Transcript Drugs treating congestive heart failure

Treatment of congestive heart failure
Overview of congestive heart failure
Congestive heart failure (CHF) is a condition in which the heart is
unable to pump sufficient blood to meet the needs of body. CHF can be
increased workload imposed on the heart. CHF is accompanied by
abnormal increases in blood volume and interstitial fluid; the heart,
veins, and capillaries are therefore generally dilated with blood. Hence
the term “congestive(充血性)” heart failure, since the symptoms include
pulmonary congestion with life heart failure, and peripheral edema with
right heart failure. Underlying causes of CHF include arteriosclerotic
heart disease, hypertensive heart disease, valvular heart disease(心瓣
膜病), dilated cardiomyopathy(扩张性心肌病), and congenital heart
disease(先天性心脏病). Left systolic dysfunction secondary to
coronaryartery disease is the most common cause of heart failure.
Heart Failure
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Final common pathway for many
cardiovascular diseases whose natural
history results in symptomatic or
asymptomatic left ventricular dysfunction
Cardinal manifestations of heart failure
include dyspnea, fatigue and fluid retention
Risk of death is 5-10% annually in patients
with mild symptoms and increases to as
high as 30-40% annually in patients with
advanced disease
Main causes

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


Coronary artery disease
Hypertension
Valvular heart disease (心瓣膜病)
Cardiomyopathy (心肌病)
Cor pulmonale
Compensatory changes in
heart failure
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Activation of SNS
Activation of RAS
Increased heart rate
Release of ADH
Release of atrial natriuretic peptide心钠素
Chamber enlargement 心室腔扩大
Myocardial hypertrophy 心室肥厚
Classification of heart
failure
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Class I: No limitation of physical
activity
Class II: Slight limitation of physical
activity
Class III: Marked limitation of physical
activity
Class IV: Unable to carry out physical
activity without discomfort
New classification of
heart failure
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Stage A: Asymptomatic with no heart
damage but have risk factors for heart
failure
Stage B: Asymptomatic but have signs
of structural heart damage
Stage C: Have symptoms and heart
damage
Stage D: End stage disease
ACC/AHA guidelines, 2001
CHF的病理生理过程及可能治疗的环节
心功能障碍
正性肌力药
收缩功能
舒张功能
改善舒张功能药
输出量
心率
长期病情
血管收缩
阻抗
顺应性
后负荷
心肌1受体
神经激素
RAA
CA
心缩
力
顺应
性
抗RAA系统药
减后负荷药
血管肥厚、重构
恢复心血管病理形态的药
受体阻断药
钠水潴留
利尿药
心肌肥大、重构
血容量
前负荷
静脉淤血
减前负荷药
Strategy of treatment of CHF
The therapeutic goal for CHF is to increase
cardiac output.
1)
Inotropic agents that increase the strength of
contraction of cardiac muscle
2)
PDEI (phosphodiesterase inhibitors) agents that
increase cAMP to induce systoles and vasodilatation
3)
Calcium sensitizers extracellular fluid volume
4)
 adrenergic agonist
5)
 adrenergic antagonist
6)
Vasodilators: Calcium channel blocker
7)
Decreasing RAS activity: ACEI and AT1 antagonist
8)
Diuretic agents
Treatment of congestive heart failure
Classification
1 Positive inotropic drugs
 Cardiac glycosides
 β-adrenergic agonists (New dopamine receptor agonist)
 phosphodiesterase inhibitors
 Calcium sensitizers
2 Diuretics
3 Vasodilators
 Calcium channel blocker
 Nitryl-vasodilators
 Hydralazine
4 RAAS inhibitors: antiotensin converting enzyme inhibitor
and AT1 antagonist
5 β-receptor blocker
Classification1 Positive inotropic drugs
Cardiac glycosides/强心苷类
structure-activity relationship
A cardiac glycoside molecule consists of
an aglycone苷元 or genin配基, which
possesses the same pharmacologic
activity as the whole molecule
combined chemically with one or more
sugars.
