Antiarrhythmic Agents
Chapter 45: Antiarrhythmic Agents
The Conducting System of the Heart
The heart's electrical conduction system comprises specific structures responsible for generating and transmitting electrical impulses, leading to coordinated cardiac muscle contraction.
SA node: Sinoatrial node, often called the natural pacemaker, initiates the electrical impulse.
AV node: Atrioventricular node, receives impulses from the atria and delays them before transmitting to the ventricles.
Bundle of His: A bundle of specialized muscle fibers that transmit electrical impulses from the AV node to the ventricles.
Left and Right Atrium: Upper chambers of the heart.
Left and Right Ventricle: Lower chambers of the heart.
Left bundle branch: Part of the bundle of His that conducts impulses to the left ventricle.
Right bundle branch: Part of the bundle of His that conducts impulses to the right ventricle.
Purkinje fibers: Specialized conductive fibers that rapidly distribute impulses throughout the ventricular muscle, causing contraction.
Five Phases of the Action Potential of the Cardiac Muscle Cell
The action potential in cardiac muscle cells is a rapid change in membrane voltage that allows for electrical signal propagation and muscle contraction. It consists of five distinct phases:
Phase 0 (Depolarization): Occurs when the cell reaches a point of stimulation. Fast sodium ion (\text{Na}^{+}) channels open, leading to a rapid influx of \text{Na}^{+} ions, causing rapid depolarization (the membrane potential becomes positive).
Phase 1 (Early Repolarization): A short period following depolarization when the fast \text{Na}^{+} channels close, and there is a decreased permeability of sodium. There's a small, transient outward current of potassium (\text{K}^{+}) ions.
Phase 2 (Plateau Stage): Occurs as the cell membrane becomes less permeable to potassium, and calcium (\text{Ca}^{2+}) slowly enters the cell through L-type calcium channels. This influx of \text{Ca}^{2+} balances the outward \text{K}^{+} current, maintaining depolarization and prolonging the action potential.
Phase 3 (Rapid Repolarization): The period of rapid repolarization. The \text{Ca}^{2+} influx stops, and \text{K}^{+} channels open, allowing a rapid efflux of \text{K}^{+} ions, leading to a rapid decrease in membrane potential back to its resting state.
Phase 4 (Resting Membrane Potential): Occurs when the cell returns to its resting membrane potential. The sodium-potassium ATPase pump actively works to restore ion concentrations to their pre-depolarization levels, preparing the cell for the next action potential.
Arrhythmias
Definition: Arrhythmias (or dysrhythmias) involve changes to the automaticity (the ability of a cell to spontaneously depolarize and generate an action potential) or conductivity (the speed at which electrical impulses travel) of the heart cells.
Factors contributing to arrhythmias:
Electrolyte disturbances: Imbalances in ions like potassium, sodium, and calcium (\text{K}^{+}), (\text{Na}^{+}), and (\text{Ca}^{2+}) can alter the action potential.
Decreased oxygen delivery to cells: Hypoxia can impair cellular function and alter action potentials.
Structural damage: Changes to the conduction pathway due to conditions like myocardial infarction (MI) or cardiomyopathy.
Acidosis or waste product accumulation: Metabolic disturbances can affect cardiac cell excitability.
Drugs: Medications that directly alter the action potential or cardiac conduction.
**Causes of Cardiac Arrhythmias (specific types):
Changes in rate:
Tachycardia: A faster-than-normal heart rate.
Bradycardia: A slower-than-normal heart rate.
Stimulation from ectopic focus: Electrical impulses originating from a site other than the SA node.
Premature atrial contractions (PACs): Early beats originating in the atria.
Premature ventricular contractions (PVCs): Early beats originating in the ventricles.
Atrial flutter: Rapid, regular atrial contractions.
Atrial fibrillation (AF): Irregular, rapid atrial contractions.
Ventricular fibrillation (VF): Rapid, uncoordinated ventricular contractions, leading to ineffective pumping.
Alterations in conduction through the muscle: Issues with the transmission of electrical impulses within the cardiac muscle itself.
