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Flashcards in Antiarrhythmic Drug Therapy Deck (36):
1

strategies to combat tachyarrhythmia initiated by automaticity

hyperpolarize the membrane

decrease the slope of depolarization during Phase 4

increase the threshold potential

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treatment for EADs and DADs

modifying circumstances that allow these phenomena to manifest

EAD - shorten action potential duration

DAD - reversing the underlying cause rather than addressing the depolarizations themselves

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treatments for reentry

increasing refractor yperiod fo the slow conducting tissue that is part of the reentrant circuit

further slowing conduction

suppressing premature beats that often set up the physiology

4

major indications for antiarrhythmic drug therapy

disruption of reentrant supraventricular tachycardias

treatment of atrial fibrillation, atrial flutter, atrial tachycardia

suppression of ventricular tachycardia and symptomatic premature ventricular contractions (PVCs)

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Class 1A drugs

Na+-channel blocking

prolongs effective refractory period

ex. procainamide, quinidine, disopyramide

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Class 1B drugs

Na+-channel blocking

ex. lidocaine, mexilitine, phenytoin

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Class 1C drugs

Na+-channel blocking

potent effects on phase 0

ex. flecainide, propafenon

8

Class II drugs

beta-blocking

ex. metoprolol, esmolol

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Class III drugs

K+-channel blocking

ex. amiodarone, dronedarone, sotalol, ibutilide, dofetilide

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Class IV drugs

Ca2+ - channel blocking

ex. verapamil, diltiazem

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non-classified drugs

ex. digoxin, adenosine, magnesium

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order of Na+-channel blocking effect potency of Class I antiarrhythmics

1C > 1A > 1B

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order of K+-channel blocking effect potency of Class I antiarrhythmics

1A > 1C >>> 1B (no blocking effect)

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Procainamide

Class IA antiarrhythmic

Mechanism: Blocks INa and also IKr to some degree. Therefore this drug slows the action potential upstroke and prolongs the action potential duration.

Major Clinical Uses:
Termination of sustained ventricular tachycardia – but not first line (electrical cardioversion is; amiodarone is the usual first drug choice or drug adjuct to electricity)
Ventricular Tachycardia after Myocardial Infarctionsrarely used for this indication as amiodarone and lidocaine are more effective.  The mechanism of how procainamide is useful in this condition is unclear because how this rhythm disturbance arises is not well established.
• You might also read that this drug is useful in patients in atrial fibrillation for maintaining sinus rhythm or converting patients to sinus rhythm.  However the drug is almost never used for these indications in modern clinical practice.

Pharmacokinetics:  IV only in the United States.  Half-life of 3-5 hours. First pass metabolism in liver to N-acetylprocainamide and elimination through the kidneys.

Side Effects:
Drug Induced Lupus – from long-term therapy characterized by arthralgia, pleuritis, and pericarditis.  Obviated as a real clinical concern as this occurs only with longterm administration and this drug is no longer available PO in the US. However this point may still show up on boards.
Fever, Agranulocytosis.

Proarrhythmic Effects:
Torsades de Pointes – The first pass metabolite, N-acetylprocainamide, has significant K+ channel blocking activity, and can therefore prolong the QT-interval and can set up Torsades de Pointes.
Heart Block

Contraindications:
Second or Third Degree Heart Block – this drug can produce block in the His-Purkinje system by slowing Phase 4 repolarization.
Lupus

15

Quinidine

Class IA antiarrhythmic

Mechanism: Blocks INa and also IKr to some degree, just like procainamide. Also has vagolytic effects by binding the M2 muscarinic receptor.  Related to quinine, isolated from cinchona bark.

Major Clinical Uses:
• Can be used to convert atrial fibrillation or atrial flutter to sinus rhythm but rarely used as other agents are more effective
• Can be used to maintain sinus rhythm in patients with atrial fibrillation, but meta-analyses suggest higher mortality
• Suggestion that this drug may be helpful in Brugada syndrome
• More effective anti-malarial than antiarrhythmic?? 

