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Antiarrhythmic Drugs Background of Cardiac Electrophysiology

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1 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 : resting potential, low -50~ -70mv (sinus, atrioventri slow depolarization, Ca 2+ influx cular (AV) nodel action potential propagates slowly cells, impaired fast Response cells)


3 K+,Cl- Channel currents
Phase 0 : depolarization Phase 1,2,3 : repolarization Phase 4 : diastolic voltage time course 0 ~ 3 : action potential duration APD K+,Cl- Channel currents Pump Exchanger K+ Ca2+ Na+ 100ms Outside 0mV intside Membrance -85mV 1 2 3 4 Fast response

4 Excitability: relationship between threshold potential and restingpotential level
Automaticity: 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” .


6 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

7 ② formation of abnormal autonomic mechanism
non-autonomic cell: atrial muscles ventricular muscles autonomic cell resting potential : -60mv abnormal autonomy repetitive impulse arrhythmias

8 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.


10 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

11 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

12 Reentry(折返) : circus movement
one impulse reenters and excites areas of the heart more than once

13 Mechanism of the reentry
正常心肌 单向传导阻滞 折返形成

14 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

15 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.

16 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?

17 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

18 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

19 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 ?

20 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)

21 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)

22 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*

23 Classification of Antiarrhythmic Drugs
Class IV-Characteristics Blockade of calcium entry via slow inward channel (prolong the PR interval) Examples Verapamil Diltiazem

24 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

25 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


27 Class Ia Antiarrhythmic Agents
Quinidine (奎尼丁) Procainamide (普鲁卡因胺) Disopyramide(丙吡胺)

28 Quinidine (奎尼丁) 1 Quinidine depresses pacemaker rate, especially that
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

29 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.

30 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)

31 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


33 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

34 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.

35 Toxicity 1 Toxic dosage depresses conduction of sinoatrial, atrial-ventricular 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.

36 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

37 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

38 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)

39 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

40 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

41 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)

42 1 2 0mV 3 4 -85mV ERP ADP

43 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

44 Therapeutic use 1 ventricular arrhythmias
ventricular tachycardia and fibrillation 2 ventricular arrhythmias caused by acute myocardial infarction 3 open-heart surgery and digitalis toxication

45 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

46 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 .

47 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.

48 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 ( negtive potential) Amplitude of action potential Conduction velocity Abolishing reentry.

49 3.Responsiveness and conduction.
Increasing phase-0 depolarization rate of atrial muscle, atrioventricular node, Purkinje fibers of digitalis toxicity. Improving conduction.

50 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

51 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)

52 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, His-Purkinje system and accessory pathways Slight increase in the ventricular refractory period Prolong ERP and APD, increasing ERP/APD


54 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

55 Dose Drug Interactions Pharmacokinetics 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)

56 Class II Antiarrhythmic Agents
Propranolol Esmolol Sotalol other beta-adrenoceptor antagonists

57 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

58 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;

59 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

60 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


62 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

63 Decreasing aotumaticity: Decreasing conductivity: Prolong ERP:
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

64 Classification V: Miscellaneous Antiarrhythmic Agents
Adenosine Digoxin

65 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

66 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

67 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

68 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

69 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

70 Adenosine on the Atrioventricular Node
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 • increases the AV node refractory period • decreases AV node conduction velocity Actions of Adenosine of the AV Node

71 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

72 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

73 The End

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