Class 3 Antiarrhythmic Drugs

Class 3 antiarrhythmics are drugs that block cardiac tissue K channels. The medications in this class include amiodarone, dronedarone, sotalol, ibutilide, dofetilide, and bretylium. The main mechanism of action includes blocking the cardiac K channels to prolong repolarization. However, some medications in this class also exert effects on Na channels, calcium channels, and adrenergic receptors. Indications vary among the medications, but include both atrial and ventricular arrhythmias. Because these medications prolong the QT interval, torsades de pointes is a potential complication of therapy.

Last update:

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Cardiac action potential

  • The trajectory followed by the action potential will depend 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 the 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 through voltage-dependent Na channels
  • Phases 1–3:
    • Represents repolarization
    • Prominent efflux of K
    • Phase 2: efflux of K is balanced by the transient influx of calcium (Ca) → causes the action potential to plateau
The cardiac action potential

The cardiac action potential

Image: “Action Potential Heart Contraction, Illustration from Anatomy & Physiology” by OpenStax College. License: CC BY 3.0, cropped by Lecturio.

Vaughan-Williams classification

  • Most commonly used classification for antiarrhythmic drugs
  • 5 classes based on the general effect (mechanism of action) of the drug class:
    • 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: Ca channel blockers
    • Class 5: agents that cannot be categorized into the above groups
Cardiac action potential 1 antiarrhythmic drugs

Diagram demonstrating a cardiac action potential and the phases of action for different antiarrhythmic drug classes:
The cycle starts with phase 4, the resting potential. Phase 0 is when rapid depolarization happens due to an influx of sodium ions into the cell. Repolarization follows, with an efflux of potassium through fast potassium channels in phase 1, calcium influx in phase 2, and efflux of potassium through delayed potassium channels in phase 3. Potassium channel blockers typically affect phase 3.

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

General mechanism of action

  • Normal physiology:
    • Primary role of K is repolarization
    • Cardiac K channels open → efflux of K → repolarize the cell
  • K channel blockers: 
    • Bind to K channels → block K movement
    • This prevents the efflux of K → prolong repolarization (phase 3)
    • Results in ↑ action potential duration (APD) and ↑ effective refractory period (ERP)
    • Electroconvulsive therapy effect: ↑ QT interval
Image representing the action of 3 antiarrhythmics on phase 3 of the action potential

Image representing the action of class 3 antiarrhythmics on phase 3 of the action potential:
By blocking the potassium channels, phase 3 is prolonged, leading to an increase in the effective refractory period (ERP).

Image by Lecturio.

Medications within this drug class

Class 3 antiarrhythmics include a variety of medications that vary in K channel selectivity and other antiarrhythmic effects:

  • Amiodarone
  • Dronedarone 
  • Sotalol 
  • Ibutilide 
  • Dofetilide 
  • Bretylium 

Amiodarone

Mechanism of action

  • Multifactorial mechanism affecting:
    • K channels (class 3 effect) 
    • Na channels (class 1 effect)
    • Alpha- and beta-adrenergic receptors (class 2 effect)
    • Ca channels (class 4 effect)
  • Blocks rapid delayed rectifier channels (IKr) on:
    • Atrial tissue
    • Ventricular tissue
  • In addition to the typical effects of K blockers: 
    • ↓ Atrioventricular (AV) conduction 
    • ↓ Sinus node rate 
  • 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. Normal Electrocardiogram (ECG):
    • ↑ PR interval
    • Slight QRS complex widening
    • ↑ QT interval

Pharmacokinetics

  • Absorption:
    • Oral: slow
    • IV: onset of action is quicker
  • Distribution:
    • Lipophilic:
      • ↑ Volume of distribution
      • Slow to reach the intended serum concentration → long loading period
    • Distributes to a wide range of tissues
    • Protein binding: > 96%
  • Metabolism:
    • Hepatic metabolism via CYP2C8 and 3A4
    • Active metabolite
    • Note: amiodarone is an inhibitor of CYP3A4: → ↑ concentration of drugs metabolized by CYP3A4
  • Excretion: 
    • Urine
    • Bile → feces 
    • Enterohepatic recirculation (drug excreted in bile reabsorbed in the intestines)

