Antidysrhythmic Agents

• Antidysrhythmics are drugs used to treat abnormal heart rhythms.
• Barry Silver, MD is credited in this presentation on antidysrhythmics.

Objectives of Antidysrhythmic Agents

• Overview of cardiac impulse formation and conduction
• Recognize antidysrhythmic agents, including Class I (Sodium channel blockers), Class II (Beta-blockers), Class III (Potassium channel blockers), Class IV (Calcium channel blockers), and miscellaneous agents
• Discuss the indications for the above antidysrhythmic agents

Antidysrhythmics Overview

• Depolarization occurs when channels in a cell's membrane allow various ions to leave or enter the cell
• This results in a change in the electrical charge (action potential) ultimately producing an electrical impulse seen on an EKG

Cardiac Automaticity

• Specialized "pacemaker" cells in the heart exhibit automaticity, generating action potentials without external stimuli
• The sinoatrial node (SA node) is the primary (1°) pacemaker of the heart and it is located in the wall of the right atrium.

Cardiac Conduction

• The action potential originates in the SA node.
• Normal cardiac conduction proceeds through the internodal pathway, atrioventricular (AV) node, Bundle of His, and Purkinje system.
• Generation of an electrical impulse leads to muscle contraction.
• Dysfunction of impulse formation or conduction can cause dysrhythmia.

Abnormal Impulse Formation

• Abnormal automaticity means various sites compete with the SA node, creating ectopic pacemakers.
• Competing stimuli can result in dysrhythmias.
• Antidysrhythmic agents may suppress automaticity in ectopic pacemakers, but have minimal effect on the SA node.

Abnormal Impulse Conduction: Reentry

• Impulses are normally conducted down pathways bifurcating to activate the ventricular surfaces
• Unidirectional blocks happen if the refractory period is prolonged for any reason
• Refractory period is the time after an action potential when the cardiac cell cannot initiate another one
• Reentry happens when a unidirectional block allows early excitation of cardiac muscle via retrograde impulse conduction

Abnormal Impulse Conduction

• Cardiac impulses are normally conducted in an antegrade (forward) direction.
• Prolongation of the refractory period in damaged cardiac tissue prevents propagation of the impulse in a normal antegrade direction
• The damaged cardiac tissue activates earlier than normal in abnormal retrograde direction
• A single premature contraction or sustained dysrhythmia may result
• Antidysrhythmic agents can block retrograde conduction through the reentrant path.

Antiarrhythmics Overview

• The goal is to restore normal sinus rhythm (NSR).
• NSR = P wave before every QRS complex + heart rate of 60-100 bpm
• Mechanisms of action may include Na channel blockade (Class I), beta-receptor blockade (Class II), K channel blockade (Class III), & Ca channel blockade (Class IV).
• Many antiarrhythmics have dangerous proarrhythmic effects.

Class I Agents: Sodium Channel Blockers

• These block voltage-sensitive Na channels.
• Divided into subclasses (IA, IB, and IC) based on their effect on the action potential
• Sodium channel blockers primarily block cells discharging abnormally without disrupting normally functioning cells.
• Use of these drugs has declined due to proarrhythmic effects, these are primarily prescribed by cardiologists
• Proarrhythmic effects are high in patients with decreased left ventricular (LV) function or coronary artery disease (CAD)

Class IA: Sodium Channel Blockers

• Primarily bind to open Na channels, preventing Na influx
• Also block K channels (Class III) & Ca channels (Class IV)
• Slow conduction velocity and increase the refractory period (FF)
• PEARL: concomitant class III activity of these drugs may precipitate fatal ventricular dysrhythmias including ventricular fibrillation

Class IA Agents

• First-line agents include quinidine, procainamide, & disopyramide
• Used for atrial fibrillation, atrial flutter, AV junctional dysrhythmias & ventricular dysrhythmias.
• Use of Class IA agents has decreased in favor of electrical therapy and safer antidysrhythmics.
• Procainamide (IV) is still used in ACLS (advanced cardiac life support) protocols.

Class IA: Sodium Channel Blockers - Risks

• Risks include proarrhythmic effects & worsening of congestive heart failure (CHF).
• Should be avoided in patients with CHF or CAD.
• Quinidine may cause cinchonism (headaches, blurred vision, tinnitus) and multiple drug interactions.
• Procainamide may result in hypotension and QRS widening
• Disopyramide can cause anticholinergic toxicity.
• Always discuss potential side effects with patients.