Pharmacokinetics:  Very available orally, but qid dosing.

Side Effects:
Nausea, vomiting, diarrhea quite common
CinchonismCNS toxicity inlcuding tinnitus, hearing loss, delerium, and psychosis.

Proarrhythmic Effects:
Torsades de Pointes because of inhibition of K+-channels. 
Heart Block
• Faster Ventricular Response in Atrial Fibrillation – because of vagolytic effects.

Contraindications:
• Second or Third Degree Heart Block

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Disopyrimide

Class IA antiarrhythmic

Mechanism:  Blocks INa and also IKr.  Binds M2 receptor. More antimuscarinic effects than quinidine. Also has negative inotropic effects.

Major Clinical Uses:
Hypertrophic Obstructive Cardiomyopathy - May be of benefit as this drug has antiarrhythmic effects that reduce ventricular tachycardia, and negative inotropic effects that may reduce the dynamic outflow obstruction seen in some patients with HCM.  Not commonly used, however.

Pharmacokinetics:  Good oral bioavailability, renally cleared.

Side Effects:
Antimuscarinic side effects – urinary retention, constipation, blurred vision, dry mouth, closed-angle glaucoma

Proarrhythmic Effects: essentially the same as Quinidine
Torsades de Pointes because of inhibition of K+-channels. 
Heart Block
Faster Ventricular Response in Atrial Fibrillation – because of vagolytic effects.

Contraindications:
Left ventricular systolic dysfunction – because of the drug’s negative inotropy

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Lidocaine

Class IB antiarrhythmic

Mechanism:  The mechanism of action of Lidocaine is elegant.  The drug exhibits very rapid binding kinetics, and binds to the INa+ channel in both its activated and inactivated states, but not really to the INa+ channel in its resting state.  This means that in normal tissue, there is little effect.  However, “sick” myocardium is ischemic and often partially depolarized –meaning that the INa+ channel is more often in the activated and inactivated, rather than the resting, conformations– this means that lidocaine preferentially binds to sodium channels in sick tissue as compared to normal tissue.

Major Clinical Uses:
Ventricular arrhythmias, particularly post-myocardial infarction – amiodarone and lidocaine are both quite commonly used for this condition.

Pharmacokinetics:  Intravenous only.  Very rapid half life so often given as an IV infusion.

Side Effects:
CNS toxicity:  confusion, delerium, parasthesias, grand mal seizures

Proarrhythmic Effects:
• Relatively uncommon.

Contraindications:
• Few. Can exacerbate heart block.

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Mexelitine

Class IB antiarrhythmic

Mechanism:  Orally bioavailable. Structurally similar to lidocaine with similar mechanisms.

Major Clinical Uses:
Chronic suppression of ventricular arrhythmias – not first line for this indication but sometimes used.

Pharmacokinetics:  Elimination half life around 12 hours, allowing for bid dosing

Side Effects:
Nausea, vomiting

Proarrhythmic Effects:
• Can exacerbate ventricular arrhythmias
Sinus bradycardia

Contraindications:
No major meaningful contraindications

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Flecainide

Class IC antiarrhythmic

Mechanism:  Potent Sodium channel blockerProlongs conduction time in cardiac tissues.  Negative inotropic effects.

Major Clinical Uses:
Acute conversion of atrial fibrillation to sinus rhythm
Maintenance of sinus rhythm in atrial fibrillation
• Quite effective at suppressing premature ventricular contractions (PVCs) – but it is rarely used for this as mortality is increased.

Pharmacokinetics:  Long elimination half life of about 20 hours, but dosed twice daily.

Side Effects:
Confusion, irritability

Proarrhythmic Effects:
Heart block – because of marked slowing of conduction.
Worsening of ventricular arrhythmias

Contraindications:
Heart block
Left ventricular systolic dysfunction

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Propafenone

Class IC antiarrhythmic

Mechanism:  Potent Sodium channel blocker.  Also has some beta-blocking activityNegative inotropic effects.

