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1、DRUGS USED IN CONGESTIVE HEART FAILURE 医学院药理学研究所 丁 华,CHAPTER 27,Congestive heart failure(CHF):the definition of CHF Essence:Cardiomyopathy of overload,Section 1 Pathophysiology of Heart Failure and The Treatment Drugs,A.Change of cardiac function and configuration B.Change of neuroendocrine system N
2、A、RAAS、AVP、ET、TNF ANP、NO、PGI2C.Change of signal transmit of-R,Pathophysiology of Heart Failure,心功障碍（收缩功能，舒张功能）输出量 血管收缩 神经激素 心肌1R（RAS、CA）阻抗 水钠潴留 心缩力 后负荷 顺应性 血容量 血管肥厚、重构 心肌肥大、重构 静脉淤血 前负荷心功障碍的病理生理学与药物作用的环节,CHF治疗的演变,20世纪20年代洋地黄开始应用（一）纠正血流动力学异常（20世纪 5080年代）19481968 强心苷、利尿药19691978 血管扩张药19781988 新型正性肌力药,（
3、二）修复衰竭心肌的生物学性质（90年代2001年）90年代以来 ACEI、受体阻断药(三）逆转心肌异常（2001年起）1扩大、强化对心衰时激活的神经 激素-细胞因子的抑制:ET、AVP、TNF 2基因治疗,药物治疗CHF的目的,1改善血流动力学状况并尽快缓解症状。2防止心肌继续损害并延缓自然病程。3降低病死率，延长存活期。,Rationale for pharmacologic intervention in CHF,The goals in treating heart failure are to improve the patients quality of life and to pr
4、olong it.Improving hemodynamics with inotropic drugs does not decrease mortality;long-term treatment directed towards neurohormonal factors with ACE inhibitors and beta-blockers can decrease mortality,Section 2 Cardiac Glycosides,Digoxin（地高辛）Digitoxin（洋地黄毒苷）Cedilanide（毛花苷丙,西地兰）Strophanthin K（毒毛花苷 k)
5、Digitalis,A.Effect on cardiac1.Positive inotropic action(1)both the force and the velocity of myocardial contraction,prolong diastolic.(2)the cardiac output.(3)myocardial oxygen consumption,Pharmacological actions:,Mechanism:,Cardiac glycosidesNa+K+ATPase Na+i Na+/Ca2+exchange Ca2+i myocardial contr
6、action,2.Negative chronotropic actiona.vagal stimulation b.Resume sensitivity of carotid sinus baroreceptor.c.sensitivity of cardiac muscle to Ach.,3.Electrophysiological effect AV conduction shorten ERP of atria P-f automaticity，shorten ERP,强心苷对心肌电生理的作用电生理特性 窦房结 心房 房室结 浦肯野纤维自律性 降低 增高传导性 减慢有效不应期 缩短
7、缩短,B.Effect on nerve-incretion:,1.sympathetic activity2.pneumogastric(vagal)activity3.renin secretion,RAS4.ANP secretion,C.Diuresis effect,1.CO renal blood flow2.Na+-K+-ATPase Na+reabasorption in the tubules H2O and Na+retention.,drugs absorp%t1/2 H-E cir%last digitoxin 90100 5d 27 23 w digoxin 60 8
8、5 36h 7 57dstroph K 25 19h 0 13d,Pharmacokinetics,1.CHF Digoxin:0.1250.25mg/d，67d get to Css 2.Certain types of arrhythmia(1)Atrial fibrillation,atrial flutter(2)Paroxysmal supraventracular tachycardia,Clinical uses,临床评价：,1997年DIG 试验(Digitalis Investigation Group trial）6800例,应用地高辛0.25mg/d，治疗 2858个月。
9、随访3.5年。地高辛能改善症状，降低再入院率，减少 CHF恶化所致的病死率与住院率，但对总病 死率(34.8%:35.1%)无影响。,Toxicity,Prevention and Management,toxicity,1.Gastrointestinal reactions Nausea and vomiting2.CNS disturbance Changes in color vision 3.Cardiac toxicity ventricular premature contraction ventricular tachycardia ventricular fibrillati
10、on sinus bradycardia atria-ventricular block,Treatment of digitalis toxicity,1)Stop using cardiac glycosides and K+-depleting diuretics.2)AntiarrhythmicKCL is administered orally or by slow,careful intravenous infusion if hypokalemia is present;Phenytoin can be given for ventricular and atrial arrhy
11、thmia.Lidocaine can be used to treat ventricular tachyarrhymias.Atropine can be used to treat A-V block.3)Digoxin antibodies,Section 3 ACEI and AT1-R Antagonist,ACEI(angiotensin-converting enzyme inhibitor)：Captopril(卡托普利)Enalapril(依那普利)Ramipril(雷米普利）,Pharmacological action,1.Influence nerve-increti
12、on:(1)Ang II(2)Inhibit bradykinin degradation bradykinin levels NO,EDHF,PGI2(3)ALD secretion,2.Improve hemodynamics,a.Dilate blood vessels,peripheral resistance;b.Dilate coronary,improve cardiac function c.renal blood flow,3.Inhibit remodeling of cardiac muscle and vessel,Angand ALD formation,Inhibi