Indications

  • Pharmacologic cardioversion and maintenance of sinus rhythm in 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
  • Rate control in critically ill individuals with hemodynamic compromise and 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 or atrial flutter Atrial flutter Atrial flutter is a regular supraventricular tachycardia characterized by an atrial heart rate between 240/min and 340/min (typically 300/min), atrioventricular (AV) node conduction block, and a "sawtooth" pattern on an electrocardiogram (ECG). Atrial Flutter 
  • Other supraventricular tachycardia Supraventricular tachycardia Supraventricular tachycardias are related disorders in which the elevation in heart rate is driven by pathophysiology in the atria. This group falls under the larger umbrella of tachyarrhythmias and includes paroxysmal supraventricular tachycardias (PSVTs), ventricular pre-excitation syndromes (i.e. Wolff-Parkinson-White syndrome), atrial flutter, multifocal atrial tachycardia, and atrial fibrillation. Supraventricular Tachycardias (SVT):
    • AV nodal reentrant tachycardia
    • AV reentrant tachycardia
    • Focal atrial tachycardia
  • Ventricular arrhythmias: 
    • Ventricular fibrillation Ventricular fibrillation Ventricular fibrillation (VF or V-fib) is a type of ventricular tachyarrhythmia (> 300/min) often preceded by ventricular tachycardia. In this arrhythmia, the ventricle beats rapidly and sporadically. The ventricular contraction is uncoordinated, leading to a decrease in cardiac output and immediate hemodynamic collapse. Ventricular Fibrillation
    • Ventricular tachycardia

Adverse effects

Adverse effects of amiodarone are seen mainly in long-term oral therapy (rather than short-term IV therapy).

Cardiovascular effects:

  • Bradycardia 
  • Atrioventricular block Atrioventricular block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block 
  • Sinoatrial arrest 
  • Prolonged QT and torsades de pointes (less common than other class 3 medications)
  • 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:
    • Most commonly seen with IV administration
    • Related to rate of medication administration

Pulmonary toxicity:

  • Pulmonary fibrosis Pulmonary Fibrosis Idiopathic pulmonary fibrosis is a specific entity of the major idiopathic interstitial pneumonia classification of interstitial lung diseases. As implied by the name, the exact causes are poorly understood. Patients often present in the moderate to advanced stage with progressive dyspnea and nonproductive cough. Pulmonary Fibrosis 
  • Eosinophilic pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia
  • Bronchiolitis obliterans Bronchiolitis obliterans Bronchiolitis obliterans is an obstructive lung disease triggered by a bronchiolar injury, which leads to inflammatory fibrosis and narrowing of the distal bronchioles. The triggering bronchiolar injury is often due to inhalation of a noxious substance, infection, or drug toxicity. Bronchiolitis Obliterans organizing pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia (BOOP)
  • Alveolar hemorrhage
  • ARDS ARDS Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema without cardiac failure. Sepsis is the most common cause of ARDS. The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). Acute Respiratory Distress Syndrome

Thyroid dysfunction: 

  • Hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
  • Hypothyroidism Hypothyroidism Hypothyroidism is a condition characterized by a deficiency of thyroid hormones. Iodine deficiency is the most common cause worldwide, but Hashimoto's disease (autoimmune thyroiditis) is the leading cause in non-iodine-deficient regions. Hypothyroidism

Hepatotoxicity:

  • ↑ Transaminases
  • Hepatitis
  • Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis 
  • Intrahepatic cholestasis

Neurologic toxicity: 

  • Peripheral neuropathy and paresthesias
  • Tremor
  • Ataxia

Ocular effects:

  • Corneal microdeposits 
  • Optic neuropathy

Cutaneous reactions: 

  • Photosensitivity
  • “Blue man syndrome” (blue-gray discoloration of the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)

Contraindications

  • Hypersensitivity to iodine 
  • Sick sinus syndrome Sick Sinus Syndrome Sick sinus syndrome (SSS), also known as sinus node dysfunction, is characterized by degeneration of the sinoatrial (SA) node, the heart's primary pacemaker. Patients with SSS may be asymptomatic or may present with tachycardia or bradycardia. Sick Sinus Syndrome 
  • 2nd- or 3rd-degree AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block 
  • Cardiogenic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock 
  • Wolff-Parkinson-White (WPW) syndrome

