drugs for treatment of congestive heart failure ( chf ) 1
TRANSCRIPT
Drugs for Treatment of Congestive Heart Failure ( CHF )
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病 例 回 顾患者 ××× ,男, 61 岁。因反复胸闷、气促 3 年,再发伴加重半月入院。现病史:患者 3 年前无明显诱因出现胸闷、气促,好高枕卧位。无胸骨后疼痛,无畏寒发热,无咳嗽,无头晕黑蒙,无晕厥及视物模糊。前往某医院就诊,诊断为“扩张型心肌病,急性左心衰”,给予“地高辛”、“双克”、“氨苯蝶啶”、“鲁南欣康”、“参麦”、“葛根素”等治疗,症状好转后出院。此后上述症状反复发作,曾多次入院治疗。半个月前患者因感冒、咳嗽、咳痰导致上述症状再次发作,静息时即感到胸闷、气促,稍作体力活动后症状加重。夜间睡眠不能平卧,有时端坐呼吸。无发热、畏寒,有咳嗽,咳大量白色粘痰,为求进一步诊治,以“扩张型心肌病”、“肺部感染”、“心功能不全 III 度”收住入院。入院体检: T 36.5℃ , P 90 次 / 分, R 20 次 / 分, BP 125/95mmHg , 呼吸音粗,左下肺有湿罗音,心浊音界扩大,双下肢轻度水肿
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病 例 回 顾入院医嘱:第一天 2pm :心内科护理常规、 I 级护理、低盐普食、吸氧必要时速尿(呋塞米) 20mg qd
安体舒通(螺内酯) 20mg qd
欣康(单硝酸异山梨酯) 40mg qd
FDP( 果糖二磷酸钠 ) 10g qd
来立信(左氧氟沙星) 0.3g ,静滴, bid
……( 各种检查 )
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病 例 回 顾
第二天 1am :
计 24 小时尿量
米力农 10mg ,静滴, qd
地高辛 0.125g qd
洛汀新(贝那普利) 10mg qd
吉诺通(粘痰溶解药) 1 tid
第三天…………… . (利尿药)
第七天达力全(卡维洛尔) 3.125mg qd
倍他乐克(美托洛尔) 120mg bid
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(1) Systolic failure: the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced.
(2) Diastolic failure: stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. e.g. Pericarditis ( 心包炎 )
(3) High-output failure: can result from hyperthyroidism (甲亢 ), beriberi(脚气病 ), anemia(贫血 ), and arteriovenous shunts ( 动静脉分流 ).
OVERVIEW---Types of heart failure
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OVERVIEW---Grades
Grades of CHF according to symptoms:
Class I: no limitation is experienced in any activities; no symptoms from ordinary activities.
Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion.
Class III: marked limitation of any activity; the patient is comfortable only at rest.
Class IV: any physical activity brings on discomfort and symptoms occur at rest.
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Grades of CHF according to progress:
Stage A: a high risk HF in the future but no structural heart disorder;
Stage B: a structural heart disorder but no symptoms at any stage;
Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment;
Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care
OVERVIEW---Grades
At risk
HF
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Myocardial injury Fall in cardiac output
Activation of SNS, RAAS and others
Myocardial toxicityPeripheral vasoconstrictionHemodynamic alterations
Remodeling andprogressiveworsening ofLV function Heart failure symptomsMorbidity and mortality
ANPBNP
Fonarow GC. Rev Cardiovasc Med..2001;2:7–12.
1. OVERVIEW--Pathophysiological changes of CHF
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Cardiac failure
Cardiac output
Venous pressure
Venous hyperemia
Pulmonary circulation
(cough, emptysis, dyspnea)
Systemic circulation(jugular vein
distension, edema)
Blood pressure
Renal blood flow
Renin, angiotension II
Aldosterone
Sodium and waterretention
Changes of hemodynamics in CHF9
• Constricts vessels, increases peripheral resistance and returned blood volume.
• Increases sympathetic tension, promotes release of sympathetic transmitter.
• Stimulates release of aldosterone ( 醛固酮 ).
• Induces expression of c-fos 、 c-myc 、 c-jun rapidly, promotes proliferation and remodeling.
Actions of angiotensin II
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Changes of receptor signal transduction in CHF
---Density of 1 receptors
---Uncoupling of 1receptors and Gs protein
---Amount and/or activity of Gs protein
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OVERVIEW--- Therapeutic strategies in CHF
A To inhibit RAAS: ACEIs, ARBs
B To decrease sympathetic activity: ACEIs, β blockers
C To increase contractility of the cardiac muscle:
glycosides, PDE III inhibitors, other positive
inotropes ( 正性肌力药物 )
D To dilate vessels: vasodilators
E To decrease circulation volume: diuretics
F To retard or reverse remodeling: ACEIs, amlodipine
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ACEIs (captopril, enalapril)
Actions
Inhibit the production of Ang II
Inhibit the degradation of bradykinin
ACEIs and ARBs
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Angiotensin II
Angiotensin I
ACECirculation and
local tissues
ACEIsACEIsACE
Circulation and local tissues
(—)
B2
receptor
PGI2 NO
ACEIsACEIs(—)
Brandykinin
Inactive peptide
VasodilatationAnti-proliferation, anti-hypertrophy
Actions of ACEIs
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ACEIs
Actions
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 as well as vascular remodeling
Increase ANP and anti-free radical effect
ACEIs and ARBs
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ACEIs
Clinical uses:
CHF
- increase motor tolerance
- decrease mortality
Hypertension
ACEIs and ARBs
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ACEIs
Adverse effects:
Hypotension
Cough and angioedema
Hyperpotassemia: aldosterone inhibition
Contraindication: Pregnant or lactation women, stenosis of renal artery
ACEIs and ARBs
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ARBS
Compared with ACEIs:
Block actions of angiotensin II directly
No influence on bradykinin metabolism
Protect renal function
Used for CHF and hypertension
ACEIs and ARBs
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CV Risk: reduction in future cardiovascular events;
DN: diabetic nephropathy;
H: hypertension;
HF: heart failure;
Post MI: reduction in heart failure or other cardiac events following myocardial infarction.
