Transcript CHAPTER 25

CHAPTER 25
ANTIARRHYTHMIC DRUGS
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Arrhythmia:
Arrhythmias consist of cardiac depolarizations
that deviate from the sinus rhythm--ie, There
is an abnormality in the site of origin of the
impulse, its rate or regularity , or its
conduction .
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The types of Arrhythmia:
缓慢型 : 窦性心动过缓 (sinus bradycardia)
房室传导阻滞 (atrio-ventricular block)
快速型 : 房性早搏 (atrial premature contraction)
房性心动过速 (atrial tachycardia,AT)
心房颤动 (atrial fibrillation, AF)
心房扑动 (atrial flutter, AFL)
阵发性室上性心动过速
(paroxysmal
supraventricular
tachycardia)
室 性 早 搏
(ventricular premature
contraction)
室性心动过速 (ventricular tachycardia,VT)
心室颤动 (ventricular fibrillation, VF) 4
Section 1
The Physiological Basis of
Arrhythmia
1. The electrophysiology of normal
cardiac rhythm
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2. The electrophysiological mechanism
of arrhythmias
(1) Disturbances in impulse formation:
Increased automaticity
(2) Afterdepolarization and triggered activity:
Early afterdepolarization (EAD)
Delayed afterdepolarization (DAD)
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(3) Disturbances in impulse
conduction


1) Simple conduction disturbances:
conduction ↓
conduction block
2) Reentry (circus movement)
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Section 2
The Basic Electrophysiology
Action of Antiarrhythmic Drugs
and The Classification of Drugs
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1. The basic
electrophysiology action

1)↓automaticity (autorhythmicity)
a.↓slope of phase 4 depolarization:
↓Na+in or Ca2+in
b.↑Threshold potential
c.↑maximum diastolic potential:
↑K+out
+
↑APD
↓
K
D.
out
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2)↓EAD or DAD:

Accelerate repolarization,

Block Na+ in or Ca2+ in
3) Avoid reentry:

a.↑conduction:↓unidirectional block

b.↓conduction : unidirectional block
→ bidirectional block

c.↑ERP
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2.The classification
Class by Vaughan Williams
(1971)
 ClassⅠ Sodium channel-blocking
agents: IA , IB, IC
 ClassⅡ β-R blockers
 Class Ⅲ Prolonging APD agents
 Class Ⅳ Calcium channel blockers
Sicilian gambit (1991)
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Section 3
Specific Antiarrhythmic Agents
1. ClassⅠ Sodium channelblocking agents
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钠通道阻滞剂的分类
分类 药物 钠阻滞强度 结合/解离常数 心电图表现 状态依赖
IA
IB
奎尼丁
普鲁卡因胺
++
1—10秒
延长QT
激活态
利多卡因
美西律
+
<1秒
不明显
失活态
IC 普罗帕酮
氟卡尼
+++
>10秒
QRS增宽
激活态
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1) ClassⅠA


a. Inhibit Na+ influx moderately :
↓Vmax, ↓conduction
↓phase 4 slope, ↓automaticity
b. ↓ K+ efflux , Increase the ERP
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Quinidine(奎尼丁)
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
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Pharmacological Effects:
Cardiac Effects:
↓autorhythmicity;↓conduction;↑ERP
↓myocardial contractility
Extracardiac Effects:
α-adrenergic blocking
anticholinergic effect
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Therapeutic Uses:
Broad-spectrum
 Atrial fibrillation; Atrial flutter;
 Supraventricular and ventricular
tachycardia;
 Supraventricular and ventricular
premature beat
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Toxicity:


CVS: Heart failure; hypotension;
quinidine syncopy
Chichonic reaction(金鸡纳反应)
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2) Class IB

