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1、Part 4Drugs for Treatment of Congestive Heart Failure,Contents,Overview ACE inhibitors Diuretics ? receptor blockers Cardiac glycoside Others,Heart (cardiac) failure is said to have occurred when the heart is

2、no longer able to maintain the circulation to the tissues for normal metabolism.,1. Pathophysiological changes of congestive heart failure (CHF)(1) Function and structure changes(2) Increased sympathetic activity a

3、nd down-regulation of ? receptor(3) Activated renin-angiotensin-aldosterone system (RAAS),A. Overview,,,Pathophysiological changes of CHF,,,,Pathophysiological changes of CHF,Cardiac failure,Cardiac output,V

4、enous pressure,Venous hyperemia,Pulmonary circulation:cough, emptysis, dyspnea,Systemic circulation hyperemia :jugular vein distension, edema,,,,,Blood supply,Renal blood flow,Renin - angiotension Ⅱ,,Aldosterone,,Sodi

5、um and waterretention,,,,,,,,,,,,,,,,,Changes in hemodynamics of CHF,,,A. Overview,2. Grades of CHF Ⅰ(A): no symptoms Ⅱ(B): physical activities were limited and symptoms could be induced by general activit

6、y Ⅲ(C): physical activities were markedly limited Ⅳ(D): symptoms appear even at rest,3. Therapeutic strategies in CHF(1) Increasing contractility of the cardiac muscles(2) Inhibiting RAAS (3) Reducin

7、g sympathetic activity (4) Dilating vessels(5) Diuresis,,A. Overview,? Cardiacremodeling,Decreaseoverload,,,,,,,,,,Drug therapy for CHF,ACEI: captopril 卡托普利 enalapril 依那普利AT1 receptor antago

8、nists: losartan 氯沙坦 irbesartan 伊白沙坦,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,,,Cardiovascular remodeling,vasodilatation,,Systemic and local,ACEI1. Phar

9、macological effectsInhibiting the production of Ang II vasoconstriction ?; sodium retention ?; cardiac remodeling (myocardial hypertrophy) ?Inhibiting the degradation of bradykinin

10、 vasodilatation ?Increasing ANP and scavenging free radicals,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,Box Actions of angiotensin II through activating AT1 r

11、eceptorsConstricting vessels, increase peripheral resistance and returned blood volume.Increasing sympathetic tension, promote release of sympathetic transmitter.Stimulating release of aldosterone.Rapidly inducing

12、expression of c-fos, c-jun, Egr-1, c-myc, etc.,Cardiovascular effects Decrease resistance of peripheral vessels Dilate coronary artery, increase blood supply of heart and kidney, improve cardiac and renal functi

13、on Reverse myocardial hypertrophy and ventricular remodeling,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensi

14、n receptor antagonists,2. Clinical uses(1) CHF increase motor tolerance decrease mortality(2) Hypertension,,3. Adverse effects HypotensionCough and angioedemaHyperpotassemia Rashes and altered ta

15、stesContraindications: pregnancy and stenosis of renal artery,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,AT1 receptor antagonistsCompared with ACEI:Blocking actions of a

16、ngiotensin II directlyNot affecting bradykinin metabolismProtecting renal functionUsed for CHF and hypertension,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,1. Pharmacologic

17、al effects Reduce blood volume by increasing Na+ and water excretionReduce Na+-Ca2+ exchange in vascular smooth muscle cells2. Clinical usesCHF: grand I – IV (mainly used in II –III), alone or combined with other d

18、rugs Edema, hypertension, etc.3. Adverse effects imbalance of electrolytes/acid-base; plasma level of renin ?; hypokalemia; hyperuricemia; hyperglycemia/hyperlipidemia,C.

19、Diuretics,,Therapeutic effects of diuretics in CHF,Main diuretics,Thiazides,,Loop diuretics,,K+ sparing diuretics,,Commonly used: carvedilol 卡維地洛, bisoprolol 比索洛爾, sustained-release metoprolol 緩釋型美托洛爾 1. Pharmacolo

20、gical effects(1) Blocking effects of catecholamines on myocardium: decreasing heart rate and cardiac oxygen demand(2) Up-regulating ? receptor(3) Inhibiting RAAS and VP (vosopressin, 加壓素): anti- myocardial hypertroph

21、y and remodeling (4) Reducing cardiac oxygen remand, vasodilatation (? receptor block)(5) Anti-arrhythmic and anti-hypertensive effects,D. ? receptor blockers,2. Clinical uses(1) CHF: grand II - III

