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1

Waht are the 3 mechanisms of arrhythmia?

} Enhanced automaticity

} Triggered activity

} Reentry

2

Explain how enhanced automaticity leads to arrhythmia?

} Due to accelerated firing of cells

} Often due to autonomic inputs, increased

sympathetic tone

} Can be due to medications

} Examples: Inappropriate sinus tachycardia,

accelerated junctional rhythm

3

What is triggered activity? How does it cause arrhythmias? In what patients does it occur?

} Often result from early and delayed

afterdepolarizations

} Depolarizing currents generated by calcium influx

} Often occur in patients with coronary artery

disease or heart failure

◦ Cytosolic calcium overload from energy starvation

4

What are early after depolarizations? When do they occur? What are they related to? What about delayed after depolarizations?

Early Afterdepolarizations (EAD’s)

} Occur during phase 3 of the cardiac action
potential

} Tend to be related to bradycardia

} Common mechanism to arrhythmia in Long QT
syndromes

Delayed Afterdepolarization (DAD’s)

} Occur during phase 4 of the cardiac action
potential

} Can be related to ischemia, drug effects (digoxin)

} Tends to be related to tachycardia

} Calcium influx from cell during phase 4 is
typical mechanism

5

What is reentry? What are some examples? What are 3 requirements?

} Most common mechanism of arrhythmia

} Continuous activation loop leading to arrhythmia

} Examples: atrial flutter, AVRT, AVNRT, scar
related ventricular tachycardia

REQUIREMENTS

◦ Two separate (anatomic or functional) pathways

◦ Separate conduction properties (fast/slow) in the two pathways

◦ Unidirectional block in fast pathway

6

Explain how AVRNT works?

} Common arrhythmia within the AV node

} Two separate pathways exist in the AV node (Fast

pathway and Slow pathway)

} Early activation causes block in the fast pathway

with conduction in the slow pathway

} When conduction passes through the slow

pathway, fast pathway has recovered excitability

and conduction occurs retrograde through the fast

pathway and back to the slow pathway

7

How do you stop or treat reentry? What are 3 general principles of antiarrhythmic drugs?

} Increase tissue refractory period

} Increase conduction rate through tissue

} General Principles

◦ Considerable risk in use

◦ High side effect profiles

◦ Proarrhythmia

8

List the Vaughn-Williams classification.

} Vaughan Williams Classification

◦ Class I – Sodium Channel Blockers
– Subclassified into A, B, C

◦ Class II – Beta-blockers

◦ Class III – Potassium Channel Blockers

◦ Class IV – Calcium Channel Blockers

9

What is use dependents? Reverse use dependents?

} Use dependence

◦ Trait of antiarrhythmics where drug blocks/binds more

with increased heart rates

– Example: Lidocaine

◦ Reverse use dependence

– Drug binds more in the open state, more effective at

decreased heart rates

– Example: Sotalol

10

List the different classes of antiarrhythmics, how they work, and examples of each.

} Class IA
◦ Moderate phase 0 depression
◦ Moderately slows conduction
◦ Prolongs repolarization
◦ Examples: Quinidine, Procainamide

} Class IB
◦ Minimal Phase 0 depression
◦ Minimal slowing of conduction
◦ Shorten Repolarization
– Blockade of slow sodium currents that continue through phase 2 of action potential
◦ Examples: Lidocaine, Mexiletine

} Class IC
◦ Marked Phase 0 depression
◦ Marked Slowing of conduction
◦ Minimal repolarization changes
◦ Prolong refractory period in AV node, accessory pathways
◦ Examples: Flecainide, Propafenone

Class II
Beta-blockers
} Reduce catecholaminergic effects on pacemaker cells
} Decrease conduction velocity in sinoatrial and AV nodes
◦ Increase effective refractory period in AV node
} Weak antiarrhythmic properties
} Examples: Metoprolol, Carvedilol, Propanolol

Class III Antiarrhythmics
} Potassium channel blockers
} Prolong refractoriness
} Examples: Sotalol, Amiodarone, Dofetilide

Class IV antiarrhythmics
} L-type calcium channel blockers
} Blocks/slows conduction through the AV node
} Weak antiarrhythmic properties
} Examples: Verapamil, diltiazem

11

Quinidine

Class IA

} Very rarely used, however still shows up occasionally on board exams

} Has sodium and potassium channel blocking properties

} Can be used for both atrial and ventricular arrhythmias

} Poorly tolerated due to GI side effects (Nausea, diarrhea)

} Liver clearance

} Serious side effects include proarrhythmia, thrombocytopenia, Cinchonism (CNS toxicity)

} Increases serum digoxin concentrations and should not be used in combination with digoxin

} Has been shown to increase mortality in patients with Atrial Fibrillation

12

Procainamide

Class IA

} Can be used for atrial and ventricular arrhythmias

} Oral and IV formulations
◦ Oral form no longer available in U.S.

