临床药理Arrhyth.ppt

1、治疗心律失常药物Antiarrhythmic agents,一、Basic Concept 正常心率（窦性心律）：The electrical impulse that triggers a normal cardiac contraction originates at regular intervals in the sinoatrial node , usually at a frequency of 60-100 beats per minute. This impulse spreads rapidly through the atria and enters the atriove

2、ntricular node, then propagates over the His-Purkinje system and invades all parts of the ventricles.,心律失常： Arrhythmias consist of cardiac depolarizations that deviate from the above description in one or more aspectsie, there is an abnormality in the site of origin of the impulse, its rate or regul

3、arity, or its conduction 。,心律失常分类,总的可分快速型和过缓型 （然后根据发生部位和性质再分） 快速型：房早，房速，房颤； 室早，室速，室颤 过缓型（缓慢型）：房室传导阻滞，束支传导阻滞，窦性心动过缓等，阿托品，拟肾上腺素药物等有一定作用。,心律失常的治疗学分类,就临床治疗的观点，心律失常可分为三类： 良性（无器质性病变）benign arrhythmias: VPBs, sinus tachycardia using Anxiolytics and Sedatives 可能恶性（轻中度器质性病变）potential malignant arrhythmias： P

4、aroxysmal Supraventricular Tachycardia, monomorphic ventricular tachycardia, atrial fibrillation 恶性（重度器质性病变）malignant arrhythmias (life-threatening arrhythmias)：sustained ventricular tachycardia, polymorphic ventricular tachycardia, ventricular fibrillation,二、Pathophysiology,Arrhythmias develop beca

5、use of abnormal impulse generation, abnormal propagation or both Bradyarrhythmias Which arise through abnormalities of intrinsic automatic behavior or conduction, principally within the atrioventricular node and the His-Purkinjes network.,Tachyarrhythmias Three mechanisms have been associated with m

6、any tachyarrhythmias Altered automaticity: Factors that increase automaticity include mechanical stretch beta-adrenergic stimulation hypokalemia Triggered automaticity: Early Afterdepolarization (EAD)早后除极 which is associated with significant prolongation of the action potential duration. Factors tha

7、t predispose to EAD: bradycardia low extracellular K+ certain drugs, including some antiarrhythmics,Torsades de pointes, a polymorphic ventricular arrhythmia- associated with Prolongation of cardiac repolarization (prolonged Q-T interval) Possibly induced by early afterdepolarizations Delayed afterd

8、epolarization (DAD)迟后除极. Factors that predispose to DAD include: excessive adrenergic activity digitalis toxicity high intracellular Ca2+ reentry: Most clinically significant tachyarrhythmias are probably due to reentry.,Afterdepolarizations and triggered activity,Symptoms and Signs Palpitations (aw

9、areness of the heartbeat) are often disagreeable and may arise equally from increased force of contraction and from rhythm disturbance. They should be investigated to define the cause and to allay anxiety. Arrhythmias that cause hemodynamic upset are usually sustained bradycardias or tachycardias an

10、d may be life threatening. Resulting dizziness and syncope are common. These arrhythmias require urgent attention and, often, hospitalization.,Some arrhythmias cause few or no symptoms but are associated with an adverse prognosis. Much evidence suggests that prognosis is not necessarily improved by

11、their suppression. Other arrhythmias, although symptomatic, are benign. The nature and severity of underlying heart disease are often of greater prognostic significance than is the arrhythmia itself.,Treatment,Most cardiac arrhythmias cause no symptoms, have no hemodynamic importance, and have no pr

12、ognostic significance but may cause anxiety in a patient who becomes aware of them. Some patients with benign arrhythmias remain disabled despite reassurance. Behavior modification therapy often helps when reassurance has failed. In rare cases, a precipitating factor may be identified and modified (

13、eg, excessive intake of caffeine or alcohol).,Drug treatment: Antiarrhythmic drug therapy is the mainstay of management for most important arrhythmias. There is no universally effective drug; all have important safety limitations and can aggravate or promote arrhythmias (arrhythmogenesis, proarrhyth

