Download 第20章治疗心律失常药物Antiarrhythmic agents

第20章 治疗心律失常药物
Antiarrhythmic agents
一、Basic Concept
正常心率（窦性心律）：The electrical
impulse that triggers a normal cardiac
contraction originates at regular intervals
in the sinoatrial node , usually at a
frequency of 60-100 beats per minute. This
impulse spreads rapidly through the atria
and enters the atrioventricular node, then
propagates over the His-Purkinje system
and invades all parts of the ventricles.
心律失常：
Arrhythmias consist of cardiac
depolarizations that deviate from the
above description in one or more
aspects—ie, there is an abnormality
in the site of origin of the impulse,
its rate or regularity, or its
conduction 。
二、Pathophysiology
• Arrhythmias develop because of
abnormal impulse generation,
abnormal propagation or both
• Bradyarrhythmias
• Which arise through abnormalities of
intrinsic automatic behavior or
conduction, principally within the
atrioventricular node and the HisPurkinje's network.
• Tachyarrhythmias
• Three mechanisms have been
associated with many
tachyarrhythmias
1. Altered automaticity: Factors that
increase automaticity include
mechanical stretch beta-adrenergic
stimulation hypokalemia
2. Triggered automaticity:
– Early Afterdepolarization (EAD)早后除极
which is associated with significant
prolongation of the action potential
duration. Factors that predispose to
EAD:
bradycardia low extracellular K+
– Torsades de pointes, a polymorphic
ventricular arrhythmia- associated with
Prolongation of cardiac repolarization
(prolonged Q-T interval) Possibly
induced by early afterdepolarizations
– Delayed afterdepolarization (DAD)迟后
除极. Factors that predispose to DAD
include:
excessive adrenergic activity digitalis
toxicity high intracellular Ca2+
3. reentry: Most clinically significant
tachyarrhythmias are probably due to
reentry.
Afterdepolarizations and triggered activity
• Symptoms and Signs
• Palpitations (awareness of the heartbeat)
are often disagreeable and may arise
equally from increased force of
contraction and from rhythm disturbance.
They should be investigated to define the
cause and to allay anxiety.
• Arrhythmias that cause hemodynamic
upset are usually sustained bradycardias
or tachycardias and may be life
threatening. Resulting dizziness and
syncope are common. These arrhythmias
require urgent attention and, often,
hospitalization.
• Some arrhythmias cause few or no
symptoms but are associated with
an adverse prognosis. Much
evidence suggests that prognosis is
not necessarily improved by their
suppression. Other arrhythmias,
although symptomatic, are benign.
• The nature and severity of
underlying heart disease are often
of greater prognostic significance
than is the arrhythmia itself.
•
心律失常的治疗学分类
就临床治疗的观点，心律失常可分为三类：
1. 良性（无器质性病变）benign arrhythmias:
VPBs, sinus tachycardia using Anxiolytics
and Sedatives
2. 可能恶性（轻中度器质性病变）potential
malignant arrhythmias： Paroxysmal
Supraventricular Tachycardia, monomorphic
ventricular tachycardia, atrial fibrillation
3. 恶性（重度器质性病变）malignant
arrhythmias (life-threatening arrhythmias)：
sustained ventricular tachycardia,
polymorphic ventricular tachycardia,
ventricular fibrillation
Treatment
• Most cardiac arrhythmias cause no
symptoms, have no hemodynamic
importance, and have no prognostic
significance but may cause anxiety in a
patient who becomes aware of them.
Some patients with benign arrhythmias
remain disabled despite reassurance.
Behavior modification therapy often helps
when reassurance has failed. In rare cases,
a precipitating factor may be identified and
modified (eg, excessive intake of caffeine
or alcohol).
• Drug treatment:
• Antiarrhythmic drug therapy is the
mainstay of management for most
important arrhythmias.
• There is no universally effective
drug; all have important safety
limitations and can aggravate or
promote arrhythmias
(arrhythmogenesis, proarrhythmia).
• Drug selection is difficult and often
involves trial and error.
抗心律失常药物分类
•
•
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•
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•
Willams分类法分为四类：
Ⅰ类：钠通道阻断剂，又再分为a,b,c三亚类
Ⅱ类：beta-受体阻断剂
Ⅲ类：钾通道阻断剂（动作电位时程延长药）
Ⅳ类：钙通道阻断剂
其它类：强心苷、腺苷、镁，等
• Class I drugs are Na channel
blockers,
including
older
antiarrhythmic drugs (eg, quinidine).
All reduce the maximal rate of
depolarization of the action potential
and thereby slow conduction.
• They are subclassified based on the
kinetics of their receptor effects:
– class Ia--drugs with intermediate
onset and offset;
– class Ib--drugs with short effects;
• 第Ⅰ类药钠通道阻滞药
Ⅰa类代表药
主要有奎尼丁（quinidine）、普鲁卡因胺
(procainamide)
Ⅰb类代表药
主要有利多卡因（lidocaine）、苯妥英钠
(phenytoin sodium)、美西律（mexiletine）
Ⅰc类代表药
主要有心律平（普罗帕酮，propafenone），氟
卡尼(flecainide，氟卡胺)，恩卡尼
(encainide，恩卡胺)
• Class II drugs may be the least toxic and most
powerful
drugs
available,
yet
their
antiarrhythmic effects are often overlooked.