↓Na+ influx lightly

↑K+ efflux, shorten the APD>ERP ,
ERP/APD ↑
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Lidocaine (利多卡因)
Pharmacological effects:
 Act on Purkinje fibers and
ventricular cells
 a. ↓autorhythmicity
↓the slope of phase 4 and ↑the
threshold for excitability.
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

b. Altering the conduction:
Myocardial ischemia →↓conduction,
unidirectional block→bidirectional block
K+↓→↑K+ efflux →↑conduction →
↓unidirectional block
c. Relative increase ERP: ERP/APD↑
Pharmacokinetics:
Therapeutic use:
Ventricular arrhythmias
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Phenytoin sodium
It has been used in the acute and
chronic ventricular arrhythmias,
especially in digitalis intoxication.
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3) Class IC
Severely depress Na+ influx,
markedly↓Vmax , ↓conduction.
 ↓phase 4 slope. ↓automaticity
 Serious adverse reactions are
provocation of potentially lethal
arrhythmias.

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
CAST试验I(心律失常抑制试验)
心律失常抑制标准:室早减少80%以上,室速
减少90%以上。
入选病人2309例。结果可见1727例心律失常抑制
良好;135例部分抑制;447例室性心律失常增加,治
疗组死亡率7.3%,安慰剂组死亡率3.0%。其中心律失
常或心跳骤停者治疗组4.5%,安慰剂组1.7%。
结果说明英卡尼和氟卡尼虽能较好的抑制MI后
的心律失常,但明显增加所致死亡率及总病死率,其
原因为该类药物有负性肌力作用,另外其致心律失常
作用亦不容忽视。
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Propafenone(普罗帕酮)
Block Na+and Ca+ channel,
also blockβ-R
 ↓conduction, ↓automaticity, ↑ERP
 Used to treat Supraventricular and
ventricular tachycardia;
Supraventricular and ventricular
premature beat, Atrial fibrillation.

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Class Ⅱ β-R Blockers
Propranolol
 Metoprolol
 Atenolol
1) β-R blocking action
2) Membrane-stabilizing effect(↓Na+in)

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Pharmacological effects:

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

a.↓autorhythmicity,↓afterdepolarization
by CA, prevent triggered activity.
b.↓ conduction of AV node and P-f ( >100ng/ml)
c.↑ERP of AV node,↓reentry
d. Improve myocardial ischemic
Therapeutic uses
Supraventricular arrhythmias
Acute myocardial infarction(AMI)
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BHAT(急性心肌梗死后普萘洛尔对室
性心律失常的影响)
美国,加拿大37个临床中心采用多中心,随机
安慰剂双盲对照试验。入选标准: AMI后5-21天经
ECG检查发现频发室性早搏,短阵室速,共入选
3837例。
药物用法为第一天普萘洛尔20mg或安慰剂,
如无副作用第二天用40mg,每日三次,之后逐渐
增加到80mg,每日三次,最长随访时间36个月。
结果可见6周后安慰剂组心律失常减少
1.6%,治疗组减少15.4%,安慰剂组死亡率9.8%,
治疗组7.2%(P<0.005)。研究结果说明普萘洛尔
用于AMI可明显降低死亡率,并可长期应用,安全
有效。
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Class Ⅲ
Prolonging APD agents
Blocking K+ channel , ↓ K+ efflux ,
↑ repolarization, ↑ APD and ERP
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Amiodarone(胺碘酮)
Pharmacological effects:
↓ions channel: K+, Na+, Ca2+
Blocking α,βreceptor
 1) ↑APD and ERP, no reverse use-dependence
 2) ↓autorhythmicity
 3) ↓ conduction of AV node and Purkinje fibers
 4) Dilatation coronary artery,
↓ myocardial oxygen consumption
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Pharmacokinetics:
F: 40%, t1/2 40 d, last 4~6 w
Therapeutic uses:
Broad-spectrum antiarrhythmic drug
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Adverse effects:



CVS reactions:
Sinus bradycardia
Atrio-ventricular block
Torsades de pointes(Tdp,
long QT syndrome, LQTS)
Pulmonary fibrosis
Hypo- or hyperthyroidism
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BASIS(巴塞尔心肌梗死后心律失常研究);
CASCADE (西雅图胺碘酮和其他抗心律失常药物
对心脏骤停作用的评价);CAMIAT (加拿大心肌
梗死后胺碘酮抗心律失常试验);EMIAT (欧洲
心肌梗死后胺碘酮试验);IAMT (静脉内胺碘酮
抗心律失常研究)。
入选病人多数为AMI后室性心律失常患者,服
药方法为:第一周每天800mg,第二周每天400mg
用6天,持续12个月,有显著心动过缓,QT间期明
显延长者剂量减少至100mg/日。
结果显示:胺碘酮组心脏性死亡率明显减少
(P=0.048),严重室性心律失常的发生率胺碘酮
组7.5%,对照组19.5%(P< 0.001)
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Sotalol (索他洛尔)
Nonselective β-R antagonist
Block Ik, ↑APD、ERP
F=90%~100%
Broad-spectrum
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
Dofetilide(多非利特)
阻滞Ikr,延长不应期但不减慢传导,无负
性肌力和负性血流动力学效应,用于房颤复律和
维持窦律,有效且不增加心衰死亡率,左室功能
重度障碍者可用。
具有reverse use-dependence, 主要
副作用为Tdp(2%~4%)应监测QTc变化。
Ibutilide (伊波利特)
Sematilide (司美利特)
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
Ikur只分布于心房肌,在调控心房复极
中起重要作用 ,而对心室肌无影响,开发
选择性Ikur阻滞剂用于治疗房性心律失常,
是III类药物开发方向之一。胺碘酮、氨巴
利特(ambasilide)对Ikur有阻滞作用。
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Class Ⅳ
Calcium channel
blocking agents
Block the L-Ca2+ channel of
cardiac,↓sinus and AV node.
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Verapamil(维拉帕米)
Major clinical uses:
Supraventricular arrhythamias.
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Others
Adenosine(腺苷)
Act on A-R, ↑KACh ,↑K+ efflux
↓cAMP-induced Ca2+ influx, ↑ERP of
AV node.
 Choice for prompt conversion of
paroxysmal supraventricular
tachycardia.

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抗心律失常药的合理应用
用药原则
1.
先单用药,后联合用药。
2.
小剂量, 个体化用药, 。
3.
充分注意药物的不良反应,
特别是致心律失常作用。
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药物的致心律失常作用
The proarrhythmia action of drugs
应用抗心律失常药物过程中,原有心
律失常加重或恶化,或出现新的心律失常。
发生率:6%~30%
所有抗心律失常药物都有引起折返性
心动过速的基础,因此是双刃剑。
防治:明确指征,纠正诱因,抗心律
失常( β阻断药、胺碘酮)
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The Choice of Drug Therapies
1. Sinusal tachycardia:
β- Blockers or Verapamil
2. Atrial premature beat:
β- Blockers , Verapamil
3. Atrial fibrillation, Atrial flutter:
Verapamil, β- Blockers ,
Amiodarone, Cardiac glycosides,
4. Supraventricular tachycardia:
Verapamil, Cardiac glycosides,
β- blockers, Adenosine.
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5. Ventricular premature beat:
Lidocaine, Amiodarone ,Propafeone
6. Ventricular tachycardia:
Lidocaine, Amiodarone, Propafeone
7. Ventricular fibrillation:
Lidocaine, Amiodarone.
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抗心律失常药物作用最佳靶点假说
在心肌细胞膜上存在多种离子通道及亚型。
正常情况下,各通道间有一定数目和比例,保
持一定的平衡。当某种通道数目上调或下调到
一定范围,通道间比例失调,将出现心律失常。
与心律失常发生发展有关的通道,称为抗心律
失常药作用的靶点。在心律失常发生发展中起
主导作用的通道,称为抗心律失常药作用的最
佳靶点。一个理想的抗心律失常药应对最佳靶
点有作用,且至少对两种或两种以上的离子通
道有作用。
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