抗心律失常药物2011

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 (

2、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,Electrophysiology of normal cardiac

3、 rhythm,Action 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,Incr

4、eased automaticity 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: pre

5、mature stroke; Repeated reentry: AF, AFL, VT, VF.,Classification of Antiarrhythmic Drugs,Class: sodium channel-blocking agents IA: 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 fleca

6、inide, encainide, propafenone; 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

7、4 slope, automaticity； K+ efflux , 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。,Pharma

8、cological effects:,Qunidine (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.,Toxicity: 6 g/ml GI sy

9、stem: 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 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。,Cl

10、ass IB,轻度抑制Na+内流: 降低自律性，改善传到 K+外流: 缩短APDERP，ERP/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: phas

11、e 0 Na+ infflux conduction，unidirectional blockade bidirectional blockade Depoleration caused by hypokalemia and stress: K+ efflux conduction unidirectional block APD 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。,Therapeuti

12、c use: ventricular arrhythmia Ventricular 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), b

13、lurred vision, HR , sinus stop, AV block and hypotension (overdose).,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.

14、Low therapeutic index; Serious adverse reactions: provocation of lethal 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 inotro

15、pic effects. Clinical use: Supraventricular and ventricular tachycardia; Supraventricular and ventricular premature beat; Atrial fibrillation.,Class -Blockers,Representative drugs: propranolol, metoprolol. Pharmacological actions: -AR blocking and membrane-stabilizing effects (Na+in): automaticity o

16、f 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 effects,Therapeutic use: Supr

17、aventricular 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

18、 Prolongation agents,Pharmacological 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),Pharma

19、cokinetics: F: 30%40%, t1/2 40 d, lasts for 46w. Therapeutic uses: 广谱抗心律失常药物 Adverse effects: CVS reactions: sinus bradycardia, atrio-ventricular block, Torsades de; Pulmonary fibrosis; Hypo- or hyperthyroidism; Corneal microdeposits and hepatic dysfunction.,Non selective -AR antagonist Block Ik:APD

20、、ERP of atrial and ventricular myocytes, AV node and P-k fibers; Automaticity of SA node 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 diltiaze

21、m are used in supraventricular arrhythmia.,Others,Agonist A-R : activates ACh sensitive K+ 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. Establish