心力衰竭知識(shí)

1、Chapter 26Anti-congestive heart failure drugs,,,,LNMU Pharmacology,Chronic 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

2、 CHF is a decrease in cardiac contractility, resulting in inadequate cardiac output,The Causes of Heart Failure,,The characterizations of CHF,Decrease in cardiac contractility, inadequate cardiac output.Intravascular vo

3、lume expansion and ventricular filling pressures↑, systemic and pulmonary hypertentension, dyspnea呼吸困難.Activation of sympathetic nervous and RASMyocardial dysfunction.Ventricular remodeling.,,Ventricular remodeling af

4、ter acute infarction,Ventricular remodeling in diastolic舒張 and systolic收縮 heart failure,Initial infarct,Expansion of infarct(hours to days),Global remodeling(days to months),Normal heart,Hypertrophied heart(diastolic

5、heart failure),Dilated heart(systolic heart failure),Myocardial remodeling in Calcineurin transgenic hearts(Cell, Vol 93, 215-228,1998),Heart failure,Reduced cardiac output,Sympathetic nervous system activation,Vasoco

6、nstriction,Elevated cardiac filling pressure,Sodium and water retention,Angiotensin Ⅰ,Renin,Cardiac remodeling,Aldosterone,AngiotensinⅡ,Pathophysiological mechanisms of heart failure and major sites of drug action,,,,,

7、,,,,,,,,,,,,,digoxin,β -blockers, digoxin,Vasodilators,ACE inhibitors,Diuretics,Spironolactone,Classification of drugs used in CHF,1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) angⅡ recepto

8、r blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, furosemide3. ?-receptor blocker Metoprolol, carvedilol4. positive inotropic agents(1)Cardiac glycosides digoxin

9、, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside sodium6.calcium sensitizer and calcium channel blockers amlodipine,Section IIInhibitors of renin-angiotensin-aldosterone s

10、ystem (RAAS),Renin-Angiotensin System (RAS),angiotensinogen,,renin,AngiotensinⅠ,,糜酶旁路,ACE,Angiotensin Ⅱ,AT1receptor,1.  vasoconstriction, aldosterone↑：BP↑2.  hypertrophy and proliferation

11、 cardiovascular remodeling,,,Kallikrein-Kinin System (KKS),kininogenase,,Bradykinin,,降解產(chǎn)物,,,AT2receptor,,NO ↑, part fight AT1receptor,,Vasodilation, BP↓,,ACEI,,(—),The composition and physiological

12、60;role of RAS,,,,,,,AT1 Blocker,,,,spironolactone,,,,① Ⅰ angiotensin-converting enzyme inhibitor，ACEI: captopril, enalapril② Ⅱ angiotensin receptor (AT1) blocker, ARB: losartan氯沙坦③ Ⅲ antagonist for the aldosterone re

13、ceptor: spironolactone,The classification of Inhibitors RAAS,1. ACEI,卡托普利（captopril）（開(kāi)搏通）依那普利（enalapril）（悅寧定）賴諾普利（lisinopril） （帝益洛）苯那普利（benazepril （洛丁新 /諾華）福辛普利（fosinopril） （蒙諾/施貴寶）喹那普利（quinapril）（益恒）雷米普利（ramipril

14、） （瑞泰）培哚普利（perindopril）（雅施達(dá)）西拉普利（cilazapril） （一平蘇）,治療慢性心衰的ACEI及其劑量,The mechanism for anti-congestive heart failure effect,1. ↓peripheral vascular resistance, ↓cardiac afterload 2. ↓aldosterone 3. ↓myocardial and v

15、entricular remodeling4. changes of hemodynamics 5. ↓the activity of sympathetic nervous system,,ACEI,1.↓peripheral vascular resistance, ↓cardiac afterload,,ACEI,內(nèi)皮衍生超極化因子(Endothelium Derived Hyperpolarizing Factor)

16、,5. antisympathetic effect,↓AT1 receptor in presynaptic membrane of sympathetic nerve→ ↓NA ↓AT1 receptor in adrenal medella→ ↓NA ↓AT1 receptor in CNS→↓central sympathetic impulse transmission → ↓heart load and damag

17、e,,ACEI,1) The salt and water retention↓ 2) The preload and afterload↓3) The long-term remodeling of the heart and vessels↓ ﹡Mortality and morbidity↓↓,Therapeutic applications,CHFHypertension,Clinical using:

18、,,ACEI,AT1 blocker, ARB,氯沙坦(losartan)纈沙坦(valsartan)厄貝沙坦(irbesartan)坎地沙坦(candesartan)依普沙坦(eprosartan)替米沙坦(telmisartan),Renin-Angiotensin System (RAS),angiotensinogen,,renin,AngiotensinⅠ,,糜酶旁路,ACE,Angiotensi

19、n Ⅱ,AT1receptor,1.  vasoconstriction, aldosterone↑：BP↑2.  hypertrophy and proliferation cardiovascular remodeling,,,Kallikrein-Kinin System (KKS),kininogenase,,Bradykinin,,降解產(chǎn)物,,

20、,AT2receptor,,NO ↑, part fight AT1receptor,,Vasodilation, BP↓,,The composition and physiological role of RAS,ARB,,,,,↑,Section III Diuretics,High-efficacy diuretics (loop diuretics)Furosemide Moderate-efficacy

21、diuretics Thiazides; Low-efficacy diureticsSpironolactone；They can promote the loss of sodium and water from the body and provide a reduction in preload and afterload.,Cardiogenic edema relieve the symptoms mil

22、d CHF← Thiazides moderate CHF←Thiazides + SpironolactoneIf it fails or for the serious CHF←loop diuretics；But Cautions: A large dose diuretics↓cardiac output; ↑sympathetic nerve activity↑aldosterone and hypokalemi

23、a. ← Coadministration with spironolactone,Diuretics,Section IV ?-receptor blocker,1. Drugs acting on ?-receptor (1) Carvedilol— α, ?-receptor blocker . (2) Metoprolol－?1-receptor blocker,Pharmacological effects,

24、Inhibition of sympathetic activity catecholamines↓→Ca2+ infux↓→ myocardial necrosis↓myocardial remodeling↓renin↓→angiotensin↓up-regulating βR↓ sensitivity of βR to catecholaminesAnti-arrhythmic and anti-ischemic e

25、ffects,?-R blocker,Therapeutic 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 initi

26、ated with low doses.,?-R blocker,Bronchospasm, bradycardia and hypotensionOthers: depression, nightmares, fatigue, and sexual dysfunction; asthma; masking hypoglycemic symptoms,Adverse Effects,?-R blocker,,Classificatio

27、n of drugs used in CHF,1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) angⅡ receptor blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, fur

28、osemide3. ?-receptor blocker Metoprolol, carvedilol4. positive inotropic agents(1)Cardiac glycosides digoxin, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside sodium6.calc

29、ium sensitizer and calcium channel blockers amlodipine,Heart failure,Reduced cardiac output,Sympathetic nervous system activation,Vasoconstriction,Elevated cardiac filling pressure,Sodium and water retention,Angiotens

30、in Ⅰ,Renin,Cardiac remodeling,Aldosterone,AngiotensinⅡ,Pathophysiological mechanisms of heart failure and major sites of drug action,,,,,,,,,,,,,,,,,,digoxin,β -blockers, digoxin,Vasodilators,ACE inhibitors,Diuretics,Spi

31、ronolactone,,Digitoxin 洋地黃毒苷Digoxin 地高辛 Deslanoside 毛花苷丙Strophantin K 毒毛花苷K,Section V Cardiac glycosides,,甾核Steroid,不飽和內(nèi)酯環(huán)Lactone ring,三分子洋地黃毒糖 tri-digitoxose (↑苷元的作用強(qiáng)度和時(shí)間）,Chemical structure of Digoxin,,苷元agl

32、ycone(正性肌力),（C3 、C14) –OH；C17具β構(gòu)型。否則苷元失去強(qiáng)心作用。,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,3,14,17,B,A,C,D,,,,,Effects of cardiac glycosides on heart(a highly selective for heart),1. Positive inotropic action(1) Cardiac glycosides

33、 → the maximum force↑→ the contractility of cardiac muscle↑ →the velocity of cardiac muscle contraction↑→ diastole relative extension↑,CHF patients: Cardiac glycosides → cardiac output↑→ cardiac filling pressures↓ →

34、heart size↓ and venous and capillary pressures↓.,(2) Cardiac output↑,,In normal individuals: contractility ↑→ myocardial minute oxygen consumption (MVO2) ↑.b. In patients with CHF: ventricular volume ↓→ MV