22、 decreasing mortality(2) Other uses: hypertension, arrhythmias, angina, etc.,D. ? receptor blockers,Therapeutic effects of ? receptor antagonists on cardiac function in CHF patients,D. ? receptor block

23、ers,3. Adverse effectsInhibition of cardiac functionContraindications: severe heart failure severe A-V block hypotension worsening bronchial asthma,D. ? receptor bloc

24、kers,E. Cardiac glycoside (digitalis),Cardiac glycoside : It is a kind of glycoside compounds which can selectively act on cardiac muscle, and increase the force of myocardial contraction.,Digoxin 地高辛,E. Cardiac glyco

25、side (digitalis),,1. Pharmacological effects(1) Positive inotropic effects inhibiting Na+-K+-ATPase ? free Ca2+ ? ? excitation-contraction coupling ? cardiac output ? ? organ blood supply ? Vma

26、x ? ? diastolic duration ? ? venous return ? ? coronary blood supply ? cardiac oxygen consumption ?,E. Cardiac glycoside (digitalis),Inhibition of

27、Na+-K+-ATPase by digitalis and potentiation of cardiac muscle contraction,,,,,(2) Negative chronotropic effects Reflex inhibition of sympathetic activity cardiac output ? ? Sympathetic activity ? ? HR ?Increasin

28、g vagal activity directly Reducing AV conduction: ventricular rate ?,E. Cardiac glycoside (digitalis),(3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction, especial

29、ly AV conduction increasing automaticity of Purkinje fibres shortening ERP of fast response cellsMechanisms: intracellular Na+ ?, K+ ?, Ca2+ ?? ? MDP ?, afterdepolar

30、ization,E. Cardiac glycoside (digitalis),Overdose:Na+ ?, K+ ?, Ca2+ ? ? ? MDP ?? afterdepolarization,Electrophysiological basis for digitalis overdose,ECG: P-R ?; S-T/T wave ?; various arrhythmias,,,,P-R ?,S-T/T wave

31、 ?,prematural ventricular beat,(4) Other effectsVessels: vasoconstriction Central nervous system: CTZ dopamine D2 receptor mental and vision disordersKidney increase blood supply of kidney

32、diuretic effect: decrease Na+ reabsorption,E. Cardiac glycoside (digitalis),2. Clinical uses(1) Congestive heart failure (CHF) especially associated with atrial fibrillation and sinus tachycardia(2) Arrhythmias

33、 atrial fibrillation / atrial flutter: paroxysmal surpraventricular tachycardia,E. Cardiac glycoside (digitalis),3. Adverse effects(1) Gastrointestinal effects nausea, vomiting, etc.(2) CNS effects

34、 alteration of color perception（色視, such as yellow vision 黃視）; headache, fatigue, confusion, etc.,E. Cardiac glycoside (digitalis),(3) Cardiac toxicity arrhythmias：prematural beats, tachycardia， atrioventric

35、ular block, sinus bradycardia, etc.Prevention：Dose individualization Avoiding provocation factors: plasma K+ ?, and drug interactions, etc.Treatment： KCl, phenytoin or lidocaine, i.v.

36、 Atropine: A-V block, sinus bradycardia Fab segment of digoxin antibody, i.v.,E. Cardiac glycoside (digitalis),Drug interactions that probably induce digitalis cardiotoxi

37、city,4. Administration(1) Loading + maintaining dosesfull dose (digitalization) + maintaining dosesfor severe patients(2) Maintaining dose given daily reaching steady state of plasma concentration with 1 wee

38、k (digoxin) for stable patients,E. Cardiac glycoside (digitalis),5. ADME and properties of different digitalis drugs(1) Moderate-acting: digoxin 地高辛(2) Long-acting：digitoxin 洋地黃毒苷

39、 digitalization + maintaining doses(3) Short-acting：deslanoside 西地蘭, 去乙酰毛花苷 acute attack of CHF,E. Cardiac glycoside (digitalis),,,,,1. ? receptor agonists dobutamin

40、e 多巴酚丁胺Positive inotropic drugsArrhythmias, etc.2. PDE-III inhibitors milrinone 米力農(nóng), vesnarinone 維司力農(nóng)， amrinone 安力農(nóng)Positive inotropic drugsHypotension, thrombocytopenia, etc.,F. Other drugs,3. Vasodilat