Antiarrhythmic Drugs Background of Cardiac Electrophysiology Membrane potential of cardiac cells...

Antiarrhythmic DrugsAntiarrhythmic DrugsBackground of Cardiac ElectrophysiologyMembrane potential of cardiac cellsFast response : resting potential, High -80 ~ -95mv(Atrial muscles the rate of rise of phase 0 is rapidVentricular muscles propagation will be rapidPurkinje fiber) Na+ influx, rapid depolarization

Slow response : resting potential, low -50~ -70mv

(sinus, atrioventri- slow depolarization, Ca 2+ influx

cular (AV) nodel action potential propagates slowly cells, impaired fastResponse cells)

Phase 0 : depolarizationPhase 1,2,3 : repolarizationPhase 4 : diastolic voltage time course0 ~ 3 : action potential duration APD

K+,Cl-

Channel currents

Pump

Exchanger

K+ Ca2+

Na+Na+Ca2+

100ms

Outside

0mV

Na+

intsideMembrance

-85mV

0

1 2

3

4

Fast response

1. Excitability: relationship between threshold potential and restingpotential level

2. Automaticity: 3. Conductivity: conductive rate is dependent on membrane r

esponsiveness Membrane responsiveness: relationship between Vmax

of phase 0 and membrane potential level4. Effective refractory period, ERP The time between phase 0 and sufficient recovery of so

dium 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 ventricular muscles

autonomic cell resting potential : -60mv

abnormal autonomy 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 reentryMechanism of the reentry

正常心肌单向传导阻滞

折返形成

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 of Potassium channels

Classification of AntiarrhytClassification of Antiarrhythmic Drugshmic Drugs

Antiarrhythmic agents are divided into FOUR classes Antiarrhythmic agents are divided into FOUR classes

Assignment to the respective classes is made on the bAssignment to the respective classes is made on the b

asis of drug-induced alterations in ion channel function asis of drug-induced alterations in ion channel function

and cardiac electrophysiologic properties and cardiac electrophysiologic properties

The classification, while helpful, is not absolute and ovThe classification, while helpful, is not absolute and ov

erlapping properties exist among the many drugs.erlapping properties exist among the many drugs.

• A. Antiarrhythmic drugs can depress Na + inward of non-autonomic 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 DrugsClassification of Antiarrhythmic Drugs

• Class Ia-Characteristics Meddle level sodium channel block ， weak level potassi

um 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 IClassification I ：： sodium channel blocking 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 ?


Class Ic- Characteristics

Strong level sodium channel block ， and weak level calcium channel block– Marked slowing of conduction velocity (prolongs PR a

nd QRS) – No change in refractoriness or repolarization

• Examples – Flecainide*

– Propafenone (also Class II)

– Moricizine (also Class Ib)

– Encainide (discontinued)


• Class II-Characteristics – Produce beta-adrenergic receptor blockade (p

rolongs PR; slows heart rate) – Decrease in refractory period duration (decrea

se in QT) • Examples

– Propranolol* – Acebutolol – Esmolol – Sotalol (also Class III)


• 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*

• Class IV-Characteristics

• Blockade of calcium entry via slow inward channel (prolong the PR interval) – Examples

• Verapamil • Diltiazem


Other Miscellaneous AgentsOther Miscellaneous Agents

• Adenosine – Depresses sinus node automaticity – Depresses atrioventricular node conduction

• Uses – Acute termination of AV nodal tachycardia – Acute termination of AV nodal reentrant tachy

cardia

• Digitalis (Digoxin) – Prolongs atrioventricular nodal conduction time and in

creases 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 ventr

icular rate – AV nodal reentrant tachycardia

Other Miscellaneous AgentsOther Miscellaneous Agents

Class Ia Antiarrhythmic Agents Class Ia Antiarrhythmic Agents

• Quinidine （奎尼丁）• Procainamide （普鲁卡因胺）• Disopyramide （丙吡胺）

Quinidine Quinidine （奎尼丁）（奎尼丁）

Pharmacologic action

1 Quinidine depresses pacemaker rate, especially that

of ectopic pacemakers ( abnormal automaticity) depress automaticity of atrial, ventricular muscles, Purkinje, and sinoatrial nodes

Electrophysiologyinhibit Na+ inward ， inhibit K+ outward ， inhibit calcium inward in high concentration, depress slope phase 4 diastolic depolarization

