Agents Used in Cardiac Arrhythmias

抗心律失常药
Agents used in
cardiac arrhythmias
南开大学医学院
张京玲王侃
Antiarrhythmias
目的
了解抗心律失常药的不良反
应与临床应用，掌握各类抗心
律失常药对心肌电生理活动的
影响及临床应用、不良反应。
Antiarrhythmias
内容
复习心肌电生理的有关基本知识：
包括动作电位各时相及离子运动。膜
反应性与传导速度的关系，不应期，
快反应，慢反应电活动，折返激动，
心律失常发生的原因。抗心律失常药
的分类：第Ⅰ类药（ A ， B ， C ）；
第Ⅱ类药；第Ⅲ类药；第Ⅳ类药。
Antiarrhythmias
内容
 钠通道阻滞药（第Ⅰ类） 1 ）奎尼丁（ A ）：降低
膜对钠的通透性，也降低膜对钾，钙的通透性。表现
为降低自律性，减慢传导速度，延长有效不应期，减
弱心肌收缩力。这些作用在心电图上的反映。奎尼丁
用于治疗心房颤动，扑动，房性或室性心动过速等。
不良反应，奎尼丁晕厥及用药注意事项。 2 ）普鲁卡
因胺：与奎尼丁的比较 3 ）利多卡因（ B ）：促钾
外流，也抑钠内流，主要作用于希浦氏系统。降低自
律性，加速受损纤维的传导速度，缩短不应期和动作
电位时程。用于治疗室性心律失常，体内过程及不良
反应。 4 ）苯妥英钠：作用特点，与利多卡因的比较。
5. 心律平（普罗帕酮），氟卡胺等（ C ）的作用特
点。
Antiarrhythmias
 受体阻断药（第Ⅱ类）普奈洛尔抗心律
失常作用与受体阻滞及膜效应的关系。其
左旋体与右旋体的作用区别。临床应用。不
良反应及禁忌症。其它受体阻断药的应用
。
 延长动作电位时程的药物（第Ⅲ类）胺碘
酮（乙胺碘呋酮），溴苄铵延长动作电位时
程和不应期。临床应用和不良反应。
 钙通道阻滞药（第Ⅳ类）维拉帕米（戊脉
安）对心肌细胞膜，慢通道的选择性阻滞作
用。临床应用与不良反应。
Antiarrhythmic agents
I. Electrophysiology of normal
cardiac rhythm
II. Mechanisms of arrhythmias
III. Mechanisms of action of the
antiarrhythmic agents
IV. Classification of the
I. Sodium channel-blocking drugs
(class Ⅰ)
II. Beta adrenoceptor-blocking
drugs (class Ⅱ)
III. Drugs that prolong effective
refractory period by prolonging
action potential (class Ⅲ)
• Calcium channel-blocking
drugs (class Ⅳ)
• Principles in the clinical use of
I. Electrophysiology of normal
cardiac rhythm
1. Ionic basis of membrane
electrical activity
2. The active cell membrane
3. The effect of resting potential
on action potentials
1. Ionic basis of membrane electrical
activity
The transmembrane potential of
cardiac cells is determined by the
concentrations of several ions—
chiefly Na+, K+, and Ca2+—on either
side of the membrane and the
permeability of the membrane to
each ion.
These water-soluble ions are
unable to freely diffuse across the
lipid cell membrane in response to
their electrical and concentration
gradients; they require aqueous
channels for such diffusion.
Ions move across cell membranes
in response to their gradients only
at specific times during the cardiac
cycle when these ion channels are
open.
The movements of these ions
produce currents that form the
basis of the cardiac action
potential. Individual channels are
relatively ion-specific, and the flux
of ions through them is thought to
be controlled by “gates” .
Each type of channel has its own
type of gate, and each type of gate
is opened and closed by specific
transmembrane voltage, ionic, or
metabolic conditions.
At rest, most cells are not
significantly permeable to sodium,
but at the start of each action
potential, they become quite
permeable. Similarly, calcium
enters and potassium leaves the
cell with each action potential.
Therefore, the cell must have a
mechanism to maintain stable
transmembrane ionic conditions by
establishing and maintaining ion
gradients.
The most important of these active
mechanisms is the sodium pump—
Na+/K+ ATPase. This pump and other
active ion carriers contribute indirectly
to the transmembrane potential by
maintaining the gradients necessary
for diffusion through channels.
1. The active cell membrane
In normal atrial, Purkinje, and
ventricular cells, the action
potential upstroke (phase 0) is
dependent on sodium current.
