治疗心力衰竭的药物DrugsfortheTreatmentofCongestiveHeart课件.ppt

1、OutlinesCHF概述概述CHF的治疗策略的治疗策略 治疗治疗CHF的药物的药物12概述概述-CHF的定义和症状的定义和症状l充血性心力衰竭是指在充血性心力衰竭是指在静脉回流正常静脉回流正常的情况下，由于原发的的情况下，由于原发的心脏损害引起心脏损害引起心排血量减少心排血量减少，不能满足组织代谢需要的一种不能满足组织代谢需要的一种综合征。导致心衰的疾病包括冠心病，缺血性心脏病，心肌综合征。导致心衰的疾病包括冠心病，缺血性心脏病，心肌病，高血压，心瓣膜病，肾病等。病，高血压，心瓣膜病，肾病等。l临床上以临床上以肺循环和肺循环和(或或)体循环淤血体循环淤血以及以及组织血液灌注不足组织血液灌注不

2、足为为主要特征，包括无力、水肿、咳嗽、喘鸣，咯血，头晕，心主要特征，包括无力、水肿、咳嗽、喘鸣，咯血，头晕，心律失常、心绞痛等。律失常、心绞痛等。(1)收缩功能衰竭收缩功能衰竭:the mechanical pumping action(contractility)and the ejection fraction of the heart are reduced.(2)舒张功能衰竭舒张功能衰竭:stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejectio

3、n fraction may be normal.e.g.Pericarditis(心包炎)(3)高输出型衰竭高输出型衰竭:can result from hyperthyroidism(甲亢),beriberi(脚气病),anemia(贫血),and arteriovenous shunts(动静脉分流).概述概述-心力衰竭的类型心力衰竭的类型3概述概述-心功能分级心功能分级根据症状对心功能分级（根据症状对心功能分级（NYHA法）法）:Class I:体力活动不受限制，一般体力活动不引起心衰的症状体力活动不受限制，一般体力活动不引起心衰的症状Class II:体力活动轻度受限。休息无症状，但

4、一般体力活动可体力活动轻度受限。休息无症状，但一般体力活动可引起心衰症状引起心衰症状 Class III:体力活动明显受限。休息无症状，轻微活动即可引起体力活动明显受限。休息无症状，轻微活动即可引起心衰症状心衰症状 Class IV:体力活动能力完全丧失。休息亦有症状，活动时加重体力活动能力完全丧失。休息亦有症状，活动时加重4根据疾病进程对根据疾病进程对CHF分级分级:Stage A:高危（高危（e.g 严重高血压），无器质性心脏病或心严重高血压），无器质性心脏病或心衰症状衰症状 Stage B:有器质性心脏病（有器质性心脏病（e.g 心室肥厚），无心衰症状心室肥厚），无心衰症状;Stage

5、C:有器质性心脏病伴心衰症状，药物治疗可以控制有器质性心脏病伴心衰症状，药物治疗可以控制;Stage D:病情恶化，需要特殊干预治疗（住院、心脏移植病情恶化，需要特殊干预治疗（住院、心脏移植或姑息治疗）或姑息治疗）概述概述-心衰的分级心衰的分级At riskHF5Cardiac failure心输出量心输出量静脉压静脉压静脉淤血静脉淤血肺循环淤血（咳嗽，肺循环淤血（咳嗽，咯血，呼吸困难）咯血，呼吸困难）体循环（颈静脉怒张，体循环（颈静脉怒张，水肿）水肿）血压血压肾血流肾血流Renin,angiotension IIAldosterone 水钠潴留水钠潴留6概述概述-CHF的血液动力学改变的血液

6、动力学改变心输出量减少心输出量减少SNS和和RAAS 激活激活心肌肥厚（心肌肥厚（hypertrophy）心血管重构（心血管重构（remodeling）心衰症状心衰症状死亡死亡ANPBNP概述概述-CHF的病理生理学的病理生理学7左室功能进行性恶化左室功能进行性恶化AVPETATIIConstricts vessels,increases peripheral resistance and returned blood volume.Increases sympathetic tension,promotes release of sympathetic transmitter.Stimula

