Antiarrhythmic Drugs
Background of Cardiac Electrophysiology
Membrane potential of cardiac cells
Fast response :
resting potential, High -80 ~ -95mv
(Atrial muscles
the rate of rise of phase 0 is rapid
Ventricular muscles
propagation will be rapid
Purkinje fiber)
Na+ influx, rapid depolarization
Slow response :
(sinus, atrioventricular (AV) nodel
cells, impaired fast
Response cells)
resting potential, low -50~ -70mv
slow depolarization, Ca 2+ influx
action potential propagates slowly
Phase 0 : depolarization
Phase 1,2,3 : repolarization
Phase 4 : diastolic voltage time course
0 ~ 3 : action potential duration APD
1
0mV
0
-85mV
2
100ms
Na+
Fast response
3
Ca2+
Outside
Membranc
e
intside
4
Na+ Na+
K+
K+,ClChannel currents
Pump
Ca2+
Exchanger
1. Excitability: relationship between threshold potential and
restingpotential level
2. Automaticity:
3. Conductivity: conductive rate is dependent on membrane
responsiveness
Membrane responsiveness: relationship between Vmax
of phase 0 and membrane potential level
4. Effective refractory period, ERP
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” .
二 Mechanisms of arrhythmias
1. Disturbances of impulse formation (冲动形成障碍)
① The changes of normal autonomic mechanism
Change of pacemaker current (cell) of diastolic
autonomic depolarization can cause autonomic alteration
such as : mental stress (tension)
drug toxicity
fever
excitation
② formation of abnormal autonomic mechanism
non-autonomic cell: atrial muscles
autonomic cell
abnormal autonomy
ventricular muscles
resting potential : -60mv
repetitive impulse
arrhythmias
2. triggered activity (触发活动) and Afterdepolarization （后除极）
A Early afterdepolarization （EAD，早后除极）
Occur in phase 2, 3 , low potassium, Ca 2+ inward
E.A. is secondary depolarization that occur before
repolarization is complete. secondary depolarization commences at
membrane potentials close to those present during the plateau of
the action potential
B delayed afterdepolarization ( DAD, 迟后除极)
Occur in phase 4, Ca 2+ overload in cell, Na + inward.
D.A. is a secondary depolarization that occurs early in diastole,
that is, after full repolarization has been achieved.
3. Disturbances of impulse conduction （冲动传导障碍）
A causing partial and complete block
B reentry---fibrillation心室纤颤 and flutter心室扑动
tachycardia
extra beats ( extrasystoles)
formation unidirectional block of cardial tissue
of reentry circuiting tract
shortening the effective refractory period
Reentry circuit established
1 forward impulse obstructed and extinguished
2 decremental conduction（递减传导） and unidirectional
block (单向阻滞) of antegrade（顺行） impulse
3 retrograde（逆行） impulse conducted across depressed
region
4 reentry circuit established
Arrhythmia may be manifest as one or a few extra beats or as
a sustained tachycardia
Reentry(折返) : circus movement
one impulse reenters and excites areas of the heart more
than once
Mechanism of the reentry
正常心肌
折返形成
单向传导阻滞
4. Genetics/gene mutation
• Long Q-T SYNDROME, LQTS
• 3 mutation genes:
SCN5A /chromosome 3: coding sodium channel in
myocardia;
HERG/ chromosome 7: coding Ikr potassium channel
（内向整流钾通道）;
KVLQT1/ chromosome 11: coding Iks potassium
channel （延迟整流钾通道）;
5. Disturbances of Potassium channels
Classification of
Antiarrhythmic Drugs
Antiarrhythmic agents are divided into FOUR classes
Assignment to the respective classes is made on the
basis of drug-induced alterations in ion channel
function and cardiac electrophysiologic properties
The classification, while helpful, is not absolute and
overlapping properties exist among the many drugs.
• A. Antiarrhythmic drugs can depress Na + inward of nonautonomic cell in phase 4 or depress Ca 2+ inward of
autonomic cell in phase 4 depress automaticity
• B. Antiarrhythmic drugs can accelerate K+ outward of
phase 3, increase maximum diastolic potential (more
negative ) increase voltage difference between maximum
diastolic potential and threshold potential depress
automaticity
Question: How about the conduction?
Classes of antiarrhythmic agents
1. sodium channel blocking drugs.
