AntiCHF drugs

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CHAPTER
27
DRUGS USED IN
CONGESTIVE HEART FAILURE
医学院药理学研究所
丁 华
Congestive heart failure (CHF) :
the definition of CHF
Essence: Cardiomyopathy
of overload
Section 1
Pathophysiology
of Heart Failure and The
Treatment Drugs
Pathophysiology of Heart Failure
A. Change of cardiac function and
configuration
B. Change of neuroendocrine system
NA、RAAS、AVP、ET、TNFα↑
ANP、NO、PGI2↓
C. Change of signal transmit of β-R
心功障碍
(收缩功能↓①,舒张功能↓⑧ )
输出量↓
血管收缩
肌β1R↓⑦
神经激素↑
心
(RAS↑④、CA↑)
阻抗↑
心缩力↓
后负荷↑②
顺应性↓
水钠潴留 ⑤
血容量↑
血管肥厚、重构⑥
大、重构⑥
心肌肥
静脉淤血
前
负荷↑③
CHF治疗的演变
20世纪20年代洋地黄开始应用
(一)纠正血流动力学异常(20世纪
50~80年代)
 1948~1968
强心苷、利尿药
 1969~1978
血管扩张药
 1978~1988
新型正性肌力药

(二)修复衰竭心肌的生物学性质
(90年代~2001年)
90年代以来 ACEI、β受体阻断药
(三)逆转心肌异常(2001年起)
1.扩大、强化对心衰时激活的神经
激素-细胞因子的抑制: ET、AVP、
TNFα
2.基因治疗
药物治疗CHF的目的
1.改善血流动力学状况并尽快缓解
症状。
 2.防止心肌继续损害并延缓自然病
程。
 3.降低病死率,延长存活期。

Rationale for pharmacologic
intervention in CHF
The goals in treating heart failure are to improve
the patient's quality of life and to prolong it.
Improving hemodynamics with inotropic drugs does
not decrease mortality; long-term treatment directed
towards neurohormonal factors with ACE inhibitors
and beta-blockers can decrease mortality
Section 2
Cardiac Glycosides
Digoxin(地高辛)
Digitoxin(洋地黄毒苷)
Cedilanide(毛花苷丙, 西地兰
)
Strophanthin K(毒毛花苷 k)
Digitalis
Pharmacological actions:
A. Effect on cardiac
1. Positive inotropic action
(1) ↑ both the force and the velocity
of myocardial contraction, prolong
diastolic.
(2) ↑ the cardiac output.
(3) ↓ myocardial oxygen
consumption
Mechanism:
Cardiac glycosides
↓Na+-K+ATPase
[Na+] i↑
Na+/Ca2+ exchange
[Ca2+] i ↑
myocardial contraction ↑

2. Negative chronotropic action
a. ↑vagal stimulation
b. Resume sensitivity of carotid
sinus baroreceptor.
c.↑sensitivity of cardiac muscle
to Ach.

3. Electrophysiological effect
↓AV conduction
shorten ERP of atria
↑ P-f automaticity,
shorten ERP
强心苷对心肌电生理的作用
电生理特性
野纤维
自律性
增高
窦房结
心房
房室结
降低
传导性
慢
有效不应期
缩短
浦肯
减
缩短
B.Effect on nerve-incretion:
1. ↓ sympathetic activity
2. ↑ pneumogastric (vagal) activity
3. ↓ renin secretion, ↓RAS
4. ↑ ANP secretion
C. Diuresis effect
1.↑CO
renal blood flow↑
2.↓Na+-K+-ATPase
↓Na+
reabasorption in the tubules
↓ H2O and Na+ retention.
Pharmacokinetics
drugs
absorp%
digitoxin 90~100
digoxin 60~ 85
stroph K 2~5
t1/2 H-E cir % last
5d
36h
19h
27
7
0
2~3 w
5~7d
1~3d
Clinical uses
1. CHF
Digoxin: 0.125~0.25mg/d,
6~7d get to Css
2. Certain types of arrhythmia
(1) Atrial fibrillation , atrial flutter
(2) Paroxysmal supraventracular
tachycardia
临床评价:
1997年 DIG 试验(Digitalis Investigation
Group trial)
6800例, 应用地高辛0.25mg/d,治疗
28~58个月。随访3.5年。
地高辛能改善症状,降低再入院率,减少
CHF恶化所致的病死率与住院率,但对总病
死率(34.8% : 35.1%)无影响。
Toxicity, Prevention and
Management
toxicity
1. Gastrointestinal reactions
Nausea and vomiting
2. CNS disturbance
Changes in color vision
3. Cardiac toxicity
ventricular premature contraction
ventricular tachycardia
ventricular fibrillation
sinus bradycardia
atria-ventricular block
Treatment of digitalis toxicity