35、O2↓.,(3) Myocardial oxygen consumption,Myocardial oxygen consumption,ventricular pressure(afterload),ventricular volume(preload),contractility,heart rate,ventricular wall tension,,,,O2 demand,,,,,Inhibit the membrane-

36、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

37、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

38、with contractile proteins → Ca2+ ↑ → positive inotropic effect,說(shuō)教學(xué)過(guò)程,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Na+Ca2+K+,,,,,intracellular,extracellular,NKA,NCE,×,NKA: Na+-K+-ATPaseNCE: Na+-Ca

39、2+ exchanger,The mechanism for positive inotropic effect,說(shuō)教學(xué)過(guò)程,,,,×,CICR: Calcium induced calcium release,,Ca2+,,,[Ca]2+i與AP和心肌收縮的關(guān)系,The mechanism for positive inotropic effect,The mechanism for positive inotropic e

40、ffect,Cardiac glycosides,MLCK: Myosin light chain kinase肌球蛋白輕鏈激酶,SERCA: Sarco-endoplasmic Reticulum Calcium Atpase肌漿網(wǎng)鈣泵,SOCE: store-operated calcium entry channels鈣池操縱鈣離子通道,RYR: Ryanodine receptor蘭尼堿受體,,,,強(qiáng)心苷 ↓

41、 ↓Na+-K+ -ATPase ↓ Na+-K+ 交換↓Cell內(nèi)Na+短暫↑ C內(nèi)Na+ 超負(fù)荷， 失K+ ↓ ↓ ↓ 影響Na+ - Ca2+ 交換機(jī)制 Ca2+超負(fù)荷 異位節(jié)律點(diǎn)↓

42、 ↓ 自律性↑ Na+ 外流↑，Ca2+內(nèi)流↑ 遲后去極 Na+ 內(nèi)流↓，Ca2+外流↓ ↓ C內(nèi)[ Ca2+] i ↑ 心律失常 ↓ 正性肌力,,,,治療

43、量,中毒量,,,CICR,CICR: Calcium induced calcium release,說(shuō)教法,HR↓,,Mechanism：A：CO↑→activating vagus nerve B：↑sensitivity of vagusSignificance：負(fù)性頻率→心動(dòng)周期↑→舒張期↑→ 心室充盈好 心肌自身供血↑ 心肌獲充分休息,心

44、功能改善,,,Effects of cardiac glycosides on heart,2. Negative chronotropic action,↓竇房結(jié)自律性↓房室傳導(dǎo)↓心房ERP↑浦肯野纖維自律性，↓ERP、傳導(dǎo),與增加迷走神經(jīng)活性有關(guān),,3. Electrophysiological effects,抑制Na+-K+-ATP酶,,增加迷走神經(jīng)活性,→Ca2+內(nèi)流↓→房室傳導(dǎo)↓,→房撲轉(zhuǎn)為房顫,a. therapeu

45、tic dose,3. Electrophysiological effects,→竇房結(jié)細(xì)胞KAch開(kāi)放頻率↑→K+外流↑→靜息期膜電位↑（多負(fù)）→自律性↓→竇性頻率↓,→K+外流↑→心房ERP縮短,,促K+外流↑ → 心房肌靜息電位加大 → 零相除極速度↑ → 心房傳導(dǎo)速度↑,(—)Na+-K+-ATP酶→[K+]i↓→最大舒張電位↓（少負(fù)）→接近閾電位→自律性↑；,c. toxic dose,b. high dose（提高普氏纖維

46、自律性）,→Central sympathetic activity↑,[Ca2+]i↑；ERP↓（中毒時(shí)室速或室顫的機(jī)制）,K+外流↓→ERP↓,最大舒張電位↓→除極發(fā)生在較小的膜電位,,與增加迷走神經(jīng)活性有關(guān),抑制Na+-K+-ATP酶,是強(qiáng)心苷引起室早、室性心律失常的原因之一,治療房顫、房撲,使房撲轉(zhuǎn)為房顫,3. Electrophysiological effects,With more toxic concentration,

47、 resting membrane potential is reduced as a result of inhibition of the sodium pump and reduced intracellular potassium.Glycosides toxicity: atrioventricular junctional rhythm, premature ventricular depolarization, big

48、eminal rhythm, and atrioventricular blockade.,3. Electrophysiological effects,Regulation of neuroendocrine activity,--Parasympathomimetic effectsAt lower dose: mainly affects atrial and atrioventricular nodal function.