Major Clinical Uses:
Acute conversion of atrial fibrillation to sinus rhythm
Maintenance of sinus rhythm in atrial fibrillation
• Also used for ventricular arrhythmias

Pharmacokinetics:  Elimination half-life of 5-8 hours, but a sustained release formulation is most often used in clinical practice allowing bid dosing.  

Side Effects:
• Can exacerbate bronchospasm (beta-blocking effects).

Proarrhythmic Effects:
Heart block – because of marked slowing of conduction.
Worsening of ventricular arrhythmias

Contraindications:
Left ventricular systolic dysfunction

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beta-blocking agents

Class II antiarrhythmic

Mechanism:  Beta-blockers decrease the slope of Phase 4 of the action potential in the SA node, and decrease the upstroke velocity in the sinoatrial node and AV node, slowing conduction in these tissues.

Major Clinical Uses:
Slowing of the ventricular response in atrial fibrillation
Disrupting re-entrant arrhythmias (AV node reentrant tachycardia, Atrioventricular reentrant tachycardia, atrial tachycardia)
Suppressing PVCs or Atrial premature beats
• Decrease overall mortality and incidence of sudden death post-myocardial infarction

Pharmacokinetics:  Varies depending on the beta blocker used.   Most commonly used intravenous compound is esmolol.

Side Effects:
bronchospasm
depression
cognitive impairment
hypotension

Proarrhythmic Effects:
bradycardia
heart block

Contraindications:
High degree heart block (that is, type II second degree AV block or third degree AV block)

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Amiodarone

Class III antiarrhythmic

Mechanism:  Blocks potassium channels and increases action potential duration and the effective refractory period.  Also blocks Na+ channels (Class I-like effects), beta receptors (Class II-like effects), and Ca2+ channels (Class IV-like effects).   Broadly speaking it is the most effective antiarrhythmic agent but has side effects that limit its use long term.  A congener, dronedarone, is now available with fewer side effects.

Major Clinical Uses:
Suppression of ventricular tachycardia – however defibrillators are still more effective at saving lives
Maintenance of sinus rhythm in atrial fibrillation or atrial flutter
Acute conversion to sinus rhythm from atrial fibrillation

Pharmacokinetics:  Very long half life with two phases of elimination.  There is an initial half-life of about 1 week, and a terminal half life of about 2 months.

Side Effects:
Hypothyroidism and Hyperthyroidism – amiodarone is a heavily iodinated compound.  Furthermore it blocks conversion of T4 to T3. 
Pulmonary fibrosis
Liver Toxicity
Grayish-blue skin discoloration / phtodermatitis

Patients on amiodarone should have thyroid levels, pulmonary function testing, and liver function tests done yearly.

Proarrhythmic Effects:
Sinus bradycardia
AV block
Despite QT prolongation (the ECG correlate of lengthening the action potential), Torsades de Pointes with this agent is rare

Contraindications:
Pulmonary disease
Liver disease
Certain forms of thyroid disease

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Sotalol

Class III antiarrhythmic

Mechanism:  Blocks K+ channels and also has beta-blocking activity.

Major Clinical Uses:
Maintenance of sinus rhythm in atrial fibrillation, atrial flutter
Prevention of AVNRT, AVRT
Ventricular tachyarrhythmias

Pharmacokinetics:  Orally bioavailable.  Excreted by the kidneys, so dose must be adjusted based on creatinine clearance and must be reduced if excessive QT prolongation is seen on the electrocardiogram.  Typically BID dosing.  

Side Effects:
Beta blocker-like side effects.

Proarrhythmic Effects:
• Can cause new or worsened ventricular tachyarrhythmias by lengthening the QT interval, including Torsades de pointes.

Contraindications:
Similar to those of beta blockers.

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Dofetilide

Class III antiarrhythmic

Mechanism:  Blocks K+ channels.  Also has some Na+ channel-blocking activity.

Major Clinical Uses:
Maintenance of sinus rhythm in atrial fibrillation, atrial flutter

Pharmacokinetics:  Orally bioavailable.  Typically BID dosing.  