Depolarization to the threshold
voltage results in opening of the
activation (m) gates of sodium
channels. If the inactivation (h)
gates of these channels have not
already closed, the channels are
now open or activated, and sodium
permeability is markedly increased,
greatly exceeding the permeability
for any other ion.
Most calcium channels become
activated and inactivated in what
appears to be the same way as
sodium channels, but in the case of
the most common type of cardiac
calcium channel, the transitions occur
more slowly and at more positive
potentials.
The action potential plateau
(phases 1 and 2) reflects the
turning off of most of the sodium
current, the waxing and waning of
calcium current, and the slow
development of a repolarizing
potassium current.
Final repolarization (phase 3) of the
action potential results from
completion of sodium and calcium
channel inactivation and the growth of
potassium permeability, so that the
membrane potential once again
approaches the potassium equilibrium
potential.
1. The effect of resting potential on
action potentials
A key factor in the pathophysiology
of arrhythmias and the actions of
antiarrhythmic drugs is the
relationship between the resting
potential of a cell and the action
potentials that can be evoked in it.
Because the inactivation gates of
sodium channels in the resting
membrane close over the potential
range -75 to -55 mV, fewer sodium
channels are “available” for diffusion of
sodium ions when an action potential
is evoked from a resting potential of
-60 mV than when it is evoked from a
resting potential of -80 mV.
Important consequences of the
reduction in peak sodium permeability
include reduced upstroke velocity
(called Vmax, for maximum rate of
change of membrane voltage),
reduced action potential amplitude,
reduced excitability, and reduced
conduction velocity.
During the plateau of the action
potential, most sodium channels
are inactivated. Upon
repolarization, recovery from
inactivation takes place, making
the channels again available for
excitation.
The time between phase 0 and
sufficient recovery of sodium channels
in phase 3 to permit a propagated
response to external stimulus is the
“refractory period.” Changes in
refractoriness can be important in the
genesis or suppression of certain
arrhythmias.
Another important effect of less
negative resting potential is
prolongation of this recovery time.
The prolongation of recovery time
is reflected in an increase in the
effective refractory period.
I. Mechanisms of arrhythmias
1. Disturbances of impulse
formation
conduction
3. Both of above
formation
a. Increase of pacemaker rate
b. Afterdepolarization and trigger
action
a. Increase of pacemaker rate
The interval between
depolarizations of a pacemaker cell
is the sum of the duration of the
action potential and the duration of
the diastolic interval. Shortening of
either duration results in an
increase in pacemaker rate.
The more important of the two,
diastolic interval, is determined
by three factors:
b. Maximum diastolic potential,
c. Slope of phase 4 depolarization,
d. Threshold potential,
Latent pacemakers are particularly
prone to acceleration by the above
mechanisms. All cardiac cells, may
show repetitive pacemaker activity
when depolarized under
appropriate conditions, especially
if hypokalemia is also present.
a. Afterdepolarization and trigger
action
Afterdepolarizations are
depolarizations that interrupt phase
3 (early afterdepolarizations, EADs)
or phase 4 (delayed
afterdepolarizations, DADs).
Early afterdepolarizations (EADs)
are usually exacerbated at slow
heart rates and are thought to
contribute to the development of
long QT-related arrhythmias.
Delayed afterdepolarizations (DADs)
often occur when intracellular calcium
is increased. They are exacerbated by
fast heart rates and are thought to be
responsible for some arrhythmias
related to digitalis excess, to
catecholamines, and to myocardial
ischemia.
conduction
a. Simple conduction blockade
b. Reentry
a. Simple conduction blockade
a. Atrioventricular nodal block
b. Atrioventricular bundle branch
block
a. Reentry (circus movement)
In which one impulse reenters and
excites areas of the heart more
than once.
Some forms of reentry are strictly
anatomically determined.
In order for reentry to occur, three
conditions must coexist:
b. There must be an obstacle
(anatomic or physiologic) to
homogeneous conduction, thus
establishing a circuit around which
the reentrant wavefront can
propagate;
a. There must be unidirectional block
at some point in the circuit,
conduction must die out in one
direction but continue in the
opposite direction.
a. Conduction time around the circuit
must be long enough so that the
retrograde impulse does not enter
refractory tissue as it travels around
the obstacle, the conduction time
must exceed the effective refractory
period.
Importantly, reentry depends upon
conduction that has been
decreased by some critical
amount, usually as a result of
injury or ischemia.