13、te proliferation and hypertrophy of myocardial cells and VSMC,improve cardiovascular function.,Clinical Uses,1.CHF2.Hypertension,39项8308例随机时照临床试验评价:ACEI使CHF总死亡率降低24%，显著改善心梗后CHF患者预后，缓解临床症状，提高运动耐力，改善生活质量，防止和逆转心肌肥厚。ACEI可作为各型CHF的首选药，常与利尿药，地高辛合用。,临床评价:,ACE inhibitors are now considered to be a cornerston
14、e in the management of most forms of heart failure and many forms of cardiac hypertrophy,Braunwald&BristowCirculation 2000,Untoward Reaction,hypotension,dry cough,angioedema,hyperkalemia Contraindication:Pregnant woman Renal artery stenosis,Angiotensin II receptor antagonist,Losartan（氯沙坦）Valsartan（缬
15、沙坦）Irbesartan（伊白沙坦）,Characteristics:,Arrest Ang II combine with AT1R(1)More selective blockers of Ang II than ACEI(2)No effect on bradykinin metabolism,ACEI与ARB特点比较,ARB完全阻滞ACE和非ACE途径生成的AngII与受体结合只阻滞AT1受体效应不影响AT2、AT3、AT4受体不影响缓激肽系统不发生咳嗽无AngII、Ald逃逸,ACEI只阻滞ACE途径生成的AngII抑制AT1、AT2、AT3、AT4受体效应加强缓激肽系统作用咳嗽相
16、对常见有AngII、Ald逃逸,Section 4-receptor blockers(adrenergic antagonists):,1.The mechanism of action in treatment of CHF(1)Anti-sympathetic activitya.Up-regulate 1-R in failing heart,can restore catecholamine responsiveness.b.inhibit RAAS cardiac load c.myocardial damage from CA,reduce HR and myocardial o
17、xygen consumption(2)Anti-arrhythmia and anti-myocardial ischemia(3)Antioxidation carvedilol,适应症：,所有NYHA心功能、级病情稳定，LVEF10000例NYHA心功能、级患者，长期应用阻断剂治疗，死亡率降低34%。,美托洛尔提高扩张型心肌病的左心室射血分数,*P0.05*P0.0001#P=0.013，与标准治疗比较,4035302520,左心室射血分数(),标准治疗美托洛尔,基线 第一天 第一月 第三月,*,*,#,Application attention:,1.选择合适的制剂 Selective
18、 1-R blocker:Metoprolol、Bisoprolol(美多洛尔）(比索洛尔)Nonselective and 1-R blocker:Carvedilol(卡维地洛）,2、应用恰当的剂量,起始量必须极小。Metoprolol 12.5mg/d Bisoprolol 1.25mg/dCarvedilol 3.125mg/d 每24周剂量加倍，达最大耐受量或目标剂量后长期维持。,3、合用利尿药、ACEI、地高辛。4、密切观察可能出现的不良反应：血流动力学恶化，心动过缓，低血 压。5、禁忌症：支气管哮喘、心动过缓（心率 60 次/分）、度以上房室传导阻滞、低血压。,Section 5
19、 Diuretics,Mechanism:decreased salt&water retention(blood volume)leads to decreased ventricular preload Clinical Effect:decreased symptoms of heart failure(ie.edema)decreased cardiac size leads to improved cardiac function Administration:start with a thazide diuretic and switch to a more powerful ag
20、ent as required(furosemide)check serum electrolytes to prevent K+loss,Aldosterone antagonists,Spironolacton(螺内酯)Actions:Competitive inhibition of the aldosterone receptor.H2O and Na+retention,hypertrophy of myocardial cells and myocardial remodeling arrhythmias and sudden death.,Section 6 Vasodilato
21、rs,Nitrate esters(硝酸酯类)Hydralazine（肼屈嗪）Sodium nitroprusside（硝普钠)Prazosin(哌唑嗪),Mechanism of Action,1.Dilate vein preload lung congestive 2.Dilate artery afterload cardiac outputDefects:Sympathetic and RAAS activity,H2O and Na+retention.,常用扩血管药及特点,药物 作用部位 动脉 静脉 硝酸酯类+肼屈嗪+-硝普钠+哌唑嗪+,-Adrenoceptor Agonist
22、 Dobutamine(多巴酚丁胺）Ibopamine(异波帕胺）Phosphodiesterase Inhibitors Amrinone（氨力农）Milrinone（米力农）Vesnarinone(维司力农）,Section 7 Others,-sti PDEI(+)(-)AC PDE ATP cAMP 5-AMP,Mechanism of action:,Machanism of Action of PDEI,1.Inhibit PDE-III cAMP PKA Ca2+in cardiac contractility 2.Dilate blood vessel,cardiac load
23、 clinical uses Serious CHF 35d,IV,Calcium sensitizers,sensitive of troponin C（TnC）to Ca2+，cardiac contractilityPimobendan(匹莫苯）Sulmazole(硫马唑)Levosimendan（左西孟坦）sensitive to Ca2+，PDE,Long-acting:amlodipine(氨氯地平)Mechanism：1.Dilate artery vessel,cardiac load 2.Dilate coronary artery,improve myocardial is
24、chemia3.Ca2+influx,improve cardiac diastole function Uses:Diastolic heart failure,Calcium Antagonist,心衰的常规治疗,过去:强心、利尿、扩血管现在:以神经内分泌拮抗剂为主的三大类或四大类药物的联合应用,即利尿剂、ACEI、受体阻断剂的联合应用，必要时再加地高辛。,病 例,赵X,62岁。患者2年前开始常感劳动后心悸、气短。近半年来，病人病情加重，经常心慌、气促、咳嗽、胃纳差，下肢浮肿，有时痰中带血，曾在当地医院用青霉素、双氢克尿噻、速尿、地高辛治疗，症状有所缓解。近日来，症状较前明显加重，稍动即喘、呼吸困难、不能平卧、少尿。颈静脉怒张，肝于肋下4cm，双下肢呈凹陷性水肿（+），心率每分钟96次，心尖部可闻及II级收缩期杂音和中度舒张期杂音，口唇轻度紫绀。入院诊断为：充血性心力衰竭。心功能级，讨论：对该病人应选用哪些药物治疗？简述用药依据。,