Side Effects:
Headaches
Gastrointestinal Complaints

Proarrhythmic Effects:
Lengthens the QT-interval and can cause new or worsened ventricular tachyarrhythmias, including Torsades de pointes.

Patients are monitored in the hospital for at least 5 doses while loading on this drug.  Risk is higher in patients who are hypokalemic.

Contraindications:
• Concomittant use with several drugs including verapamil and hydrocholorothiazide.

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Ibutilide

Class III antiarrhythmic

Mechanism: Blocks K+ channels. 

Major Clinical Uses:
Acute termination of atrial fibrillation and atrial flutter

Pharmacokinetics:  IV only. Extensive first pass metabolism, with metabolites cleared by the kidney.

Side Effects:
Few extracardiac side effects
Gastrointestinal Complaints

Proarrhythmic Effects:
Lengthens the QT-intervalRisk of Torsades de Pointes is confined to the first few hours after administration.

Therefore patients given this agent are monitored with continuous ECG monitoring (called “telemetry” for short clinically) for several hours after administration.

Contraindications:
Patients with severe structural heart disease

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Verapamil (and Diltiazem)

Class IV antiarrhythmic

Mechanism:  Calcium channel blockers that are useful electrophysiologically include verapamil and diltiazem.  These drugs block L-type calcium channels (ICa,L) and prolong conduction time and refractory periods in the AV node.

Major Clinical Uses:
Heart rate control in the setting of atrial fibrillation or atrial flutter
Can be used to terminate supraventricular tachycardias

Pharmacokinetics:  Half life is 6-7 hours.  Verapamil is available as oral or intravenous formulations.

Side Effects:
Constipation and peripheral edema are the most commonly encountered side effects.  Constipation arises from interference with smooth muscle function in the gut, and the peripheral edema arises from vasodil
Hypotension

Proarrhythmic Effects:
Sinus bradycardia
Heart block

Contraindications:
Advanced heart failure
High degree AV block

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Adenosine

Non-classified antiarrhythmic

Mechanism:  Adenosine is a naturally occurring compound with a very short halflife.  It interacts directly with A1 adenosine receptors in the heart, activating K+ channels, and indirectly leads to decreases in L-type calcium channel activity and If (the “funny current” Na+ current found in pacemaking cells).  The net effect of all this is marked hyperpolarization and transient elective heart block.

Major Clinical Uses:
Drug of choice for diagnosis and termination of supraventricular tachycardias by producing a transient heart block.  For example, it is very easy to see atrial flutter waves on the electrocardiogram without QRS complexes. Furthermore, by acting as a “reset button”, this drug is quite effective in terminating reentrant rhythms.

Pharmacokinetics:  Very short half life.  Clinically given as a 6 mg bolus, followed by a 12 mg bolus, and another 12 mg bolus as needed.  

Side Effects:
Flushing, chest pressure, chest burning.  All transient.

Proarrhythmic Effects:
Can occasionally cause atrial fibrillation. 

Contraindications:
• Few, and none that are M2-level appropriate.  For the record patients presenting with atrial fibrillation and ventricular pre-excitation as in Wolff-Parkinson-White syndrome should not receive adenosine because the AV nodal block can redirect the fibrillation to be conducted to the ventricles through the accessory pathway, sometimes at very high rates that can degenerate into ventricular fibrillation.

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Digoxin

Non-classified antiarrhythmic

Mechanism:  Digoxin has multiple mechanisms of action that contribute to its usefulness as an antiarrhythmic agent.  These effects are complex, dose-dependent, and can be broadly broken down into direct membrane effects mediated by its blocking of the Na+/K+ ATPase, and indirect effects which at lower doses are mostly vagomimetic.  In the therapeutic dose range, the predominant clinically useful effect of digoxin is its vagomimetic effect.  This leads to a slowing of conduction mainly in the SA node, the atria, and the atrioventricular node—parts of the heart supplied with rich vagal innervation.