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, atrial-ventri

cular 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


• 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/Lidocaine/ 利多卡因利多卡因

• Action1. 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 i

nfarction region the drug can inhibit Na+ inward decrease conduction prevent occur of reentry (from unidirecti

onal block changes to bidirectional block ) in condition of extracellular low K+ or partial depolariz

ation of myocardial tissues

the drug can enhance phase 3 K+ outward causing hyperpolarezition, improving conduction abolishing ventricular reentry (reducing unidirectional block)

0mV

-85mV

0

12

3

4

ADP

ERP

PharmacokineticsPharmacokinetics

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 useTherapeutic use

• 1 ventricular arrhythmias

ventricular tachycardia and fibrillation

• 2 ventricular arrhythmias caused by acute

myocardial infarction

• 3 open-heart surgery and digitalis toxication

Untoward effectsUntoward 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 sodiumPhenytoin sodium 苯妥英钠苯妥英钠

• 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 abolishing delayed

Purkinje fibers afterdepolarization caused

by digitalis toxicity.

The drug substanitially decrease the APD.

Complete repolarization.

Level of membrane potential ( negtive potential)

Amplitude of action potential

Conduction velocity

Abolishing reentry.

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

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


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

-receptor inhibitor and calcium channel blocker ）– Moricizine (also Class Ib) – Encainide (discontinued)

Propafenone (Propafenone ( 普罗帕酮普罗帕酮 ))

• 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, His-Purkinje 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 ve

ntricular 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, a

nd propranolol

• Pharmacokinetics – Extensive first pass metabolism – Hepatic metabolism - (P450IID6, desbriso-quin hydro

xylation phenotype)

Class II Antiarrhythmic AgentsClass II Antiarrhythmic Agents

• Propranolol

• Esmolol

• Sotalol

• other beta-adrenoceptor antagonists

Beta - Adrenoceptor Blocking AgentsBeta - Adrenoceptor Blocking Agents

• Mechanism of Antiarrhythmic Action – Antiarrhythmic effects of Class II drugs are attributed t

o actions: • blockade of postsynaptic cardiac beta - adrenoceptors • membrane stabilizing action • Otherwise, as a sodium channel blocker to suppress diastolic a

utomatic 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 BlockerCardiac 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™)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 AntiarrhythmiaClass III AntiarrhythmiaProlong the Duration of Action Potential /potassium channel blocker (weak so

dium and calcium blocker)Drugs: • Bretylium 溴苄铵• Amiodarone 胺碘酮• Sotalol 索他洛尔• Ibutilide

• Uses: • Suppression of refractory, life-threatening, recurr

ent ventricular arrhythmias – ventricular tachycardia – ventricular fibrillation

• Prevents recurrences of atrial arrhythmias – atrial flutter – atrial fibrillation – AV nodal reentrant tachycardia

AmiodaroneAmiodarone 胺碘酮

Action and mechanism

• Decreasing aotumaticity:

• Decreasing conductivity:

• Prolong ERP:

Clinical Use

• supraventricular arrhythmias

Classification IV Cardiac Actions of the Classification IV Cardiac Actions of the Calcium Channel Blocking Agents/Calcium Calcium Channel Blocking Agents/Calcium

Channel BlockersChannel Blockers

Classification VClassification V ：： Miscellaneous Antiarrhythmic AgentsMiscellaneous Antiarrhythmic Agents

• Adenosine

• Digoxin

Adenosine (Adenocard™)Adenosine (Adenocard™)

• Actions – Naturally occurring purine nucleoside – Degradation product of adenosine triphosphat

e (ATP) – Potent vasodilator of peripheral vessels and c

oronary arteries – Antiadrenergic actions – Negative chronotropic actions

Adenosine (Adenocard™)Adenosine (Adenocard™)

• Cardiac Electrophysiologic Actions – Depresses upstroke of action potential in N ce

lls 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 reentr

ant 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 MuscleAdenosine 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 NodeAdenosine 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™)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 du

e 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

Antiarrhythmic Drugs Background of Cardiac Electrophysiology Membrane potential of cardiac cells...

Documents

Transcript of Antiarrhythmic Drugs Background of Cardiac Electrophysiology Membrane potential of cardiac cells...