2. blockade of sympathetic autonomic effects in
the heart
3. prolongation of the ERP and APD
4. calcium channel blockade
Classification of Antiarrhythmic Drugs
Classification I：sodium channel blocking drugs
• Class Ia-Characteristics
Meddle level sodium channel block，weak level
potassium channel block， and weak level calcium
channel block in high concentration
– Slow the rate of rise of the membrane action potential (Phase 0;
dV/dt )
– Slow conduction velocity (PR; QRS)
– Prolong refractoriness (QT)
• Examples – Quinidine*
– Procainamide
– Disopyramide
Classification of Antiarrhythmic Drugs
• Class Ib -Characteristics
Weak level sodium channel block，and
potassium channel open
– Limited effect on dV/dt of Phase 0
– Slight slowing of conduction velocity
– No change or a decrease in refractory period
• Examples
–
–
–
–
Lidocaine*
Tocainide
Mexiletine
Moricizine ?
Classification of Antiarrhythmic Drugs
Class Ic- Characteristics
Strong level sodium channel block，and weak
level calcium channel block
– Marked slowing of conduction velocity (prolongs PR
and QRS)
– No change in refractoriness or repolarization
• Examples
–
–
–
–
Flecainide*
Propafenone (also Class II)
Moricizine (also Class Ib)
Encainide (discontinued)
Classification of Antiarrhythmic Drugs
• Class II-Characteristics
– Produce beta-adrenergic receptor blockade
(prolongs PR; slows heart rate)
– Decrease in refractory period duration
(decrease in QT)
• Examples
–
–
–
–
Propranolol*
Acebutolol
Esmolol
Sotalol (also Class III)
Classification of Antiarrhythmic Drugs
• Class III-Characteristics
potassium channel block
– Prolong the action potential duration
– Increase the refractory period (increase in the
QT)
• Examples
–
–
–
–
Amiodarone (also some Class Ia,II,III,&IV)
Bretylium
Sotalol (also Class II)
Ibutilide*
Classification of Antiarrhythmic Drugs
• Class IV-Characteristics
• Blockade of calcium entry via slow inward
channel (prolong the PR interval)
– Examples
• Verapamil
• Diltiazem
Other Miscellaneous Agents
• Adenosine
– Depresses sinus node automaticity
– Depresses atrioventricular node conduction
• Uses
– Acute termination of AV nodal tachycardia
– Acute termination of AV nodal reentrant
tachycardia
Other Miscellaneous Agents
• Digitalis (Digoxin)
– Prolongs atrioventricular nodal conduction time and
increases functional refractory period - directly and
indirectly (increase in vagal cholinergic tone)
– Slows sinus rate when ventricular function is impaired
by virtue of its direct positive inotropic effect
(withdrawal of sympathetic tone)
• Uses:
– Atrial fibrillation or flutter - primarily to control the
ventricular rate
– AV nodal reentrant tachycardia
Class Ia Antiarrhythmic Agents
• Quinidine （奎尼丁）
• Procainamide （普鲁卡因胺）
• Disopyramide（丙吡胺）
Quinidine （奎尼丁）
Electrophysiology
inhibit Na+ inward， inhibit K+ outward，inhibit calcium
inward in high concentration, depress slope phase 4
diastolic depolarization
Pharmacologic action
1
Quinidine depresses pacemaker rate, especially that
of ectopic pacemakers ( abnormal automaticity)
depress automaticity of atrial, ventricular muscles,
Purkinje, and sinoatrial nodes
2 Quinidine also lengthens the action potential duration
( APD) and effective refractory period (ERP)
depresses phase 3 K+ outward,
slow repolarization
lengthens the APD, and ERP
eliminates reentry impulses.
3 Negative conduction
blocks sodium channel, depresses Na + inward,
reduces depolarization rate of phase 0, inhibits
conduction responsiveness of membrane declines.
inhibits vagal activity, increases conduction of
atrioventri-cular (AV) nodes, slow conduction of
atrial muscles( reduce atrial bates) and increase
the ventricular bates (ventricular fibrillation心室纤
颤 and flutter心室扑动)
• treating atrial fibrillation and flutter:
combination with cardiac lycosides
(digoxin), inhibiting conduction of AV node
to prevent the ventricular bates.
• unidirectional block
bidirectional
block by abolished reentry impulse.