1) Stop using cardiac glycosides and K+-depleting
diuretics.
2) Antiarrhythmic
KCL is administered orally or by slow, careful
intravenous infusion if hypokalemia is present;
Phenytoin can be given for ventricular and atrial
arrhythmia.
Lidocaine can be used to treat ventricular
tachyarrhymias.
Atropine can be used to treat A-V block.
3) Digoxin antibodies
Section 3
ACEI and AT1-R Antagonist
ACEI (angiotensin-converting
enzyme inhibitor):
 Captopril (卡托普利)
 Enalapril (依那普利)
 Ramipril (雷米普利)

Pharmacological action
1.Influence nerve-incretion:
(1) Ang II ↓
(2) Inhibit bradykinin degradation →
↑bradykinin levels →NO,EDHF,
PGI2↑
(3) ↓ ALD secretion
2. Improve hemodynamics
a. Dilate blood vessels , ↓ peripheral
resistance;
b. Dilate coronary, improve
cardiac function
c.↑renal blood flow
3. Inhibit remodeling of cardiac
muscle and vessel

↓AngⅡand ALD formation , Inhibite
proliferation and hypertrophy
of myocardial cells and VSMC,
improve cardiovascular function.
Clinical Uses


1.CHF
2.Hypertension
临床评价:
39项8308例随机时照临床试验评价:
ACEI使CHF总死亡率降低24%,显著改
善心梗后CHF患者预后,缓解临床症状,
提高运动耐力,改善生活质量,防止和
逆转心肌肥厚。
ACEI可作为各型CHF的首选药,常
与利尿药,地高辛合用。
ACE inhibitors are now
considered to be a cornerstone
in the management of most forms
of
heart
failure
and
many
forms of cardiac hypertrophy
Braunwald
&Bristow
Circulation 2000
Untoward Reaction

hypotension, dry cough , angioedema,
hyperkalemia
Contraindication:
Pregnant woman
Renal artery stenosis
Angiotensin II receptor
antagonist
Losartan(氯沙坦)
Valsartan(缬沙坦)
Irbesartan(伊白沙坦)
Characteristics:
Arrest Ang II combine with AT1R
(1) More selective blockers of
Ang II than ACEI
(2) No effect on bradykinin metabolism
ACEI与ARB特点比较
ARB






完全阻滞ACE和非ACE途径
生成的AngII与受体结合
只阻滞AT1受体效应
不影响AT2、 AT3、 AT4受
体
不影响缓激肽系统
不发生咳嗽
无AngII、Ald逃逸
ACEI


只阻滞ACE途径生成的
AngII
抑制AT1、AT2、 AT3、 AT4
受体效应

加强缓激肽系统作用

咳嗽相对常见

有AngII、Ald逃逸
Section 4 β-receptor blockers
(adrenergic antagonists):
1. The mechanism of action in treatment of CHF






(1) Anti-sympathetic activity
a. Up-regulate β1-R in failing heart, can restore catecholamine
responsiveness.
b. inhibit RAAS →↓cardiac load
c.↓myocardial damage from CA, reduce HR and myocardial
oxygen consumption
(2) Anti-arrhythmia and anti-myocardial
ischemia
(3)Antioxidation — carvedilol
适应症:
所有NYHA心功能Ⅱ、Ⅲ级病情稳定,
LVEF<40%者,应尽早使用,平均奏效
期3个月。
20多个随机对照试验,>10000例NYHA心
功能Ⅱ、Ⅲ级患者,长期应用β阻断剂治
疗,死亡率降低34%。
美托洛尔
提高扩张型心肌病的左心室射血分数
40
标准治疗
美托洛尔
***
35
#
左心室
射血分数
(%)
30
*
25
* P<0.05
*** P<0.0001
20
# P=0.013 ,与标准治疗比较
基线
第一天
第一月
第三月
Application attention:
1. 选择合适的制剂
Selective β1-R blocker :
Metoprolol、Bisoprolol
(美多洛尔)(比索洛尔)
Nonselective β and α1-R blocker:
Carvedilol (卡维地洛)
2、应用恰当的剂量
起始量必须极小。
Metoprolol 12.5mg/d
Bisoprolol 1.25mg/d
Carvedilol 3.125mg/d
每2~4周剂量加倍,达最大耐受
量或目标剂量后长期维持。
3、合用利尿药、ACEI、地高辛。
4、密切观察可能出现的不良反应:
血流动力学恶化,心动过缓,低血
压。
5、禁忌症:
支气管哮喘、心动过缓(心率< 60
次/分)、Ⅱ度以上房室传导阻滞、
低血压。
Section 5 Diuretics





