抗心律失常药物.pptx

Antiarrhythmic drugs（抗心律失常药物）（抗心律失常药物）中南大学药学院药理学系 陈小平2011.10心律失常及病因心律失常及病因lArrhythmia:心跳频率、节律和传导的异常；lCO,life-threaten；l引起心律失常的因素：疾病（心肌梗死、高血压、心衰）和药物（如地高辛、麻醉药）。心律失常的类型心律失常的类型心动过缓（bradycardia）窦性心动过缓(sinus bradycardia);房室传导阻滞(atrio-ventricular block).心动过速（tachycardia）房性早搏(atrial premature contraction);房性心动过速(atrial tachycardia,AT);心房颤动(atrial fibrillation,AF);心房扑动(atrial flutter,AFL);阵发性室上性心动过速(paroxysmal supraventricular tachycardia);室性早搏(ventricular premature contraction);室性心动过速(ventricular tachycardia,VT);心室颤动(ventricular fibrillation,VF).心律失常的电生理基础心律失常的电生理基础Electrophysiology of normal cardiac rhythmAction potential of cardiac cells心肌缺血、缺氧时心肌缺血、缺氧时膜电位变小，快反膜电位变小，快反应细胞表现出慢反应细胞表现出慢反应电活动。应电活动。APD与与ERPElectrophysiology of arrhythmiasl异位节律点自律性升高静息点位水平负值减小最大舒张点位绝对值下降4相自动除极速率加快阈点位水平下移l后除极（afterdepolarization）与触发活动1.冲动形成障碍冲动形成障碍2.冲动传导障碍冲动传导障碍Increased automaticity of ectopic focusIncreased automaticity of ectopic focusIncreased automaticity of ectopic focusElectrophysiology of arrhythmias后除极与触发活动：后除极与触发活动：早后除极（early afterdepolarization，EAD）：发生于AP 2相或3相，Ca2+和Na+内流所致，CCBs和利多卡因可阻断；迟后除极（delayed afterdepolarization，DAD）：发生于AP 4相，Ca2+overload诱发Na+内流，强心苷中毒、儿茶酚胺类和心肌缺血可诱发。2.Abnormality in impulse conductionSingle reentry:premature stroke;Repeated reentry:AF,AFL,VT,VF.Classification of Antiarrhythmic Drugs lClass:sodium channel-blocking agentsIA:Inhibit Na+influx moderately,e.g.quinidine,procainamide;IB:Inhibit Na+influx slightly,e.g lidocaine,phenytoin sodium;IC:depress Na+influx severely,e.g flecainide,encainide,propafenone;lClass:-AR blockers,e.g.propranolol,metoprolol;lClass:prolonging APD,e.g.amiodarone,sotalol;lClass:CCBs,e.g.verapamil,diltiazem;lOthers:adenosine.Vaughan Williams(1971)Class Sodium channel-blocking agentsClass I A:l适度抑制Na+通道:Vmax,conduction,phase 4 slope,automaticity；l K+efflux,ERP and APD;l代表药物:quinidine,procainamide,disopyramide(丙吡胺).与开放态或失活态Na+通道结合：频率依赖性，对正常心肌细胞无影响。Qunidine(奎尼丁奎尼丁)l轻度抑制Na+内流，抑制K+外流和Ca2+内流，阻断和M受体l对心脏的作用:automaticity:抑制心房肌、心室肌、浦肯也氏纤维及窦房结细胞4相Na+和Ca2+内流；conduction:抑制心房肌、心室肌、浦肯也氏纤维0相Na+内流；ERP:抑制K+外流；心肌收缩力。Pharmacological effects:Qunidine(奎尼丁奎尼丁)Pharmacokinetics:口服易吸收；心肌组织中浓度为血浆中的10倍；肝脏代谢，代谢产物有活性；CHF、肝肾疾病t1/2。Therapeutic use:广谱（broad-spectrum）抗心律失常Atrial fibrillation;atrial flutter;Supraventricular and ventricular tachycardia;Supraventricular and ventricular premature beat.lToxicity:6 g/mlGI system:恶心、呕吐、腹泻、厌食CNS system:金鸡纳反应（chichonic reaction）CVS:心衰；低血压，室内传到阻滞，奎尼丁晕厥lDrug interaction:Renal clearance of digoxin;P450 inducers:quinidine metabolism;P450 inhibitors:adjust dosages.l普鲁卡因胺：作用与奎尼丁相似，阻断M受体和受体作用较后者弱，乙酰化代谢产物具有III类抗心律失常药物的作用，为光谱抗心律失常药物l丙吡胺：作用与奎尼丁相似，抗胆碱作用比奎尼丁强，抑制心肌收缩作用明显。Class IBl轻度轻度抑制Na+内流:降低自律性，改善传到lK+外流:缩短APDERP，ERP/APD；l主要作用于心室肌细胞和Purkinje纤维；lRepresentative drugs:lidocaine（利多卡因）、phenytoin sodium（苯妥英钠）、mexiletine（美西津）、tocainide（妥卡尼）等Lidocaine(利多卡因利多卡因)Pharmacological actions:l Automaticity:limited to P-k fibers;l 改善传导（improve conduction）:Myocardial ischemia:phase 0 Na+infflux conduction，unidirectional blockade bidirectional blockadeDepoleration caused by hypokalemia and stress:K+efflux conduction unidirectional blockAPD or(-)l Pharmacokinetics:首关消除明显，口服生物利用度3%；体内广泛分布，70%与血浆蛋白结合，心肌中浓度为血浆中的3倍；Therapeutic index:15 g/ml.主要经肝脏代谢，10%原型肾脏排泄。