《心力衰竭知识》ppt课件

1、Chapter 26Anti-congestive heart failure drugsLNMU PharmacologyChronic or Congestive Heart Failure，CHF CHF occurs when the cardiac output is inadequate to provide the oxygen needed by the body. The key defect in CHF is a decrease in cardiac contractility, resulting in inadequate cardiac outputThe Cau

2、ses of Heart Failure Population-attributable risk,%010203040506070MaleFemale60393410115864475Hyper-Myo- Angina Diabetes LV heart Valvulartensioncardial hyper- heartinfarction trophy diseaseThe characterizations of CHFDecrease in cardiac contractility, inadequate cardiac output.Intravascular volume e

3、xpansion and ventricular filling pressures, systemic and pulmonary hypertentension, dyspnea呼吸困难.Activation of sympathetic nervous and RASMyocardial dysfunction.Ventricular remodeling.Ventricular remodeling after acute infarctionVentricular remodeling in diastolic舒张 and systolic收缩 heart failureInitia

4、l infarctExpansion of infarct(hours to days)Global remodeling(days to months)Normal heartHypertrophied heart(diastolic heart failure)Dilated heart(systolic heart failure)Myocardial remodeling in Calcineurin transgenic hearts(Cell, Vol 93, 215-228,1998)Heart failureReduced cardiac outputSympathetic n

5、ervous system activationVasoconstrictionElevated cardiac filling pressureSodium and water retentionAngiotensin ReninCardiac remodelingAldosteroneAngiotensinPathophysiological mechanisms of heart failure and major sites of drug actiondigoxin -blockers, digoxinVasodilatorsACE inhibitorsAngiotensin-R b

6、lockersDiureticsSpironolactoneClassification of drugs used in CHF1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) ang receptor blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, furosemide3. -receptor blocker Metoprolol, carvedilo

7、l4. positive inotropic agents(1)Cardiac glycosides digoxin, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside sodium6.calcium sensitizer and calcium channel blockers amlodipineSection IIInhibitors of renin-angiotensin-aldosterone system (RAAS)Renin-Angiotensin

8、System(RAS) angiotensinogenreninAngiotensin糜酶旁路ACEAngiotensin AT1receptor1. vasoconstriction, aldosterone：BP2. hypertrophyandproliferation cardiovascularremodeling Kallikrein-KininSystem(KKS) kininogenase Bradykinin 降解产物AT2receptorNO , part fight AT1receptorVasodilation, BPACEI()The composition and

9、physiologicalrole of RASAT1 Blockerspironolactone angiotensin-converting enzyme inhibitor，ACEI: captopril, enalapril angiotensin receptor (AT1) blocker, ARB: losartan氯沙坦 antagonist for the aldosterone receptor: spironolactoneThe classification of Inhibitors RAAS1. ACEI卡托普利captopril开搏通依那普利enalapril悦宁

10、定赖诺普利lisinopril 帝益洛苯那普利benazepril 洛丁新 /诺华福辛普利fosinopril 蒙诺/施贵宝喹那普利quinapril益恒雷米普利ramipril 瑞泰培哚普利perindopril雅施达西拉普利cilazapril 一平苏药 物起始剂量目标剂量卡托普利6. 25 mg，tid50 mg，tid依那普利2. 5 mg，bid1020 mg，bid福辛普利510 mg/d 40 mg/d赖诺普利2. 55 mg/d 3035 mg/d培哚普利2 mg/d48 mg/d喹那普利5 mg，bid20 mg，bid雷米普利2. 5 mg/d5 mg，bid 或10 mg

11、/d西拉普利0. 5 mg/d12. 5 mg/d苯那普利2. 5 mg/d510 mg，bid治疗慢性心衰的ACEI及其剂量The mechanism for anti-congestive heart failure effect1. peripheral vascular resistance, cardiac afterload 2. aldosterone 3. myocardial and ventricular remodeling4. changes of hemodynamics 5. the activity of sympathetic nervous systemACE

12、I1.peripheral vascular resistance, cardiac afterloadACEI内皮衍生超极化因子(Endothelium Derived Hyperpolarizing Factor) 5. antisympathetic effectAT1 receptor in presynaptic membrane of sympathetic nerve NA AT1 receptor in adrenal medella NA AT1 receptor in CNScentral sympathetic impulse transmission heart loa

13、d and damageACEI1) The salt and water retention 2) The preload and afterload3) The long-term remodeling of the heart and vessels Mortality and morbidityTherapeutic applicationsCHFHypertensionClinical using:ACEI AT1 blocker, ARB 氯沙坦(losartan)缬沙坦(valsartan)厄贝沙坦(irbesartan)坎地沙坦(candesartan)依普沙坦(eprosar