} IV administration: Loading dose and maintenance
dose

◦ Hypotension during loading dose is common
– Treat with IVF, discontinuation of loading dose, reduced rate of loading dose

} Acetylation in Liver (NAPA), Renal clearance

} Rarely used due to development of lupus syndrome
during long term administration

} Other serious side effects include agranulocytosis,
proarrhythmia (NAPA)

13

Disopyramide

Class IA

} Can be used for atrial and ventricular arrhythmias
◦ Vagally mediated AF
◦ HCM with outflow tract obstruction

} Common side effects include anticholinergic effects
(constipation, dry mouth, urinary retention, blurred
vision)

} Serious side effects include worsening of CHF,
proarrhythmia

} Rarely used due to side effect profile

◦ Never use in patients with history of CHF or BPH

} Renal Clearance

14

Lidocaine

} Blocks INA
} Rapid onset/offset kinetics
} Little effect on atrial tissue in open state

} Pro
◦ Effective for ischemic VT
– More effective at high rates, low pH, increased extracellular K, reduced membrane potential

} Con
◦ PO equivalent (mexillitine) low potency
◦ Side effects
◦ Elevates DFT
◦ After 24 hours, clearance of drug falls

} Administration
◦ IV bolus and gtt
◦ If bolus is ineffective, gtt is also likely to be ineffective
◦ Bolus needs to administered slowly to reduce likelihood of neurologic adverse effects

◦ Heart failure: lower loading/maintenance dosing

◦ Liver disease: lower maintenance dosing (cleared by liver)

} Monitoring
◦ Levels (steady state 8-10 hours)
◦ Neurotoxicity
◦ Malignant hyperthermia (rare)

15

Mexelitine

} Similar to Lidocaine in properties

} Can affect sinus node in patients with disease, no
effect on normal sinus node

} Tablet form only

} Not generally useful in acute setting

} Limited potency

} Not very effective as monotherapy

} Often used as an adjunct with other antiarrhythmics for breakthrough

} Liver clearance, neurologic side effects

} Potential for treatment of LQT3?

16

Flecainide

} Used for atrial arrhythmias

} Prolongs PR, QRS, QT intervals

} Relatively well tolerated, but can cause dizziness,
headache, visual disturbances

} Black box warning
◦ Increased mortality in patients who are post MI
◦ Drug also known to exacerbate CHF and should not be
used in patients with history of CHF or structural heart
disease

} Can produce atrial flutter with 1:1 conduction

} Increases pacing and defibrillation thresholds

} Liver clearance

17

Propafenone

} Used primarily for atrial arrhythmias

} Well tolerated, but can cause constipation,
metallic taste, visual blurring, dizziness, nausea

} Serious side effects include CHF, proarrhythmia

} Has same black box warning as Flecainide
◦ Probably less proarrhythmic than flecainide
◦ For all intensive purposes avoid in patients with history of MI, structural heart disease, CHF

} Like Flecainide, causes increased pacing and
defibrillation thresholds, and 1:1 atrial flutter

} A small portion of the population are slow propafenone metabolizers and can develop severe bradycardia

18

Beta Blockers

Metoprolol, Carvedilol, Propanolol

} Indications
◦ Arrhythmias caused or enhanced by increased
sympathetic tone
◦ Arrhythmias related to ischemia
◦ AV nodal dependent arrhythmias (AVNRT, AVRT)

} Side effects
◦ Bradycardia
◦ Hypotension
◦ AV block
◦ Depression, fatigue
◦ Bronchospasm in patients with reactive airway disease

19

Amiodarone

} Class III antiarrhythmic
◦ Truly has Class I, II, III, and IV effects
◦ ‘Antiarrhythmic Shotgun’
◦ Prolongs APD and refractoriness
◦ Peripheral and coronary vasodilator
◦ Antiadrenergic actions
◦ Long half-life
◦ Hepatic metobolism
◦ In general the primary first line therapy for VT

} Prolongs QT interval however Torsades de Pointes is rare (<1%)
◦ Torsades de Pointes: Polymorphic ventricular tachycardia caused by QT prolongation
} Effective for atrial and ventricular arrhythmias
} Most effective drug available for AF suppression
◦ Especially effective in CHF patients

} Adverse Effects
◦ Phlebitis, severe cellulitis with peripheral IV administration
◦ Pulmonary fibrosis (1%-17%)
◦ Corneal microdeposits, optic neuritis
◦ Liver toxicity with rare progression to cirrhosis
◦ Photosensitivity, skin discoloration
◦ Hyper and Hypothyroidism
– Large iodine load
– Inhibits peripheral conversion of T4 to T3
◦ Tremor, ataxia
◦ Rare peripheral neuropathy, insomnia, memory disturbances, delirium
◦ Raises DFT

