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1、Part 4 Drugs 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 no longer able to maintain the circulation to the tissues for normal metabolism.,1. Pathophy
2、siological changes of congestive heart failure (CHF) (1) Function and structure changes (2) Increased sympathetic activity and down-regulation of receptor (3) Activated renin-angiotensin-aldosterone system (RAAS),A. Overview,Pathophysiological changes of CHF,Pathophysiological changes of CHF,Cardiac
3、 failure,Cardiac output,Venous pressure,Venous hyperemia,Pulmonary circulation: cough, emptysis, dyspnea,Systemic circulation hyperemia : jugular vein distension, edema,Blood supply,Renal blood flow,Renin - angiotension ,Aldosterone,Sodium and water retention,Changes in hemodynamics of CHF,A. Overvi
4、ew,2. Grades of CHF (A): no symptoms (B): physical activities were limited and symptoms could be induced by general activity (C): physical activities were markedly limited (D): symptoms appear even at rest,3. Therapeutic strategies in CHF (1) Increasing contractility of the cardiac muscles (2) Inhib
5、iting RAAS (3) Reducing sympathetic activity (4) Dilating vessels (5) Diuresis,A. Overview, Cardiac remodeling,Decrease overload,Drug therapy for CHF,ACEI: captopril 卡托普利 enalapril 依那普利 AT1 receptor antagonists: losartan 氯沙坦 irbesartan 伊白沙坦,B. Angiotensin converting enzyme inhibitors (ACEI) and angi
6、otensin receptor antagonists,Cardiovascular remodeling,vasodilatation,Systemic and local,ACEI 1. Pharmacological effects Inhibiting the production of Ang II vasoconstriction ; sodium retention ; cardiac remodeling (myocardial hypertrophy) Inhibiting the degradation of bradykinin vasodilatation Incre
7、asing ANP and scavenging free radicals,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,Box Actions of angiotensin II through activating AT1 receptors Constricting vessels, increase peripheral resistance and returned blood volume. Increasing sympathetic tension
8、, promote release of sympathetic transmitter. Stimulating release of aldosterone. Rapidly inducing 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 re
9、nal function Reverse myocardial hypertrophy and ventricular remodeling,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,2. Clinical uses (1) CHF increase motor tolerance dec
10、rease mortality (2) Hypertension,3. Adverse effects Hypotension Cough and angioedema Hyperpotassemia Rashes and altered tastes Contraindications: pregnancy and stenosis of renal artery,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,AT1 receptor antagonists Co
11、mpared with ACEI: Blocking actions of angiotensin II directly Not affecting bradykinin metabolism Protecting renal function Used for CHF and hypertension,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,1. Pharmacological effects Reduce blood volume by increasi
12、ng Na+ and water excretion Reduce Na+-Ca2+ exchange in vascular smooth muscle cells 2. Clinical uses CHF: grand I IV (mainly used in II III), alone or combined with other drugs Edema, hypertension, etc. 3. Adverse effects imbalance of electrolytes/acid-base; plasma level of renin ; hypokalemia; hype
13、ruricemia; hyperglycemia/hyperlipidemia,C. Diuretics,Therapeutic effects of diuretics in CHF,Main diuretics,Thiazides,Loop diuretics,K+ sparing diuretics,Commonly used: carvedilol 卡维地洛, bisoprolol 比索洛尔, sustained-release metoprolol 缓释型美托洛尔 1. Pharmacological effects (1) Blocking effects of catechola
14、mines on myocardium: decreasing heart rate and cardiac oxygen demand (2) Up-regulating receptor (3) Inhibiting RAAS and VP (vosopressin, 加压素): anti- myocardial hypertrophy and remodeling (4) Reducing cardiac oxygen remand, vasodilatation ( receptor block) (5) Anti-arrhythmic and anti-hypertensive ef
15、fects,D. receptor blockers,2. Clinical uses (1) CHF: grand II - III 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 blockers,3. Adverse effects Inhibition of
16、cardiac function Contraindications: severe heart failure severe A-V block hypotension worsening bronchial asthma,D. receptor blockers,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 myocar
17、dial contraction.,Digoxin 地高辛,E. Cardiac glycoside (digitalis),1. Pharmacological effects (1) Positive inotropic effects inhibiting Na+-K+-ATPase free Ca2+ excitation-contraction coupling cardiac output organ blood supply Vmax diastolic duration venous return coronary blood supply cardiac oxygen con
18、sumption ,E. Cardiac glycoside (digitalis),Inhibition of 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 Increasing vagal activity directly Reducing AV conduct
19、ion: ventricular rate ,E. Cardiac glycoside (digitalis),(3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction, especially AV conduction increasing automaticity of Purkinje fibres shortening ERP of fast response cells Mechanisms: intracellular Na+ , K+ , Ca2+ MDP
20、 , afterdepolarization,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 ,prematural ventricular beat,(4) Other effects Vessels: vasoconstriction Central ner
21、vous system: CTZ dopamine D2 receptor mental and vision disorders Kidney increase blood supply of kidney diuretic effect: decrease Na+ reabsorption,E. Cardiac glycoside (digitalis),2. Clinical uses (1) Congestive heart failure (CHF) especially associated with atrial fibrillation and sinus tachycardi
22、a (2) Arrhythmias atrial fibrillation / atrial flutter: paroxysmal surpraventricular tachycardia,E. Cardiac glycoside (digitalis),3. Adverse effects (1) Gastrointestinal effects nausea, vomiting, etc. (2) CNS effects alteration of color perception（色视, such as yellow vision 黄视）; headache, fatigue, co
23、nfusion, etc.,E. Cardiac glycoside (digitalis),(3) Cardiac toxicity arrhythmias：prematural beats, tachycardia， atrioventricular block, sinus bradycardia, etc. Prevention：Dose individualization Avoiding provocation factors: plasma K+ , and drug interactions, etc. Treatment： KCl, phenytoin or lidocain
24、e, i.v. Atropine: A-V block, sinus bradycardia Fab segment of digoxin antibody, i.v.,E. Cardiac glycoside (digitalis),Drug interactions that probably induce digitalis cardiotoxicity,4. Administration (1) Loading + maintaining doses full dose (digitalization) + maintaining doses for severe patients (
25、2) Maintaining dose given daily reaching steady state of plasma concentration with 1 week (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 洋地黄毒苷 digitalization + maintaining d
26、oses (3) Short-acting：deslanoside 西地兰, 去乙酰毛花苷 acute attack of CHF,E. Cardiac glycoside (digitalis),1. receptor agonists dobutamine 多巴酚丁胺 Positive inotropic drugs Arrhythmias, etc. 2. PDE-III inhibitors milrinone 米力农, vesnarinone 维司力农， amrinone 安力农 Positive inotropic drugs Hypotension, thrombocytopenia, etc.,F. Other drugs,3. Vasodilators cardiac preload and afterload , output 4. Calcium channel blocker 5. Calcium sensitizers,F. Other drugs,Action modes of positive inotropic drugs,Therapeutic strategies of CHF,