14、tan)替米沙坦(telmisartan)Renin-AngiotensinSystem(RAS) angiotensinogenreninAngiotensin糜酶旁路ACEAngiotensin AT1receptor1. vasoconstriction, aldosterone：BP2. hypertrophyandproliferation cardiovascularremodeling Kallikrein-KininSystem(KKS) kininogenase Bradykinin 降解产物AT2receptorNO , part fight AT1receptorVaso

15、dilation, BPThe composition and physiologicalrole of RASARBSection III Diuretics High-efficacy diuretics (loop diuretics)Furosemide Moderate-efficacy diuretics Thiazides; Low-efficacy diureticsSpironolactone；They can promote the loss of sodium and water from the body and provide a reduction in prelo

16、ad and afterload.Cardiogenic edema relieve the symptoms mild CHF Thiazides moderate CHFThiazides + SpironolactoneIf it fails or for the serious CHFloop diuretics；But Cautions: A large dose diureticscardiac output; sympathetic nerve activityaldosterone and hypokalemia. Coadministration with spironola

17、ctone Diuretics Section IV -receptor blocker 1. Drugs acting on -receptor (1) Carvedilol , -receptor blocker . (2) Metoprolol1-receptor blockerPharmacological effectsInhibition of sympathetic activity catecholaminesCa2+ infux myocardial necrosismyocardial remodelingreninangiotensinup-regulating R se

18、nsitivity of R to catecholaminesAnti-arrhythmic and anti-ischemic effects-R blockerTherapeutic applications Mild and moderate CHF Dilated cardiomyopathy心肌病 CHF, ischemic CHF Improve symptoms and decrease mortality Combination with diuretics and ACEI The medication should be initiated with low doses.

19、-R blockerBronchospasm, bradycardia and hypotensionOthers: depression, nightmares, fatigue, and sexual dysfunction; asthma; masking hypoglycemic symptoms Adverse Effects-R blockerClassification of drugs used in CHF1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) ang receptor

20、blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, furosemide3. -receptor blocker Metoprolol, carvedilol4. positive inotropic agents(1)Cardiac glycosides digoxin, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside s

21、odium6.calcium sensitizer and calcium channel blockers amlodipineHeart failureReduced cardiac outputSympathetic nervous system activationVasoconstrictionElevated cardiac filling pressureSodium and water retentionAngiotensin ReninCardiac remodelingAldosteroneAngiotensinPathophysiological mechanisms o

22、f heart failure and major sites of drug actiondigoxin -blockers, digoxinVasodilatorsACE inhibitorsAngiotensin-R blockersDiureticsSpironolactoneDigitoxin 洋地黄毒苷Digoxin 地高辛 Deslanoside 毛花苷丙Strophantin K 毒毛花苷KSection V Cardiac glycosides甾核Steroid 不饱和内酯环Lactone ring三分子洋地黄毒糖 tri-digitoxose (苷元的作用强度和时间Chem

23、ical structure of Digoxin 苷元aglycone(正性肌力)C3 、C14) OH；C17具构型。否那么苷元失去强心作用。OOOOHOHCH3HCH3HC18H31O531417BACDEffects of cardiac glycosides on heart(a highly selective for heart) 1. Positive inotropic action(1) Cardiac glycosides the maximum force the contractility of cardiac muscle the velocity of cardi

24、ac muscle contraction diastole relative extension 强 心 苷Anti-congestive heart failure drugsCHF patients: Cardiac glycosides cardiac output cardiac filling pressures heart size and venous and capillary pressures. (2) Cardiac output 强 心 苷Anti-congestive heart failure drugsIn normal individuals: contrac

25、tility myocardial minute oxygen consumption (MVO2) .b. In patients with CHF: ventricular volume MVO2.(3) Myocardial oxygen consumption 强 心 苷Anti-congestive heart failure drugsMyocardial oxygen consumptionventricular pressure(afterload)ventricular volume(preload) contractility heart rate ventricular

26、wall tension O2 demand 强 心 苷Anti-congestive heart failure drugsInhibit the membrane-bound Na+-K+-ATPase .Inhibition of Na+-K+-ATPase results in intracellular accumulation of Na+(and loss of intracellular K+).Accumulation of intracellular Na+ slight movement of extracellular Ca2+ into the cell second

27、ary to activation of a membrane Na+-Ca2+ carrier.The mechanism for positive inotropic effect Digoxin may interfere with the ability of the sarcoplasmic reticulum to bind Ca2+ making more Ca2+ available for interaction with contractile proteins Ca2+ positive inotropic effect说教学过程Na+Ca2+K+intracellula

28、rextracellularNKANCE 强 心 苷 Anti-congestive heart failure drugsNKA: Na+-K+-ATPaseNCE: Na+-Ca2+ exchangerThe mechanism for positive inotropic effect说教学过程 强 心 苷Anti-congestive heart failure drugsCICR: Calcium induced calcium releaseCa2+Ca2+i与AP和心肌收缩的关系The mechanism for positive inotropic effectThe mech

