抗心律失常藥物

1、Antiarrhythmic drugs（抗心律失常藥物）,中南大學(xué)藥學(xué)院藥理學(xué)系 陳小平2011.10,心律失常及病因,Arrhythmia: 心跳頻率、節(jié)律和傳導(dǎo)的異常；CO ?, life-threaten；引起心律失常的因素：疾?。ㄐ募」Ｋ?、高血壓、心衰）和藥物（如地高辛、麻醉藥）。,心律失常的類型,心動(dòng)過(guò)緩（bradycardia）竇性心動(dòng)過(guò)緩 (sinus bradycardia);房室傳導(dǎo)阻滯 (atrio-v

2、entricular block).心動(dòng)過(guò)速（tachycardia）房性早搏 (atrial premature contraction);房性心動(dòng)過(guò)速 (atrial tachycardia,AT);心房顫動(dòng) (atrial fibrillation, AF);心房撲動(dòng) (atrial flutter, AFL);陣發(fā)性室上性心動(dòng)過(guò)速 (paroxysmal supraventricular tachycardia);

3、室性早搏 (ventricular premature contraction);室性心動(dòng)過(guò)速 (ventricular tachycardia,VT);心室顫動(dòng) (ventricular fibrillation, VF).,,,,,心律失常的電生理基礎(chǔ),Electrophysiology of normal cardiac rhythm,Action potential of cardiac cells,心肌缺血、缺氧時(shí)膜電

4、位變小，快反應(yīng)細(xì)胞表現(xiàn)出慢反應(yīng)電活動(dòng)。,,,APD與ERP,Electrophysiology of arrhythmias,異位節(jié)律點(diǎn)自律性升高靜息點(diǎn)位水平負(fù)值減小最大舒張點(diǎn)位絕對(duì)值下降4相自動(dòng)除極速率加快閾點(diǎn)位水平下移后除極（afterdepolarization）與觸發(fā)活動(dòng),1. 沖動(dòng)形成障礙,2. 沖動(dòng)傳導(dǎo)障礙,Increased automaticity of ectopic focus,,,Increased au

5、tomaticity of ectopic focus,,,Increased automaticity of ectopic focus,,,Electrophysiology of arrhythmias,后除極與觸發(fā)活動(dòng)：早后除極（early afterdepolarization，EAD）：發(fā)生于AP 2相或3相，Ca2+和Na+內(nèi)流所致，CCBs和利多卡因可阻斷；遲后除極（delayed afterdepolarizati

6、on，DAD）：發(fā)生于AP 4相，Ca2+ overload誘發(fā)Na+ 內(nèi)流，強(qiáng)心苷中毒、兒茶酚胺類和心肌缺血可誘發(fā)。,,2. Abnormality in impulse conduction,Single reentry: premature stroke;Repeated reentry: AF, AFL, VT, VF.,Classification of Antiarrhythmic Drugs,ClassⅠ: sodium

7、 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, pro

8、pafenone;ClassⅡ: ?-AR blockers, e.g. propranolol, metoprolol;Class Ⅲ: prolonging APD, e.g. amiodarone, sotalol;Class Ⅳ: CCBs, e.g. verapamil, diltiazem;Others: adenosine.,Vaughan Williams (1971),ClassⅠ Sodium channel

9、-blocking agents,Class I A:適度抑制Na+通道 : ↓Vmax, ↓conduction, ↓ phase 4 slope, ↓ automaticity；↓ K+ efflux ,? ERP and APD;代表藥物: quinidine, procainamide, disopyramide (丙吡胺).,與開(kāi)放態(tài)或失活態(tài)Na+通道結(jié)合：頻率依賴性，對(duì)正常心肌細(xì)胞無(wú)影響。,Qunidine (奎尼丁)

10、,輕度抑制Na+內(nèi)流，抑制K+外流和Ca2+內(nèi)流，阻斷?和M受體對(duì)心臟的作用: ↓automaticity: 抑制心房肌、心室肌、浦肯也氏纖維及竇房結(jié)細(xì)胞4相Na+和Ca2+內(nèi)流； ↓conduction: 抑制心房肌、心室肌、浦肯也氏纖維0相Na+內(nèi)流；↑ERP: 抑制K+外流；↓ 心肌收縮力。,Pharmacological effects:,Qunidine (奎尼丁),Pharmacokinetics:口服易吸收；

11、心肌組織中濃度為血漿中的10倍；肝臟代謝，代謝產(chǎn)物有活性；CHF、肝腎疾病t1/2 ?。Therapeutic use: 廣譜（broad-spectrum）抗心律失常Atrial fibrillation; atrial flutter;Supraventricular and ventricular tachycardia;Supraventricular and ventricular premature beat.,

12、,Toxicity: >6 ?g/mlGI system: 惡心、嘔吐、腹瀉、厭食CNS system: 金雞納反應(yīng)（chichonic reaction）CVS: 心衰；低血壓，室內(nèi)傳到阻滯，奎尼丁暈厥Drug interaction:? Renal clearance of digoxin;P450 inducers: ? quinidine metabolism;P450 inhibitors: adjust

