21 药理学 抗心律失常药.ppt

第1页：抗心律失常药

• 抗心律失常药 Anti
• Arrhythmic Drug

第2页：正常心脏电生理

正常心脏电生理

第3页：Cardiac electrical

Cardiac electrical activity and ECG

第4页：Cardiac electrical

Cardiac electrical activity

第5页：Heterogeneous APs in

Heterogeneous APs in heart

第6页：Ion channels and

Ion channels and AP01234INa ICa. LIKr IKs IK1IK1ITo1INa-Ca

第7页：Ion currents

Ion currents underlying APin ventricle Inward currents INa ICa INa/Ca Outward currents IK1Ito1IKr IKs Ito2ITOSCN5ADHP receptor NCX1Kir2.x Kv4.x??HERG/Mi RP1Kv LQT1/min KPossible clone TTX, STX, lidocaine DHP, Cd2+, Co2+Ni+, NCX1-antibody Ba2+4-APDIDS, 9-ACDofetilide, sotalol Chromanol 293BBlockers

第8页：窦房结细胞动作电位时程中的参与电流

窦房结细胞动作电位时程中的参与电流（Currents underlying depolarization in SAnodal cells）

第9页：心律失常发生机制★折返★自律性升高★后除

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

第10页：折返形成机制

折返形成机制(Unidirectional block andreentry)

第11页：预激综合症中房室折返环路的形成

• 预激综合症中房室折返环路的形成 Atrioventricularreentry in the Wolff
• Parkinson
• White syndrome

第12页：心肌细胞的早后除极和迟后除极

心肌细胞的早后除极和迟后除极(Twoforms of abnormalactivity, early anddelayedafterdepolarizations)

第13页：抗心律失常药物作用★降低自律性★减少后除

抗心律失常药物作用★降低自律性★减少后除极★消除折返

第14页：降低自律性的四种方式

降低自律性的四种方式(Fourways to reducethe rate ofspontaneousdischarge inautomatic tissues)

第15页：心律失常类型

心律失常类型

第16页：Atrial flutter

Atrial flutter

第17页：Atrial fibrillation

Atrial fibrillation

第18页：Atrialfibrillation

Atrialfibrillation

第19页：Ventricularbeat

Ventricularbeat

第20页：Ventricularfibrillat

Ventricularfibrillation

第21页：Cardiacarrhythmias

• Cardiacarrhythmias Tachy-cardiac arrhythmias
• Atrial-premature beats
• Atrial flutter
• Atrial fibrillation (AF)
• Ventricular-premature beats (contractions)
• Ventricular-tachycardia (VT)
• Ventricular fibrillation (VF) Brady-cardiac arrhythmias
• Bundle branch blocks
• Sinus bradycardia (Sick Sinus Syndrome)

第22页：抗心律失常药物分类

抗心律失常药物分类

第23页：Summary of antiarrhy

• Summary of antiarrhythmic drugs Uses Actions Drug example Class VT, AFVPVTBlock of INa, IK, and ICa,
• ADP,
• ERP,
• Velocity,
• Contractility Block of INa(fast dissociation),
• APD,
• ERPBlock of INa(slow dissociation),
• Velocity,
• Contractility Quinidine, Procainamide Lidocaine, Mexiletine Flecainide, Encainide Ia Ib Ic AT, VTBlock of
• adrenoceptor
• Contractility Propranolol, Metoprolol IIAF, ATBlock of IKr,
• ADPBlock of INa(Inac), IKr,
• ADPDofetilide, Ibutilide Amiodarone IIIAFflutter Block of Ca2+channels
• APD,
• A-V velocity Verapamil, Diltiazem IV

第24页：End!

End!

第25页：Problems to be

Problems to be solved

Pro-arrhythmias of antiarrhythmicdrugs—i.e. lack of selectivity when theyare used to treat atrial fibrillation.

No effective drugs for arrhythmias inpatients with heart failure.

No drugs available for Sick Sinus Syndrome.

第26页：Pro-arrhythmia

Pro-arrhythmia ofantiarrhythmic drugs

第27页：Arrhythmogenic

• Arrhythmogenic action in rabbit heart Quinidine (5
• M) E-4031 (0.5
• M) Asonoet al. (1997) JMCC,29:831

第28页：Lack of IKurin human

Lack of IKurin human ventricle Atrial cell Ventricular cell AControl DControl B4-AP 50

MC4-AP-sensitive E4-AP 50

MF4-AP-sensitive+50–50 m V200p A30 ms Liet al(1996):Circ Res78:689

第29页：Ion currents in

Ion currents in human atrium & ventricle Inward currents Outward currents INa ICa INa/Ca IK1Ito1IKur IKr IKs Atrium Ventricle

第30页：Human atrial IKur-A

Human atrial IKur-A target for developing selectiveanti-atrial fibrillation drug

第31页：Atrial Fibrillation

Atrial Fibrillation (AF)

AF is the most common arrhythmiain elderly persons

AFisapotentriskfactorforischemicstroke,increasingtheriskofstroke5-foldandaccountingforabout15%ofallstrokesin USA.