14、mia). Drug selection is difficult and often involves trial and error.,抗心律失常药物分类,Willams分类法分为四类： 类：钠通道阻断剂，又再分为a,b,c三亚类 类：beta-受体阻断剂 类：钾通道阻断剂（动作电位时程延长药） 类：钙通道阻断剂 其它类：强心苷、腺苷、镁，等,分类 阻断钠通道 抑制0相Vmax 延长APD 阻钾外流 a类 + + + + b类 + + - - c类+ - -,Class I drugs are Na channel blockers, including older antiarrhyth

15、mic drugs (eg, quinidine). All reduce the maximal rate of depolarization of the action potential and thereby slow conduction. They are subclassified based on the kinetics of their receptor effects: class Ia-drugs with intermediate onset and offset; class Ib-drugs with short effects; class Ic-drugs w

16、ith prolonged effects.,第类药钠通道阻滞药 a类代表药 主要有奎尼丁（quinidine）、普鲁卡因胺(procainamide) b类代表药 主要有利多卡因（lidocaine）、苯妥英钠(phenytoin sodium)、美西律（mexiletine） c类代表药 主要有心律平（普罗帕酮，propafenone），氟卡尼(flecainide，氟卡胺)，恩卡尼(encainide，恩卡胺),奎尼丁（quinidine）a类代表药 药理作用：阻钠内流，阻钾外流， A传导：抑制0相，减慢传导，P-R延长。 B自律性：抑制4相钠内流除极，降低自律性，抑制异位节律 C时程：

17、延长APD，ERP，QRS增宽 另外，通过钠钙交换降低细胞内钙，抑制心肌收缩，阻断受体降血压 应用：为广谱抗心律失常药，对房性，室性，早搏、心动过速均有效。,不良反应： 较严重的为心律失常：多相性室性心动过速（尖端扭转性室速，torsade de points）,可演变成室颤。 低血压扩张血管，抑制心肌 金鸡钠反应：头痛，头晕，耳鸣，视听力减退。,利多卡因（lidocaine） b类代表药 阻钠内流，促钾外流？ 自律性：4相除极减慢，提高兴奋阈，降低自律性， 时程：缩短APD，相对延长ERP 传导：增加病变区心肌的舒张电位，改善浦氏纤维传导，消除折返 主要用于室性心动过速。首过效应大，多iv给

18、药。 副作用：嗜睡，共济失调，惊厥等中枢神经反应，心脏毒性较低，过量也可导致心律失常，传导阻滞,心律平（普罗帕酮，propafenone），氟卡胺，英卡胺等， c类 强阻钠内流，抑制0相，减慢传导，P-R显著延长，QRS增宽，降低室性早搏作用强，但无抗室颤作用，甚至可能加重（CAST结果）。但只要不用于患严重器质性心脏病的病人，还是很安全的。 心律平兼有慢通道及受体阻断作用。,Class II drugs may be the least toxic and most powerful drugs available, yet their antiarrhythmic effects are

19、often overlooked. Whereas relatively few arrhythmias are primarily caused by sympathetic overactivity, most are modulated by autonomic tone. -Blockers have poor efficacy in conventional antiarrhythmic tests (eg, VEB suppression), but they raise the threshold to VF and may be potent preventers of VF.

20、 In general, -blockers are well tolerated but may depress left ventricular function, particularly in antiarrhythmic doses. They are contraindicated in bronchospastic airway disease and should be used cautiously in other lung diseases. GI disturbances, insomnia, and nightmares may occur.,普萘洛尔（propran

21、olol） 类 用于交感神经活动亢进所致的室性、房性心律失常 交感神经兴奋或儿茶酚胺释放增多时,心肌自律性增高,传导速度增快,不应期缩短,易引起快速性心律失常。普萘洛尔则能阻止这些反应。,Class III drugs interfere with the K channel to alter the plateau phase of the action potential and increase refractoriness. Conduction velocity is little affected, but, theoretically, the discharge rate of

22、 automatic foci is reduced. These drugs can be proarrhythmic.,胺碘酮（amiodarone） 兼有1-4类的作用，以3类为主，为广谱抗心律失常药，但不良反应多，且药动学复杂。 本药有显著抗心律失常作用，临床用于多种室上性和室性心律失常。临床显示可能降低心梗后的心律失常致死率，是临床常用的抗心律失常药物。 索他洛尔 (sotalol) 原为受体阻断药,后因明显延长APD而用作类抗心律失常药。d-异构体无阻断作用，只延长ADP，有抗室性心律失常，抗室颤的作用，但可诱发尖端扭转性室速。,Amiodarone a powerful clas

