4 Excitability: relationship between threshold potential and restingpotential level Automaticity:Conductivity: conductive rate is dependent on membrane responsivenessMembrane responsiveness: relationship between Vmax of phase 0 and membrane potential level4. Effective refractory period, ERPThe 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 mechanismChange of pacemaker current (cell) of diastolic autonomic depolarization can cause autonomic alterationsuch as : mental stress (tension)drug toxicityfeverexcitation
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+ inwardE.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 potentialB 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 blockB reentry---fibrillation心室纤颤 and flutter心室扑动tachycardiaextra beats ( extrasystoles)formation unidirectional block of cardial tissueof reentry circuiting tractshortening the effective refractory period
11 Reentry circuit established 1 forward impulse obstructed and extinguished2 decremental conduction（递减传导） and unidirectional block (单向阻滞) of antegrade（顺行） impulse3 retrograde（逆行） impulse conducted across depressed region4 reentry circuit establishedArrhythmia 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
15 Classification of Antiarrhythmic Drugs Antiarrhythmic agents are divided into FOUR classesAssignment to the respective classes is made on the basis of drug-induced alterations in ion channel function and cardiac electrophysiologic propertiesThe 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 automaticityB. 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 automaticityQuestion: How about the conduction?
17 Classes of antiarrhythmic agents 1. sodium channel blocking drugs.2. blockade of sympathetic autonomic effects inthe heart3. prolongation of the ERP and APD4. calcium channel blockade
18 Classification of Antiarrhythmic Drugs Classification I：sodium channel blocking drugsClass Ia-CharacteristicsMeddle level sodium channel block，weak level potassium channel block， and weak level calcium channel block in high concentrationSlow the rate of rise of the membrane action potential (Phase 0; dV/dt )Slow conduction velocity (PR; QRS)Prolong refractoriness (QT)Examples -Quinidine*ProcainamideDisopyramide
19 Classification of Antiarrhythmic Drugs Class Ib -CharacteristicsWeak level sodium channel block，and potassium channel openLimited effect on dV/dt of Phase 0Slight slowing of conduction velocityNo change or a decrease in refractory periodExamplesLidocaine*TocainideMexiletineMoricizine ?
20 Classification of Antiarrhythmic Drugs Class Ic- CharacteristicsStrong level sodium channel block，and weak level calcium channel blockMarked slowing of conduction velocity (prolongs PR and QRS)No change in refractoriness or repolarizationExamplesFlecainide*Propafenone (also Class II)Moricizine (also Class Ib)Encainide (discontinued)
21 Classification of Antiarrhythmic Drugs Class II-CharacteristicsProduce beta-adrenergic receptor blockade (prolongs PR; slows heart rate)Decrease in refractory period duration (decrease in QT)ExamplesPropranolol*AcebutololEsmololSotalol (also Class III)
22 Classification of Antiarrhythmic Drugs Class III-Characteristicspotassium channel blockProlong the action potential durationIncrease the refractory period (increase in the QT)ExamplesAmiodarone (also some Class Ia,II,III,&IV)BretyliumSotalol (also Class II)Ibutilide*
23 Classification of Antiarrhythmic Drugs Class IV-CharacteristicsBlockade of calcium entry via slow inward channel (prolong the PR interval)ExamplesVerapamilDiltiazem
24 Other Miscellaneous Agents AdenosineDepresses sinus node automaticityDepresses atrioventricular node conductionUsesAcute termination of AV nodal tachycardiaAcute 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 rateAV 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 Electrophysiologyinhibit Na+ inward， inhibit K+ outward，inhibit calcium inward in high concentration, depress slope phase 4 diastolic depolarizationPharmacologic action1 Quinidine depresses pacemaker rate, especially thatof 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 repolarizationlengthens the APD, and ERPeliminates reentry impulses.
30 3 Negative conductionblocks 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 prolongedQRS wave is widened
33 Pharmacokinetics absorption : orally, rapid, in gastrointestinal tract binding protein : 80%bioavailability (F) :72%~87%Vd : 2~3 L/kgmetabolism : in liverexcretion : 20% unchanged in the urinet ½ 5~7 hoursurinary excretion is enhanced in acid urinet ½ may congestive heart failurebe longer hepatic or renal diseasesolder patients
34 Clinical uses1 acute and chronic ventricular and supraventricular arrhythmias2 most common indications: atrial fibrillation and fluttercombination with digoxin3Qinidine can increase blood concentration and untoward reaction of digoxin.
