1、Antiarrhythmic drugs（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,Arrhythmia: 心跳频率、节律和传导的异常；CO , life-threaten；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 t
2、achycardia,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,Electrophysiology of normal cardiac rhythm,Action
3、 potential of cardiac cells,心肌缺血、缺氧时膜电位变小，快反应细胞表现出慢反应电活动。,APD与ERP,Electrophysiology of arrhythmias,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后除极（afterdepolarization）与触发活动,1. 冲动形成障碍,2. 冲动传导障碍,Increased automaticity of ectopic focus,Increased automaticity of ectopic focus,Increased automaticity
4、of ectopic focus,Electrophysiology of arrhythmias,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 conduction,Single reentry: premature stroke;Repeate
5、d reentry: AF, AFL, VT, VF.,Classification of Antiarrhythmic Drugs,Class: 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, propaf
6、enone;Class: -AR blockers, e.g. propranolol, metoprolol;Class : prolonging APD, e.g. amiodarone, sotalol;Class : CCBs, e.g. verapamil, diltiazem;Others: adenosine.,Vaughan Williams (1971),Class Sodium channel-blocking agents,Class I A:适度抑制Na+通道 : Vmax, conduction, phase 4 slope, automaticity； K+ eff
7、lux , ERP and APD;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),轻度抑制Na+内流，抑制K+外流和Ca2+内流，阻断和M受体对心脏的作用: 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
8、),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.,Toxicity: 6 g/mlGI system: 恶心、呕吐、腹泻、厌食CNS system: 金鸡纳反应（chicho
9、nic reaction）CVS: 心衰；低血压，室内传到阻滞，奎尼丁晕厥Drug interaction: Renal clearance of digoxin;P450 inducers: quinidine metabolism;P450 inhibitors: adjust dosages.,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 IB,轻度抑制Na+内流: 降低自律性，改善传到K+外流: 缩短APDERP，ERP/
10、APD；主要作用于心室肌细胞和Purkinje纤维；Representative 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),Pharmacological actions: Automaticity: limited to P-k fibers; 改善传导（improve conduction）: Myocardial ischemia: phase 0 Na+ infflux conduction，unidirectional blockade
11、 bidirectional blockadeDepoleration caused by hypokalemia and stress: K+ efflux conduction unidirectional blockAPD or (-),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 contr
12、action, 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 (o
13、verdose).,Phenytoin Sodium,与利多卡因作用相似；Binds with Na+-K+-ATPase;用于急慢性室性心律失常;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 IC,重度阻滞Na+内流，显著Vmax, phase 4 slope,automaticity；抑制0相Na+内流，传到速度，QRS ；Representative drugs: flecainide, encainide, propafenone.Low therapeutic index;Serious adverse reactions: provocation of l
14、ethal arrhythmia.,Flecainide, 心房肌、心室肌和P-k 纤维的传到速度； automaticity; K+ outflow, 心房肌和心室肌细胞的APD；用于室上性和室性心律失常；Causes lethal arrhythmia。,Propafenone (普罗帕酮),Block Na+ and Ca2+ channels and -AR: conduction, automaticity, ERP, negative inotropic effects.Clinical use: Supraventricular and ventricular tachycard
15、ia; Supraventricular and ventricular premature beat; Atrial fibrillation.,Class -Blockers,Representative drugs: propranolol, metoprolol.Pharmacological actions: -AR blocking and membrane-stabilizing effects (Na+in):automaticity of sinoatrial node, atrial myocardiocytes and P-k fibers;conduction of A
16、V 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 effects,Therapeutic use:Supraventricular arrhythamias: sinus tachycardia owing to excessive sympathetic
17、 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 agents,Pharmacological effects: inhibit K+, Na+, Ca2+ channels
18、, 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),Pharmacokinetics: F: 30%40%, t1/2 40 d, lasts for 46w.Therapeutic uses: 广谱抗心律失常药物Adve
19、rse effects:CVS reactions: sinus bradycardia, atrio-ventricular block, Torsades de;Pulmonary fibrosis;Hypo- or hyperthyroidism;Corneal microdeposits and hepatic dysfunction.,Non selective -AR antagonistBlock Ik:APD、ERP of atrial and ventricular myocytes, AV node and P-k fibers; Automaticity of SA no
20、de and P-k fibers; AV conduction;Broad-spectrum anti-arrhythmia.,Sotalol (索他洛尔),Class Calcium channel blockers,Block L-Ca2+ channels of SA and AV node.HR, AV conduction velocity, ERP.Verapamil(维拉帕米) and diltiazem are used in supraventricular arrhythmia.,Others,Agonist A-R : activates ACh sensitive K
21、+ channels K+ efflux cAMP-induced Ca2+ influx;Choice for prompt conversion of paroxysmal supraventricular tachycardia (i.v).,Adenosine (腺苷),Principles in clinical use of antiarrhythmic drugs,Identify and remove precipitating factors: hypoxia, electrolyte disturbances, myocardial ischemia, and drugs.
22、Establish the goals of treatment: only -R blockers and amiodarone reduce mortality during long-term therapy; Minimize risks: antiarrhythmic drugs can cause arrhythmias; plasma concentration should be monitored for some drugs.,The Choice of Drug Therapies,1. Sinusal tachycardia: -AR blockers or verap
23、amil2. 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.,