Cardiac glycosides
Aglycones
Digitoxin
= H at 12 C
Digoxin = OH at 12 C
苷元
CH3
3A
O
C18 H31O9
CH3
12
17
D
C
OH
B
H
O
Unsaturated lactone
不饱和内酯环
Convey cardiotonic
activity
O
steroid nucleus
甾核
Sugars- 3 mols. of digitoxose
3分子洋地黄毒糖
Modulate potency and
pharmacokinetic distribution
Convey the
pharmacological
activity
1. The relationship between structure and effects
CH3
C3
A
O
C18 H31O9
B
CH3
C
12
17
D
C
O
C14
OH
O
H
The Indispensable
parts of activity
The number of -OH and glycose
will decide water-solubility and lipid-solubility
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活性基团activity ：C17 不饱和内酯环Unsaturated lactone 、C14羟基OH、C3 洋地黄毒糖digitoxose
脂溶性lipid-solubility： C3 洋地黄毒糖；水溶性water-solubility ：C12及其他位点的羟基数
Classification of cardiac
glycosides
1. grade 1: in plant, cedilanide
2. grade 2: extract of digitalis
Digitoxin（洋地黄毒苷）, Digoxin（地高辛）,
Deslanoside （旋花毛地黄苷）, Strophanthin K
（毒毛旋花子苷K)
3.地高辛和洋地黄毒苷C3位均联结3个洋地黄毒糖，
地高辛C12位多一个羟基，毒毛花苷K的甾核上有多
个羟基，所以脂溶性：洋地黄毒苷>地高辛>毒毛
花苷K。
Process of drug through body
Drug
Absorption Protein- Heptoe Biotran Kidney
T1/2
rate (%)
binding nteral- sformat excretion
(%)
circulati ion (%) (%)
on (%)
digitoxin
90~100
97
27
30~70
10
5~7 day
digoxin
60~85
<30
6.8
5~10
60~90
33~36 h
Cedilanide
20~40
5
Few
Quite
few
90~100
33 h
5
Few
0
90~100
12~19 h
Strophanthin 2~5
K
Pharmacologic action
I. Action of cardiac glycosides on the heart
1.Positive inotropic action：Increasing
contractility of cardiac muscle in heart
failure.
(1) characteristic:
A.myocardiac quick contraction, Q-T period↓
①rate of force ↑
②time to peak tension ↓
B. no increase oxygen consumption： the
increase in output is not accompanied by
an equivalent increase in oxygen
consumption
Factors of oxygen consumption：
1）Myocardia contractility
2）Heart rate
3）Myocadiac fiber length and tone
Factors affect consumption of
oxygen
I. The force of cardiac contraction
II. Heart rate
III. Volume of ventricular
C. Effect of positive inotropic act
① cardiac output is increased
② compensatory sympathetic tone is reduced
③ cardiac preload and afterload is decreased
④ heart rate is reduced
⑤ myocardiac fiber tone and oxygen consumption
is decreased
⑥ increasing stroke volume causes a decrease in
end-systolic volume
(2) Machanism of cardiac glycoside on
positive inotropic action
A. Inhibiting Na+-K+-ATPase in
therapeutic dose:
B. Increasing of calcium inward and
induce the releasing of calcium from
sarcoplasmic reticulum ( internal stores,
by CICR)
Mechanism of pharmacological act
Na+-K+-ATPase is a recetor of glycoside
↓
glycoside → α
↓
↓
β
Structure changes
↓
Enzyme activity ↓
↓
Na+↑, K+↓ in cell
↓
Ca2+Na+exchange↓ in cell)
→
Na+  i
Na+-K+-ATPase is the receptor of cardiac glycosides , so
cardiac glycosides act by inhibiting the membrane Na+-K+ATPase pump →  Na+  i
→by Na＋/Ca 2+exchanger
→ Ca2+ i↑
Bidirectional exchange
① Na+ enter ↓ → Ca2+ ↓ outer
② Na+ outer ↑→Ca2+ ↑ enter
→ Ca 2+ i↑
Sarcoplasmic reticulum
Ca2+ -induced Ca2+ release
Sarcoplasmic reticulum release Ca 2+
Enhance the increased cytosolic calcium concentration
2.Negative chronotropic action
A. Continuous effect of positive inotropic
action
decreasing sinus rate
heart rate is decreased
B. Increasing sensibility of myocardia to
vagus nerve (increasing of potassium
outward and resting potential, reducing
of automaticity).