Class IB: Sodium Channel Blockers

• Shorten phase 3 repolarization & decreases the action potential duration.
• Primary agents include lidocaine & mexiletine.
• Lidocaine serves as an alternative to amiodarone (Class III) in acute ventricular tachycardia and fibrillation
• Mexiletine (oral) is an alternative to amiodarone for chronic ventricular arrhythmias.

Class IB: Sodium Channel Blockers- Properties

• Lidocaine is only used in IV form.
• Lidocaine has significant CNS adverse effects like drowsiness, slurred speech, confusion, & seizures.
• Mexiletine has a narrow therapeutic index relating the therapeutic to the toxic dose.
• Mexiletine’s adverse effects include nausea, vomiting, & dyspepsia.

Class IC: Sodium Channel Blockers

• Primary meds include flecainide (Tambocor) & propafenone (Rhythmol).
• Flecainide decreases automaticity and blocks K channels prolonging the action potential.
• Propafenone decreases automaticity and has weak beta-blocker activity.
• These avoided in underlying heart disease because of proarrhythmic and negative inotropic effects.

Class IC Agents

• Flecainide maintains NSR in atrial fibrillation & atrial flutter and may be used for refractory ventricular dysrhythmias.
• Propafenone restores NSR in atrial fib & atrial flutter and used for supraventricular tachycardia prophylaxis.
• Both meds may cause blurred vision, nausea, & lightheadedness.
• Propafenone may also cause bronchospasm due to its beta-blocker activity.

Review of Main Points

• SA node is the primary pacemaker responsible for automaticity.
• Normal cardiac conduction proceeds thru the AV node to the Bundle of His & then to the Purkinje system.
• Dysfunction of impulse formation or conduction may lead to a dysrhythmia.
• Abnormalities in impulse formation and conduction can lead to dysrhythmias.
• Antiarrhythmic effects include Na channel blockade, beta-receptor blockade, K channel blockade, & Ca channel blockade

Review Cont.

• Na channel blockers are Class IA, IB, and IC
• Class IA agents include quinidine, procainamide, & disopyramide, and are used for atrial & ventricular dysrhythmias.
• Class IB agents include lidocaine & mexiletine, used for ventricular dysrhythmias.
• Class IC agents include flecainide & propafenone, to maintain NSR in atrial fibrillation & flutter.
• All these agents have proarrhythmic effects and their use has declined significantly.

Class II: Beta-blockers Overview

• Sympathetic antagonism results in decreased heart rate (HR) & contractility
• Effective in tachydysrhythmias related to increased sympathetic activity
• Used for rate control in atrial fibrillation and atrial flutter
• Prevent ventricular reentrant dysrhythmias following myocardial infarctions

Beta-blockers cont.

• Selective beta-1-blockers minimize the risk of bronchospasm.
• Metoprolol is a primary selective beta-1-blocker.
• Esmolol (IV) is the most rapid-acting beta blocker.

Selective Beta-1-blockers

• These minimize the risk of bronchospasm
• Examples are metoprolol (Lopressor, Toprol XL), esmolol (Brevibloc), acebutolol (Sectral), bisoprolol (Zebeta), and betaxolol (Kerlone).

Non-selective Beta-blockers

• Propranolol (Inderal)
• Nadolol (Corgard)
• Timolol (Blocadren)
• Penbutolol (Levatol)
• Sotalol (Betapace): (also has Class III effects)
• Pindolol (Visken)
• Beta-2 blockade may result in acute bronchospasm

Beta-blockers- Adverse Effects

• Potential adverse effects include excessive bradycardia, reduced cardiac contractility/ SV, and hypotension.
• Cardiac output = heart rate X stroke volume
• BP = cardiac output X total peripheral resistance

Beta-blockers- More Adverse Effects

• Nonselective agents (block both beta-1 & beta-2 receptors) may result in bronchospasm.
• Beta-blockers may increase the risk of hypoglycemia or mask symptoms.
• Other common side effects: fatigue, decreased exercise tolerance, depression, & erectile dysfunction.
• Rapid withdrawal may result in worsening myocardial ischemia in certain patients.

