Antiarrhythmics

Learning Objectivs

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Antiarrhythmic Drug Action

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Antiarrhythmic Drug Action

Ions

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Antiarrhythmics

Electrical Activity in the Normal Heart

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Arrhythmogenic Mechanisms

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• Enhanced Automatcity
• After depolarizations and Triggered Automaticity
• Re-entry

Arrhythmogenic Mechanisms

Enhanced Automaticity

Arrhythmogenic Mechanisms

After Depolarizations and Triggered Automaticity

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Arrhythmogenic Mechanisms

Re-Entry

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Antiarrhythmics

Drugs that Inhibit Automaticity

Mechanisms for slowing pacemaker rate

(4)

• β-Adrenergic Blockers
• Na⁺  Ca⁺⁺ Channel Blockers
• Adenosine and Muscarinic Blockers 
• K⁺ Channel Blockers

Antiarrhythmics

After Depolarizations and Triggered Automaticity

(2)

Antiarrhythmics

After Depolarizations and Triggered Automaticity

Notes

DAD

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• DAD-mediated triggered beats are more frequent when the underlying heart rate is rapid.
•  Conditions of Ca++ overload include 
• myocardial ischemia, 
• adrenergic stress, 
• digitalis intoxication or heart failure.

Antiarrhythmics

After Depolarizations and Triggered Automaticity

Notes

EAD

• EAD-related triggered depolarizations probably reflect inward current through Na+ and Ca++ channels.  
• EADs are more readily induced in Purkinjie cells and midmyocardial cells than in epicardial or endocardial cells.  
• Torsades de pointes is thought to be caused by EADs which trigger functional re-entry due to heterogeneity of action potential durations across the ventricular wall.

Antiarrhythmics

Re-Entry

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Antiarrhythmics

Example of AV Nodal Re-Entry

Common Mode

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• Common Mode
• In the Common Mode of AV Nodal reentry, the anterograde impulse is slowed as it passes through the AV node
• The retrograde pathway of the reentrant circuit is fast.

Antiarrhythmics

Example of AV Nodal Re-Entry

UN-Common Mode

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• Uncommon Mode
• In the Uncommon Mode of AV Nodal reentry, the anterograde impulse is fast as it passes through the AV node
• The retrograde pathway of the reentrant circuit is slowed.

Antiarrhythmics

Singh-Vaughan Williams Classification System

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• Based on a drug’s primary electrophysiological effects that should be antiarrhythmic
• The classification consists of four major drug classes and a miscellaneous class
• Class IA, IB, and IC (Na+ channel blockers)
• Class II (b-adrenergic blockers)
• Class III (Prolong repolarization/effective refractory period, usually by effects on K+ channel blockade)
• Class IV (Ca++ channel blockers)
• Miscellaneous actions

Antiarrhythmics

Singh-Vaughan Williams Classification (I)

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• Class I drugs, those that act by blocking the fast inward sodium channel (phase 0) and slowing intracardiac conduction, are subdivided into 3 subgroups based on their potency (*i.e., dissociation kinetics) towards blocking the sodium channel and effects on repolarization 
• Subclasses I(A,B,&C)

• *Potency is a reflection of kinetics of drug dissociation from the sodium channel:

Antiarrhythmics

Singh-Vaughan Williams Classification (I)

SubClass IA

(4)

• Intermediate to high potency sodium channel blockers and prolong repolarization (prolong QT interval):
• Quinidine
• Procainamide
• Disopyramide 

Antiarrhythmics

Singh-Vaughan Williams Classification (I)

SubClass IB

(3)

• Subclass IB  Lowest potency sodium channel blockers(liitle effect on PR, QRS, or QT interval):
• Lidocaine
• Mexilietine

Antiarrhythmics

Singh-Vaughan Williams Classification (I)

Subclass IC

(3)

• Subclass ICThe most potent sodium channel blocking agents (slow conduction the most, thusprolong PR and QRS intervals); have little effect on repolarization (no effect on QT interval):
• Flecainide
• Propafenone

Antiarrhythmics

Singh-Vaughan Williams Classification (II)

Class II

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• Class II drugs act indirectly on electrophysiological parameters by blocking beta-adrenergic receptors (may slow sinus rhythm, prolong PR intervaldepending on sympathetic tone): 
• Propranolol,
• esmolol, 
• sotalol,
• acebutolol, 
• and others

Antiarrhythmics

Singh-Vaughan Williams Classification (III)

Class III

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• Class III drugs prolong repolarization (increase refractoriness, prolong QT interval, no effect on QRS interval, little effect on rate of depolarization):
• Block fast outward K+ current: 
• Amiodarone, 
• dronedarone, 
• sotalol, 
• dofetilide, 
• ibutilide
• Block slow inward Na+ current: 
• Ibutilide