Heart rate is decreased,
Atropine can antagonize (block)
3. Affects of glycosides to
conductive tissues
A. Increasing conduction of the atrial muscle
fibers, because increasing excitation of
vagus nerve (increasing of potassium
outward).
Increasing resting potential.
Elevating rate of phase-0 depolarization.
Acceleration rate of depolarization phase-0
and atrial fibers conduction.
B. Slowing (depress) conduction at the
atrioventricular (A-V) node (inhibiting
Na-K-ATPase, reducing resting
potential), and increase effctive
refractory period
atrial fibrillation, atrial flutter,
paroxymal (and) or supraventricular
tachycardia
C. Increasing automaticity of
Purkinjie fibres： toxicity
Mechanism of toxicity act
A.
B.
If Na+-K+-ATPase was inhibited more
than 30%, cardiac glycosides would
induce toxicity by the overload of
intercellular free calcium concentration in
myocardiac. (decreasing inotropic action)
If intercellular potassium concentration
was lower level, cardiac glycosides would
easily induce toxicity in myocardiac.
(arrhythmia)
4. Affects of cardiac glycasides
to ECG (electrocardiography)
A. Therapeutic dose:
T-wave can become low, flat, isoelectric or
inverted
S-T segment falls below the isoelectric line
P-R interval is lengthened, which is associated
with slower or delayed A-V conduction
Q-T interval is shortened, ERP and APD is
shortened in Purkenje fibers
B. Higher dose: arrhythmias
The affects on ECG
T wave
It is characterized by an
descend ST segment on
the ECG
P-R
Q-T
P-P
II. Action of cardiac glycosides on neural and hormone
Directly inhibit or reflected decrease sympathetic activity
• Exciting increase the vagal activity
• Inhibit RAAS system, promote the excrete of ANP
• cause arrhythmias (toxic doses)
II. Action of cardiac glycosides on vascular and kidney
• Vasoconstriction, increase in peripheral vascular resistance
• Diuretic，increase the blood flow through kidney and inhibit
Na+-K+-ATPase → Na＋ decreased re-absorb
Clinical uses
1. Cardiac glycosides are given for CHF
Effects： Best
go with atrial fibrillation
Better hypertension congenital heart disease
not good
anaemia
lack of vitamin B1
not useful
pericarditis 心包炎
2. Some kinds of arrhythmias
Atrial fibrillation
Atrial flutter
Supraventricular Tachycardia
Toxic effects
1. Responses of stomach-intestines :
Anorexia 厌食, nausea，vomiting ,
Abdominal pain and diarrhoea
2. CNS:
visual disturbaces
3. Arrhythmia:
1) Tachycardia
2)AV block
3)Bradycardia
<60 beat/min
Prophylaxis and treatment of the toxicity
• Clear the signal of toxic and the indication of withdraw
•
Inspect the concentration of digoxin (3ng/ml), digitoxin(45ng/ml)
• If necessary ,potassium supplements and antiarrhythmic drugs
( phenytoin ,lidocaine,atropine )administered
• For severe intoxication ,antibodies specific to cardiac glycosides
are available
Method of administration
• Classical ：whole effect dose
quick or slow
(have use digoxin within two weeks)
The suitable dose to the patients
• Maintain ：4～5 t ½
Digoxin 0.25mg/day , 6～7 day ( t ½ 33～36 hours)
Classification1 Positive inotropic drugs
 -Adrenoceptor agonists
They are used intravenously in CHF emergencies
Example of  -Adrenoceptor agonists :
Dobutamine (多巴酚丁胺)
• Exciting β1 Adrenoceptor → positive inotropic action
→the volume of output↑
• Exciting β2 Adrenoceptor→dilate the vascular →
afterload↓
have benefits within short time
Classification1 Positive inotropic drugs
Phosphodiesterase-Ⅲ inhibitors
Inodilator / inodilating drugs
Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes an
increase in myocardial contractility and vasodilatation
→total peripheral resistance →cardiac output ↑
Examples:
Armirinone（氨力农）: Inhibits the excess product of NO,
TNF and affects the neurohormone, anti-the forming of thrombus