7、tes release of aldosterone(醛固酮醛固酮).Induces expression of c-fos、c-myc、c-jun rapidly,promotes proliferation and remodeling.Actions of angiotensin II89Actions of AldosteroneMcMahon EG 2001,CHF时时 受体的信号传导变化受体的信号传导变化-1 受体密度受体密度 -Gs 蛋白蛋白数量或数量或/和活性和活性 10概述概述-CHF的病理生理学的病理生理学-GRKs（G蛋白偶联受体激酶）活性蛋白偶联受体激酶）活性 CHF的

8、治疗目标和策略的治疗目标和策略治疗目标：治疗目标：A 延缓心肌重构延缓心肌重构，延长寿命，降低死亡率，延长寿命，降低死亡率 B 提高运动耐量，改善生活质量提高运动耐量，改善生活质量 策略：策略：A 抑制抑制RAAS：ACEIs,ARBs,醛固酮拮抗剂醛固酮拮抗剂 B 降低交感神经活性：降低交感神经活性：ACEIs,blockers C 正性肌力药物：正性肌力药物：强心苷类强心苷类,PDE III 抑制剂抑制剂,其他其他 D 降低循环血容量：降低循环血容量：利尿药利尿药 E 扩血管药：扩血管药：血管扩张药血管扩张药 11ACEIs Captopril(卡托普利卡托普利),enalapril(依那

9、普利依那普利),lisinopril(赖诺普利赖诺普利),benazepril(贝那普利贝那普利),fosinopril(福辛普利福辛普利),etc.ACEIs and ARBs12ARBsLosartan(氯沙坦氯沙坦),valsartan(缬沙坦缬沙坦),erbesartan(厄贝沙坦厄贝沙坦),candesartan(坎地沙坎地沙坦坦),telmisartan(替米沙坦替米沙坦),etcChymase激肽释放酶激肽释放酶激肽原激肽原血管紧张素原血管紧张素原and NOVasodilation,anti-proliferation,anti-hypertrophyACEIs and ARB

10、sACEIsActions抑制抑制Ang II合成合成(dilate vessels,decrease sympathetic activity,protect renal and cardiac function,inhibit release of aldosterone,anti-hypertrophy)抑制缓激肽降解抑制缓激肽降解(vasodilation,anti-hypertrophy,myocardial protection,improvement of insulin receptor sensitivity)ACEIs and ARBs14ACEIsClinical use

11、s:CHF -低剂量即延缓低剂量即延缓/逆转肥厚和逆转肥厚和重构重构 -增加运动耐量增加运动耐量 -降低病死率降低病死率高血压高血压 ACEIs and ARBs15ACEIs and ARBsACEIsAdverse reactions 低血压低血压(首剂现象首剂现象)肾脏损害肾脏损害(肾动脉硬化患者肾动脉硬化患者)干咳和血管性水肿干咳和血管性水肿(缓激肽刺激作用缓激肽刺激作用)高钾血症高钾血症(醛固酮抑制醛固酮抑制)皮疹和味觉改变皮疹和味觉改变(-SH相关相关)胎毒性胎毒性(妊娠中后期，妊娠中后期，pregnancy category D)CNS 和和 GI 系统的不良反应系统的不良反应A

12、CEIsContraindications 肾动脉硬化肾动脉硬化(pressure-dependent kidney perfusion in these patients)孕妇和哺乳期妇女孕妇和哺乳期妇女ACEIs and ARBsARBSActions:Block actions of angiotensin II directlyNo influence on bradykinin metabolismProtect renal functionUsed for CHF and hypertension Less adverse effects compared with ACEIsAC

13、EIs and ARBs18醛固酮逃逸现象醛固酮逃逸现象醛固酮拮抗药醛固酮拮抗药Spironolactone(螺内酯螺内酯)和和 Eplerenone(依普利依普利酮酮)可进一步降低心衰的发病和死亡率可进一步降低心衰的发病和死亡率ACEIs and ARBs19RALES:Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF*Ejection fraction 35%Class III or IV symptoms at some point in prior 2 months.Pitt B et al.N Engl

