Chapter 31 Drugs for Treatment of Congestive Heart Failure

Contents Overview § Overview § Cardiac glycoside § Diuretics § ACE inhibitors §  receptor blockers § Others

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

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 Ⅱ Aldosterone Sodium and water retention Changes of hemodynamics in CHF

A. Overview 2. Grades of CHF Ⅰ (A): no symptoms Ⅱ (B): physical activities were limited and symptoms could be induced by general activity Ⅱ (B): physical activities were limited and symptoms could be induced by general activity Ⅲ (C): physical activities were markedly limited Ⅲ (C): physical activities were markedly limited Ⅳ (D): symptoms appear even at rest Ⅳ (D): symptoms appear even at rest

3. Therapeutic strategies in CHF (1) Increasing contractility of the cardiac muscles (2) Inhibiting RAAS (3) Decrease sympathetic activity (4) Dilating vessels (5) Diuresis A. Overview  Cardiac remodeling Decreaseoverload

B. Digitalis Digoxin 地高辛

1. Pharmacological effects (1) Positive inotropic effects inhibiting Na + -K + -ATPase, free Ca 2+   excitation- contraction coupling  inhibiting Na + -K + -ATPase, free Ca 2+   excitation- contraction coupling  cardiac output   organ blood supply  cardiac output   organ blood supply  Vmax   diastolic duration   venous return  Vmax   diastolic duration   venous return   coronary blood supply   coronary blood supply  cardiac oxygen consumption  cardiac oxygen consumption  B. 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  cardiac output   Sympathetic activity   HR  Increasing vagal activitydirectly Increasing vagal activity directly B. Digitalis

(3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction slow conduction increasing automaticity of Purkinje fibres increasing automaticity of Purkinje fibres shortening ERP of fast response cells shortening ERP of fast response cellsMechanisms: intracellular Na + , K + , Ca 2+   intracellular Na + , K + , Ca 2+   MDP , afterdepolarization MDP , afterdepolarization

Overdose: Na + , K + , Ca 2+    MDP   afterdepolarization Electrophysiological basis for digitalis overdose

(4) Other effects Nervous system autonomic nervous system: NE  central nervous system: CTZ D 2 receptor central nervous system: CTZ D 2 receptor Neuroendocrine system inhibiting RAAS inhibiting RAAS increasing ANP （心房钠尿肽） increasing ANP （心房钠尿肽） Kidney Kidney increase blood supply of kidney increase blood supply of kidney diuretic effect: decrease Na + resorption diuretic effect: decrease Na + resorption B. Digitalis

2. Clinical uses (1) CHF especially associated with atrial fibrillation and sinus tachycardia especially associated with atrial fibrillation and sinus tachycardia (2) Arrhythmias atrial fibrillation atrial flutter atrial flutter paroxysmal surpraventricular tachycardia paroxysmal surpraventricular tachycardia

B. Digitalis 3. Adverse effects (1) Gastrointestinal effects nausea, vomiting, etc. nausea, vomiting, etc. (2) CNS effects alteration of color perception （色视, such as yellow vision 黄视） ; headache, fatigue, confusion, etc.

B. 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. Avoiding provocation factors: plasma K + , and drug interactions, etc. Treatment ： KCl, phenytoin sodium or lidocaine, i.v. Atropine: A-V block, sinus bradycardia Atropine: A-V block, sinus bradycardia Fab segment of digoxin antibody, i.v. Fab segment of digoxin antibody, i.v.