Major Clinical Uses:
Control of ventricular response in atrial fibrillation and atrial flutter – usually used in conjunction with a beta-blocker or calcium channel blocker
• Non-antiarrhythmic use: improve contractility in patients with left ventricular systolic dysfunction.

Pharmacokinetics: 
• Available IV or PO.  When administered intravenously typically given as a loading dose.
• Eliminated by the kidneys, dose adjustment required based on creatinine clearance.
The quintessential drug with a narrow therapeutic window.  Therapeutic digoxin levels are considered to be approximately 0.5 ng/ml – 0.8 ng/ml.  Toxicities are typically seen at levels exceeding 2.0 ng/ml.D

Side Effects:
Anorexia, nausea, vomiting
Disorientation, hallucination, “yellow vision”
• Treatment of digoxin toxicity includes correcting any electrolyte abnormalities, and administration of anti-digoxin antibody fragments (Digibind) in selected, highly symptomatic patients with either cardiac or extracardiac side effects.

Proarrhythmic Effects:

AV nodal block – mostly from increased vagal tone. 
Ventricular premature beats – these may be due to delayed afterdepolarizations arising from a substrate of elevated intracardiac calcium levels
Ventricular tachycardia – eventuating from ventricular premature beats; may also be because of reentry.

Contraindications:
• Hypersensitivity

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drugs for diagnosing supraventricular tachycardia

Adenosine – short acting, reversible, few side effects.  Can help distinguish all types of SVTs

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drugs for disruption of supraventricular tachycardia (particularly AVNRT and AVRT)

Adenosine – slows conduction through AV node by hyperpolarization

Class II – Beta blockers – slows conduction through AV node through prolonging phase 4

Class III – Amiodarone (slows conduction through AV node) – slows conduction through AV node by multiple mechanisms, including prolonging phase 4

Class IV – Calcium Channel Blockers – slows conduction through AV node through prolonging phase 4

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drugs for rate control in atrial fibrillation and atrial flutter

Class II – Beta blockers – slows conduction through AV node

Class IV – Calcium Channel Blockers – slows conduction through AV node

Digoxin – slows conduction through the AV node

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drugs for acute conversion of atrial fibrillation and atrial flutter

drugs for maintenance of sinus rhythm in atrial fibrillation and atrial flutter

Class Ia agents – used historically, but obsolete for this indication.

Class Ic – Na+ Channel blockers – slows conduction through Na+ channel block, interfering with reentry

Class III agents – K+ Channel blockers – lengthens action potential duration through K+ channel block, interfering with reentry.

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drugs for suppression of symptomatic PVCs

Class II – Beta-blockers – can slow conduction in sick (ischemic) tissue.  The mechanistic details are beyond the
scope of this lecture. 

Class Ib – Na+ channel blockers -- Lidocaine, Mexelitine – intereferes with reentry by slowing conduction. Exhibit
use dependence.

Class Ic – Na+ channel blockers – slows conduction

Class III Agents – Sotalol and Amiodarone only.  Intereferes with reentry by prolonging repolarization.

Class Ia Agents – almost obsolete for this indication. 
Disopyramide is occasionally used in hypertrophic cardiomyopathy

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drugs for suppression of symptomatic VTs

Class III agents – K+ Channel blockers – lengthens action potential duration through K+ channel block, interfering with reentry.

Class Ia agents – used historically, but obsolete for this indication.

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drugs for suppression of symptomatic PVCs, VT in the setting of MI

Class II – Beta-blockers – can slow conduction in sick (ischemic) tissue.

Class III Agents –Amiodarone only.  Intereferes with reentry by prolonging repolarization.

Class Ib – Na+ channel blockers -- Lidocaine, Mexelitine – intereferes with reentry by slowing conduction.

Class Ia Agents – almost obsolete for this indication. Procainamide is occasionally used in ischemic VT.  

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treatment of torsades de pointes

address underlying abnormality

magnesium stabilizes the electrical membrane

isoproterenol and overdrive pacing both act to increase the heart rate

phenytoin also occassionally has a role but the main therapy is electrical cardioconversion