subgroup Strength of Na channel blockade Effect on action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration Effect on ERP Effect seen on ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Electrocardiogram (ECG)
1A Intermediate
  • QT prolongation
  • QRS widening
1B Weak
  • QT shortening
  • ↑ PR duration
1C Strong Minimal to none Minimal to none*
  • No QT change
  • QRS widening
*Exception: ↑ ERP in the atrioventricular node Atrioventricular node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. Heart: Anatomy
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:
  • K channel effects:
  • Other effects:
    • Anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs 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 Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential:
Notice the delayed phase 0 upstroke, as well as increased effective refractory period and action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration

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

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Oral, IV, and IM routes
    • Rapid and significant absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
  • Distribution:
    • Protein binding:
      • ↑ For quinidine
      • ↓ For procainamide
    • Widely distributed
  • Metabolism:
    • Disopyramide and quinidine: hepatic metabolism by cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury
    • Procainamide: hepatic metabolism to an active metabolite (N-acetylprocainamide, implicated in torsades de pointes Torsades de pointes A malignant form of polymorphic ventricular tachycardia that is characterized by heart rate between 200 and 250 beats per minute, and QRS complexes with changing amplitude and twisting of the points. The term also describes the syndrome of tachycardia with prolonged ventricular repolarization, long qt intervals exceeding 500 milliseconds or bradycardia. Torsades de pointes may be self-limited or may progress to ventricular fibrillation. Ventricular Tachycardia)
  • 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 Wolff-Parkinson-White Syndrome A form of ventricular pre-excitation characterized by a short PR interval and a long QRS interval with a delta wave. In this syndrome, atrial impulses are abnormally conducted to the heart ventricles via an accessory conducting pathway that is located between the wall of the right or left atria and the ventricles, also known as a bundle of kent. The inherited form can be caused by mutation of prkag2 gene encoding a gamma-2 regulatory subunit of amp-activated protein kinase. Supraventricular Tachycardias (procainamide)
    • Brugada syndrome Brugada syndrome An autosomal dominant defect of cardiac conduction that is characterized by an abnormal st-segment in leads v1-v3 on the electrocardiogram resembling a right bundle-branch block; high risk of ventricular tachycardia; or ventricular fibrillation; syncopal episode; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac sodium channel alpha subunit. Ventricular Tachycardia (quinidine)

Adverse effects

General:

  • Proarrhythmic
  • QT prolongation → torsades de pointes Torsades de pointes A malignant form of polymorphic ventricular tachycardia that is characterized by heart rate between 200 and 250 beats per minute, and QRS complexes with changing amplitude and twisting of the points. The term also describes the syndrome of tachycardia with prolonged ventricular repolarization, long qt intervals exceeding 500 milliseconds or bradycardia. Torsades de pointes may be self-limited or may progress to ventricular fibrillation. Ventricular Tachycardia
  • Widening of the QRS complex QRS complex Electrocardiogram (ECG)
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia exacerbates cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) toxicity Toxicity Dosage Calculation.
  • Atrioventricular node Atrioventricular node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. Heart: Anatomy conduction:
    • ↑ Ventricular rate in individuals with uncontrolled atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation
    • Treatment with beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers), digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides, or calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) is required.
  • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Negative inotropes Inotropes Hypoplastic Left Heart Syndrome (HLHS) → may exacerbate heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)
  • ↓ Presynaptic acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology at the neuromuscular junction Neuromuscular junction The synapse between a neuron and a muscle. Skeletal Muscle Contraction → prolonged activity of neuromuscular blocking agents
  • Use has been associated with ↑ mortality Mortality All deaths reported in a given population. Measures of Health Status

Disopyramide:

Quinidine:

  • Drug with the highest proarrhythmic effect in its class
  • GI upset
  • Cinchonism: tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies, hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, and delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
  • Avoid in glucose-6-phosphate-dehydrogenase ( G6PD G6PD Pentose Phosphate Pathway) deficiency.
  • Avoid with monoamine oxidase Oxidase Neisseria inhibitors ( MAOIs MAOIs Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors).