Drug interactions that probably induce digitalis cardiotoxicity

4. Administration (1) Loading + maintaining doses §full dose (digitalization) + maintaining doses §for severe patients (2) Maintaining dose given daily reaching steady state of plasma concentration with 1 week (digoxin) reaching steady state of plasma concentration with 1 week (digoxin) for stable patients for stable patients B. 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 doses digitalization + maintaining doses (3) Short-acting ： deslanoside 西地兰, 去乙酰毛花苷 acute attack of CHF acute attack of CHF

Different elimination modes of digoxin and digitoxin

1. Pharmacological effects §Reduce plasma volume §Reduce Na + -Ca 2+ exchange in vessel 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 plasma level of renin  hypokalemia plasma level of renin  hypokalemia hyperuricemia hyperglycemia hyperuricemia hyperglycemia hyperlipidemia hyperlipidemia C. Diuretics

Therapeutic effects of diuretics in CHF

ACEI: captopril 卡托普利 captopril 卡托普利 enalapril 依那普利 enalapril 依那普利 AT 1 receptor antagonists: losartan 氯沙坦 losartan 氯沙坦 irbesartan 伊白沙坦 irbesartan 伊白沙坦 D. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

ACEI 1. Pharmacological effects §Inhibiting the production of Ang II § vasoconstriction  ; sodium retention  ; § cardiac remodeling (myocardial hypertrophy)  §Inhibiting the degradation of bradykinin § vasodilatation  §Increasing ANP and scavenge free radicals D. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

Angiotensin II Angiotensin I ACE Circulation and local tissues ACEI ACE (—)(—) B 2 receptor PGI 2 NO ACEI (—)(—) brandykinin Inactive peptide Vasodilatation Anti-proliferation, anti-hypertrophy Actions of ACEI

Box Actions of angiotensin II Constricting vessels, increase peripheral resistance and returned blood volume.Constricting vessels, increase peripheral resistance and returned blood volume. Increasing sympathetic tension, promote release of sympathetic transmitter.Increasing sympathetic tension, promote release of sympathetic transmitter. Stimulating release of aldosterone.Stimulating release of aldosterone. Inducing expression of c-fos 、 c-myc 、 c-jun rapidly.Inducing expression of c-fos 、 c-myc 、 c-jun rapidly.

§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 D. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

2. Clinical uses (1) CHF increase motor tolerance increase motor tolerance decrease mortality decrease mortality (2) Hypertension

3. Adverse effects Hypotension Hypotension §Cough and angioedema §Hyperpotassemia §Contraindications: pregnancy and stenosis of renal artery D. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

AT 1 receptor antagonists Compared with ACEI: §Blocking actions of angiotensin II directly §Not influencing bradykinin metabolism §Protecting renal funtion §Used for CHF and hypertension D. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

Conmmonly used: Carvedilol 卡维地洛, labetalol 拉贝洛尔 Carvedilol 卡维地洛, labetalol 拉贝洛尔 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) Blocking  -receptor and anti- free radical (5) Anti-arrhythmic and anti-hypertensive effects E.  receptor blockers

2. Clinical uses (1) CHF: grand II - III decrease of mortality decrease of mortality (2) Other uses: hypertension, arrhythmias, angina, etc. hypertension, arrhythmias, angina, etc. E.  receptor blockers

Therapeutic effects of β receptor antagonists on cardiac function in CHF patients E.  receptor blockers

3. Adverse effects §Inhibition of cardiac function §Contraindications: § severe heart failure severe A-V block severe A-V block hypotension hypotension bronchial asthma bronchial asthma E.  receptor blockers

1. PDE-III inhibitors milrinone 米力农, vesnarinone 维司力农， amrinone 安力农 amrinone 安力农 §Positive inotropic drugs §Hypotension, thrombocytopenia, etc. 2.  receptor agonists dobutamine 多巴酚丁胺 dobutamine 多巴酚丁胺 §Positive inotropic drugs §Arrhythmias, etc. F. Other drugs

3. Vasodilators cardiac preload and afterload , output  cardiac preload and afterload , output  4. Calcium channel blocker 5. Calcium sensitizers F. Other drugs

Action modes of positive inotropic drugs

Ⅳ ⅢⅡ grads strategies Low Na + thiazides Loop diuretics combined Dilator Positive inotropic drugs Limit Na + Digitalis Limit activity  blockers ACEI Therapeutic strategies of CHF