Class III Potassium Channel Blockers

• They result in an increased refractory period.
• Drugs include amiodarone (Cordarone), dofetilide (Tikosyn), dronedarone (Multaq), ibutilide (Covert), & sotalol (Betapace).
• All class III drugs may be proarrhythmogenic.

Amiodarone facts

• Commonly used to maintain NSR in atrial fibrillation & flutter.
• Used in the management of severe refractory ventricular tachydysrhythmias.
• First-line in ACLS for the management of V fib & V tach.
• Multiple potential toxicities including pulmonary fibrosis, hepatoxicity, neurotoxicity, & thyroid disease
• Amiodarone is the least proarrhythmic agent of the Class I & III drugs

Additional Class III Agents

• Dronedarone is contraindicated in patients with CHF and less effective than amiodarone in maintaining NSR in atrial fib/flutter.
• Sotalol's indications are similar to amiodarone, maintains NSR in a fib/flutter and is useful for ventricular dysrhythmias and has additional BB activity.
• Use of Sotalol comes with Risk of QT interval prolongation which necessitates initiation in an inpatient setting only.

More Class III Agents

• Dofetilide is for atrial fib with underlying CHF or CAD and carries a risk of inducing arrhythmias. and this necessitates initiation in an inpatient setting
• Ibutilide has historically been used for chemical conversion of atrial flutter but electrical cardioversion has mostly replaced it and is only available in IV form
• Both of these agents are very proarrhythmogenic.

Class IV Agents

• Calcium Channel Blockers
• They block voltage-sensitive Ca channels in the heart.
• Slow conduction in the SA & AV nodes.
• Convert supraventricular tachycardia (SVT) to NSR; control ventricular rate in atrial fib & flutter.
• Primary meds are verapamil (Calan) & diltiazem (Cardizem).
• Common adverse effects include decreased HR, decreased BP, & peripheral edema.
• CO = HR X SV and BP = CO X TPR

Miscellaneous Antidysrhythmics

• Digoxin (Lanoxin)
• Adenosine (Adenocard)
• Magnesium sulfate
• Ranolazine (Ranexa)

Digoxin facts

• Inhibits the Na/K-ATPase pump.
• Shortens the refractory period in atrial & ventricular myocardial cells.
• Prolongs the refractory period & diminishes conduction velocity in the AV node.
• Used to control ventricular rate in atrial fib & flutter.

Digoxin toxicity

• High risk of toxicity where major organ systems are affected; the CV, GI, & CNS
• Serum levels can be measured.
• Has a narrow therapeutic window where small variations in blood concentrations may lead to toxic or subtherapeutic levels

Adenosine characteristics

• It decreases conduction velocity, prolongs the refractory period & decreases automaticity in the AV node.
• It is the drug of choice for acute SVT- its only indication
• It has a very short duraion of action and therefore, it acts rapidly
• Must be given rapidly followed by IV fluid after the IV push
• Commonly results in short period of asystole

Magnesium Sulfate

• It is critical in the body for transcellular transport of Na, K, & Ca.
• It slows the rate of the SA node impulse formation
• Only the intravenous form is used for dysrhythmias.
• Drug of choice for the management of Torsades de Pointes.

Ranolazine properties

• Similar antiarrhythmic properties to mexiletine & amiodarone
• Shortens repolarization and decreases the action potential duration
• Often used in combination with other antiarrhythmics to treat refractory atrial & ventricular arrhythmias
• Has antianginal properties

Final Review

• Class II agents- beta-blockers are for rate control in atrial fib/flutter & post-MI.
• Selective beta-1-blockers limit bronchospasm.
• Class III agents- K channel blockers- include amiodarone & sotalol, and are the first-line choice for refractory ventricular dysrhythmias.

Review Continued

• Class IV agents- Ca channel blockers convert SVT to NSR; rate control for atrial fib/flutter, and 1° meds include verapamil & diltiazem
• Miscellaneous agents include digoxin- which controls ventricular rate in atrial fib/flutter but has a narrow therapeutic index; adenosine- the drug of choice for SVT and has a very short half-life; and magnesium sulfate- the drug of choice for Torsades de Pointes and ranolazine- which is used to treat refractory dysrhythmias and has antianginal properties.