Procainamide:

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • 2nd- and 3rd-degree heart block
  • Cardiogenic shock Cardiogenic shock Shock resulting from diminution of cardiac output in heart disease. Types of Shock
  • Congenital long QT syndrome Congenital long QT syndrome Long QT Syndrome
  • Myasthenia gravis Myasthenia Gravis Myasthenia gravis (MG) is an autoimmune neuromuscular disorder characterized by weakness and fatigability of skeletal muscles caused by dysfunction/destruction of acetylcholine receptors at the neuromuscular junction. MG presents with fatigue, ptosis, diplopia, dysphagia, respiratory difficulties, and progressive weakness in the limbs, leading to difficulty in movement. Myasthenia Gravis: exacerbation due to anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs effects
  • Avoid with fluoroquinolone antibiotics because of the risk of QT prolongation.

Class 1B

Overview

  • Medications:
    • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics
    • Mexiletine
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs
  • Mnemonic used for class 1B agents: “Lettuce, Mayo, Pickles”

Mechanism of action

  • Rapid binding and dissociation Dissociation Defense Mechanisms from voltage-gated Na channels Channels The Cell: Cell Membrane → 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 Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential. Notice the decrease in action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration

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

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics:
      • IV only
      • Immediate and complete absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption
    • Mexiletine:
      • Oral
      • Well absorbed
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs:
      • Oral, IM, and IV administration
      • Poor water solubility
  • Distribution:
    • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics:
      • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein binding is dependent on drug concentration.
      • Crosses the blood-brain and placental barriers by passive diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis
    • Mexiletine: plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products protein binding: 50%‒60%
    • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs:
      • Extensively bound to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis
      • Prone to competitive displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms
  • Metabolism:
    • Metabolized by the cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury system
    • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics: high 1st-pass metabolism
    • Mexiletine: low 1st-pass metabolism 
  • Excretion: Metabolites and unchanged drugs are renally excreted.

Indications

  • Ventricular arrhythmias
  • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics and mexiletine are useful in treating hemodynamically stable ventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children.
  • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs:
    • Useful for reversal of digitalis-induced arrhythmias
    • Rarely used as an antiarrhythmic
    • More commonly used as an anticonvulsant Anticonvulsant Anticonvulsant drugs are pharmacological agents used to achieve seizure control and/or prevent seizure episodes. Anticonvulsants encompass various drugs with different mechanisms of action including ion-channel (Na+ and Ca+2) blocking and GABA reuptake inhibition. First-Generation Anticonvulsant Drugs

Adverse effects

  • CNS effects:
    • Lidocaine Lidocaine A local anesthetic and cardiac depressant used as an antiarrhythmic agent. Its actions are more intense and its effects more prolonged than those of procaine but its duration of action is shorter than that of bupivacaine or prilocaine. Local Anesthetics:
      • Tremors
      • Dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson’s Disease
      • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia or drowsiness
      • Confusion
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
    • Mexiletine:
      • Tremors
      • Dysphoria
      • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
      • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
  • Cardiac Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) effects:
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Sinus slowing and bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
    • Asystole Asystole No discernible electrical activity, flatline on electrocardiogram (P waves and QRS complexes are not present). Cardiac Arrest
    • May precipitate arrhythmias
    • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia increases toxicity Toxicity Dosage Calculation.
  • Phenytoin Phenytoin An anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs. First-Generation Anticonvulsant Drugs:
    • Gingival hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation
    • Nystagmus Nystagmus Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. Albinism
    • Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • 2nd- and 3rd-degree heart block
  • Wolff-Parkinson-White syndrome Wolff-Parkinson-White Syndrome A form of ventricular pre-excitation characterized by a short PR interval and a long QRS interval with a delta wave. In this syndrome, atrial impulses are abnormally conducted to the heart ventricles via an accessory conducting pathway that is located between the wall of the right or left atria and the ventricles, also known as a bundle of kent. The inherited form can be caused by mutation of prkag2 gene encoding a gamma-2 regulatory subunit of amp-activated protein kinase. Supraventricular Tachycardias
  • Severe hepatic dysfunction (leads to restricted metabolism → ↑ toxicity Toxicity Dosage Calculation)

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 Dissociation Defense Mechanisms from voltage-gated Na channels Channels The Cell: Cell Membrane → ↑ effect
    • Prolongs the upstroke of the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential (has the greatest ↓ in the slope of phase 0)
    • No (or minimal) impact on action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration and ERP, no effect on QT interval QT interval Electrocardiogram (ECG) (exception: ↑ ERP in atrioventricular node Atrioventricular node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. Heart: Anatomy)
  • Other effects:
    • ↓ Myocardial contractility
    • Propafenone is also used as a:
      • Beta-blocker
      • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes 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 Cardiac Total Anomalous Pulmonary Venous Return (TAPVR) action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential:
Notice that this group has the greatest effect on phase 0, while the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential duration remains about the same.