23、s III antiarrhythmic. It has few cardiovascular adverse effects and, perhaps through its modest vasodilator action, produces little or no left ventricular depression. Sinoatrial node activity is little affected. Amiodarone, by prolonging refractoriness, may create homogeneous conditions of repolariz

24、ation throughout the heart. The QT interval on ECG is prolonged, and no upper safe limit to this effect has been suggested. The elimination t1/2 is 50 days, with substantial delay in onset of action. The ECG should be monitored continuously, as there is a risk of inducing atrioventricular block.,维拉帕

25、米（verapamil） 类 抑制窦房结，延长AV传导及不应期，主要用于室上性心动过速。可加重传导阻滞和心肌抑制。 一般不主张与阻断剂合用，因二者均抑制心肌传导和收缩。,Class IV drugs are Ca blockers (Ca entry blockers). verapamil and diltiazem influence atrioventricular nodal electrophysiology and may alter that of Ca-dependent ischemic cells.,其它类,地高辛（洋地黄类） 用于房颤，减慢室率。特别适用于心衰伴有房颤的患

26、者。 腺苷 iv用于终止室上性心动过速。,抗心律失常药物的致心律失常作用,几乎所有的抗心律失常药物都有或多或少的致心律失常作用。 Proarrhythmia due to sodium channel block（类 ） Four distinct forms of proarrhythmia have been associated with treatment with sodium channel blockers. 1 atrial flutter 心率慢时房室传导快，使室率快 2 slow conduction in the rim of an old myocardial infa

27、rction plays a prominent role in the genesis and maintenance of sustained monomorphic ventricular tachycardia. 3 reduces excitability of the heart. ICDs (植 入性心脏起搏器)increased output of the devices may be required.,4 CAST启示 The fourth proarrhythmia syndrome occurring during treatment with sodium chann

28、el blockers is an increase in mortality during long-term treatment. This was established by the Cardiac Arrhythmia Suppression Trial (CAST), a landmark study that tested, in a placebo-controlled, randomized, double-blind fashion, the then-prevailing wisdom that suppression of VPCs in patients conval

29、escing from a myocardial infarction would reduce the incidence of sudden death.,In CAST, patients with VPCs and a recent myocardial infarction were randomly assigned to one of three sodium channel blocker therapies, which was then titrated to the dose that appeared to suppress VPCs on a 24-hour Holt

30、er monitor. Once the effective dose and drug were established, patients were randomly assigned to continue drug or placebo. Remarkably, mortality among patients randomized to drug was 2 to 3 times that among those randomized to placebo.,The mechanism underlying this striking, and previously undefine

31、d, effect of sodium channel block remains uncertain. However, conduction slowing with an increased risk of sustained ventricular arrhythmias (including ventricular fibrillation) seems likely. *Cardiac Arrhythmia Suppression Trial (CAST) /ct/show/NCT00000526 N Engl J Med. 1989

32、;321(6):406-12 N Engl J Med. 1992;327(4):227-33,Proarrhythmia due to QT prolongation 类 In some patients, therapy with action potential prolonging drugs such as sotalol, quinidine, or ibutilide can be associated with marked prolongation of the QT interval and induction of a morphologically distinctiv

33、e polymorphic ventricular tachycardia, torsades de pointes. Torsades de pointes(尖端扭转性室速) can also occur during treatment with “noncardiovascular” drugs; common examples include terfenadine, cisapride, haloperidol, and thioridazine (Tan et al. 1995).,SWORD启示 Most recognized cases of torsades de point

34、es occur shortly after starting culprit drug(s). However, a specific IKr blocker, the dextrorotatory isomer of sotalol (d-sotalol), was found in SWORD (Survival with Oral d-Sotalol), a large study with a CAST-like design, to increase long-term mortality compared to placebo in patients judged to be a

35、t risk for sudden death (Waldo et al. Lancet. 1996;348(9019):7-12). Since the drug is not a sodium channel blocker, a mechanism different from that in CAST seems likely; torsades de pointes occurring during chronic term outpatient treatment is one leading possibility . * Survival With Oral d-sotalol