49、--Sympathomimetic effectsAt overdose, enhance the activity of sympathetic nervous centre.Anorexia厭食, nausea and vomiting, headache, fatigue, …. --RAASrenin activity↓; AgⅡ↓; aldosterone↓,1) Effects on vascular In no

50、rmal individuals: peripheral vascular resistance (direct action)In patients with CHF: peripheral vascular resistance (indirect action)2) Effects on kidney A diuretic effect.cardiac function improvementinhibiti

51、on of kidney tubular Na+-K+-ATPase,,,,Extracardiac effects,Pharmacokinetics,Serum Principal Absorption Protein Therapeutic MetabolicDrugs (Per os) Binding T1

52、/2 Concentration RouteDigoxin 60～85% 25% 36h 0.5～2.0ng KidneyDigitoxin 90～100% 97% 5～7d 10～35ng/ml Liver,,,,Therapeutic uses—CHF,2. Arrhythmias:,1.心房纖顫：350-600次/分（f波） 強(qiáng)心苷→迷走興

53、奮↑→房室傳導(dǎo)↓→ 房室結(jié)隱匿性傳導(dǎo)↑→心室率↓ 2.心房撲動(dòng)：240-430次/分（F波） 強(qiáng)心苷→↓心房ERP→撲動(dòng)變顫動(dòng)→心室率↓；有些病人在停用強(qiáng)心苷后可恢復(fù)為竇性節(jié)律 3.陣發(fā)性室上性心動(dòng)過(guò)速：迷走興奮↑（現(xiàn)已少用),房撲,Drug actions and doses,1. Action vs Effect or Response2. Pharmacological e

54、ffects and doses,Untoward effects,(1) Cardiac effects,(a) Premature ventricular beats and ventricular tachycardia and fibrillation(b) A-V block (c) Sinus bradycardia (<60 bpm),Some factors evoking toxicit

55、y,HypokalemiaHypomagnesemiaHypercalcemiaMyocarditis心肌炎Myocardial anoxia缺氧Acid base imbalanceRenal insufficiency,Treatment of untoward effects,A. digoxin and potassium-depleting diuretics are discontinued.B. Potass

56、ium chloride; C. Phenytoin.D. Lidocaine.E. Atropine.F. Digoxin-specific antibody fragment (Fab) :,(2) Anorexia, nausea and vomiting (often the earliest sign) (3) Headache, vision change, including abnormal col

57、or perception (often yellow or green vision).,1.明確中毒癥狀，停藥指征;（心電圖監(jiān)測(cè)） 2.血藥濃度監(jiān)測(cè):地高辛>3ng/ml,洋地黃毒苷>45ng/ml --停藥;3.注意藥物相互作用： 排鉀利尿藥：低血鉀— 加重毒性，注意補(bǔ)鉀； 鈣阻滯劑、胺碘酮、普羅帕酮抑制地高辛經(jīng)腎小管分泌—減量；奎尼丁能自組織置換地高辛 肝藥酶誘導(dǎo)劑 苯妥英鈉--清除↑

58、--血藥濃度↓ 擬腎上腺素藥--心肌對(duì)強(qiáng)心苷敏感性↑,【中毒預(yù)防措施】,Non-Cardioglycoside Positive Inotropic Drugs,1. PDE inhibitors. ?cAMP ↑→ Ca2+↑ →a positive inotropic effect ?vasodilation: direct action 1) Milrinone 米力農(nóng) 2) Vesna

59、rinone 維司力農(nóng) They have not been shown to reduce survival in placebo-controlled trials.,2. ?1-selective adrenoceptor agonist,Dobutamine多巴酚丁胺Ibopamine異布帕明Increase mortalityNot for regular use in CHF,Section VI Vasodi

60、lators,Effective in CHF because they provide a reduction in preload, or reduction in afterload, or both.Nitroprusside sodium: rapid afterload decrease, acute severe CHF.,3. Calcium channel blokers,AmlodipineFelodipine

61、They are effective arterial vasodilators and reduce the afterload of heart.Reduce HR, facilitating diastolic relaxation and lowering diastolic filling pressures. Not for routine use in CHF.,PDEI,PDEI,利尿藥,心力衰竭治療建議概要（20