Mechanism:
decreased salt & water retention (blood volume)
leads to decreased ventricular preload
Clinical Effect:
decreased symptoms of heart failure (ie. edema)
decreased cardiac size leads to improved cardiac
function
Administration:
start with a thazide diuretic and switch to a more
powerful agent as required (furosemide)
check serum electrolytes to prevent K+ loss
Aldosterone antagonists
Spironolacton(螺内酯)
Actions: Competitive inhibition of the
aldosterone receptor.
↓ H2O and Na+retention ,
↓hypertrophy of myocardial cells and
myocardial remodeling
↓arrhythmias and sudden death.
Section 6 Vasodilators
Nitrate esters(硝酸酯类)
Hydralazine(肼屈嗪)
Sodium nitroprusside(硝普钠)
Prazosin (哌唑嗪)
Mechanism
of Action
1. Dilate vein
↓preload
↓ lung congestive
2. Dilate artery
↓ afterload
↑cardiac output
Defects : Sympathetic and RAAS
activity ↑, H2O and Na+ retention .
常用扩血管药及特点
药物
作用部位
动脉
静脉
硝酸酯类
+++
肼屈嗪
硝普钠
+++
+
+++
+++
Section 7

Others
β-Adrenoceptor Agonist
Dobutamine(多巴酚丁胺)
Ibopamine(异波帕胺)

Phosphodiesterase Inhibitors
Amrinone (氨力农)
Milrinone (米力农)
Vesnarinone (维司力农)
Mechanism of action:
β-sti
(+)
AC
ATP
AMP
cAMP↑
PDEI
(-)
PDE
5 ’-
Machanism of Action of PDEI
1. Inhibit PDE-III ↑cAMP ↑PKA
Ca2+in cardiac contractility ↑
2. Dilate blood vessel ,↓cardiac load
clinical uses
Serious CHF
3~5d, IV
Calcium sensitizers
↑ sensitive of troponin C(TnC )
to Ca2+ ,↑ cardiac
contractility
 Pimobendan
(匹莫苯)
 Sulmazole
(硫马唑)
 Levosimendan (左西孟坦)
↑ sensitive to Ca2+ ,↓PDEⅢ
Calcium Antagonist
Long-acting: amlodipine(氨氯地平)
Mechanism :
1. Dilate artery vessel ,↓cardiac load
2. Dilate coronary artery, improve
myocardial ischemia
3.↓Ca2+ influx, improve cardiac
diastole function
Uses: Diastolic heart failure
心衰的常规治疗
过去: 强心、利尿、扩血管
现在: 以神经内分泌拮抗剂为主的三
大类或四大类药物的联合应用,即利
尿剂、ACEI、β受体阻断剂的联合应
用,必要时再加地高辛。
病例
赵X ,62岁。患者2年前开始常感劳动后心悸、
气短。近半年来,病人病情加重,经常心慌、气促、
咳嗽、胃纳差,下肢浮肿,有时痰中带血,曾在当
地医院用青霉素、双氢克尿噻、速尿、地高辛治疗,
症状有所缓解。近日来,症状较前明显加重,稍动
即喘、呼吸困难、不能平卧、少尿。颈静脉怒张,
肝于肋下4cm,双下肢呈凹陷性水肿(++),心率
每分钟96次,心尖部可闻及II级收缩期杂音和中度
舒张期杂音,口唇轻度紫绀。
入院诊断为:充血性心力衰竭。心功能Ⅳ级,
讨论:对该病人应选用哪些药物治疗?简述用药依
据。
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