36、 (SWORD) ,抗心律失常药应用原则,消除诱发和促发因素：低钾血症，低镁血症；心肌缺血缺氧；甲亢；一些药物（强心苷、抗心律失常药、茶碱、红霉素等） 选用合适药物：窦速- 阻断药、维拉帕米；房颤降低室率-强心苷，房颤转律维持-胺碘酮、奎尼丁；阵发室上速-腺苷、维拉帕米；室速-利多卡因、胺碘酮 个体化用药：根据年龄、体质、心、肝、肾功能及电解质情况调整用药方案 注意用药禁忌和不良反应：心律失常，心脏收缩力抑制，心脏传导抑制，低血压，甲状腺功能改变，肺纤维化,治疗高脂血脂药及抗动脉粥样斑块药,动脉粥样硬化 动脉粥样硬化（atherosclerosis，AS，以下简称动粥）是一种主要侵犯主动脉、冠

37、状动脉及脑动脉等大中动脉的全身动脉系统疾病，是常见的心、脑血管疾病的病理基础。在血压突然升高等一些因素的作用下，粥样斑块处就可破裂出血，或形成血栓堵塞血管，如发生在冠状动脉，则造成心肌梗死，如发生在脑血管，则形成出血性中风或缺血性中风。 动粥的病因尚不完全明了，但已知有很多因素能促进动粥病变的发生和发展，如脂质代谢紊乱、血管内皮损伤、高血压、糖尿病、肥胖、吸烟、高脂饮食等。其中血脂代谢紊乱是动粥发病的重要因素，现有的抗动粥药大多与此相关。,1 高胆固醇及高甘油三酯等高血脂症是促进动脉粥样硬化的一个重要危险因素。 LDL、IDL及VLDL，特别是前二者，都是血浆胆固醇的主要载体，与动粥形成关系最

38、为密切。LDL的蛋白部分可在肝外组织细胞内进行降解，而胆固醇则不能。如无法将其运回肝脏，则胆固醇将堆积，沉着在动脉壁，形成动粥斑块，如沉积在皮肤、肌腱处则形成各种黄色瘤。近年发现脂蛋白（a）Lp(a)也是致动粥的一种独立危险因素。Lp（a）是一种较LDL更大更致密的脂蛋白，由apo B100和apo(a) 结合而成，其中的脂蛋白apo(a)可抑制组织纤溶酶原激活物（t-PA）与纤溶酶原的结合，促进血栓及动脉粥样硬化的形成。动物实验和临床研究结果均证明，降低胆固醇和LDL，可延缓动脉粥样硬化的进展。,2 血管内皮的损伤在动粥发病过程中是一个必要因素。 细胞LDL受体介导LDL进入细胞内生成胆固醇

39、；而非受体介导的LDL进入巨噬细胞及平滑肌细胞变成泡沫细胞，沉积于动脉内膜下，形成粥样斑块。 然而，并非所有的脂蛋白浓度升高都有促动粥作用，HDL则有助于减少胆固醇经LDL进入细胞及增加胆固醇离开细胞的速率，表明HDL是对抗动脉粥样硬化的脂蛋白。,Background: Atherosclerosis is a disease of large-sized and medium-sized muscular arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build

40、up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. This buildup results in plaque formation, vascular remodeling, acute and chronic luminal obstruction, abnormalities of blood flow, and diminished oxygen supply to target organs.,Pathophysiology: The mechani

41、sms of atherogenesis remain uncertain. The ”response-to-injury”. Endothelial injury causes vascular inflammation and a fibroproliferative response ensues.,Probable oxidized low-density lipoprotein (LDL) cholesterol causes endothelial injury; infectious agents; toxins, including the byproducts of cig

42、arette smoking; hyperglycemia; and hyperhomocystinemia. Circulating monocytes infiltrate the intima of the vessel wall, and these tissue macrophages act as scavenger cells, taking up LDL cholesterol and forming the characteristic foam cell of early atherosclerosis. These activated macrophages produc

43、e numerous factors that are injurious to the endothelium.,Endothelial injury,The fatty streak may progress to form a fibrous plaque, the result of progressive lipid accumulation and the migration and proliferation of smooth muscle cells. Platelet-derived growth, insulin like growth factor, transforming growth factors alpha and beta, thrombin, and angiotensin II are potent mitogens that are produced by activated platelets, macrophages, and dysfunctional endothelial cells that characterize earl