抗心律失常课件

1、抗心律失常药Anti-Arrhythmic Drug抗心律失常课件抗心律失常课件正常心脏电生理抗心律失常课件正常心脏电生理抗心律失常课件Cardiac electrical activity and ECG抗心律失常课件Cardiac electrical activity an Cardiac electrical activity抗心律失常课件 Cardiac electrical activity抗心Heterogeneous APs in heart抗心律失常课件Heterogeneous APs in heart抗心律失Ion channels and AP01234INaICa.L

2、IKrIKsIK1IK1ITo1INa-Ca抗心律失常课件Ion channels and AP01234INaICaIon currents underlying AP in ventricleInward currentsINaICaINa/CaOutward currentsIK1Ito1IKrIKsIto2ITOSCN5ADHP receptorNCX1Kir2.xKv4.x?HERG/MiRP1KvLQT1/minKPossible cloneTTX, STX, lidocaineDHP, Cd2+, Co2+ Ni+, NCX1-antibodyBa2+4-APDIDS, 9-AC

3、Dofetilide, sotalolChromanol 293BBlockers抗心律失常课件Ion currents underlying AP in窦房结细胞动作电位时程中的参与电流（Currents underlying depolarization in SA nodal cells）抗心律失常课件窦房结细胞动作电位时程中的参与电流（Currents und心律失常发生机制折返自律性升高后除极 早后除极 迟后除极基因缺陷抗心律失常课件心律失常发生机制折返抗心律失常课件折返形成机制(Unidirectional block and reentry)抗心律失常课件折返形成机制(Unidi

4、rectional block an预激综合症中房室折返环路的形成Atrioventricular reentry in the Wolff-Parkinson-White syndrome抗心律失常课件预激综合症中房室折返环路的形成Atrioventricula心肌细胞的早后除极和迟后除极(Two forms of abnormal activity, early and delayed afterdepolarizations)抗心律失常课件心肌细胞的早后除极和迟后除极(Two forms of ab抗心律失常药物作用降低自律性减少后除极消除折返抗心律失常课件抗心律失常药物作用降低自律性抗

5、心律失常课件降低自律性的四种方式(Four ways to reduce the rate of spontaneous discharge in automatic tissues)抗心律失常课件降低自律性的四种方式(Four ways to reduc心律失常类型抗心律失常课件心律失常类型抗心律失常课件Atrial flutter 抗心律失常课件Atrial flutter 抗心律失常课件Atrial fibrillation抗心律失常课件Atrial fibrillation抗心律失常课件Atrial fibrillation抗心律失常课件Atrial fibrillation抗心律失常

6、课件Ventricular beat抗心律失常课件Ventricular beat抗心律失常课件Ventricular fibrillation抗心律失常课件Ventricular fibrillation抗心律失常课Cardiac arrhythmias Tachy-cardiac arrhythmias -Atrial-premature beats-Atrial flutter-Atrial fibrillation (AF)-Ventricular-premature beats (contractions)-Ventricular-tachycardia (VT)-Ventricul

7、ar fibrillation (VF)Brady-cardiac arrhythmias-Bundle branch blocks-Sinus bradycardia (Sick Sinus Syndrome) 抗心律失常课件Cardiac arrhythmias Tachy-card抗心律失常药物分类抗心律失常课件抗心律失常药物分类抗心律失常课件Summary of antiarrhythmic drugsClassDrug exampleActions UsesIaIbIcQuinidine, ProcainamideLidocaine, MexiletineFlecainide, En

8、cainideBlock of INa, IK, and ICa, ADP, ERP, Velocity, ContractilityBlock of INa (fast dissociation), APD, ERPBlock of INa (slow dissociation), Velocity, ContractilityVT, AFVP VTIIPropranolol, MetoprololBlock of -adrenoceptor ContractilityAT, VTIIIDofetilide, IbutilideAmiodaroneBlock of IKr, ADPBlock

9、 of INa (Inac), IKr, ADPAF, ATIVVerapamil, Diltiazem Block of Ca2+ channelsAPD, A-V velocityAFflutter抗心律失常课件Summary of antiarrhythmic drugEnd!抗心律失常课件End!抗心律失常课件Problems to be solvedPro-arrhythmias of antiarrhythmic drugsi.e. lack of selectivity when they are used to treat atrial fibrillation.No effe

10、ctive drugs for arrhythmias in patients with heart failure.No drugs available for Sick Sinus Syndrome. 抗心律失常课件Problems to be solvedPro-arrhyPro-arrhythmia of antiarrhythmic drugs抗心律失常课件Pro-arrhythmia of antiarrhythArrhythmogenic action in rabbit heartQuinidine (5 M)E-4031 (0.5 M)Asono et al. (1997)

11、JMCC,29:831 抗心律失常课件Arrhythmogenic action in rabbiLack of IKur in human ventricleAtrial cellVentricular cellA ControlD ControlB 4-AP 50 MC 4-AP-sensitiveE 4-AP 50 MF 4-AP-sensitive+50 50 mV200pA30 ms Li et al (1996): Circ Res 78:689抗心律失常课件Lack of IKur in human ventriclIon currents in human atrium & v

12、entricleInward currentsOutward currentsINaICaINa/CaIK1Ito1IKurIKrIKsAtriumVentricle抗心律失常课件Ion currents in human atrium &Human atrial IKur-A target for developing selective anti-atrial fibrillation drug抗心律失常课件Human atrial IKur-A target foAtrial Fibrillation (AF)AF is the most common arrhythmia in eld