14、J Med.1999;341:709-717.HR=hazard ratio;RR=risk reduction.20EPHESUS Co-Primary Endpoint:Total MortalityAdapted from Pitt B et al.N Engl J Med.2003;348:1309-1321.HR=hazard ratio.21美托洛尔美托洛尔metoprolol,比索洛尔比索洛尔bisoprolol,卡卡维地洛维地洛carvedilolActions阻断儿茶酚胺的心脏毒性作用阻断儿茶酚胺的心脏毒性作用抑制抑制RAAS和和VP(vosopressin,加压素加压素)降

15、低心率和心肌耗氧量降低心率和心肌耗氧量抗心律失常，抗高血压，抗心绞痛效应抗心律失常，抗高血压，抗心绞痛效应阻断阻断 受体及抗自由基作用（受体及抗自由基作用（carvedilol）blockers 22Clinical uses:CHF -,特别是对伴扩张性心肌病的患者特别是对伴扩张性心肌病的患者 -降低病死率降低病死率高血压，心律失常，心绞痛等高血压，心律失常，心绞痛等 blockers 23The Use of Beta Adrenergic Blocking Agents in Heart FailureInitial hemodynamic deterioration followed

16、by reverse remodeling(decrease in EDV and ESV)with improved ventricular function over time(increased LVEF)24US Carvedilol Heart Failure Trials Program1094 Class II-IV CHF pts on triple therapy(ACEI,digoxin,diuretics)Carvedilol 6.25 bid test 2 weeks,then 12.5 bid,then 25 bid vs placeboPacker NEJM 199

17、6;334:1349-55P0.00125MERIT-HF3991 pts with CHF Class II-IV,ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd,target dose 200 mg qdLancet 1999;353:2001-07 26-Blockers Differ in Their Long-Term Effects on Mortality in HFBisoprolol1Bucindolol2Carvedilol3-5Metoprolol tartrat

18、e6Metoprolol succinate7Nebivolol8Xamoterol9Propranolol10Beneficial No effectBeneficialNot well studiedBeneficialMinor effectHarmfulHarmful+Beneficial1CIBIS II Investigators and Committees.Lancet.1999;353:9-13.2The BEST Investigators.N Engl J Med 2001;344:1659-1667.3Colucci WS,et al.Circulation 1996;

19、94:2800-2806.4Packer M,et al.N Engl J Med 2001;344:1651-1658.5The CAPRICORN Investigators.Lancet.2001;357:1385-1390.6Waagstein F,et al.Lancet.1993;342:1441-1446.7MERIT-HF Study Group.Lancet.1999;353:2001-2007.8SENIORS Study Group.Eur Heart J.2005;26:215-225.9The Xamoterol in Severe heart Failure Stu

20、dy Group.Lancet.1990;336:1-6.10 BHAT study Group.Circulation.1986;73(3):503-10.27比索洛尔比索洛尔布新洛尔布新洛尔卡维地洛卡维地洛美托洛尔美托洛尔那必洛尔那必洛尔扎莫特罗扎莫特罗普萘洛尔普萘洛尔不良反应不良反应:心功能抑制心功能抑制禁忌症禁忌症:严重心力衰竭，严重严重心力衰竭，严重AV阻滞，低血阻滞，低血压，支气管哮喘压，支气管哮喘 blockers 28Cardiac glycosides(强心苷强心苷,digitalis,洋地黄）洋地黄）29毛地黄毛地黄Digoxin(地高辛地高辛)ActionsPositiv

21、e inotropic action(正性肌力作用正性肌力作用):-诱导快速敏捷的收缩，延长舒张期，不增加心肌耗氧量诱导快速敏捷的收缩，延长舒张期，不增加心肌耗氧量 -Na+-K+ATPase 抑制剂抑制剂Digitalis30Ca2+iMechanism of digitalis NKANa+i2 K+3 Na+Na+-K+-ATPaseNCENa+-Ca2+exchangeAPK+i31强心苷强心苷 DigoxinActions:Negative chronotropic action负性频率作用负性频率作用 -抑制交感神经活性抑制交感神经活性 -增加迷走神经活性增加迷走神经活性(Ach