Whereas relatively few arrhythmias are
primarily caused by sympathetic overactivity,
most are modulated by autonomic tone. βBlockers have poor efficacy in conventional
antiarrhythmic tests (eg, VEB suppression),
but they raise the threshold to VF and may be
potent preventers of VF.
• In general, β-blockers are well tolerated but
may depress left ventricular function,
particularly in antiarrhythmic doses. They are
contraindicated in bronchospastic airway
disease and should be used cautiously in other
• Class III drugs interfere with the
K channel to alter the plateau
phase of the action potential
and increase refractoriness.
Conduction velocity is little
affected, but, theoretically, the
discharge rate of automatic foci
is reduced. These drugs can be
proarrhythmic.
胺碘酮（amiodarone）
兼有1-4类的作用，以3类为主，为广谱抗心
律失常药，但不良反应多，且药动学复杂。
索他洛尔 (sotalol)
原为β受体阻断药,后因明显延长APD而用作
Ⅲ类抗心律失常药。d-异构体无β阻断作用，
只延长ADP，有抗室性心律失常，抗室颤的
作用，但可诱发尖端扭转性室速。
• Amiodarone
• a powerful class III antiarrhythmic. It has
few cardiovascular adverse effects and,
perhaps through its modest vasodilator
action, produces little or no left ventricular
depression. Sinoatrial node activity is little
affected. Amiodarone, by prolonging
refractoriness, may create homogeneous
conditions of repolarization throughout the
heart. The QT interval on ECG is prolonged,
and no upper safe limit to this effect has
been suggested. The elimination t1/2 is > 50
days, with substantial delay in onset of
action. The ECG should be monitored
continuously, as there is a risk of inducing
atrioventricular block.
• Class IV drugs are Ca blockers (Ca
entry blockers).
• verapamil and diltiazem influence
atrioventricular nodal electrophysiology
and may alter that of Ca-dependent
ischemic cells.
抗心律失常药物的致心律失常作用
• 几乎所有的抗心律失常药物都有或多或少的致
心律失常作用。
Proarrhythmia due to sodium channel block（Ⅰ
类）
• Four distinct forms of proarrhythmia have
been associated with treatment with sodium
channel blockers.
• 1 atrial flutter 心率慢时房室传导快，使室率快
• 2 slow conduction in the rim of an old
myocardial infarction plays a prominent role
in the genesis and maintenance of sustained
monomorphic ventricular tachycardia.
• 3 reduces excitability of the heart. ICDs
increased output of the devices may be
• 4 CAST启示
• The fourth proarrhythmia syndrome
occurring during treatment with sodium
channel blockers is an increase in
mortality during long-term treatment. This
was established by the Cardiac
Arrhythmia Suppression Trial (CAST), a
landmark study that tested, in a placebocontrolled, randomized, double-blind
fashion, the then-prevailing wisdom that
suppression of VPCs in patients
convalescing from a myocardial infarction
would reduce the incidence of sudden
death.
• In CAST, patients with VPCs and a
recent myocardial infarction were
randomly assigned to one of three
sodium channel blocker therapies,
which was then titrated to the dose
that appeared to suppress VPCs on
a 24-hour Holter monitor. Once the
effective dose and drug were
established, patients were randomly
assigned to continue drug or
placebo. Remarkably, mortality
among patients randomized to drug
was 2 to 3 times that among those
randomized to placebo.
• The mechanism underlying this
striking, and previously undefined,
effect of sodium channel block
remains uncertain. However,
conduction slowing with an
increased risk of sustained
ventricular arrhythmias (including
ventricular fibrillation) seems likely.
Proarrhythmia due to QT prolongation Ⅲ类
• In some patients, therapy with action
potential prolonging drugs such as sotalol,
quinidine, or ibutilide can be associated
with marked prolongation of the QT
interval and induction of a
morphologically distinctive polymorphic
ventricular tachycardia, torsades de
pointes.
• Torsades de pointes can also occur during
treatment with “noncardiovascular” drugs;
common examples include terfenadine,
cisapride, haloperidol, and thioridazine
(Tan et al. 1995).
• SWORD启示
• Most recognized cases of torsades de
pointes occur shortly after starting culprit
drug(s). However, a specific IKr blocker,
the dextrorotatory isomer of sotalol (dsotalol), was found in SWORD (Survival
with Oral d-Sotalol), a large study with a
CAST-like design, to increase long-term
mortality compared to placebo in patients
judged to be at risk for sudden death
(Waldo et al. 1996). Since the drug is not a
sodium channel blocker, a mechanism
different from that in CAST seems likely;
torsades de pointes occurring during
chronic term outpatient treatment is one
leading possibility .
抗心律失常药应用原则
• 消除诱发和促发因素：低钾血症，低镁血症；
心肌缺血缺氧；甲亢；一些药物（强心苷、抗
心律失常药、茶碱、红霉素等）
• 选用合适药物：窦速- β阻断药、维拉帕米；房
颤降低室率-强心苷，房颤转律维持-胺碘酮、
奎尼丁；阵发室上速-腺苷、维拉帕米；室速利多卡因、胺碘酮
• 个体化用药：根据年龄、体质、心、肝、肾功
能及电解质情况调整用药方案
• 注意用药禁忌和不良反应：心律失常，心脏收
缩力抑制，心脏传导抑制，低血压，甲状腺功
能改变，肺纤维化