Use of Antiarrhythmic Agents Across the Lifespan
Children:
Antiarrhythmic agents are used less frequently than in adults.
Close monitoring is required for children needing these drugs, especially after cardiac surgery or due to congenital heart problems, to manage adverse effects.
Digoxin: Approved for use in children for arrhythmias with an established recommended dose.
Other Antiarrhythmics: Doses must be carefully calculated based on weight and age and double-checked.
Commonly Used Drugs (for supraventricular arrhythmias): Adenosine, propranolol, procainamide, and digoxin. Propranolol and digoxin are preferred for long-term management.
Ablation Techniques: Increasingly used to destroy arrhythmia-producing cells (e.g., Wolff-Parkinson-White syndrome).
Lidocaine: Used for ventricular arrhythmias (post-cardiac surgery or digoxin toxicity); requires regular serum level monitoring and continuous cardiac monitoring due to potential for proarrhythmias and other serious adverse effects.
Adults:
Often receive antiarrhythmic drugs as emergency measures.
Routine patient monitoring and careful evaluation of the entire drug regimen are crucial for effectiveness and minimizing adverse effects.
Frequent monitoring and medical follow-up are important.
Pregnancy and Lactation:
Safety during pregnancy is not established.
Avoid during the first trimester if possible.
Only use if the benefit clearly outweighs potential risk to the fetus.
Drugs enter human milk and can cause adverse effects in neonates.
Class I, III, and IV agents should be avoided while breastfeeding; an alternative feeding method should be used if necessary.
First-line recommendations for SVT prevention in pregnant patients: Beta-1 selective blockers (except atenolol) or verapamil.
Older Adults:
Frequently prescribed antiarrhythmic drugs.
More likely to have renal and/or hepatic impairment, affecting drug metabolism and excretion.
Doses may need to start lower than for other adults and be adjusted based on patient response.
Close monitoring is essential, especially when other drugs are added or removed from the regimen.
Classifications of Antiarrhythmic Agents
Generally categorized based on their mechanism of action according to the Vaughan Williams classification:
Class 0: (Discussed in Chapter 44, not detailed here)
Class I: Sodium Channel Blockers
Class II: Act on Autonomic Receptors (primarily beta-blockers)
Class III: Act on Potassium Channels
Class IV: Modulate Calcium Channels (calcium channel blockers)
Class I Antiarrhythmics
Mechanism of Action: Sodium Channel Blockers
Stabilize the cell membrane by binding to sodium channels, depressing phase 0 of the action potential and altering its overall duration.
Subclasses and Specific Actions:
Class Ia:
Drugs: disopyramide (Norpace), procainamide (generic), quinidine (generic).
Action: Depress phase 0 of the action potential and prolong the duration of the action potential.
Class Ib:
Drugs: lidocaine (Xylocaine), mexiletine (generic).
Action: Depress phase 0 somewhat and shorten the duration of the action potential.
Class Ic:
Drugs: flecainide (generic), propafenone (Rythmol).
Action: Markedly depress phase 0, leading to an extreme slowing of conduction; little effect on the duration of the action potential.
Class Id:
Drug: ranolazine (Ranexa, discussed in Chapter 46).
Action: Inhibits late sodium current after the rapid influx of sodium during an action potential.
Indications:
Preferable in conditions such as tachycardia.
Treatment of potentially life-threatening ventricular arrhythmias.
Some are used for symptomatic paroxysmal atrial arrhythmias in patients without structural heart disease.
Pharmacokinetics:
Widely distributed after injection or rapid GI absorption.
Undergo extensive hepatic metabolism.
Excreted in the urine.
Cross the placenta and are found in human milk.
Contraindications:
Known allergy.
Pre-existing bradycardia or heart block.
Heart failure, hypotension, or shock.
Electrolyte disturbances.
Cautions:
Renal or hepatic dysfunction.
Pregnancy and lactation.
Adverse Effects:
Associated with their membrane-stabilizing effects.
CNS effects: Dizziness, lightheadedness, fatigue, confusion.