13、erly personsAF is a potent risk factor for ischemic stroke, increasing the risk of stroke 5-fold and accounting for about 15% of all strokes in USA. Symptomatic AF may also reduce quality of life, functional status, and cardiac performance.It is associated with higher medical costs as well as an inc

14、reased risk of death.抗心律失常课件Atrial Fibrillation (AF)AF is Go, A. S. et al. JAMA 2001;285:2370-2375.Projected Number of Adults With Atrial Fibrillation in the United States Between 1995 and 2050抗心律失常课件Go, A. S. et al. JAMA 2001;285A population-based study of the long-term risks associated with atrial

15、 fibrillation 20-year follow-up of the Renfrew/Paisley study Stewart et al. Am J Med. 2002;113:359-64抗心律失常课件A population-based study of thIt is important to develop selective anti-atrial fibrillation drugs抗心律失常课件It is important to develop selLife-threatening VF in heart failure抗心律失常课件Life-threatenin

16、g VF in heart Heart failure-mortality15%Within 1 year after diagnosisKannel, et al. Br Heart J 1994;72:S3-S9抗心律失常课件Heart failure-mortality15%With80%In 6 years after diagnosisHeart failure-mortalityKannel, et al. Br Heart J 1994;72:S3-S9抗心律失常课件80%In 6 years after diagnosisHOf deaths, up to 50% are su

17、dden or unexpected50%Heart failure-mortalityTendera & Ochala Curr Opin Cardiol 2001;16:180 抗心律失常课件Of deaths, up to 50% are suddeLethal arrhythmias: VT or VFVFVT抗心律失常课件Lethal arrhythmias: VT or VFVFProlongation of ECG Q-T interval in HF patients Choy et al. Am Heart J, 1998; 136:664-71抗心律失常课件Prolonga

18、tion of ECG Q-T intervCellular mechanisms of arrhythmias in HFVTVFEADsControlHFDADsHF抗心律失常课件Cellular mechanisms of arrhythAPs and Ito, IKs in dog ventricleLiu et al. Circ. Res. 1993;72:671, 1995;76:351抗心律失常课件APs and Ito, IKs in dog ventriQuestion How the heterogeneous electrophysiology of the transm

19、ural ventricular wall is remodeled in heart failure?抗心律失常课件Question抗心律失常课件Dog HF model and human HFHuman explanted heart抗心律失常课件Dog HF model and human HFHumanRegional ventricular cells抗心律失常课件Regional ventricular cells抗心律失EndoM cellEpiEADsEADsEADsEADs in regional cells from dog HF抗心律失常课件EndoM cellEpiE

20、ADsEADsEADsEADs No change of ICa in cells from dog HF AControlHeart failure-50 mV0 mV500 pA100 msTP (mV)-3003060ICa (pA/pF)-9-6-30EndoMEpimV-40-200204060ICa (pA/pF)-9-6-30EndoMEpiBCControlHeart failure抗心律失常课件No change of ICa in cells fromIK1 reduction in dog HFControlHeart failure 2 nA 100 ms-40-110

21、 mVAB抗心律失常课件IK1 reduction in dog HFControlReduction of regional IK1 in dog HFControlTP (mV)-80-70-60-50-40-30Current (pA/pF)02468*HF-110-90-70-50-30-30-20-10010HFControl*TP (mV)Current (pA/pF)AB抗心律失常课件Reduction of regional IK1 in dReduction of regional Ito1 in dog HFTP (mV)-3003060246810Epi M Endo A

22、TP (mV)-3003060246810EpiMEndoControlHeart FailureB抗心律失常课件Reduction of regional Ito1 in Down-regulation of IKs in dog HFEpiMEndoIKs.tail (+30mV)BCurrent (pA/pF)02468AControlEpiMEndoDEpiMEndo 400 pA 2 sec-60+50mV-30IKs.tail (+30 mV)Current (pA/pF)02468EpiMEndoHeart failureC 400 pA 2 sec抗心律失常课件Down-reg

23、ulation of IKs in dog No change of IKr in dog HF+40 mVControlE-4031E-4031-sensitive +20 mV0 mV*I = 0A170 pA 1.3 sec+40 mV-60-30 TP (mV)-20-10010203040IKr (pA/pF)0.00.81.0Epi M EndoEpi MEndoBControl:HF:抗心律失常课件No change of IKr in dog HF+40 抗心律失常课件抗心律失常课件No change of ICa in human HFTP (mV)-40-

24、200204060Current (pA/pF)-12-10-8-6-4-20ControlHFABControlHF抗心律失常课件No change of ICa in human HFTPIK1 reduction in human HFControlHeart failureCurrent (pA/pF)BTP (mV)-100-80-60-40-20-18-15-12-9-6-303Control FH *ATP (mV)-80-60-40-200.00.51.01.52.02.5*抗心律失常课件IK1 reduction in human HFContrReduction of It

25、o1 in human HFATP (mV)-3003060pA/pF246810ControlFH*ControlHFB抗心律失常课件Reduction of Ito1 in human HFAAControlHF250 pA1.2 sec-50+50-30BTP (mV)-30-20-10010203040500.00.8ControlHF*Down-regulation of IKs in human HF抗心律失常课件AControlHF250 pA1.2 sec-50+50-SummaryIKsIK1Ito1抗心律失常课件SummaryIKsIK1Ito1抗心律失常课件SummaryFibrillationVT0EADs抗心律失常课件SummaryFibrillationVT0EADs抗心律IK1, IKs activatorsFuture perspectiveEADs抗心律失常课件IK1, IKs activatorsFuture persSick Sinus Syndrome抗心律失常课件Sick Sinus Syndrome抗心律失常课件 Car