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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 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 and 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,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 waterretention,Changes in hemodynamics of CHF,A. Overview,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) Inhibiting RAAS (3) Reducing 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 antagonists: 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. Pharmacological effectsInhibiting the production of Ang II vasoconstriction ; sodium retention ; cardiac remodeling (myocardial hypertrophy) Inhibiting the degradation of bradykinin 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 receptorsConstricting vessels, increase peripheral resistance and returned blood volume.Increasing sympathetic tension, 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 renal 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 decrease mortality(2) Hypertension,3. Adverse effects HypotensionCough and angioedemaHyperpotassemia Rashes and altered tastesContraindications: pregnancy and stenosis of renal artery,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,AT1 receptor antagonistsCompared with ACEI:Blocking actions of angiotensin II directlyNot affecting bradykinin metabolismProtecting renal functionUsed for CHF and hypertension,B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists,1. Pharmacological 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 drugs Edema, hypertension, etc.3. Adverse effects imbalance of electrolytes/acid-base; plasma level of renin ; hypokalemia; hyperuricemia; 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 catecholamines 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 effects,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 effectsInhibition of cardiac functionContraindications: 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 myocardial 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 consumption ,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 conduction: 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 cellsMechanisms: intracellular Na+ , K+ , Ca2+ MDP , 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 effectsVessels: vasoconstriction Central nervous system: CTZ dopamine D2 receptor mental and vision disordersKidney 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 tachycardia(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, confusion, 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 lidocaine, 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 dosesfull dose (digitalization) + maintaining dosesfor severe patients(2) Maintain