Antiarrhythmics

Singh-Vaughan Williams Classification (IV)

Class IV

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• Class IV drugs are relatively selective AV nodal L-type calcium-channel blockers (slow sinus rhythm, prolong PR interval): 
• Verapamil, 
• diltiazem

Antiarrhythmics

Singh-Vaughan Williams Classification (Misc)

Miscellaneous Mechanisms

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• In addition to the standard classes (IA, IB, IC, II, III, and IV) there is also a miscellaneous group of drugs that includes 
• digoxin, 
• adenosine, 
• magnesium sulfate 
• and other compounds whose primary mechanisms of action differ from the standard Vaughan Williams classes 

Advantages of the Singh-Vaughan Williams Antiarrhythmic Drug Classification System

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• It is a convenient means to classify the many antiarrhythmic drugs by their primary mechanism of action
• It is a useful conversational shorthand
• Drugs within a specific class or subclass often exhibit similar adverse effects and toxicities
• It is a useful starting point for deciding which drug to use for treating a particular patient

Torsades De Pointes

(2)

• "Twisting of the points"
• a polymorphic proarrhythmia associated with drugs that prolong the QT interval

• A sustained MOnomorphic proarrhythmia first seen in the CAST clinical trial of IC agents

Class Toxicities of Antiarrhythmic Drugs

Class I

Na Channel Blockers

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• Proarrhythmic effects
• IA-Torsades de pointes
• IC-CASR proarrhythmia
• Negative Ionotropic Effect
• IC drugs
• Intranodal Conduction Block

Class Toxicities of Antiarrhythmic Drugs

Class II

β-Blockers

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• Sinus Bradycardia
• AV Block
• Depression of LV function
• All are Adrenergic-dependent

Class Toxicities of Antiarrhythmic Drugs

Class III

Prolong Repolarization

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• Sinus Bradycardia
• Proarrhythmic Effects
• Torsades de pointes

Class Toxicities of Antiarrhythmic Drugs

Class IV

Ca Channel Blockers

• AV block
• Negative ionotropic effect

Proarrhythmias

(6)

• Proarrhythmias are drug-induced arrhythmias (see Table 34-1, Goodman & Gilman Manual)
• Digitalis-induced proarrhythmias have been recognized for many years, as has “quinidine syncope”
• Two recently recognized ventricular proarrhythmias seen with antiarrhythmic drugs:
• Torsades de pointes
• See AHA/ACCF Scientific Statement: Prevention of Torsades de Pointes in Hospital Settings, Drew et al., Circulation 121:1047, 2010)
• CAST proarrhythmia

Torsades de Pointes

("Twisting of the Points")

Antiarrhythmic Drug Causes

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• Torsades is a polymorphic arrhythmia that can rapidly develop into ventricular fibrillation
• Associated with drugs that have Class III and Class IA actions (potassium channel blockers and drugs that prolong repolarization) and that cause Drug-Induced Long QT Syndrome (DILQTS)
• Quinidine (2-8% of patients, can occur at subtherapeutic doses)
• Sotalol (common, but dose-dependent)
• N-acetylprocainamide (metabolite of procainamide)
• Amiodarone (DILQT is common, but torsades is uncommon)
• Ibutilide (4-8%)
• Dofetilide (1-3%)

Torsades de Pointes

Can Be Caused By a Variety of Drugs

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• Also seen with many other classes of drugs (seewww.qtdrugs.org):
• Antiinfectives (e.g., erythromycin, sparfloxacine)
• Antipsychotics (e.g., chlorpromazine, haloperidol)
• Antiemetics (e.g., domperidone, droperidol)
• Opiates (e.g., methadone, levomethadyl)
• The FDA now requires QT testing for all new drugs as part of the New Drug Application (NDA) process
• Combinations of any of drugs that prolong QT interval can be additive or synergistic with regard to increasing the risk of torsades de pointes
• Patients who have congenital LQTS or other genetic polymorphisms of channel proteins are at higher risk of torsades when taking LQT drugs  

Torsades de Pointes

General 

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Torsades de Pointes

Other Risk Factors

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• Concurrent use of multiple LQT drugs
• Rapid IV infusion of LQT drug
• Heart disease, 
• advanced age, 
• female sex
• Hereditary LQT

Torsades de Pointes

Onset

• Onset of TdP in a young male with a history of drug addiction treated with chronic methadone therapy who presented to a hospital emergency department after ingesting an overdose of prescription and over-the-counter drugs from his parent’s drug cabinet. 