} Administration
◦ IV bolus and gtt
◦ PO loading dose, maintenance dose
} Monitoring
◦ Pulmonary: CXR (yearly), PFT w/ DLCO
◦ Thyroid: TSH, T4, T3 (q6 months)
◦ Liver: LFT’s (q6 months)
◦ Routine eye exams

20

Dofetilide

Class III
} Specific blocker of Ikr
} Virtually no extracardiac pharmacologic effects
} Used for atrial arrhythmias, specifically atrial fibrillation

} Can only be prescribed by certified practioners

} Must be initiated in the hospital due to risk of QT
prolongation/TdP

} Renal clearance

} Verapamil, HCTZ (among other drugs) interfere
with clearance and are contraindicated

Reverse use dependence
◦ Can lead to excessive QT prolongation and TdP post
cardioversion

21

Ibutilide

} Used for acute conversion of atrial fibrillation/atrial
flutter

◦ IV formulation only
} Increases APD by blockade of Ikr
} Causes mild slowing of HR and AV node
conduction
} Most effective in recent onset-arrhythmias

} Reduces defibrillation threshold
◦ Useful for failed DCCV
} Can be used safely in patients on chronic amiodarone therapy

} Administration: 1mg over 10 minutes
◦ If unsuccessful, can be repeated x 1
◦ Dose should be reduced for patients less than 60kg
◦ Infusion should be stopped once cardioversion occurs
} Patients must be monitored on telemetry for 4
hours post infusion due to risk of TdP (3.6-8.3% of
patients)

22

Sotalol

} Nonspecific beta-blocker
} Prolongs repolarization
} Modest negative ionotropic effect
} Reverse use dependence

} Pro
◦ Well tolerated
◦ Limited side effect profile
◦ Improves DFT

} Con
◦ QT monitoring/Proarrhythmic
– Torsades risk 2%
◦ Contraindicated w/ renal disease and severe
cardiomyopathy

} Administration

◦ PO dosing, generally BID

◦ Higher doses have more class III properties where lower
doses have more beta-blocking properties

} Monitoring
◦ Continuous telemetry monitoring during initiation/dose
increase w/ serial ECG for QT interval
◦ Renal function

23

Dronederone

} Noniodinated congener of amiodarone
◦ Class III agent, however blocks multiple ion channels
◦ Much shorter half life in comparison to amiodarone
◦ Not associated with significant tissue accumulation
◦ Relatively new medication, long term toxicity data not yet available
} Approved for rhythm control of atrial fibrillation and
atrial flutter
◦ Studies show more effective than compared to placebo
◦ Lost to amiodarone in head to head study

} Multiple drug-drug interactions
◦ Antifungals
◦ Calcium channel blockers
◦ QT prolonging medications
◦ Digoxin
◦ Warfarin, dabigatran, rivaroxaban
◦ Metoprolol
◦ Statins

} Side effects/Contraindications
◦ Not to be used as a rate control agent
◦ Class III/IV CHF
◦ Liver toxicity
◦ Lung toxicity
◦ GI effects

24

Calcium Channel blockers

Verapamil, diltiazem

} Indications
◦ Treatment of reentrant supraventricular arrhythmias
◦ Slowing conduction through the AV node to decrease
ventricular response to atrial arrhythmias (atrial
fibrillation, atrial flutter, atrial tachycardia)
◦ Treatment of some ventricular ectopy/arrhythmias
– Rare use

} Side effects
◦ Bradycardia
◦ Hypotension
◦ AV block
◦ CNS side effects (headache, fatigue, anxiety)

25

ADenosine

} Adenosine
◦ Slows automaticity
◦ Hyperpolarizes cardiocytes
– Activates potassium channels
◦ Decreases cAMP by inhibiting adenylate cyclase
◦ Primary effect on AV node
– Induces AV block
◦ Short half life (10 seconds)

◦ Indication: Termination of nodal dependent reentrant
arrhythmias
– AVNRT, AVRT

26

Digoxin

} Digoxin

◦ Cardiac glycoside used primarily for heart failure
symptoms

◦ Has properties that causes slowing of conduction through the AV node
– Rate control for atrial fibrillation, flutter, SVT

◦ Enhances vagal tone and reduces sympathetic activity
– Easily overcome by increases in sympathetic tone

◦ Very small therapeutic window

◦ Renal clearance

◦ Toxicity can cause life threatening arrhythmias
– Increase in resting potential
– Decreased action potential duration
– Increased cellular automaticity
– Increased intracellular calcium

} Digoxin toxicity can lead to:
◦ Sinus bradycardia/sinoatrial block
◦ AV block
◦ APC’s/VPC’s
◦ Accelerated junctional rhythm
◦ Ventricular tachycardia