I. Mechanisms of action of the
1. Reduce automaticity of
ectopic pacemakers
2. Decrease afterdepolarization
and tiggered activity
1. Modify conduction
2. Lengthening of the refractory
period in reentry circuits to
disable circus movement
Antiarrhythmic drugs decrease the
automaticity of ectopic pacemakers
more than that of the sinoatrial
node. They also reduce conduction
and excitability and increase the
refractory period to a greater extent
in depolarized tissue than in
normally polarized tissue.
This is accomplished chiefly by
selectively blocking the sodium or
calcium channels of depolarized cells.
Therapeutically useful channel-
blocking drugs have a high affinity for
activated channels (during phase 0) or
inactivated channels (during phase 2)
but very low affinity for rested
channels.
These drugs block electrical
activity when there is a fast
tachycardia (many channel
activations and inactivations per
unit time) or when there is
significant loss of resting potential
(many inactivated channels during
rest).
This type of drug action is often
described as use-dependent or
state-dependent, ie, channels that
are being used frequently, or in an
inactivated state, are more
susceptible to block.
a. Sodium channel blockade
b. Blockade of sympathetic
autonomic effects in the heart
c. Prolongation of the effective
refractory period
d. Calcium channel blockade
I. Classification of the
The antiarrhythmic agents have
traditionally been divided into
four distinct classes on the
basis of their dominant
mechanism of action.
Class Ⅰ action is sodium channel
block
They are frequently subdivided
according to their effects on action
potential duration or on the kinetics
of their interactions with cardiac
sodium channels:
Class ⅠA drugs, such as quinidine,
procainamide, disopyramide,
lengthen the action potential duration;
Class ⅠB drugs, such as lidocaine,
mexiletine, tocainide, phenytoin,
shorten the action potential duration;
Class ⅠC drugs, such as flecainide,
have no effect or may minimally
increase action potential duration.
Class Ⅱ action is sympathoplegic,
drugs include those that reduce
adrenergic activity in the heart,
especially β-blockers.
Class Ⅲ action is prolongation of the
action potential duration—by block of
outward or augmentation of inward
currents.
Class Ⅳ action is block of cardiac
calcium currents, which may slow
conduction and increase refractory
period in calcium-dependent
tissues such as the AV node.
I. Sodium channel-blocking drugs
(class Ⅰ)
1. Quinidine
2. Procainamide
3. Disopyramide
4. Lidocaine*
1. Phenytoin sodium
2. Mexiletine
3. Propafenone*
4. Flecainide
5. Encainide and lorcainide
1. Quinidine
a. Pharmacological effects
a.Depresses pacemaker rate,
especially that of ectopic
pacemakers
b.Depresses conduction
a. Depresses excitability, especially in
depolarized tissue, depresses
excitability and conduction in
depolarized tissue more than in
normal tissue.
b. Lengthens ERP & APD, slows
repolarization, reduces the
maximum reentry frequency and
can slow tachycardias
a. Anti-muscarinic actions in the
heart that inhibit vagal effects
This can overcome some of its
direct effects, sinus rate↑, A-V
conduction↑
α. α-R blocking properties, cause
vasodilation and a reflex
increase in sinoatrial nodal rate.
They are most prominent after
intravenous injection.
a. Mechanism of action
Quinidine can bind to and block
activated sodium channels. Block of
potassium channels with a
reduction in repolarizing outward
current is responsible for the effect
of slowing repolarization.
a. Pharmacokinetics
Administration orally, rapidly
absorbed from GI, 80% bound to
plasma proteins, metabolized in the
liver, 20% excreted unchanged in
the urine, urinary excretion is
enhanced in acid urine.
T1/2 =6 hrs, may be longer in
congestive heart failure or hepatic or
renal disease, therapeutic
concentration in plasma is 3 ～ 5
μg/ml, if serum concentration is ＞
5 μg/ml, toxic effects may occur.
a. Therapeutic use
It has been used in nearly every
form of arrhythmia. Its most
common indications are atrial
fibrillation and flutter and,
occasionally, ventricular
tachycardia.
a. Toxicity
a. Cardiac toxicity
 HR↑, atrioventricular conduction↑, in
atrial fibrillation or flutter, this effects
on the AV node may result in an
excessively high ventricular rate.
This can be prevented by prior
given of a calcium-blocker, a β-
blocker, or digitalis.
Quinidine syncope, characterized by
recurrent lightheadedness and
episodes of fainting, recur frequently
or even be fatal by degenerating into
ventricular fibrillation.
Precipitating arrhythmias or asystole
Widening of the QRS duration by
30% by quinidine administration is
usually considered premonitory of
serious toxicity.
Depress contractility and lower blood
pressure
a. Extracardiac
 The most common adverse effects
are gastrointestinal, diarrhea, nausea,
and vomiting.