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

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Administered orally
    • Well absorbed
    • Flecainide: ↓ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption when taken with milk
  • Distribution:
    • Flecainide: 40% protein bound
    • Propafenone: 95% protein bound
  • Metabolism:
    • Hepatic: cytochrome P450 Cytochrome P450 A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism. Drug-induced Liver Injury system
    • Propafenone:
      • 2 active metabolites
      • 2 genetically distinct metabolic groups of individuals: poor and extensive metabolizers
  • Excretion: urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat and feces

Indications

  • Paroxysmal atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation/flutter
  • Prevention of paroxysmal supraventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children
  • Prevention of ventricular arrhythmias
  • Propafenone: treatment of life-threatening ventricular arrhythmias

Adverse effects

General:

  • Proarrhythmic effects:
    • Premature Premature Childbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization). Necrotizing Enterocolitis ventricular contractions
    • Ventricular tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children/fibrillation
    • Disturbances in K and magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes levels can cause arrhythmias.
  • ↑ Risk of death in individuals with MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • May aggravate or precipitate heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR)

Flecainide:

  • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
  • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Tremors

Propafenone:

  • Metallic taste
  • Dizziness Dizziness An imprecise term which may refer to a sense of spatial disorientation, motion of the environment, or lightheadedness. Lateral Medullary Syndrome (Wallenberg Syndrome)
  • Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias
  • Bronchospasm Bronchospasm Asthma Drugs possible in individuals with asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma due to beta-blockade

Contraindications Contraindications A condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks). Noninvasive Ventilation

  • 2nd- and 3rd-degree heart block
  • Brugada syndrome Brugada syndrome An autosomal dominant defect of cardiac conduction that is characterized by an abnormal st-segment in leads v1-v3 on the electrocardiogram resembling a right bundle-branch block; high risk of ventricular tachycardia; or ventricular fibrillation; syncopal episode; and possible sudden death. This syndrome is linked to mutations of gene encoding the cardiac sodium channel alpha subunit. Ventricular Tachycardia
  • Structural heart disease: ↑ mortality Mortality All deaths reported in a given population. Measures of Health Status in individuals with heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) and MI MI MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction
  • To be used with caution in individuals with hepatic and renal impairment → ↓ elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy

Comparison of Antiarrhythmic Drug Classes

Table: Comparison of antiarrhythmic drug classes 1‒4
Class Mechanism of action Effects Arrhythmia indications
1 1A
  • ↓ Phase 0 slope
  • ↓ Conduction velocity in non-nodal tissues
  • Atrial and ventricular
  • WPW syndrome
1B Ventricular
1C Mostly atrial
2
  • Block beta receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
  • Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) influx into myocardial cells
  • Affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment refractory period
  • ↓ Phase 4 slope
  • ↑ Phase 4 duration
  • ↓ Conduction velocity in nodal and non-nodal tissues
Atrial and ventricular
3 Atrial and ventricular
4
  • Block Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) channels Channels The Cell: Cell Membrane
  • Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts) influx into myocardial cells
  • Affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment phase 2 Phase 2 Skin: Structure and Functions in non-nodal tissues
  • ↓ Phase 0 slope in nodal tissues
  • ↓ Conduction velocity in nodal tissues
Atrial
Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts): calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes
WPW: Wolff-Parkinson-White

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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/
  6. Falk, R.H. (2001). Atrial fibrillation. N Engl J Med; 344, 1067. https://pubmed.ncbi.nlm.nih.gov/11287978/
  7. 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/
  8. 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
  9. King, S., et al. (2021). Antiarrhythmic medications. StatPearls. Retrieved July 11, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK482322/

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