GI effects: Nausea, vomiting, diarrhea, constipation.
CV effects: Arrhythmias (risk of new or more dangerous arrhythmias - proarrhythmia), cardiac arrest, hypotension.
Respiratory depression.
Other effects: Rash, hypersensitivity reactions, loss of hair, potential bone marrow suppression.
Procainamide (boxed warning): Risk of development of a positive antinuclear antibody (ANA) test, indicating a lupus-like syndrome.
Drug-Drug Interactions:
Other drugs known to cause arrhythmias (additive effects).
Quinidine and digoxin (increased digoxin levels).
Class Ia antiarrhythmics and cimetidine (increased plasma levels of antiarrhythmics).
Warfarin (altered anticoagulant effects).
Drug-Food Interactions:
Foods that alkalinize the urine (e.g., citrus juice, vegetables, antacids, milk products) can affect drug excretion.
Grapefruit juice (can inhibit drug metabolism).
Prototype Summary: Lidocaine (Class Ib Antiarrhythmic)
Indications: Management of acute ventricular arrhythmias during cardiac surgery or MI; treatment of refractory ventricular arrhythmias.
Actions: Decreases depolarization, reducing automaticity of ventricular cells; increases ventricular fibrillation threshold, making the heart less susceptible to VF.
Pharmacokinetics:
Route: IM (Onset: 5-10 \text{ min}, Peak: 5-15 \text{ min}, Duration: 2 \text{ h})
Route: IV (Onset: Immediate, Peak: Immediate, Duration: 10-20 \text{ min})
T_{1/2}: 10 \text{ minutes}, then 1.5 \text{ to } 3 \text{ hours}; metabolized in the liver and excreted in the urine.
Adverse Effects: Dizziness, lightheadedness, fatigue, arrhythmias (proarrhythmia), cardiac arrest, nausea, vomiting, anaphylactoid reactions, hypotension, vasodilation.
Class II Antiarrhythmics
Mechanism of Action: Many are beta-adrenergic blockers that block beta-receptors, primarily depressing phase 4 of the action potential (reducing spontaneous depolarization) and/or acting on other autonomic nervous system pathways.
More detail on beta-blockers is available in Chapter 31.
Therapeutic Actions:
Competitively block beta-receptor sites in the heart (eta1) and kidneys (eta1).
Result: Decreased heart rate, cardiac excitability, and cardiac output; slowing of conduction through the AV node; decreased renin release from the kidneys.
Other specific actions vary by drug.
Indications:
Treatment of rapid atrial fibrillation (AF), atrial flutter, paroxysmal supraventricular tachycardias (SVTs).
Also used as an antihypertensive, antianginal, and for premature ventricular contractions (PVCs) and ventricular tachycardia.
Pharmacokinetics:
Absorbed from the GI tract.
Undergo hepatic metabolism.
Excreted in the urine.
Contraindications:
Sinus bradycardia and AV block (second or third degree).
Cardiogenic shock or severe respiratory depression.
Adenosine (specific contraindications): Second- or third-degree AV block, sinus node disease, known hypersensitivity to adenosine.
Cautions:
Diabetes and thyroid dysfunction (can mask symptoms of hypoglycemia or hyperthyroidism).
Asthma or chronic obstructive pulmonary disease (COPD) (can cause bronchospasm).
Pregnancy and lactation.
Renal and hepatic dysfunction.
Adverse Effects:
Related to blocking beta-receptors in the sympathetic nervous system (SNS).
CNS effects: Dizziness, insomnia, dreams, fatigue.
CV effects: Hypotension, bradycardia, AV block, arrhythmias (proarrhythmia), alterations in peripheral perfusion.
Respiratory effects: Bronchospasm, dyspnea.
GI effects: Nausea, vomiting, anorexia, constipation, diarrhea.
Other effects: Loss of libido, decreased exercise tolerance, alterations in blood glucose levels.
Drug-Drug Interactions:
Verapamil or diltiazem: Increased risk of bradycardia and heart block.
Antidiabetic medications: Can mask symptoms of hypoglycemia.
