Part 4
Drugs for Treatment of
Congestive Heart Failure
Contents
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.
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Overview
ACE inhibitors
Diuretics
 receptor blockers
Cardiac glycoside
Others
A. Overview
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)
Pathophysiological
changes of CHF
Pathophysiological changes of CHF
Cardiac failure
Cardiac output
Blood supply
Venous pressure
Venous hyperemia
Renal blood flow
Renin - angiotension Ⅱ
Aldosterone
Pulmonary
circulation:
cough, emptysis,
dyspnea
Systemic circulation
hyperemia :
jugular vein
distension, edema
Sodium and water
retention
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 activity
III (C): physical activities were markedly limited
IV (D): symptoms appear even at rest
A. Overview
3. Therapeutic strategies in CHF
(1) Increasing contractility of the cardiac muscles
(2) Inhibiting RAAS
 Cardiac
(3) Reducing sympathetic activity
remodeling
(4) Dilating vessels
(5) Diuresis
Decrease
overload
Drug therapy for CHF
B. Angiotensin converting enzyme
inhibitors (ACEI) and angiotensin
receptor antagonists
ACEI:
captopril 卡托普利
enalapril 依那普利
AT1 receptor antagonists:
losartan 氯沙坦
irbesartan 伊白沙坦
Systemic and local
vasodilatation
Cardiovascular remodeling
B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
ACEI
1. Pharmacological effects
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Inhibiting the production of Ang II
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vasoconstriction ;
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cardiac remodeling (myocardial hypertrophy) 
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sodium retention ;
Inhibiting the degradation of bradykinin
vasodilatation 
Increasing ANP and scavenging free radicals
Box Actions of angiotensin II
through activating AT1 receptors
• Constricting 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.
B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
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Cardiovascular effects
Decrease resistance of peripheral vessels
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Dilate coronary artery, increase blood supply
of heart and kidney, improve cardiac and renal
function
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Reverse myocardial hypertrophy and
ventricular remodeling
B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
2. Clinical uses
(1) CHF
increase motor tolerance
decrease mortality
(2) Hypertension
B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
3. Adverse effects
Hypotension
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Cough and angioedema
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Hyperpotassemia
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Rashes and altered tastes
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Contraindications: pregnancy and stenosis of
renal artery
B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
AT1 receptor antagonists
Compared with ACEI:
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Blocking actions of angiotensin II directly
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Not affecting bradykinin metabolism
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Protecting renal function
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Used for CHF and hypertension
C. Diuretics
1. Pharmacological effects
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Reduce blood volume by increasing Na+ and water excretion
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Reduce Na+-Ca2+ exchange in vascular smooth muscle cells
2. Clinical uses
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CHF: grand I – IV (mainly used in II –III), alone or
combined with other drugs
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Edema, hypertension, etc.
3. Adverse effects
imbalance of electrolytes/acid-base;
plasma level of renin ; hypokalemia;
hyperuricemia; hyperglycemia/hyperlipidemia
Therapeutic effects of
diuretics in CHF
D.  receptor blockers
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): antimyocardial 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 effects
 Inhibition of cardiac function
 Contraindications:
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severe heart failure
severe A-V block
hypotension
worsening bronchial asthma
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.
E. Cardiac glycoside (digitalis)
Digoxin
地高辛
E. Cardiac glycoside (digitalis)
1. Pharmacological effects
(1) Positive inotropic effects
inhibiting Na+-K+-ATPase  free Ca2+   excitationcontraction coupling 
cardiac output   organ blood supply 
Vmax   diastolic duration   venous return 
 coronary blood supply 
cardiac oxygen consumption 
Inhibition of Na+-K+-ATPase by digitalis and
potentiation of cardiac muscle contraction
E. Cardiac glycoside (digitalis)
(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 cells
Mechanisms:
intracellular Na+ , K+ , Ca2+  
MDP , afterdepolarization
Overdose:
Na+ , K+ , Ca2+  
 MDP 
 afterdepolarization
Electrophysiological basis for digitalis overdose
P-R 
S-T/T wave 
prematural ventricular beat
ECG: P-R ; S-T/T wave ; various arrhythmias
E. Cardiac glycoside (digitalis)
(4) Other effects
Vessels: vasoconstriction
Central nervous 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
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.
Drug interactions
that probably
induce digitalis
cardiotoxicity
E. Cardiac glycoside (digitalis)
4. Administration
(1) Loading + maintaining doses
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full dose (digitalization) + maintaining doses
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for severe patients
(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 doses
(3) Short-acting：deslanoside 西地兰, 去乙酰毛花苷
acute attack of CHF
F. Other drugs
1.  receptor agonists
dobutamine 多巴酚丁胺
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Positive inotropic drugs
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Arrhythmias, etc.
2. PDE-III inhibitors
milrinone 米力农, vesnarinone 维司力农，
amrinone 安力农
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Positive inotropic drugs
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Hypotension, thrombocytopenia, etc.
F. Other drugs
3. Vasodilators
cardiac preload and afterload , output 
4. Calcium channel blocker
5. Calcium sensitizers
Action modes of positive inotropic drugs
Therapeutic strategies of CHF