Drug interactions

  • QT prolongation:
    • QT-prolonging antiarrhythmics
    • Azithromycin and erythromycin
    • Domperidone
    • Antipsychotics (e.g., haloperidol, clozapine)
    • Citalopram
    • Ondansetron
  • ↑ Concentration of (due to interference with hepatic metabolism):
    • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins → ↑ of rhabdomyolysis Rhabdomyolysis Rhabdomyolysis is characterized by muscle necrosis and the release of toxic intracellular contents, especially myoglobin, into the circulation. Rhabdomyolysis
    • Digoxin → ↑ risk of digoxin toxicity
    • Warfarin → ↑ of supratherapeutic INR
  • ↑ Bradycardia effect: 
    • Beta blockers
    • 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)

Dronedarone

Mechanism of action

  • Similar to amiodarone in structure (except it lacks iodine) and mechanism 
  • Multifactorial mechanism affecting:
    • K channels (class 3 effect) 
    • Na channels (class 1 effect)
    • Alpha- and beta-adrenergic receptors (class 2 effect)
    • Ca channels (class 4 effect)

Pharmacokinetics

  • Absorption: well absorbed orally  
  • Distribution: 
    • Less lipophilic than amiodarone
    • Highly protein-bound
  • Metabolism: 
    • Extensive 1st-pass metabolism
    • Hepatic metabolism via CYP3A4
    • Active metabolite 
  • Excretion: 
    • Feces
    • Urine

Indications

  • Maintenance of sinus rhythm in individuals with:
    • 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
    • Persistent 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
  • Ineffective for pharmacologic cardioversion
  • Note: Unlike amiodarone, dronedarone is not used to treat ventricular tachyarrhythmias.

Adverse effects

  • Cardiovascular:
    • Prolonged QT interval
    • Bradycardia
  • Renal: ↑ serum creatinine 
  • GI:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Nausea and vomiting
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Dyspepsia
  • Neurologic: weakness
  • It is believed that dronedarone is less likely than amiodarone to cause:
    • Thyroid dysfunction
    • Hepatotoxicity
    • Pulmonary toxicity

Contraindications

  • Permanent 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
  • Symptomatic or severe heart failure (associated with ↑ mortality)
  • 2nd- or 3rd-degree heart block
  • Sick sinus syndrome Sick Sinus Syndrome Sick sinus syndrome (SSS), also known as sinus node dysfunction, is characterized by degeneration of the sinoatrial (SA) node, the heart's primary pacemaker. Patients with SSS may be asymptomatic or may present with tachycardia or bradycardia. Sick Sinus Syndrome
  • Concurrent QT-prolonging agents
  • Severe hepatic impairment
  • Previous amiodarone toxicity
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care and breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding

Drug interactions

  • ↑ QT prolongation: 
    • Other QT-prolonging antiarrhythmics
    • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants
    • Macrolide antibiotics
  • ↑ Serum concentration of:
    • Statins Statins Statins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides. Statins
    • Digoxin
    • Warfarin (milder than amiodarone)

Sotalol

Mechanism of action

  • Racemic mixture of d- and l-isomers
  • Dual mechanism:
    • Beta blocker (only from the l-isomer): 
      • Not cardioselective
      • No membrane-stabilizing or intrinsic sympathomimetic Sympathomimetic Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs activity
    • IKr blocker:
      • Prolongation of both atrial and ventricular action potentials
      • Effective refractory prolongation of atrial, ventricular, and atrioventricular accessory pathways 
  • Affects tissue in:
    • Atria
    • Ventricles
    • AV node
    • Antegrade and retrograde bypass tracts (if present)
  • 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. Normal Electrocardiogram (ECG) effects:
    • ↑ QT interval (HR-rate dependent): longer with slower HRs
    • Slight ↑ PR interval

Pharmacokinetics

  • Absorption:
    • Well absorbed orally 
    • ↓ Absorption with food
  • Distribution: 
    • Hydrophilic
    • Not protein-bound
  • Metabolism: none
  • Excretion: urine

Indications

  • Atrial arrhythmias (maintenance of sinus rhythm after cardioversion):
    • Atrial fibrillation
    • Atrial flutter
  • Ventricular arrhythmias