Methylxanthines (e.g., theophylline and caffeine): Reduced bronchodilation effects of methylxanthines.
Prototype Summary: Propranolol (Class II Antiarrhythmic)
Indications: Treatment of cardiac arrhythmias, especially supraventricular tachycardia; treatment of ventricular tachycardia induced by digitalis or catecholamines; also used as an antihypertensive, antianginal, and antimigraine headache drug.
Actions: Competitively blocks beta-adrenergic receptors in the heart and kidney; has a membrane-stabilizing effect; decreases the influence of the sympathetic nervous system, leading to reduced heart rate and contractility.
Pharmacokinetics:
Route: Oral (Onset: 20-30 \text{ min}, Peak: 60-90 \text{ min}, Duration: 6-12 \text{ h})
Route: IV (Onset: Immediate, Peak: 1 \text{ min}, Duration: 4-6 \text{ h})
T_{1/2}: 3 \text{ to } 5 \text{ hours}; metabolized in the liver and excreted in the urine.
Adverse Effects: Bradycardia, heart failure, cardiac arrhythmias (proarrhythmia), heart blocks, cerebrovascular accident, pulmonary edema, gastric pain, flatulence, nausea, vomiting, diarrhea, impotence, decreased exercise tolerance.
Class III Antiarrhythmics
Mechanism of Action: Potassium Channel Blockers
Block potassium channels, which slows the outward movement of potassium during phase 3 of the action potential, thereby prolonging repolarization and the effective refractory period.
Indications:
Treatment of life-threatening ventricular arrhythmias.
Maintenance of sinus rhythm in patients with symptomatic atrial fibrillation (AF) or atrial flutter.
Pharmacokinetics:
Well absorbed after oral administration.
Immediately available after IV administration.
Widely distributed throughout the body.
Metabolized in the liver; excreted in the kidneys.
Contraindications:
Generally, none when used for life-threatening arrhythmias (benefits outweigh risks).
Ibutilide and dofetilide (specific): AV block.
Dronedarone (specific): Permanent AF, decompensated heart failure requiring hospitalization or Class IV heart failure, second- or third-degree AV block or sick sinus syndrome, liver or lung toxicity, prolonged QT interval, bradycardia, pregnancy.
Cautions:
Shock, hypotension, or respiratory depression.
Prolonged QTc interval (increased risk of Torsades de Pointes).
Renal or hepatic disease.
Amiodarone (specific): Thyroid or pulmonary disease (due to associated toxicities).
Adverse Effects:
Related to changes in action potentials.
Common: Nausea, vomiting, weakness, dizziness, hypotension.
Bradycardia or AV block (which could progress to heart failure).
Drug-Drug Interactions:
Digoxin or quinidine: Increased levels of these drugs.
Antihistamines, phenothiazines, tricyclic antidepressants: Can prolong the QT interval, increasing the risk of arrhythmias when combined with Class III agents.
Other specific drug-drug interactions vary with individual drugs.
Prototype Summary: Amiodarone (Class III Antiarrhythmic)
Indications: Treatment of life-threatening ventricular arrhythmias.
Actions: Acts directly on heart muscle cells to prolong repolarization and the refractory period, increasing the threshold for ventricular fibrillation; also acts on peripheral smooth muscle to decrease peripheral resistance (vasodilation).
Pharmacokinetics:
Route: Oral (Onset: 2-3 \text{ d}, Peak: 3-7 \text{ h}, Duration: Prolonged)
Route: IV (Onset: Immediate, Peak: 20 \text{ min} for infusion, Duration: Prolonged)
T_{1/2}: 10 \text{ days}; metabolized in the liver and excreted in the urine; active metabolites and redistribution prolong the half-life.
Adverse Effects: Malaise, fatigue, dizziness, heart failure, cardiac arrhythmias (proarrhythmia), cardiac arrest, constipation, nausea, vomiting, hepatotoxicity, pulmonary toxicity, corneal microdeposits, vision changes, phototoxicity (may cause a blue-gray discoloration of the skin).