29、anism for positive inotropic effectCardiac glycosidesMLCK: Myosin light chain kinase肌球蛋白轻链激酶SERCA: Sarco-endoplasmic Reticulum Calcium Atpase肌浆网钙泵SOCE: store-operated calcium entry channels钙池支配钙离子通道RYR: Ryanodine receptor兰尼碱受体 强 心 苷Anti-congestive heart failure drugs 强心苷 Na+-K+ -ATPase Na+-K+ 交换Cell

30、内Na+短暂 C内Na+ 超负荷， 失K+ 影响Na+ - Ca2+ 交换机制 Ca2+超负荷 异位节律点 自律性 Na+ 外流，Ca2+内流 迟后去极 Na+ 内流，Ca2+外流 C内 Ca2+ i 心律失常 正性肌力治疗量中毒量CICRCICR: Calcium induced calcium release说教法HRMechanism：A：COactivating vagus nerve B：sensitivity of vagusSignificance：负性频率心动周期舒张期 心室充盈好 心肌本身供血 心肌获充分休憩心功能改善Effects of cardiac glycosides

31、 on heart2. Negative chronotropic action 强 心 苷Anti-congestive heart failure drugs窦房结自律性房室传导心房ERP浦肯野纤维自律性，ERP、传导与添加迷走神经活性有关3. Electrophysiological effects抑制Na+-K+-ATP酶0 -50If , Ik and Na+-Ca2+ exchangeCa2+ channelK+ channel添加迷走神经活性Ca2+内流房室传导房扑转为房颤a. therapeutic dose3. Electrophysiological effects 强 心

32、 苷Anti-congestive heart failure窦房结细胞KAch开放频率K+外流静息期膜电位多负自律性窦性频率K+外流心房ERP缩短0 -50If , Ik and Na+-Ca2+ exchangeCa2+ channelK+ channel 促K+外流 心房肌静息电位加大 零相除极速度 心房传导速度 ()Na+-K+-ATP酶K+i最大舒张电位少负接近阈电位自律性；c. toxic doseb. high dose提高普氏纤维自律性Central sympathetic activityCa2+i；ERP中毒时室速或室颤的机制 强 心 苷Anti-congestive he

33、art failure drugsK+外流ERP最大舒张电位除极发生在较小的膜电位 强 心 苷Anti-congestive heart failure drugs电生理 特性窦房结心房房室结浦肯野纤维自律性传导性ERP与添加迷走神经活性有关抑制Na+-K+-ATP酶是强心苷引起室早、室性心律失常的缘由之一治疗房颤、房扑使房扑转为房颤3. Electrophysiological effectsWith more toxic concentration, resting membrane potential is reduced as a result of inhibition of the

34、 sodium pump and reduced intracellular potassium.Glycosides toxicity: atrioventricular junctional rhythm, premature ventricular depolarization, bigeminal rhythm, and atrioventricular blockade.3. Electrophysiological effectsRegulation of neuroendocrine activity-Parasympathomimetic effectsAt lower dos

35、e: mainly affects atrial and atrioventricular nodal function.-Sympathomimetic effectsAt overdose, enhance the activity of sympathetic nervous centre.Anorexia厌食, nausea and vomiting, headache, fatigue, . -RAASrenin activity; Ag; aldosterone 强 心 苷Anti-congestive heart failure drugs1) Effects on vascul

36、ar In normal individuals: peripheral vascular resistance (direct action)In patients with CHF: peripheral vascular resistance (indirect action)2) Effects on kidney A diuretic effect.cardiac function improvementinhibition of kidney tubular Na+-K+-ATPaseExtracardiac effects 强 心 苷Anti-congestive heart f

37、ailure drugsPharmacokinetics Serum Principal Absorption Protein Therapeutic MetabolicDrugs (Per os) Binding T1/2 Concentration RouteDigoxin 6085% 25% 36h 0.52.0ng KidneyDigitoxin 90100% 97% 57d 1035ng/ml Liver 强 心 苷Anti-congestive heart failure drugsTherapeutic usesCHF 强 心 苷Anti-congestive heart fai

38、lure drugs2. Arrhythmias:1.心房纤颤：350-600次/分f波 强心苷迷走兴奋房室传导 房室结隐匿性传导心室率 2.心房扑动：240-430次/分F波 强心苷心房ERP扑动变颤抖心室率；有些病人在停用强心苷后可恢复为窦性节律 3.阵发性室上性心动过速：迷走兴奋现已少用)房扑房颤fff 强 心 苷Anti-congestive heart failure drugsDrug actions and doses 1. Action vs Effect or Response2. Pharmacological effects and doseslethaltoxic max. effectivemin. effective submedicalTherapeutic or medical doseUntowar