22、促进促进 K+efflux)Digitalis32Digoxin ActionsActions on cardiac electrophysiology -降低窦房结自律性降低窦房结自律性(vagal stimulation)-减慢房室传导减慢房室传导(vagal stimulation)-不均一缩短快反应细胞不均一缩短快反应细胞ERP(K+efflux,ERP；大剂量时；大剂量时K+i,舒张电位舒张电位，ERP进一步缩短进一步缩短)-增加普肯耶纤维自律性增加普肯耶纤维自律性(大剂量时大剂量时K+i，舒张电位上抬，舒张电位上抬，自律性自律性 ，Ca2+i,ERP；中毒剂量时中枢交感活动；中毒剂

23、量时中枢交感活动)Digitalis33DigoxinActions对中枢神经系统的作用对中枢神经系统的作用 -D2 receptor activation,emetic effect对神经内分泌的作用对神经内分泌的作用 -inhibits RAAS -increases ANP(心房钠尿肽心房钠尿肽)Digitalis34DigoxinActions对肾脏的作用对肾脏的作用(diuretic effect）-增加肾脏血供增加肾脏血供 -减少减少Na+重吸收重吸收(inhibition of Na+-K+ATP ase)Digitalis35DigoxinClinical uses：CHF(收

24、缩性收缩性 CHF)对对外周阻力增高外周阻力增高的的CHF效果较好效果较好，特别适用于窦特别适用于窦性心律伴房颤或室率快的患者。性心律伴房颤或室率快的患者。对对肺源性心脏病，活动性心肌炎或严重心肌损伤肺源性心脏病，活动性心肌炎或严重心肌损伤疗效疗效较差。较差。不适用于舒张性不适用于舒张性CHF，CHF伴扩张性心肌病和心伴扩张性心肌病和心肌肥厚。肌肥厚。Digitalis36DigoxinClinical uses：某些心律失常某些心律失常 -心房颤动心房颤动:抑制抑制A-V传导，降低心室率传导，降低心室率 -心房扑动：转心房扑动为颤动心房扑动：转心房扑动为颤动 -阵发性室上性心动过速阵发性室上

25、性心动过速 Digitalis37DigoxinDirections：负荷剂量法负荷剂量法loading method:loading dose(洋地黄化洋地黄化)+maintaining dose维持剂量法维持剂量法：maintaining dose everydayDigitalis38Effect of Digoxin on Mortality in Heart FailureDIG(Digitalis Investigation Group):6,800 patients with LVEF 45%randomized to digoxin(n=3,403)or placebo(n=3

26、,397)in addition to therapy with diuretics and ACEI followed for 37 months.The DIGITALIS Investigation Group.N Engl J Med.1997;336:525532.39DigoxinAdverse reactions：胃肠道反应：胃肠道反应：severe nausea,vomit,diarrhea中枢神经系统反应：中枢神经系统反应：-alteration of color perception(chromatopsia，色视，色视)-headache,dizziness,insomn

27、ia,fatigue,delirium谵妄谵妄 Digitalis40DigoxinAdverse reactions：心脏反应心脏反应 -arrhythmias：tachycardia atrioventricular block sinus bradycardiaDigitalis41Symptoms to stop digitalis administration：-Severe vomit -Chromatopsia -Ventricular premature -Heart rate 80 yo Women men Multisystem disease diabetes,thyro

28、id,liver Perioperative period Major trauma Electrolyte imbalance Metabolic acidosis Hypoxia Infection Large quantities of grapefruit juice(1 qt./day)Alcohol abuse Drug interactions72Jacobson TA.Expert Opin Drug Saf 2003;2:269-86Davidson MH.Am J Cardiol 2002;90(suppl):50K-60KStatinsCholesterol absorp

29、tion inhibitors73 Ezetimibe(依折麦布依折麦布)Resins(cholestyramine,考来烯胺；考来烯胺；colestipol，考来替泊，考来替泊)Ezetimibe Mechanisms and effects:Blocks cholesterol absorption at the intestinal brush border Reduces LDL 74Ezetimibe 18 1 8Resins 15-30 3-5 /NeutralFibrates 5-20 10-35 20-50Statins 18-60 5-15 7-30Niacin 5-25 1

30、5-35 20-50Expert Panel on the Detection,Evaluation,and Treatment of High Blood Cholesterol in Adults.JAMA.2001;285:2486-2497.LDL-C HDL-C TGDrug class (%)(%)(%)75Ezetimibe Mechanisms and effects:No effect on absorption of lipid-soluble vitamins Interruption of enterohepatic circulation(肝肠循环肝肠循环)Minim