milrinone（米力农）: stronger 20 time
vesnarinone（维司力农）: myocardial contract element’s
the sensitivity to calcium
Classification1 Positive inotropic drugs
Calcium sensitizers
Pimobendan 匹莫苯:
Inhibit PDE Ⅲ ; increase TnC’s sensitivity to calcium
Tn troponin—肌钙蛋白；myosin－肌球蛋白；tropomyosin－原 ；Actin 肌动蛋白
Classification 2 Diuretics
Diuretics inhibit sodium and water retention, →reduce the volume of
blood, →venous pressure and the thus cardiac preload are reduced↓,
increasing the efficiency of the heart as a pump→ cardiac output ↑, so
reduce oedema due to heart failure
Heart failure
• Low-grade
: Thiazides hydrochlorothiazide 氢氯噻嗪
• Higher-grade : Acute left heart failure
loop diuretics --- furosemide 呋塞米（速尿）
Spironolacton 螺内酯
（anti-aldosterone ,keep potassium and diuretics)
Classification 3 Vasodilators
Antiotensin converting enzyme
inhibitor (ACEI) and AT1 antagonist
 Calcium channel blocker
 Nitryl-vasodilators
 Hydralazine

ACEI and AT blocker
bradykinin
aldosterone
Classification 3 Vasodilators
Angiotensin-converting-enzyme inhibitor (ACEI )
Captopril Enalapril
Methanism of anti-CHF:
1) Humour: Inhibit ACE→angiotensin Ⅱ and aldosterone levels↓,
reduce sodium retention, increase bradykinin levels , ANP、
NO、PGI2↑, reduce the release of NA ET and renew the
expression of βreceptor
2) This therefore causes vasodilatation (include coronary artery)
→reduction in peripheral resistance→ increase the cardiac output,
Increase the blood flow of kidney so Improve the function of
kidney
3) Prevent the remodel of the heart
AT1 antiagonists
Losartan （氯沙坦）
The function just like ACEⅠ
It dosen’t influence bradykinin levels
Clinical utilize:
• CHF
•
Protection of kidney
Calcium-channel blockers
Amlodipine 氨氯地平
Vessel
Dilate artery
Dilate the coronary
Alleviate the LV Wall Tension
Others --- Vasodilators
mechanism
Dilatation of the veins→ decreases preload
Dilatation of the artery→ decreases afterload
Decrease the oxygen demand of the heart
Nitrate esters: nitroglycerin , nitroprusside sodium 硝普纳
Hydralazine
Prazosin
肼屈嗪
哌唑嗪
direct dilate the vascular
ɑ- receptor blocker
Classification 4  receptor blocker
Carvedilol 卡维地洛
labetalol 拉贝洛尔
Bisoprolol 比索洛尔
Carvedilol 卡维地洛
mechanism
• Anti RAAS system
• Anti-arrthymias
• Anti-myocardial ischemia
Cardiomyopathy
心肌病
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Good Luck！
二 other action of
cardiac gylcosides
1.
Nerve system
Toxic concentration:enhancing
sympathetic activity
increasing sympathetic impulse of
preganglial and afterganglial fibers,
can cause atrial fibrillation and
ventricular tachycardia.
Therapeutic dose: increasing
parasympathetic center in brain stem
excitation------slowing rate of
heart,inhibiting conduction
2. Effect of cardiac
glycosides to kidney
①increasing renal blood flow and
filtering rate of glomerulus
②competitive antagonism with
aldosterone in proximal tubule
Clinical uses
1. Congestive heart failure
*Depends in part on the cause of the
failure
*Depends in part on the severity of
cardiac damage
A. The best therapeutic effect is the
chronic, low-output form
Such as: heart failure with atrial
fibrillation an rapid heart rate
B. The better therapy is
heart failure caused by hypertension,
heart disease caused by coronary
atherosclerosis
Valvular stenosis(瓣膜狭窄）
Rheumatic valvulitis（风湿性瓣膜炎）
C. No better
Thyrotoxicosis（甲状腺中毒症）
Thyroidism（甲状腺功能亢进）
Serious anemia
Vitamin B deficiency
Advanced valvular stenosis
D. No use
pulmonocardiac disease
activity carditis
serious myocardia injured
(1) Activity rheumatic
(2) other forms of infectious or toxic
myocarditis , pulmonocardiac disease
(3) advanced cardiomyopathy心肌病
(4) badly damaged hearts
cardiopericarditis 心包炎
E. Acute heart failure
Use strophanthin K
iv.