 Cinchonism, headache, dizziness,
tinnitus, diplopia, delirium and
psychataxia
 Rashes, angioneurotic edema, fever,
hepatitis, and thrombocytopenia.
1. Procainamide
a. Similar to those of quinidine,
the most important difference
between quinidine and
procainamide is the less
prominent antimuscarinic
action of procainamide.
 Procainamide has ganglion-
blocking properties, reduces
peripheral vascular resistance
and hypotension.
a. Therapeutic use
Like quinidine, is effective against
most atrial and ventricular
arrhythmias. It’s the drug of second
choice, after lidocaine, for the
treatment of sustained ventricular
arrhythmias associated with acute
myocardial infarction.
a. Toxicity of procainamide
 Cardiotoxic effects are similar to
those of quinidine, new
arrhythmias.
 The most troublesome adverse
effect of long-term therapy is a
syndrome resembling lupus
erythematosus, usually consisting
of arthralgia and arthritis.
1. Disopyramide
Very similar to those of quinidine,
cardiac antimuscarinic effects are
even more marked than those of
quinidine.
Effective in treatment of
supraventricular and ventricular
arrhythmias.
Toxic concentration of disopyramide
can cause cardiotoxic effects like
quinidine. Atropine-like adverse
effects, urinary retention, dry mouth
blurred vision, constipation, and
worsening of preexisting glaucoma.
1. Lidocaine
It is used only by iv. It has a low
incidence of toxicity and a high
degree of effectiveness in
arrhythmias associated with
acute myocardial infarction.
Rapidly blocks both activated and
inactivated sodium channels, as a
result, a large fraction ( ＞ 50%) of
the unblocked sodium channels
become blocked during each action
potential in purkinje fibers and
ventricular cells,
They have long plateaus and
correspondingly long periods of
inactivation. During diastloe,
most of the sodium channels in
normally polarized cells rapidly
become drug-free.
Since lidocaine may shorten the
action potential duration, diastole
may be prolonged, thereby
extending the time available for
recovery.
a. Therapeutic use
It is the agent of choice for
suppression of recurrences of
ventricular tachycardia and
fibrillation after termination of
the arrhythmia by cardioversion.
a. Toxicity of lidocaine
a. Cardiac
It’s one of the least cardiotoxic of
the currently used sodium
channel blockers, in large doses,
lidocaine may cause hypotension,
partly by depressing myocardial
contractility.
a. Extracardiac
The most common adverse
effects are neurological,
paresthesias, tremor, nausea of
central origin, lightheadedness,
hearing disturbances, slurred
speech, and convulsions.
1. Phenytoin sodium
2. Mexiletine
1. Propafenone
Its spectrum of action is very similar
to that of quinidine, its potency as a
sodium channel blocker is similar to
that of flecainide, used primarily for
supraventricular arrhythmias, the
most common adverse effects are a
metallic taste and constipation,
arrhythmia exacerbation.
I. Beta adrenoceptor-blocking
drugs (class Ⅱ)
1. Propranolol
2. Metoprolol
3. Esmolol
β-R antagonists are effective in
treatment of both supraventricular
and ventricular arrhythmias. By
increasing the atrioventricular nodal
refractory period, it slows ventricular
response rates in atrial flutter and
fibrillation.
Reduce ventricular ectopic beats,
particularly if the ectopic activity
has been precipitated by
catecholamines.
They prevent recurrent infarction
and sudden death in patients
recovering from acute myocardial
infarction.
Sotalol is a nonselective β-R blocking
drug that prolongs the action
potential (class Ⅲ action).
Esmolol is a short-acting β-R blocker
used primarily as an antiarrhythmic
drug for intraoperative and other
acute arrhythmias.
I. Drugs that prolong effective
refractory period by prolonging
action potential (class Ⅲ)
1. Amiodarone
2. Bretylium
3. Sotalol
1. Amiodarone
For use only in serious ventricular
arrhythmias, it’s very effective against
a wide variety of arrhythmias. It has
prominent adverse effects and
unusual pharmacokinetic properties
that make it a difficult drug to use
appropriately.
a. Cardiac effects
 a powerful inhibitor of abnormal
automaticity,
 slows the sinus rate and A-V
conduction, markedly prolongs the
QT interval, and prolongs QRS
duration,
Markedly lengthens APD, increases
atrial, A-V nodal, and ventricular
refractory periods. It sustains its
lengthening of APD quite well at fast
heart rate.