31、al systemic exposure and very well tolerated Additive in combination with statins 1-STEP COADMINISTRATION3-STEP TITRATION%Reduction in LDL-C5%-6%5%-6%Statin starting dose1st2nd3rd5%-6%Statin starting dose+Zetia10 mg15%-18%Doubling Mechanisms:-Binds to bile acid in the intestines,interrupting enteroh

32、epatic circulation and increasing fecal excretion-LDL receptors Efficacy:LDL 15-30%76Resins 77Indications:-High LDL -Can be used to relieve pruritis in patients who have cholestasis胆汁淤积 and bile salt accumulation;and/or to relieve diarrhea in post-cholecystectomy patients-May be useful in digitalis

33、toxicity.Resins Adverse effects:-Constipation,bloating,indigestion,nausea,large doses may impair absorption of fats(脂肪痢)or fat soluble vitamins(A,D,E,and K)-Affect absorption of other drugs,should be given 1 hour before the resin or 4 hours after.78Gemfibrozil（吉非贝齐）（吉非贝齐）Fenofibrate（非诺贝特）（非诺贝特）Benza

34、fibrates（苯扎贝特）（苯扎贝特）Fibrates Mechanisms Act as PPAR ligands(peroxisome proliferator-activated receptor-,过氧化物酶体增殖物激活受体过氧化物酶体增殖物激活受体)a nuclear receptor that regulates lipid metabolism and glucose homeostasis FA oxidation in muscle and liver Apo CIII(key to VLDL catabolism).lipoprotein lipase,clearance

35、 of VLDL,VLDL production Antioxidant,anti-proliferation and anti-inflammation effects79Fibrates Efficacy:TG 40-55%,HDL 10-25%,LDL 10%Indications:High TG and/or low HDL Adverse effects:Rashes,GI upset,gallstones(increase biliary cholesterol saturation)Use with caution in pts with biliary tract diseas

36、e hepatic or renal dysfunction Increase risk of statin-induced myopathy Displaces warfarin from plasma albumin since drug is highly protein bound.80Fibrates Nicotinic acid and Acipimox81 Nicotinic acid(烟酸烟酸,Vitamin B3)Acipimox(阿昔莫司阿昔莫司)Nicotinic Acidapo B-100apo Capo E VLDL VLDLRemnant LDLLiverDecre

37、ased VLDLProductionOther sitesIncreased VLDLclearance through LPL Mechanisms -Suppress synthesis of VLDL,IDL,&LDL in the liver.-Increase clearance of VLDL via the LPL pathway,TG catabolism -May HDL catabolism82Nicotinic acid and Acipimox Efficacy:TC 25%,LDL 10-25%,HDL 10-40%,TG 20-50%Indications:Hig

38、h LDL(and/or VLDL)Combined hyperlipidemia(including low levels of HDL-Niaspan,approved for elevating HDL levels)Adverse effects:Flushing(very uncomfortable,aspirin may helpful)Pruritis,rashes,dry skin Nausea and abdominal discomfort83 Rare hepatotoxicity Hyperuricemia(occurs in about 1/5 of pts,occa

39、sionally precipitates gout)Reversible carbohydrate tolerance may be moderately impaired(hyperglycemia)Related to elevated risk of cardiovascular eventsNicotinic acid and AcipimoxProbucol(普罗布考普罗布考)Action:Taken up by LDL particles and endothelial cells,inhibits oxidation of LDL and prevents ingestion

40、by macrophage foam cells,decreases HDL production.Effects:1)decreases atherosclerotic plaque formation;2)small reduction in serum LDL;3)greater reduction of serum HDL.Clinical uses:may be used in combination therapy with other drugs that lower serum LDL.Disadvantages:not effective in single drug the

41、rapy;no long term clinical data.84Antioxidants EPA,DHA(-3 PUFAs)Reduce plasma TG Only highly purified preparation(96%).Risk in increasing LDL-C(more strongly associated wih coronary artery diseases)The effects on cardiac morbidity or mortality is unproven(although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)85Polyunsaturated fatty acids 86http:/circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.short?rss=1&%3bssource=mfr