4 Electrocardiogram (ECG)
• QT interval is prolonged
• QRS wave is widened
Pharmacokinetics
absorption : orally, rapid, in gastrointestinal tract
binding protein : 80%
bioavailability (F) :72%~87%
Vd : 2~3 L/kg
metabolism : in liver
excretion : 20% unchanged in the urine
t ½ 5~7 hours
urinary excretion is enhanced in acid urine
t ½ may
congestive heart failure
be longer
hepatic or renal diseases
older patients
Clinical uses
1 acute and chronic ventricular and supraventricular arrhythmias
2 most common indications: atrial fibrillation and flutter
combination with digoxin
3Qinidine can increase blood concentration and
untoward reaction of digoxin.
• Toxicity
• 1 Toxic dosage
• depresses conduction of sinoatrial, atrialventricular nodes and Purkinje, cause
conductive block of atrioventricle and
intraventricle.
• severe toxication: automaticity of Purkinje can
be enhanced,
• cause ventricular tachycardia and ventricular
fibrillation (may be fatal) iv NaHCO3, K+ inward,
K+ in blood is decreased, toxicity is decreased.
2 hypotention
Quinidine can block α- receptor, blood vessels relaxation
( vasodilation), inhibit myocardial concentrating force
3 thromboembolism
patient with atrial fibrillation easy to occur.
4 cinchonism 金鸡钠中毒
headache, dizziness, tinnitus(耳鸣）,confused vision(视力模
糊), double vision(复视), gastrointestinal discomfort,
fainting晕厥, psycholeptic episodes 精神失常
( psychataxia mentation), confusion(神志不清)
5 others
diarrhea, nausea and vomiting,
thrombocytopenia(血小板减少症), bleeding
• 4 cinchonism 金鸡钠中毒
• headache, dizziness, tinnitus(耳鸣）,confused
vision(视力模糊),double vision(复
视),gastrointestinal discomfort,
• fainting晕厥, psycholeptic episodes 精神失常
• ( psychataxia mentation) ,confusion(神志不清)
• 5 others
diarrhea , nausea and vomiting,
thrombocytopenia(血小板减少症), bleeding
Classification of Antiarrhythmic Drugs
• Class Ib -Characteristics
weak inhibit Na + inward
enhance K+ outward
depress slope phase 4 diastolic
• Examples
– Lidocaine* （利多卡因）
– Phenytoin sodium（苯妥英钠）
Lidocaine/利多卡因
• Action
1. depressing automaticity (therapeutic dose)
lidocaine can suppress automaticity of Purkinje fibers,
because of:
weak inhibit Na + inward
enhance K+ outward
depress slope phase 4 diastolic depolarization
2. duration of the action potential (APD) and effective refractory
period (ERP)
in Purkinje fibers and ventricular muscle: the drug can
decrease (shorten) APD and ERP, but decreased APD >
decreased ERP.
ERP is prolonged relatively
APD is shortened
Repolarization is rapid and complete, velocity of phase 0
depolarization can be quickened
3. conductivity
in condition of ischemic Purkinje fibers of myocardial
infarction region
the drug can inhibit Na+ inward
decrease conduction
prevent occur of reentry (from
unidirectional block changes to bidirectional block )
in condition of extracellular low K+ or partial
depolarization of myocardial tissues
the drug can enhance phase 3 K+ outward causing
hyperpolarezition, improving conduction abolishing
ventricular reentry (reducing unidirectional block)
1
2
0mV
0
3
4
-85mV
ERP
ADP
Pharmacokinetics
1 very extensive first- pass hepatic metabolism ,only 3%
of orally administered lidocaine appears in plasma
the concentration in plasma is low
Thus, lidocaine must be given parenterally. im. iv.
2 protein binding rate is about 70%
3 t ½ is about 100 min
5~7h
Css
Therapeutic use
• 1 ventricular arrhythmias
ventricular tachycardia and fibrillation
• 2 ventricular arrhythmias caused by acute
myocardial infarction
• 3 open-heart surgery and digitalis toxication
Untoward effects
• 1 CNS lightheadedness 头晕 headache
paresthesias 感觉异常 (often perioral 口周的)
muscle twitching 抽搐
convulsion 惊厥
slurred speech 少言少语
hearing disturbances 听力失调
respiratory arrest 呼吸停止
• 2 hypotension (partly by depressing myocardial
contractility)
sinoatrial nodal standstill 窦性停搏
impaired conduction
• Contraindication
ⅡⅢ---atrioventricular conduction block
Phenytoin sodium苯妥英钠
• The drug for the treatment of seizures（癫
痫病发作）
• Clinical usefulness for ventricular
arrhythmias，especially those associated
with digitalis toxicity .