It has antianginal effects.
a. Extracardiac effects
Amiodarone causes peripheral
vascular dilation.
a. Mechanism of action
 a very effective blocker of sodium
channels
 blocking K+ channels
 a weak calcium channel blocker
 a noncompetitive inhibitor of α-R
& β-R
Unlike quinidine, it has a low affinity for
activated channels, combining
instead almost exclusively with
channels in the inactivated state. The
sodium-blocking action of
amiodarone is most pronounced in
tissues that have long action
potentials, frequent action potentials,
or less negative diastolic potentials.
a. Therapeutic use
a. Very effective against both
supraventricular and ventricular
arrhythmias
b. Low maintenance dosages (100-
200 mg/d) can be used against
paroxysmal atrial fibrillation
a. Quite effective against
supraventricular arrhythmias in
children, ralatively safe
b. Iv is used in patients with recurrent
ventricular tachycardia or
fibrillation, with initial doses of 150
mg over 30’ or 1g over the first day,
arrhythmias are often promptly
suppressed.
a. Toxicity
a. Cardiac toxicity
In patients with sinus or A-V nodal
disease, drug causes bradycardia
or heart block.
a. Extracardiac toxicity
 Yellowish-brown microcrystals
deposits appear in the cornea, a
few weeks after initiation of
therapy
 Photodermatitis results from skin
deposits, grayish-blue skin
discoloration
Neurologic effects are common, such
as parestheisas, tremor, ataxia and
headaches
Thyroid dysfunction, both hypo- and
hyperthyroidism
GI, 20% constipation; hepatocellular
necrosis;
Pulmonary inflammation and
fibrosis, the latter may be fatal in
5-15% of patients
Hypotension and bradycardia are
the common adverse effects
1. Bretylium
It interferes with the neuronal
release of catecholamines but also
has direct antarrhythmic properties.
a. Cardiac effects
b. Therapeutic use
c. Adverse effects
a. Cardiac effects
a. Lengthens the ventricular but not
the atrial APD and ERP, most
pronounced in ischemic cells
which have shortened APD.
Bretylium may reverse the
shortening of APD caused by
ischemia.
a. Markedly increases the ventricular
fibrillation threshold
b. It causes an initial release of
catecholamines, has some positive
inotropic actions when first
administered, this action may
precipitate ventricular arrhythmias
and must be watched for at the
onset of therapy
a. Therapeutic use
Bretylium is usually used in an
emergency setting, often during
attempted resuscitation from
ventricular fibrillation when
lidocaine and cardioversion have
failed.
a. Adverse effects
The major daverse effects is
postural hypotension.
Nausea and vomiting may
occur after iv.
1. Sotalol
It is a nonselective β-R blocker, also
slows repolarization and prolongs
APD; used in both supraventricular
and ventricular arrhythmias. It is
excreted unchanged by the
kidneys. Only lower dosages are
usually used in atrial fibrillation.
I. Calcium channel-blocking
drugs (class Ⅳ)
1. Verapamil
2. Diltiazem
1. Verapamil
a. Cardiac effects
Blocks both activated and inactivated
calcium channels, its effect is more
marked in tissues that fire frequently, those
that are less completely polarized at rest,
and those in which activation depends
exclusively on the calcium current, such as
the sinoatrial and A-V nodes.
a. A-V nodal conduction and ERP are
invariably prolonged by therapeutic
concentration
b. suppress both early and delayed
afterdepolarizations, and may
antagonize slow responses arising
in severely depolarized tissue
a. Slows the sinoatrial node rate by its
direct action, increases the rate by
its indirect action (reflex action of its
hypotensive action)
b. Extracardiac effects
Peripheral vasodilation
a. Therapeutic use
Reentrant supraventricular
tachycardia is the major arrhythmia
indication for verapamil.
Reduce the ventricular rate in atrial
fibrillation and flutter.
a. Toxicity
a. Negative inotropic effects
b. A-V block when large doses, can
be treated by atropine, or
calcium, or β-R agonist
c. Constipation, lassitude,
nervousness, peripheral edema
I. Principles in the clinical use of
1. Principles
2. Choice of antiarrhythmic
agents
I. Principles in the clinical use of
1. Principles
2. Choice of antiarrhythmic
agents
Bradycardia atropine
isoprenaline
supraventricular atrial flutter digitoxin
Tachycardia atrial fibrillation quinidine
paroxysmal
Supraventricular verapamil
tachycardia
lidocaine
Ventricular phenyltoin sodium
Tachycardia mexiletine
disopyramide
propafenone
Sinus tachycardia propranolol

Agents Used in Cardiac Arrhythmias

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抗心律失常药

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