Torsades de Pointes

ECG

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• Classic ECG features evident in this rhythm strip include:
• prolonged QT interval with distorted T-U complex
• initiation of the arrhythmia after a short-long-short cycle sequence by a PVC that falls near the peak of the distorted T-U complex
• “warm-up” phenomenon with initial R-R cycles longer than subsequent cycles
• abrupt switching of QRS morphology from predominately positive to predominately negative complexes (asterisk).

Torsades de Pointes

Pic on pg 24

•       TdP degenerating into ventricular fibrillation in an 83-year-old female hospitalized in the intensive care unit for pneumonia. She was started on intravenous erythromycin several hours before cardiac arrest.

•       Bottom rhythm strip, ECG 1 hour before the onset of TdP shows extreme prolongation of the QT interval (QTc 730ms), and other anomalies (ventricular doublet, T wave alternans).

•       Discontinuation of the culprit drug and administration of magnesium most likely would have prevented the subsequent cardiac arrest.

• Monomorphic, sustained ventricular tachycardia first recognized in CAST trials with encainide and flecainide (Class IC drugs)
• Patients with underlying sustained ventricular tachycardia, coronary artery disease, and poor left ventricular function (left ventricular ejection fraction <40%) are at greater risk to develop this form of proarrhythmia (these were the patients enrolled in the CAST trials)

Drawbacks of the Singh-Vaughan Williams Antiarrhythmic Drug Classification System

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• Drugs within a class do not necessarily have clinically similar effects
• Almost all of the currently available drugs have multiple actions
• The metabolites of many of the drugs may contribute significantly to the antiarrhythmic actions or side effects
• Due to polymorphisms in drug metabolizing enzymes, there can be large differences in efficacy and/or toxicities between patients

Sicilian Gambit Classification

(5)

• An alternative classification system, known as the 'Sicilian Gambit', has been proposed that is based on arrhythmogenic mechanisms and multiple clinical effects of most antiarrhythmic drugs

• This system identifies one or more 'vulnerable parameters' associated with a specific arrhythmogenic mechanism

• A vulnerable parameter is an electrophysiological property or event whose modification by drug therapy will result in the termination or suppression of the arrhythmia with minimal undesirable effects on the heart

• Unlike the Vaughan Williams classification system, this system can readily accommodate drugs with multiple actions (channel blockers, pump blockers, receptor agonists, and receptor antagonists)

• This multidimensional classification system is significantly more complex than the standard Vaughan Williams system, but provides a more flexible framework 

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia: 

Premature atrial, nodal, or ventricular depolarizations

(3)

• Common Mechanism
• Unknown
• Acute Therapy 
• None indicated
• Chronic Therapy
• None indicated

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia: 

Atrila Fibrilation

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• Common Mechanism
• Disorganized "Functional" Re-entry
• Continual AV node stimulation leading to irregular, rapid ventricular rate
• Acute Therapy
• AV nodal block to control ventricular response
• Restore sinus rhythm: DC cardioversion
• Chronic Therapy
• AV nodal block to control ventricular response
• Maintain normal rhythm
• K⁺ Channel block
• moderate to high affinity Na⁺ channel block
• Ablation

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia:

AV Nodal Reentrant Tachycardia (PSVT)

(10)

• Common Mechanism
• Reentrant circuit w/in or near the AV node
• Acute Therapy
• *Adenosine
• AV nodal block 
• Chronic Therapy
• *AV nodal Block
• Flecainide
• Propafenone
• *Ablation

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia:

Ventricular Tachycardia w/ Remote Myocardial Infarction

(11)

• Common Mechanism
• Reentry near the rim of the healed myocardial infarction
• Acute Therapy
• Amiodarone
• Procainamide
• DC Cardioversion
• Chronic Therapy
• *ICD
• *Amiodarone
• K⁺ channel block
• Na⁺ channel block

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia: 

Ventricular Fibrilation

(12)

• Common Mechanism
• Disorganized reentry
• Acute Therapy
• * DC cardioversion
• Amiodarone
• Lidocaine
• Procainamide
• Chronic Therapy
• *ICD 
• *Amiodarone
• K⁺ channel block
• Na⁺ channel block

Mechanistic Approach to Antiarrhythmic Therapy

Arrythmia: 

TdP (Congenital or Acquired)

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• Common Mechanism
• EAD-related triggered activity
• Acute Therapy
• Pacing
• Magnesium
• Isoproterenol
• Chronic Therapy
• Beta blockade
• Pacing