Symptomatic AF may also reduce quality of life, functionalstatus,and cardiac performance.

It is associated with highermedical costs as well as anincreased risk of death.

第32页：Go, A. S. et al.

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

第33页：A population-based

A population-based study of the long-term risksassociated with atrial fibrillation—20-year follow-up of the Renfrew/Paisley study Stewart et al. Am J Med.2002;113:359-64

第34页：It is important to

It is important to develop selectiveanti-atrial fibrillation drugs

第35页：Life-threatening

Life-threatening VFin heart failure

第36页：Heart failure-mortal

Heart failure-mortality15%Within 1 year after diagnosis Kannel,etal. Br Heart J1994;72:S3-S9

第37页：80%In 6 years after

80%In 6 years after diagnosis Heart failure-mortality Kannel,etal. Br Heart J1994;72:S3-S9

第38页：Of deaths

Of deaths, up to 50% are sudden or unexpected50%Heart failure-mortality Tendera & Ochala Curr Opin Cardiol 2001;16:180

第39页：Lethal arrhythmias

Lethal arrhythmias: VT or VFVFVT

第40页：Prolongation of ECG

Prolongation of ECG Q-T interval in HF patients Choy et al. Am Heart J, 1998; 136:664-71

第41页：Cellular mechanisms

Cellular mechanisms of arrhythmias in HFVTVFEADs Control HF

第42页：APs and Ito

APs and Ito, IKsin dog ventricle Liu et al. Circ. Res. 1993;72:671, 1995;76:351

第43页：Question How the

Question How the heterogeneouselectrophysiology of thetransmural ventricular wall isremodeled in heart failure?

第44页：Dog HF model and

Dog HF model and human HFHumanexplanted heart

第45页：Regional ventricular

Regional ventricular cells

第46页：

第47页：No change of ICain

No change of ICain cells from dog HFAControl Heart failure-50m V0m V500p A100ms

第48页：IK1reduction in dog

IK1reduction in dog HFControl Heart failure2n A100ms-40-110m V

第49页：Reduction ofregional

Reduction ofregional IK1in dog HFControl TP (m V)-80-70-60-50-40-30Current (p A/p F)02468********HF-110-90-70-50-30-30-20-10010HFControl***********TP (m V) Current (p A/p F) AB

第50页：Reduction of

Reduction of regional Ito1in dog HFTP (m V)-3003060246810Epi MEndo ATP (m V)-3003060246810Epi MEndo Control Heart Failure B

第51页：Down-regulation of

Down-regulation of IKsin dog HFEpi MEndo IKs.tail(+30m V) BCurrent (p A/p F)02468AControl Epi MEndo DEpi MEndo400p A2sec-60+50m V-30IKs.tail(+30 m V) Current (p A/p F)02468Epi MEndo Heart failure C400p A2sec

第52页：No change of IKrin

No change of IKrin dog HF

第53页：

第54页：No change of ICain

No change of ICain human HFTP (m V)-40-200204060Current (p A/p F)-12-10-8-6-4-20Control HFABControl HF

第55页：IK1reduction in

IK1reduction in human HFControl Heart failure Current (p A/p F) BTP (m V)-100-80-60-40-20-18-15-12-9-6-303Control FH***ATP (m V)-80-60-40-200.00.51.01.52.02.5********

第56页：Reduction of Ito1in

Reduction of Ito1in human HFATP (m V)-3003060p A/p F246810Control FH*******Control HFB

第57页：AControl HF250p

AControl HF250p A1.2sec-50+50-30BTP (m V)-30-20-10010203040500.00.20.40.60.8Control HF*************Down-regulation of IKsin human HF

第58页：Summary IKs IK1Ito1

Summary IKs IK1Ito1

第59页：Summary Fibrillation

Summary Fibrillation VT

第60页：IK1, IKsactivators

IK1, IKsactivators Future perspective

第61页：Sick Sinus Syndrome

Sick Sinus Syndrome

第62页：Cardiac electrical

Cardiac electrical activity

第63页：ECG—Sick Sinus

ECG—Sick Sinus Syndrome Bradycardiac and tachycardia are seen in Sick Sinus Syndrome

第64页：Atriaficial pacemake

Atriaficial pacemaker

第65页：Threshold potential

Threshold potential Diastolic potential(~–60 m V)034Pacemaker cell action potentials ICa IKIf Pacemaker potential Sinoatrial node (SA node)

第66页：Pacemaker potential

Pacemaker potential and If–35 m V–85 m V–5 m VFrom Difrancesco:Cardiovasc Res1995;29:449-456

第67页：Modulation of If

Modulation of If ACBFrom Difrancesco:Cardiovasc Res1995;29:449-456

第68页：Ifand cloned HCN

Ifand cloned HCN channels From Ludwig et al.:Nature1998;393:587-591HCN:Hyperpolarization-activated,cyclicnucleotide-gatedchannels,the HCNfamilyincludesthemembers HCN1-HCN4.