Therapeutic use:ventricular arrhythmiaVentricular premature contraction,ventricular tachycardia,and ventricular fibrillation caused by AMI;Ventricular arrhythamias caused by heart disease;Ventricular arrhythamias caused by cardiac glycosides and operation.Adverse reactions:CNS(dizyness,excitement),blurred vision,HR,sinus stop,AV block and hypotension(overdose).Phenytoin Sodiuml与利多卡因作用相似；lBinds with Na+-K+-ATPase;l用于急慢性室性心律失常;l强心苷类药物中毒引起房室传到阻滞或室性心律失常的首选药物。Class ICl重度阻滞Na+内流，显著Vmax,phase 4 slope,automaticity；l抑制0相Na+内流，传到速度，QRS；lRepresentative drugs:flecainide,encainide,propafenone.lLow therapeutic index;lSerious adverse reactions:provocation of lethal arrhythmia.Flecainidel 心房肌、心室肌和P-k 纤维的传到速度；l automaticity;l K+outflow,心房肌和心室肌细胞的APD；l用于室上性和室性心律失常；lCauses lethal arrhythmia。Propafenone(普罗帕酮)lBlock Na+and Ca2+channels and-AR:conduction,automaticity,ERP,negative inotropic effects.lClinical use:Supraventricular and ventricular tachycardia;Supraventricular and ventricular premature beat;Atrial fibrillation.Class -BlockerslRepresentative drugs:propranolol,metoprolol.lPharmacological actions:-AR blocking and membrane-stabilizing effects(Na+in):automaticity of sinoatrial node,atrial myocardiocytes and P-k fibers;conduction of AV node and P-k fibers(100 ng/ml);Affect APD and ERP:APD and ERP(therapeutic concentration);APD and ERP(high concentration);ERP of AV node,reentry.Improve myocardial ischemia.Pharmacological effectsTherapeutic use:Supraventricular arrhythamias:sinus tachycardia owing to excessive sympathetic stimulation,supraventricular tachycardia triggered by reentry,ventricular tachycardia triggered by physical or emotional stress,and phaochromocytoma(嗜铬细胞瘤);congenital long QT syndrome.Arrhythmia owing to AMI.Class APD Prolongation agentsPharmacological effects:inhibit K+,Na+,Ca2+channels,blocks-and-AR:APD and ERP(inhibits K+);Automaticity:inhibits Na+,Ca2+channels and-AR;AV node and P-k fibers conduction:inhibits Na+,Ca2+channels;Dilates CA,myocardial O2 consumption.Amiodarone(胺碘酮胺碘酮)lPharmacokinetics:F:30%40%,t1/2 40 d,lasts for 46w.lTherapeutic uses:广谱抗心律失常药物lAdverse effects:CVS reactions:sinus bradycardia,atrio-ventricular block,Torsades de;Pulmonary fibrosis;Hypo-or hyperthyroidism;Corneal microdeposits and hepatic dysfunction.lNon selective-AR antagonistlBlock Ik:APD、ERP of atrial and ventricular myocytes,AV node and P-k fibers;l Automaticity of SA node and P-k fibers;l AV conduction;lBroad-spectrum anti-arrhythmia.Sotalol(索他洛尔索他洛尔)Class Calcium channel blockerslBlock L-Ca2+channels of SA and AV node.lHR,AV conduction velocity,ERP.lVerapamil(维拉帕米)and diltiazem are used in supraventricular arrhythmia.OtherslAgonist A-R:activates ACh sensitive K+channels K+efflux cAMP-induced Ca2+influx;lChoice for prompt conversion of paroxysmal supraventricular tachycardia(i.v).Adenosine(腺苷腺苷)Principles in clinical use of antiarrhythmic drugslIdentify and remove precipitating factors:hypoxia,electrolyte disturbances,myocardial ischemia,and drugs.lEstablish the goals of treatment:only-R blockers and amiodarone reduce mortality during long-term therapy;lMinimize risks:antiarrhythmic drugs can cause arrhythmias;plasma concentration should be monitored for some drugs.The Choice of Drug Therapies1.Sinusal tachycardia:-AR blockers or verapamil2.Atrial premature beat:-AR blockers,verapamil3.Atrial fibrillation,Atrial flutter:verapamil,-AR blockers,amiodarone,cardiac glycosides,4.Supraventricular tachycardia:verapamil,cardiac glycosides,-AR blockers,adenosine.5.Ventricular premature beat:Lidocaine,amiodarone,propafeone 6.Ventricular tachycardia:Lidocaine,amiodarone,propafeone 7.Ventricular fibrillation:Lidocaine,amiodarone.