1. 第 20 章 治疗心律失常药物 Antiarrhythmic agents

2. 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 atrioventricular node, then propagates over the His-Purkinje system and invades all parts of the ventricles.

3. 心律失常： Arrhythmias consist of cardiac depolarizations that deviate from the above description in one or more aspects — ie, there is an abnormality in the site of origin of the impulse, its rate or regularity, or its conduction 。

4. 二、 Pathophysiology Arrhythmias develop because 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- Purkinje's network.

5. Tachyarrhythmias Three mechanisms have been associated with many tachyarrhythmias 1.Altered automaticity: Factors that increase automaticity include mechanical stretch beta-adrenergic stimulation hypokalemia 2.Triggered automaticity: –Early Afterdepolarization (EAD) 早后除极 which is associated with significant prolongation of the action potential duration. Factors that predispose to EAD: bradycardia low extracellular K+ certain drugs, including some antiarrhythmics

6. –Torsades de pointes, a polymorphic ventricular arrhythmia- associated with Prolongation of cardiac repolarization (prolonged Q-T interval) Possibly induced by early afterdepolarizations –Delayed afterdepolarization (DAD) 迟后 除极. Factors that predispose to DAD include: excessive adrenergic activity digitalis toxicity high intracellular Ca2+ 3.reentry: Most clinically significant tachyarrhythmias are probably due to reentry.

7. Afterdepolarizations and triggered activity

8. Symptoms and Signs Palpitations (awareness 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 and may be life threatening. Resulting dizziness and syncope are common. These arrhythmias require urgent attention and, often, hospitalization.

9. Some arrhythmias cause few or no symptoms but are associated with an adverse prognosis. Much evidence suggests that prognosis is not necessarily improved by 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.

10. 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： 1. 良性（无器质性病变） benign arrhythmias: VPBs, sinus tachycardia using Anxiolytics and Sedatives 2. 可能恶性（轻中度器质性病变） potential malignant arrhythmias ： Paroxysmal Supraventricular Tachycardia, monomorphic ventricular tachycardia, atrial fibrillation 3. 恶性（重度器质性病变） malignant arrhythmias (life-threatening arrhythmias) ： sustained ventricular tachycardia, polymorphic ventricular tachycardia, ventricular fibrillation

11. Treatment Most cardiac arrhythmias cause no symptoms, have no hemodynamic importance, and have no prognostic 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 (eg, excessive intake of caffeine or alcohol).

12. 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, proarrhythmia). Drug selection is difficult and often involves trial and error.

13. 抗心律失常药物分类 Willams 分类法分为四类： Ⅰ类：钠通道阻断剂，又再分为 a,b,c 三亚类 Ⅱ类： beta- 受体阻断剂 Ⅲ类：钾通道阻断剂（动作电位时程延长药） Ⅳ类：钙通道阻断剂 其它类：强心苷、腺苷、镁，等

14. Class I drugs are Na channel blockers, including older antiarrhythmic 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 with prolonged effects.

15. 第Ⅰ类药钠通道阻滞药 Ⅰ a 类代表药 主要有奎尼丁（ quinidine ）、普鲁卡因胺 (procainamide) Ⅰ b 类代表药 主要有利多卡因（ lidocaine ）、苯妥英钠 (phenytoin sodium) 、美西律（ mexiletine ） Ⅰ 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 )

16. Class II drugs may be the least toxic and most powerful drugs available, yet their antiarrhythmic effects are often overlooked. Whereas relatively few arrhythmias are primarily caused by sympathetic overactivity, most are modulated by autonomic tone. β - 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. In general, β -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.

17. 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 automatic foci is reduced. These drugs can be proarrhythmic.

18. 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。 索他洛尔 (sotalol) 原为 β 受体阻断药, 后因明显延长 APD 而用作Ⅲ 类抗心律失常药。 d- 异构体无 β 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。

19. Amiodarone a powerful class 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 repolarization 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.

20. 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.

21. 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 （Ⅰ 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 infarction plays a prominent role in the genesis and maintenance of sustained monomorphic ventricular tachycardia. 3 reduces excitability of the heart. ICDs increased output of the devices may be required

22. 4 CAST 启示 The fourth proarrhythmia syndrome occurring during treatment with sodium channel 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 convalescing from a myocardial infarction would reduce the incidence of sudden death.

23. 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 Holter 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.

24. The mechanism underlying this striking, and previously undefined, effect of sodium channel block remains uncertain. However, conduction slowing with an increased risk of sustained ventricular arrhythmias (including ventricular fibrillation) seems likely.

25. Proarrhythmia due to QT prolongation Ⅲ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 distinctive polymorphic ventricular tachycardia, torsades de pointes. Torsades de pointes can also occur during treatment with “ noncardiovascular ” drugs; common examples include terfenadine, cisapride, haloperidol, and thioridazine (Tan et al. 1995).

26. SWORD 启示 Most recognized cases of torsades de pointes occur shortly after starting culprit drug(s). However, a specific I Kr 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 at risk for sudden death (Waldo et al. 1996). 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.

27. 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 - β 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