13、dosages.,,普魯卡因胺：作用與奎尼丁相似，阻斷M受體和?受體作用較后者弱，乙?；x產(chǎn)物具有III類抗心律失常藥物的作用，為光譜抗心律失常藥物丙吡胺：作用與奎尼丁相似，抗膽堿作用比奎尼丁強(qiáng)，抑制心肌收縮作用明顯。,Class IB,輕度抑制Na+內(nèi)流: 降低自律性，改善傳到K+外流↑: 縮短APD>ERP，ERP/APD↑；主要作用于心室肌細(xì)胞和Purkinje纖維；Representative drugs: li

14、docaine（利多卡因）、 phenytoin sodium（苯妥英鈉）、mexiletine（美西津）、tocainide（妥卡尼）等,Lidocaine (利多卡因),Pharmacological actions: ↓Automaticity: limited to P-k fibers; 改善傳導(dǎo)（improve conduction）: Myocardial ischemia: phase 0 Na+ infflu

15、x ↓ → ↓ conduction，unidirectional blockade → bidirectional blockadeDepoleration caused by hypokalemia and stress: ↑K+ efflux →↑c(diǎn)onduction →↓unidirectional blockAPD ↓ or (-),,Pharmacokinetics:首關(guān)消除明顯，口服生物利用度3% ；體內(nèi)廣泛分布，

16、70%與血漿蛋白結(jié)合，心肌中濃度為血漿中的3倍；Therapeutic index: 1~5 ?g/ml.主要經(jīng)肝臟代謝，10%原型腎臟排泄。,,Therapeutic use: ventricular arrhythmiaVentricular premature contraction, ventricular tachycardia,and ventricular fibrillation caused by AMI;Ve

17、ntricular 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 hypotens

18、ion (overdose).,Phenytoin Sodium,與利多卡因作用相似；Binds with Na+-K+-ATPase;用于急慢性室性心律失常;強(qiáng)心苷類藥物中毒引起房室傳到阻滯或室性心律失常的首選藥物。,Class IC,重度阻滯Na+內(nèi)流，顯著↓Vmax, ↓phase 4 slope,↓automaticity；抑制0相Na+內(nèi)流，↓傳到速度，QRS ?；Representative drugs: flec

19、ainide, encainide, propafenone.Low therapeutic index;Serious adverse reactions: provocation of lethal arrhythmia.,Flecainide,? 心房肌、心室肌和P-k 纖維的傳到速度；? automaticity;? K+ outflow, ?心房肌和心室肌細(xì)胞的APD；用于室上性和室性心律失常；Causes let

20、hal arrhythmia。,Propafenone (普羅帕酮),Block Na+ and Ca2+ channels and ?-AR: ↓conduction, ↓automaticity, ↑ERP, negative inotropic effects.Clinical use: Supraventricular and ventricular tachycardia; Supraventricular and ve

21、ntricular premature beat; Atrial fibrillation.,Class Ⅱ ?-Blockers,Representative drugs: propranolol, metoprolol.Pharmacological actions: ?-AR blocking and membrane-stabilizing effects (↓Na+in):↓automaticity of sinoat

22、rial 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,

23、↓reentry.Improve myocardial ischemia.,Pharmacological effects,Therapeutic use:Supraventricular arrhythamias: sinus tachycardia owing to excessive sympathetic stimulation, supraventricular tachycardia triggered by reent

24、ry, ventricular tachycardia triggered by physical or emotional stress, and phaochromocytoma (嗜鉻細(xì)胞瘤); congenital long QT syndrome.Arrhythmia owing to AMI.,Class Ⅲ APD Prolongation agents,Pharmacological effects: inhibit

25、 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

26、consumption.,Amiodarone (胺碘酮),,Pharmacokinetics: F: 30%~40%, t1/2 40 d, lasts for 4~6w.Therapeutic uses: 廣譜抗心律失常藥物Adverse effects:CVS reactions: sinus bradycardia, atrio-ventricular block, Torsades de;Pulmonary f

27、ibrosis;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 node and

28、 P-k fibers;? AV conduction;Broad-spectrum anti-arrhythmia.,Sotalol (索他洛爾),Class Ⅳ Calcium channel blockers,Block L-Ca2+ channels of SA and AV node.?HR, ? AV conduction velocity, ? ERP.Verapamil(維拉帕米) and diltiazem a

29、re 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).,

30、Adenosine (腺苷),Principles in clinical use of antiarrhythmic drugs,Identify and remove precipitating factors: hypoxia, electrolyte disturbances, myocardial ischemia, and drugs.Establish the goals of treatment: only ?-R b

31、lockers 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. Sinu

32、sal tachycardia: ?-AR blockers or verapamil2. Atrial premature beat: ?-AR blockers, verapamil3. Atrial fibrillation, Atrial flutter: verapamil, ?-AR blockers, amiodarone, cardiac glycosides, 4. Supraventricular tachyc

33、ardia: verapamil, cardiac glycosides, ?-AR blockers, adenosine.,,5. Ventricular premature beat: Lidocaine, amiodarone ,propafeone 6. Ventricular tachycardia: Lidocaine, amiodarone, propafeone 7. Ventricula