}
cedilanide
2. Atrial fibrillantion
Atrial rate :400~650/min
↓
Ventricular rate ↑
↓
Circulative blood flow ↓
↓
Heart failure
Cardiac gylcosides
↓
ventricular rate ↓
(atrial fibrillation)
↓
Circulative blood flow volume ↑
↓
(relive) sysptoms of heart failure
•In atrial fibrillation, the same vagomimetic
action helps control ventricular rate, thereby
improving ventricular filling and increasing
cardiac output.
•Slowing conduction in A-V node,increasing
concealed conduction（隐匿性传导）,slowing
ventricular rate.
Concealed conduction

The impulses arriving at the AV node
are rapid and random in time. Most of
these impulses either fail to enter the
AV node because it is refractory or
propagate only partway through it and
give rise to the phenomenon of
concealed conduction.
3. Atrial flutter
atrial rate : 320~360 beats/min, rapid and
regular
In atrial flutter, the depressant effect of the
drug on atrioventricular conduction will help
control an excessively high ventricular rate.
The effects of the drug on the atrial
musculature may convert flutter to
fibrillation, with a further decrease in
ventricular rate
Therapeutic action:
(1)Increasing block and ERP in
atrioventricular (AV) node
heart rate decrease (ventricular rate)
(2) Shortening ERP of atrium
(convert) atrial flutter →atrial fibrillation
(3) After withdrawal cardiac
glycosides, sinus rhythm may
return, ERP increase (prolong ERP
of shortened ERP in atrium)
(4) Quinidine may convert atrial
flutter to sinus rhythm , but may
increase the risk of cardiac
glycosides toxicity.
3. Paroxysmal
supraventricular tachycardia
Increasing function of vagal nerve
Enhance vagal activity
Decrease excitation of atrium
No use: supraventricular tachycardia
caused by glycosides------intoxication
Toxicity of cardiac
glycosides
1. Gastrointestinal and centre nerve systom
occasions sickness , vomiting , purging泄泻 ,
giddiness眩晕 , confused vision , green
vision or yellow vision , anorexia厌食 ,
nausea , diarrhea , abdominal discomfort or
pain , headache , fatigue
the drugs may stimulate the chemoreceptor of
trigger zone (CTZ) in the area postrema of
the medulla(延髓极后区，化学感受区）
2. Toxic effects on the heart
(1)Tachycardiac rhythm
abnormalities (arrhythmia)
Atrioventricular (AV) node
Artial
Ventricular
}
fibrillation
Tachycardia
death
Bigeminy 二联律 , trigeminy三联律
machanism
Severe inhibiting Na+-K+-ATPase
↓
Depletion of K+ in cell
↓
Resting potential or
Change small
maximal diastolic potential
(negative value)
}
↓
(1)Automaticity
easy to depolarization
(2) Delaying after depolarization↑迟后
(2) AV block
★ the development of AV block is due in
part to the vagal effect of glycosides
+-K+-ATPase is strongly depressed
Na
★
Resting potential↓
↓
Phase 0 depolarization rate ↓
↓
Conduction slows
(3)Sinus bradycardia
Sinus atrial node is depressed
↓
Automaticity ↓
Prevention of cardiac
intoxication
1.Intoxication symptoms and signs
Gastrointestinal effects
Neurological effects
Drug concentration in blood can be
measured
2. Pathological situations
Ion
pH of blood
Oxygen deficiency
Age
Drug interaction
Treatment of cardiac
glycosides introxication
1. Administration K+ , orally or iv
2. Administration of phenytoin treats
severe tachycardiac rhythm
abnormalities
ventricular tachycardia
bigeminy二联律
recovering activity of enzyme
Lidocaine :
ventricular tachycardia
Ventricular fibrillation
Atropine:
Sinus bradycardia
AV conduction block
} severe
Administration
1 Digitalization
 Slow approach to “ digitalization”
Is the safest dosing technique.
 Rapid approach to “digitalization”
can be achieved quickly with a large
loading dose (divided into three or
four portions and given over 24~36
hours) followed by maintenance dose
2 Maintenance doses
3 Therapeutic method of Digoxin
t1/2 36 hours
0.25 mg/day
4~6 t1/2 (6~7 days) to approach
steady-state level (Css)
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