Adverse effects

  • Cardiovascular:
    • 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
    • Bradycardia
    • AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block
    • QT prolongation and torsades de pointes
  • Neurologic:
    • Dizziness
    • Fatigue
    • Asthenia (weakness/lack of energy)
    • Headache
  • Pulmonary: 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
  • GI:
    • Nausea and vomiting 
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Contraindications

  • Sinus bradycardia
  • 2nd- or 3rd-degree AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block
  • Sick sinus syndrome Sick Sinus Syndrome Sick sinus syndrome (SSS), also known as sinus node dysfunction, is characterized by degeneration of the sinoatrial (SA) node, the heart's primary pacemaker. Patients with SSS may be asymptomatic or may present with tachycardia or bradycardia. Sick Sinus Syndrome
  • Prolonged QT
  • Decompensated heart failure or cardiogenic shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock
  • Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Bronchospastic disease
  • Severe renal impairment

Drug interactions

  • QT prolongation:
    • QT-prolonging antiarrhythmics
    • Macrolide antibiotics
    • Citalopram
    • Antipsychotics
    • Methadone
    • Ondansetron
  • ↑  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
    • Antipsychotics
    • Barbiturates
    • Antihypertensives
    • Pentoxifylline
  • ↑ Bradycardia: 
    • Beta blockers
    • Alpha-2 agonists 
    • Rivastigmine
  • ↓ Serum concentration of sotalol: antacids

Ibutilide

Mechanism of action

  • IKr blocker
  • Activates slow inward Na currents
  • Affects: 
    • Atria
    • Ventricles
  • 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. Normal Electrocardiogram (ECG):
    • ↑ QT interval (HR-dependent)
    • No change to PR or QRS

Pharmacokinetics

  • IVAbsorption:
    • Route of administration: IV 
    • Poor oral bioavailability
  • Metabolism:
    • Hepatic
    • 1 active metabolite 
  • Excretion:  
    • Urine (primary) 
    • Feces 

Indications

Ibutilide is used to pharmacologically convert AF or atrial flutter Atrial flutter Atrial flutter is a regular supraventricular tachycardia characterized by an atrial heart rate between 240/min and 340/min (typically 300/min), atrioventricular (AV) node conduction block, and a "sawtooth" pattern on an electrocardiogram (ECG). Atrial Flutter to sinus rhythm.

Adverse effects

  • Prolonged QT interval and torsades de pointes 
  • Monomorphic ventricular tachycardia Ventricular tachycardia Ventricular tachycardia is any heart rhythm faster than 100 beats/min, with 3 or more irregular beats in a row, arising distal to the bundle of His. Ventricular tachycardia is the most common form of wide-complex tachycardia, and it is associated with a high mortality rate. Ventricular Tachycardia
  • Supraventricular tachycardia 
  • Headache

Drug interactions

Increased QT prolongation can occur with:

  • QT-prolonging antiarrhythmics
  • Macrolide antibiotics
  • Citalopram
  • Antipsychotics
  • Methadone
  • Ondansetron

Dofetilide

Mechanism of action

  • IKr-selective
  • 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. Normal Electrocardiogram (ECG):
    • ↑ QT interval (HR-dependent)
    • No change to PR or QRS

Pharmacokinetics

  • Absorption:
    • Well absorbed orally
    • Bioavailability: > 90% 
  • Metabolism: 
    • Hepatic metabolism via CYP3A4
    • Inactive metabolites
  • Excretion: urine

Indications

Dofetilide is used for cardioversion and maintenance of sinus rhythm in 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 and atrial flutter Atrial flutter Atrial flutter is a regular supraventricular tachycardia characterized by an atrial heart rate between 240/min and 340/min (typically 300/min), atrioventricular (AV) node conduction block, and a "sawtooth" pattern on an electrocardiogram (ECG). Atrial Flutter.