Action
1. Automaticity
Hastening k+ outward
Decreasing the slope of normal phase-4
depolarization in Purkinje fibers (increasing maximal
diastolic potential.)
automaticity of
Purkinje fibers
abolishing delayed
afterdepolarization caused
by digitalis toxicity.
2. APD and ERP in ventricular muscle and Purkinje fibers
APD and ERP are shortened,
but shortened APD >shortened EPR, so, EPR is rolonged relatively
The drug substanitially decrease the APD.
Complete repolarization.
Level of membrane potential
Amplitude of action potential
Conduction velocity
Abolishing reentry.
( negtive potential)
3.Responsiveness and conduction.
Increasing phase-0 depolarization rate of atrial
muscle, atrioventricular node, Purkinje fibers of
digitalis toxicity.
Improving conduction.
•
•
•
•
Therapeutic uses:
1.Ventricular arrhythmias.
2.Paroxysmal atrial flutter or fibrillation.
3.Supraventricular arrhythmias
(tachycardia)
• 4.Ventricular arrhythmias caused by acute
myocardial infarction, open-heart surgery
and digitalis toxication
Classification of Antiarrhythmic Drugs
Class Ic- Characteristics: Sodium channel blocker
– Marked slowing of conduction velocity (prolongs PR and
QRS)
– No change in refractoriness or repolarization
• Examples
– Flecainide* 氟尼卡 (also has potassium channel blocking)
– Propafenone (also Class II) 普罗帕酮（also has functions of
b-receptor inhibitor and calcium channel blocker）
– Moricizine (also Class Ib)
– Encainide (discontinued)
Propafenone (普罗帕酮 )
• Class Ic antiarrhythmic drug：strong sodium channel blok
• Possesses weak beta-adrenoceptor blocking properties
• Has weak calcium channel blocking properties (Negative
inotropic action)
• Slows conduction in the atria, ventricles, AV node, HisPurkinje system and accessory pathways
• Slight increase in the ventricular refractory period
• Prolong ERP and APD, increasing ERP/APD
• Clinical Uses
• Acute termination or long term suppression of
ventricular arrhythmias, particularly recurrent
ventricular tachycardia
• In treatment of patients with life-threatening
ventricular arrhythmias
• Immediate termination and long term prevention
of supraventricular reentrant tachyarrhythmias
involving the AV node or accessory pathways
• Long term suppression or refractory,
symptomatic atrial fibrillation and flutter
• Dose
– Initially 150 mg every 8 hours
– May be increased at three to four day intervals to 225
mg every 8 hours
• Drug Interactions
– Increases serum concentrations of digoxin, warfarin,
and propranolol
• Pharmacokinetics
– Extensive first pass metabolism
– Hepatic metabolism - (P450IID6, desbriso-quin
hydroxylation phenotype)
Class II Antiarrhythmic Agents
•
•
•
•
Propranolol
Esmolol
Sotalol
other beta-adrenoceptor antagonists
Beta - Adrenoceptor Blocking Agents
• Mechanism of Antiarrhythmic Action
– Antiarrhythmic effects of Class II drugs are attributed
to actions:
• blockade of postsynaptic cardiac beta - adrenoceptors
• membrane stabilizing action
• Otherwise, as a sodium channel blocker to suppress diastolic
automatic depolarization in 4 phase (decreasing automaticity)
and conductivity in 0 phase.