35 Toxicity1 Toxic dosagedepresses 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.
38 Classification of Antiarrhythmic Drugs Class Ib -Characteristicsweak inhibit Na + inwardenhance K+ outwarddepress slope phase 4 diastolicExamplesLidocaine* （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 + inwardenhance K+ outwarddepress 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 relativelyAPD is shortenedRepolarization is rapid and complete, velocity of phase 0depolarization can be quickened
41 3. conductivityin condition of ischemic Purkinje fibers of myocardial infarction regionthe drug can inhibit Na+ inwarddecrease conductionprevent occur of reentry (from unidirectional block changes to bidirectional block )in condition of extracellular low K+ or partial depolarization of myocardial tissuesthe drug can enhance phase 3 K+ outward causing hyperpolarezition, improving conduction abolishing ventricular reentry (reducing unidirectional block)
43 Pharmacokinetics1 very extensive first- pass hepatic metabolism ,only 3%of orally administered lidocaine appears in plasmathe concentration in plasma is lowThus, lidocaine must be given parenterally. im. iv.2 protein binding rate is about 70%3 t ½ is about 100 min5~7h Css
44 Therapeutic use 1 ventricular arrhythmias ventricular tachycardia and fibrillation2 ventricular arrhythmias caused by acutemyocardial infarction3 open-heart surgery and digitalis toxication
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 Action1. AutomaticityHastening k+ outwardDecreasing the slope of normal phase-4 depolarization in Purkinje fibers (increasing maximal diastolic potential.)automaticity of abolishing delayedPurkinje fibers afterdepolarization causedby 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 relativelyThe drug substanitially decrease the APD.Complete repolarization.Level of membrane potential ( negtive potential)Amplitude of action potentialConduction velocityAbolishing reentry.
49 3.Responsiveness and conduction. Increasing phase-0 depolarization rate of atrialmuscle, atrioventricular node, Purkinje fibers ofdigitalis 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 blockerMarked slowing of conduction velocity (prolongs PR and QRS)No change in refractoriness or repolarizationExamplesFlecainide* 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 blokPossesses weak beta-adrenoceptor blocking propertiesHas weak calcium channel blocking properties (Negative inotropic action)Slows conduction in the atria, ventricles, AV node, His-Purkinje system and accessory pathwaysSlight increase in the ventricular refractory periodProlong ERP and APD, increasing ERP/APD
54 Clinical UsesAcute termination or long term suppression of ventricular arrhythmias, particularly recurrent ventricular tachycardiaIn treatment of patients with life-threatening ventricular arrhythmiasImmediate termination and long term prevention of supraventricular reentrant tachyarrhythmias involving the AV node or accessory pathwaysLong 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 hoursDrug InteractionsIncreases serum concentrations of digoxin, warfarin, and propranololPharmacokineticsExtensive first pass metabolismHepatic metabolism - (P450IID6, desbriso-quin hydroxylation phenotype)
56 Class II Antiarrhythmic Agents PropranololEsmololSotalolother beta-adrenoceptor antagonists
57 Beta - Adrenoceptor Blocking Agents Mechanism of Antiarrhythmic ActionAntiarrhythmic effects of Class II drugs are attributed to actions:blockade of postsynaptic cardiac beta - adrenoceptorsmembrane stabilizing actionOtherwise, 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 rateDecreasing 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 flutteratrial fibrillationAV nodal reentrant tachycardiaselected ventricular arrhythmiasPrevents 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
65 Adenosine (Adenocard™) ActionsNaturally occurring purine nucleosideDegradation product of adenosine triphosphate (ATP)Potent vasodilator of peripheral vessels and coronary arteriesAntiadrenergic actionsNegative chronotropic actions
66 Adenosine (Adenocard™) Cardiac Electrophysiologic ActionsDepresses upstroke of action potential in N cells of the AV nodeIntravenous administration of adenosinesuppresses sinus node automaticitydepresses AV nodal conduction velocityincreases AV nodal refractoriness
67 UsesFirst-line therapy for acute termination of AV nodal reentrant tachycardia and other supraventricular tachycardias in which the reentry loop involves the atrioventricular nodeWhen 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 DoseIntravenously, rapidly 6 mg over one to two secondsIf the arrhythmia is not controlled within one to two minutes, 12 mg may be given as a rapid intravenous injectionThe 12 mg dose may be repeated if neededDo not give more than 12 mg as an individual dose
69 Adenosine on Atrial Muscle ControlAfterAdenosineNa+Ca++K+Delayed Rectifier Channel opens duringrepolarization resulting in potassium ioneffluxATP Dependent Potassium Channel opensduring repolarization resulting in an enhancedpotassium ion efflux that:• terminates inward calcium ion movement via the slow inward channel • decreases the atrial refractory period • increases atrial muscle conduction velocityActions of Adenosine of the Atrial Muscle
70 Adenosine on the Atrioventricular Node ControlAfterAdenosineNa+Ca++K+Delayed Rectifier Channel opens duringrepolarization resulting in potassium ioneffluxATP Dependent Potassium Channel opensduring repolarization resulting in an enhancedpotassium ion efflux that:• terminates inward calcium ion movement via the slow inward channel • increases the AV node refractory period • decreases AV node conduction velocityActions of Adenosine of the AV Node
71 Digitalis Glycosides (Digoxin; Lanoxin™) Actions and Uses:Complex direct and indirect cardiac actionsIndirect action due to enhanced vagal tone:lengthening of AV nodal refractory periodslowing of AV nodal conductiondecrease atrial muscle refractory periodincrease atrial muscle conduction velocityAntiadrenergic actionPositive inotropic effect
72 Uses and Actions (continued) Atrial flutter and atrial fibrillation - to control the ventricular responseatrial flutter may convert to atrial fibrillation due to effects of increased vagal tone upon atrial refractory period and conduction velocityTerminates AV nodal reentrant tachycardia (PAT) after vagal maneuvers and other antiarrhythmic drugs have failed