Adverse effects

  • Cardiovascular:
    • Prolonged QT interval and torsades de pointes 
    • Ventricular fibrillation Ventricular fibrillation Ventricular fibrillation (VF or V-fib) is a type of ventricular tachyarrhythmia (> 300/min) often preceded by ventricular tachycardia. In this arrhythmia, the ventricle beats rapidly and sporadically. The ventricular contraction is uncoordinated, leading to a decrease in cardiac output and immediate hemodynamic collapse. Ventricular Fibrillation and/or tachycardia
    • Bradycardia 
  • CNS:
    • Dizziness 
    • Headache
    • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache 
    • 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
  • GI:
    • Nausea
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea

Contraindications

  • Congenital or acquired prolonged QT syndromes
  • Severe renal impairment

Drug interactions

  • Avoid medications that prolong QT interval.
  • Drugs that inhibit CYP3A4 → ↑ serum dofetilide:
    • Ketoconazole
    • Erythromycin
    • Verapamil
    • Metformin

Bretylium

Mechanism of action

  • IKr blocker affecting:
    • Purkinje fibers
    • Ventricular tissue
  • Blocks release of norepinephrine from nerve terminals → ↓ sympathetic activity

Pharmacokinetics

  • Route of administration: 
    • IV
    • IM
  • Distribution: not protein-bound
  • Metabolism: not metabolized
  • Excretion: urine

Indications

Bretylium is used for ventricular arrhythmias:

  • Prophylaxis or treatment
  • Consider if arrhythmia is resistant to conventional therapies

Adverse effects

  • Cardiovascular:
    • 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
    • Bradycardia
    • Dizziness
  • GI:
    • Nausea
    • Vomiting 

Contraindications

  • Digoxin toxicity (digitalis-induced arrhythmia)
  • Renal impairment

Comparison of Antiarrhythmic Drug Classes

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

Table: Comparison of antiarrhythmic drug classes 1–4
Class Mechanism of action Effects Arrhythmia indications
1 1A
  • Block fast Na channels
  • ↓ Na entry into myocardial cells
  • Affects depolarization
  • ↓ Phase 0 slope
  • ↓ Conduction velocity in nonnodal tissue
  • Atrial and ventricular
  • WPW syndrome
1B Ventricular
1C Mostly 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 out of myocardial cells
  • Affects repolarization
  • ↑ Phase 3 duration
  • Most ↓ 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

References

  1. Roden, D. M. (2016). Pharmacogenetics of potassium channel blockers. Card Electrophysiol Clin 8:385–393. Retrieved September 23, 2021, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893809/
  2. Kumar, K., Zimetbaum, P. J. (2020). Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: clinical trials. UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/antiarrhythmic-drugs-to-maintain-sinus-rhythm-in-patients-with-atrial-fibrillation-clinical-trials
  3. Makielski, J. C., Eckhardt, L. L. L. (2019). Cardiac excitability, mechanisms of arrhythmia, and action of antiarrhythmic drugs. UpToDate. Retrieved September 22, 2021, from https://www.uptodate.com/contents/cardiac-excitability-mechanisms-of-arrhythmia-and-action-of-antiarrhythmic-drugs
  4. Giardina, E. G., Passman, R. (2021). Amiodarone: Adverse effects, potential toxicities, and approach to monitoring. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/amiodarone-adverse-effects-potential-toxicities-and-approach-to-monitoring
  5. Giardina, E. G., Passman, R. (2021). Amiodarone: Clinical uses. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/amiodarone-clinical-uses
  6. Passman, R., Giardina, E. G. (2020). Clinical uses of dronedarone. UpToDate. Retrieved September 21, 2021, from https://www.uptodate.com/contents/clinical-uses-of-dronedarone
  7. Giardin, E. G., Passman, R. (2020). Clinical uses of sotalol. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/clinical-uses-of-sotalol
  8. Giardina, E.G. (2020). Therapeutic use of ibutilide. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/therapeutic-use-of-ibutilide
  9. Woosley, R. L., Passman, R., Giardina, E. G. (2021). Clinical use of dofetilide. UpToDate. Retrieved September 23, 2021, from https://www.uptodate.com/contents/clinical-use-of-dofetilide
  10. Somberg, J., Molnar, J. (2020). What is new in pharmacologic therapy for cardiac resuscitation? Cardiology Research 11:141–144. Retrieved September 22, 2021, from https://cardiologyres.org/index.php/Cardiologyres/article/view/1058/1056
  11. Hume, J. R., Grant, A. O. (2012). Agents used in cardiac arrhythmias. In Katzung, B. G., Masters, S. B., and Trevor, A. J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, pp. 227–250. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

User Reviews

0.0

()

¡Hola!

Esta página está disponible en Español.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details