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Pharmacologic Approaches to
Arrhythmia Suppression
Jaemin Shim, MD
Yonsei University Health System
Depolarization and Repolarization
Depolarization and Contraction
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Repolarization and Relaxation
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Action Potential of Myocyte
Arrhythmia Mechanism
Enhanced Automaticity
 Non-pacemaker cells begin to spontaneously


and abnormally initiate an impulse.
Reduced (more positive) resting membrane
potential bringing it closer to the threshold
potential.
Ischemia and electrolyte imbalances
Automaticity
NORMAL AUTOMATICITY
ABNORMAL AUTOMATICITY
(depolarized Purkinje myocyte)
(SA myocyte)
1 sec
200 ms
DD
Emax
50 mV
50 mV
Eth
block IK1
Triggered Activity (Afterdepolarization)
 Triggered activity (afterdepolarizations):
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
Spontaneous depolarizations requiring a
preceding impulse (triggering beat)
Early afterdepolarizaiton (EAD)
− During phase 2 or 3
− Drug induced Torsade de pointes
Delayed afterdepolarization (DAD)
− During phase 4
− Digoxin toxicity
Early afterdepolarizaiton (EAD)
Delayed afterdepolarizaiton (EAD)
EAD vs. DAD
EAD
(during phase 2 or 3)
EAD
DAD
(during phase 4)
DAD
Inciters
QT prolonging drugs
Digitalis, catecholamine
Exaggerated by
Slow rates, ↓K+
Rapid rates
Blunted by
Rapid rates, K+, Mg2+
Ca2+ channel block
Mechanism
Net↑ inward plateau
current
Intracellular Ca2+ overload
Putative clinical
rhythm
Torsades pointes
Digitalis toxicity, ischemia
Reentry
Action of Antiarrhythmic Drugs
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Blocking the sodium channel
Blocking the potassium channel
Blocking the calcium channel
Blocking the adrenergic receptor
Slowing conduction (Na+ channel blockade)
Lengthening the refractory period (K+ channel blockade)
Reducing automaticiy of abnormal tissue
Vaughan Williams Classification
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Class I – Fast sodium channel blocker
Class II – Non-competitive beta-blocker
Class III – Potassium channel blocker
Class IV – Calcium channel blocker
Class I Antiarrhythmic Agents
 Class IA (QT↑): quinidine, procainamide,
 Class IB (QT↓): lidocaine, mexiletine
 Class IC (QT→, QRS↑): flecainide (Tambocor),
propafenone (Rytmonorm)
Flecainide (Tambocor)
 Class IC antiarrhythmics
 Depresses sodium current, decreases

conduction velocity
− Lesser effect on refractoriness
Use dependence
− The faster the rate, the more binding and the
drug’s anti arrhythmic effect
 Dual elimination
− Kidney and Liver
 Contraindicated in CAD or HF
M/80, palpitation with dizziness
flecainide 100mg bid for AF
TLC 320 ms, LBBB, LAD
Wide QRS tachycardia probably due to
flecainide related use dependency
Rhythm strip after verapamil 5 mg IV bolus
II
Atrial flutter 1:1 conduction
2:1 conduction with normal QRS
Cardiac Arrhythmia Suppression Trial
(CAST trial)
 1498 pts: 432 encainide, 323 flecainide
 Double-blinded, placebo controlled trial of
PVC suppression with encainide and
flecainide following MI
Echt et al. NEJM 1991; 324:781-788
Cardiac Arrhythmia Suppression Trial
(CAST trial)
 Study halted due to increased all-cause mortality in treatment arm
 3.6 fold increase in fatal arrhythmias and non-fatal cardiac arrest
Echt et al. NEJM 1991; 324:781-788
Beta Blockers
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Class II
Metoprolol, Esmolol, Propranolol
Inhibits normal sympathetic effects
Decrease cardiac automaticity
Decrease AVN conduction velocity
Increases AVN refractoriness
Cardio-protective: ↓myocardial contraction,
O2 demand
Sotalol
 Class III
 K+ channel blocker with beta blocking
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properties
Renal excretion
Serious side effect: Torsade de pointes
The corrected QT (QTc) interval must be
watched carefully for excess prolongation
Amiodarone
 Class III
 Na+ channel, alpha and beta adrenoreceptor,
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and Ca2+ channel blockade
Very long half-life: 40-50 days
Hepatic excretion
It rarely causes torsade de pointe and is
safely used in patients with advanced
cardiovascular disease
항부정맥 효과가 높고, 심근기능 저하가 적다.
구조적 심질환이 있는 환자에 적합
Amiodarone
 장기 사용시 부작용 위험이 높다.
−
−
−
−
−
−
Pulmonary fibrosis (5-10%, 10% 사망율)
Hypo or hyperthyroidism
Elevated liver enzyme
Skin blue discoloration
Corneal deposit
Upto 25% of patients will have to discontinue it
due to side effects.
M/67, on amiodarone
Pulmonary fibrosis
Blue discoloration
DLCO 67%
Choi JS, # 3220914
Canadian Trial of AF Investigation
NEJM 2000;342:913-20
Dronedarone
 Class III
 Iodine moieties in amiodarone play a role in
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
mediating side effects
Dronedarone is a derivative of amiodarone
that lacks the iodine moieties
Elimination half life is reduced to 1 day
Dronedarone
 ADONIS / EURIDIS – moderately effective AAD in
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low risk non-permanent AF / AFL
ATHENA –reduces adverse CV events in moderate
risk non-permanent AF / AFL patients.
PALLAS – dronedarone increases adverse
cardiovascular outcomes in high risk permanent AF
/ AFL patients.
Dronedarone should not be used in patients in
permanent AF / AFL, in patients with a history of
CHF, or in patients with reduced LVEF
Calcium Channel Blockers
 Class IV
 Verapamil (Isoptin), Diltiazem (Herben)
 Blocks both activated and inactivated slow ICa
− Decrease AVN conduction velocity
− Increase AVN ERP
− Reduce ventricular rate
− Reduce Phase 4 potential -↓automaticity
 Mainly used in SVT and rate control in AF
Other Drugs
 Adenosine
− Negative dromotropic and chronotropic effects
mainly on the SA and AV nodes.
− May lead to transient complete AV block.
− Quickly cleared with an elimination half-life of 10
seconds or less
 Digoxin
− Enhances vagal activity and thus slows sinus node
automaticity and prolongs AV nodal conduction
− Used to control the ventricular rate in AF
− Hypokalemia augments digitalis toxicity
Take-home Messages
 항부정맥제는 부정맥 억제에 효과적이지 못하다.
 항부정맥제는 안전하지 않으며 일부 환자에서 오히려 사망률
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을 증가시킨다 (CAST, SWORD, AFFIRM Trials).
구조적 심장질환이 있는 사람에서는 proarrhythmia의 위험
이 있으므로 amiodarone, dronedarone 이외에는 피한다.
항부정맥제의 급성/만성적 부작용에 대한 지속적인 모니터링
이 필수적이다.
심전도로 증명이 된 부정맥에 한해서 심전도로 효과를 확인
한 최소 용량을 선택적으로 사용한다.
Non-pharmacologic Tx에 병용한 Hybrid Tx가 효과적이다.
Thank you for you attention
Action Potential of Myocyte