Class IV Antiarrhythmics
Mechanism of Action: Modulate Calcium Channels (Calcium Channel Blockers - CCBs)
Block the movement of calcium ions (\text{Ca}^{2+}) across the cell membrane in cardiac and vascular smooth muscle cells.
Result: Depresses the generation of action potential; delays phases 1 and 2 of repolarization; slows conduction through the AV node.
Indications:
Antihypertensives.
Treatment of angina.
Treatment of rapid supraventricular dysrhythmias (e.g., rapid AF, atrial flutter, paroxysmal SVT).
Pharmacokinetics:
Well absorbed after oral administration.
Highly protein-bound; metabolized in the liver; excreted in the urine.
Cross the placenta and enter human milk.
Contraindications:
Known allergy to any CCB.
Sick sinus syndrome or heart block (second or third degree).
Severe heart failure or hypotension.
Cautions:
Pregnancy and lactation.
Idiopathic hypertrophic subaortic stenosis.
Impaired renal or liver function.
Adverse Effects:
Related to vasodilation of blood vessels throughout the body.
CNS effects: Dizziness, lightheadedness, headache, asthenia.
GI effects: Nausea, constipation.
CV effects: Hypotension, heart failure, shock, arrhythmias (proarrhythmia), AV block, peripheral edema, flushing.
Drug-Drug Interactions:
Verapamil:
Beta-blockers: Increased risk of bradycardia and heart block.
Digoxin: Increased digoxin levels.
Carbamazepine, prazosin, quinidine: Increased levels of these drugs.
Many other potential interactions.
Diltiazem:
Cyclosporine: Increased cyclosporine levels.
Other antihypertensive and/or negative chronotropic medications: Additive hypotensive and bradycardic effects.
Other negative inotropic medications: Additive myocardial depression.
Prototype Summary: Diltiazem (Class IV Antiarrhythmic)
Indications: Extended-release preparation used to treat hypertension and angina in adults; other preparations are used for angina and cardiac dysrhythmias (rapid AF, atrial flutter, and paroxysmal supraventricular tachycardia).
Actions: Blocks the movement of calcium ions across the cell membrane, depressing the generation of action potentials, delaying phases 1 and 2 of repolarization, and slowing conduction through the AV node.
Pharmacokinetics:
Route: Oral (Onset: 30-60 \text{ min}, Peak: 2-3 \text{ h}, Duration: 6-8 \text{ h})
Route: IV (Onset: Immediate, Peak: 2-3 \text{ min}, Duration: Unknown)
T_{1/2}: 3.5 \text{ to } 6 \text{ hours}; metabolized in the liver and excreted in the urine.
Adverse Effects: Dizziness, lightheadedness, headache, asthenia, peripheral edema, bradycardia, AV block, flushing, nausea, hepatic injury.
Self-Assessment Questions
Question #1
Statement: One factor in the development of cardiac arrhythmias is a decrease in oxygen delivered to cells.
Answer: True
Rationale: Arrhythmias involve changes to the automaticity or conductivity of the heart cells. These changes can result from several factors, including electrolyte imbalances that alter the action potential, decreased oxygen delivery to cells that changes their action potential, structural damage that changes the conduction pathway, or acidosis or waste product accumulation that alters the action potential. In some cases, changes to the heart's automaticity or conductivity may result from drugs that alter the action potential or cardiac conduction.
Question #2
Question: Which of the following is an adverse effect of the class II antiarrhythmics?
A. Bronchospasm
B. Flatus
C. Colitis
D. Centralized edema
Answer: A. Bronchospasm
Rationale: The adverse effects associated with Class II antiarrhythmics are related to the effects of blocking beta-receptors in the SNS. CNS effects include dizziness, insomnia, dreams, and fatigue. Cardiovascular symptoms can include hypotension, bradycardia, AV block, arrhythmias, and alterations in peripheral perfusion. Respiratory effects can include bronchospasm and dyspnea. GI problems frequently include nausea, vomiting, anorexia, constipation, and diarrhea. Other effects to anticipate include a loss of libido, decreased exercise tolerance, and alterations in blood glucose levels.