Antiarrhythmics

Use(Rate)-Dependent Channel Blockade

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Antiarrhythmics

Affinity of Channel Blocker Drugs for Different Channel States

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• Channel blocker drugs with higher affinity for the Active and Inactive states of the ion channel will demonstrate positive use-dependence
• Drugs with fast dissociation kinetics (low potency) will only show efficacy in rapidly depolarizing tissue

Antiarrhythmics

Possible Mechanisms for Differential Affinity of Channel Blocking Drugs for Diff Channel States

(2)

• Drug binding sites of use-dependent drugs might only be accessible to drug when the ion channel is in specific states
• This might be due to the drug’s limited access to the drug-binding site from within the channel or because conformational ‘gates’sterically block the drug’s access to the binding site

Antiarrhythmics

Examples of Channel Blockers Showing

Use-Dependent Blockade

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• Quinidine, procainamide, and disopyramide preferentially bind to the Active state of the sodium channel
• Amiodarone binds almost exclusively to the Inactive state of the sodium channel
• Lidocaine binds Active and Inactive states of the sodium channel
• Verapamil and diltiazem bind Active and Inactive states of the calcium channel
• Quinidine and sotalol show reverse use-dependence with regard to potassium channel blockade

Antiarrhythmics

Therapeutic Considerations (and Challenges)

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• The two principles guiding the use of antiarrhythmic drugs can be simply stated: "Safety first. Efficacy second."
• Most of the currently available antiarrhythmic drugs are hazardous, unpredictable, and often ineffective
• The therapeutic index of most antiarrhythmic drugs is narrow
• The choice of a drug should be based on an assessment of the benefits vs risks of treatment
• The benefits of therapy may be difficult to establish, particularly in relatively asymptomatic patients
• Patients most likely to benefit are those most at risk for adverse drug effects (e.g., recent MI, CAD, HF, renal disease, liver disease)
• Results of the CAST study indicate that the identification of an arrhythmia (e.g., PVDs) does not necessarily indicate that therapy should be instigated
• Any factors that might be causing or predisposing to arrhythmia should be corrected before therapy is started
• Electrolyte abnormalities, particularly hypokalemia
• Proarrhythmic drugs
• Myocardial ischemia

Antiarrhythmics

Optimizing Antiarrhythmic Drug Therapy

Trial and Error

(7)

• Three trial-and-error approaches are widely used to determine the appropriate antiarrhythmic drug:
• Empiric.  
• Based upon the clinician's past experience
• Serial drug testing guided by electrophysiological study (EPS).  
• Requires cardiac catheterization and induction of arrhythmias by programmed electrical stimulation of the heart, followed by a delivery of test drugs
• Drug testing guided by electrocardiographic monitoring (Holter monitoring).  
• Continuous 24-hour recording of a  ECG before and during each drug test to predict optimal efficacy

Antiarrhythmics

Optimizing Antiarrhythmic Drug Therapy

ESVEM

The Electrophysiologic versus Electrocardiographic Monitoring (ESVEM) study concluded that there may not be any significant difference between the predictive value of these latter two techniques

Antiarrhythmics

Optimizing Antiarrhythmic Drug Therapy

Hereditary Long QT syndromes

(2)

• With hereditary long QT syndromes, genotyping may be useful in choosing the appropriate agent that can prevent, rather than precipitate sudden cardiac death. 
• Such genotyping is not yet available for any of the several known polymorphisms associated with hereditary long QT.

Antiarrhythmics

Non-Drug Antiarrhythmic Therapies

(4)

• Drug therapy is rarely indicated in benign arrhythmias (e.g., PVAs and PVCs) except to relieve debilitating symptoms (e.g., syncope, dizziness)
• Several surgical procedures have become first-line therapies for arrhythmias
• Radiofrequency (RF) catheter ablation
• Implantable cardioverter/defibrillator devices (ICDs)

Antiarrhythmics

Non-Drug Antiarrhythmic Therapies

Radiofrequency (RF) Catheter Ablation

(4)

• Wolff-Parkinson-White syndrome
• AV nodal reentry
• Atrial ectopic tachycardia & atrial fibrillation
• Some types of monomorphic ventricular tachycardias

Antiarrhythmics

Non-Drug Antiarrhythmic Therapies

Implantable Cardioverter/Defibrilator Devices (ICDs)

(3)

• Can pace, cardiovert, and defibrillate
• Considered by some to be superior to Class I and Class III drugs in treating ventricular tachycardiasA significant number of patients with an ICD will still require drug therapy to prolong battery life and reduce inappropriate shocks
• Some antiarrhythmic drugs can decrease defibrillation threshold (e.g.,azimilide), but others can increase it (e.g., flecainide, amiodarone)

Key Concepts in Antiarrhythmic Therapy

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