– The former, blockade of beta - adrenoceptors is the
more important action, the latter may require higher
concentrations than achieved with therapeutic doses
Cardiac Effects of beta - Adrenoceptor Blocker
• Decreasing automaticity: as an adrenoceptor blocker
to reduce the heart rate
• Decreasing conductivity: membrane stabilizing action
(Lengthening of atrioventricular conduction time and
minimal prolongation ventricular in refractoriness (Sotalol prolongs the refractory period, Class III) )
• APD and ERP:
Clinical concentration: shorten APD and ERP;
Higher concentration: prolong APD and ERP;
Propranolol (Inderal™)
• Uses:
– Major indications for propranolol as an antiarrhythmic
are:
•
•
•
•
atrial flutter
atrial fibrillation
AV nodal reentrant tachycardia
selected ventricular arrhythmias
– Prevents or terminates arrhythmias associated with
excess cardiac sympathetic stimulation - e.g. exercise
induced arrhythmias
Class III Antiarrhythmia
Prolong the Duration of Action Potential
/potassium channel blocker (weak
sodium and calcium blocker)
Drugs:
• Bretylium 溴苄铵
• Amiodarone 胺碘酮
• Sotalol 索他洛尔
• Ibutilide
Amiodarone胺碘酮
• Uses:
• Suppression of refractory, life-threatening,
recurrent ventricular arrhythmias
– ventricular tachycardia
– ventricular fibrillation
• Prevents recurrences of atrial arrhythmias
– atrial flutter
– atrial fibrillation
– AV nodal reentrant tachycardia
Classification IV Cardiac Actions of the
Calcium Channel Blocking Agents/Calcium
Channel Blockers
Action and mechanism
• Decreasing aotumaticity:
• Decreasing conductivity:
• Prolong ERP:
Clinical Use
• supraventricular arrhythmias
Classification V：
Miscellaneous Antiarrhythmic Agents
• Adenosine
• Digoxin
Adenosine (Adenocard™)
• Actions
– Naturally occurring purine nucleoside
– Degradation product of adenosine
triphosphate (ATP)
– Potent vasodilator of peripheral vessels and
coronary arteries
– Antiadrenergic actions
– Negative chronotropic actions
Adenosine (Adenocard™)
• Cardiac Electrophysiologic Actions
– Depresses upstroke of action potential in N
cells of the AV node
– Intravenous administration of adenosine
• suppresses sinus node automaticity
• depresses AV nodal conduction velocity
• increases AV nodal refractoriness
• Uses
• First-line therapy for acute termination of AV nodal
reentrant tachycardia and other supraventricular
tachycardias in which the reentry loop involves the
atrioventricular node
• When administered to patients in sinus rhythm, who
have a history of paroxysmal supraventricular
tachycardia, adenosine may reveal latent preexcitation
by slowing or blocking conduction to the ventricles via
the AV node, thereby uncovering the presence of a
concealed bypass tract
• Dose
• Intravenously, rapidly 6 mg over one to two
seconds
• If the arrhythmia is not controlled within one to
two minutes, 12 mg may be given as a rapid
intravenous injection
• The 12 mg dose may be repeated if needed
• Do not give more than 12 mg as an individual
dose
Adenosine on Atrial Muscle
•
•
•
•
•
•
•
•
•
•
•
•
•
Control
After
Adenosine
Na+
Ca++
K+
Delayed Rectifier Channel opens during
repolarization resulting in potassium ion
efflux
ATP Dependent Potassium Channel opens
during repolarization resulting in an enhanced
potassium ion efflux that:
• terminates inward calcium ion movement
•
via the slow inward channel
• decreases the atrial refractory period
• increases atrial muscle conduction velocity
Actions of Adenosine of the Atrial Muscle
Adenosine on the Atrioventricular Node
Control
• After
• Adenosine
• Na+
• Ca++
• K+
• Na+
• Ca++
• K+
• Delayed Rectifier Channel opens during
• repolarization resulting in potassium ion
• efflux
• ATP Dependent Potassium Channel opens
• during repolarization resulting in an enhanced
• potassium ion efflux that:
• • terminates inward calcium ion movement
via the slow inward channel
• increases the AV node refractory period
• decreases AV node conduction velocity
• Actions of Adenosine of the AV Node
Digitalis Glycosides (Digoxin; Lanoxin™)
• Actions and Uses:
– Complex direct and indirect cardiac actions
– Indirect action due to enhanced vagal tone:
•
•
•
•
lengthening of AV nodal refractory period
slowing of AV nodal conduction
decrease atrial muscle refractory period
increase atrial muscle conduction velocity
– Antiadrenergic action
– Positive inotropic effect
• Uses and Actions (continued)
• Atrial flutter and atrial fibrillation - to control
the ventricular response
– atrial flutter may convert to atrial fibrillation
due to effects of increased vagal tone upon
atrial refractory period and conduction velocity
• Terminates AV nodal reentrant tachycardia
(PAT) after vagal maneuvers and other
antiarrhythmic drugs have failed