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Additional:
Aldosterone antagonists
Spironolactone (螺内酯 ) and Eplerenone (依普利酮 ) get additional function to decrease morbidity
and mortality in patients with severe heart failure
who are also receiving ACE inhibitors and other
standard therapy.
ACEIs and ARBs
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RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF
*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.
Spironolactone (25 mg) + standard care (n = 822)Placebo + standard care (n = 841)
Pro
bab
ilit
y o
f S
urv
ival
(%
)
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0
3 6 912 15 18 21 24 27
Months
HR = 0.70 (95% CI, 0.60 to 0.82)
0
0.45
30 33 36
P<.001
Pitt B et al. N Engl J Med. 1999;341:709-717.
HR = hazard ratio; RR = risk reduction.
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EPHESUS Co-Primary Endpoint:Total Mortality
Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.
Eplerenone + standard care (n = 3319)
Placebo + standard care (n = 3313)
Cu
mu
lati
ve I
nci
den
ce (
%)
22
20
18
16
14
12
10
8
6
4
2
0
3 6 912 15 18 21 24 27
Months Since Randomization
HR = 0.85 (95% CI, 0.75 to 0.96)P = .008
0
(16.7%)
(14.4%)
HR = hazard ratio.
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metoprolol, carvedilol, bisoprololActions
Block effects of catecholamine on myocardium
Inhibit RAAS and VP (vosopressin, 加压素 )
Decrease heart rate and cardiac oxygen demand
Antiarrhythmias, antihypertenstion and antianginal effects
Anti- myocardial hypertrophy and remodeling
Block -receptor and anti- free radical
blockers
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Clinical uses:
CHF
- Ⅱ ~ Ⅲ
- decrease mortality
Hypertension, arrhythmias, angina, etc
blockers
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The Use of Beta Adrenergic Blocking Agents in Heart Failure
0 6 12 18 24
Time (weeks)
0
5
10
15
-5
-10
LVE
F %
cha
nge
Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF)
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US Carvedilol Heart Failure Trials Program
1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics)Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placeboPacker NEJM 1996;334:1349-55
0 50 100 150 200 250 300 350 400
Follow-up (days)
50
60
70
80
90
100Survival Proportion
Carvedilol
PlaceboP<0.001
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Effect of Metoprolol CR/XL in Heart FailureEffect of Metoprolol CR/XL in Heart Failure
MERIT-HF
3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qdLancet 1999;353:2001-07
0 3 6 9 12 15 18 21
Follow-up (months)
80
85
90
95
100Survival Proportion
Metoprolol CR/XL
Placebo
RR 0.66 (0.53-0.81)P=0.0062
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-Blockers Differ in Their Long-Term Effects on Mortality in HF
Bisoprolol1
Bucindolol2
Carvedilol3-5
Metoprolol tartrate6
Metoprolol succinate7
Nebivolol8
Xamoterol9
Propranolol10
Beneficial
No effect
Beneficial
Not well studied
Beneficial
Minor effect
Harmful
Harmful+Beneficial
1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6. 10 BHAT study Group. Circulation. 1986;73(3):503-10.
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Adverse effects:
Inhibition of cardiac function
Contraindications: severe heart failure
severe AV block
hypotension
bronchial asthma
blockers
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Digitalis
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毛地黄
Digoxin( 地高辛 )
Actions
Positive inotropic action- induces rapid and prompt
contraction, prolongs diastolic period, no change or
decease in oxygen consumption
- Inhibitor of Na+- K+ATPase
Digitalis
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[Ca2+]i
Mechanism of digitalis
NKA
[Na+]i
2K+3 Na+
Na+-K+-ATPase
NCE
Na+-Ca2+ exchange
AP[K+]i
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Digitalis
Digoxin
Actions:
Negative chronotropic action
- inhibits sympathetic activities
- improves vagal activities (accelerate K+ efflux)
Digitalis
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Digoxin
Actions
Actions on cardiac electrophysiology
- decreases automaticity of sinoatrial node
- slows conduction
- increases automaticity of Pukinje fibres
- shortens ERP of fast reaction cells
Digitalis
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Digoxin
Actions
Actions on the nervous system
- autonomic nervous system
- central nervous system (D2 receptor )
Actions on neuroendocrine system
- inhibits RAAS
- increases ANP ( 心房钠尿肽 )
Digitalis
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Digoxin
Actions
Actions on kidney (diuretic effect )
- increases blood supply of the kidney
- decreases Na+ resorption (inhibition of Na+-K+ ATP ase)
Digitalis
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Digoxin
Clinical uses :CHF
Especially associated with atrial fibrillation and ventricular tachycardia
Digitalis
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Digoxin
Clinical uses :Some arrhythmias
- atrial fibrillation
- atrial flutter
- paroxysmal surpraventricular tachycardia
Digitalis
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Digoxin
Directions :Typical method:
full dose(digitalization)+maintaining dose
No-loading method : maintaining dose everyday
Digitalis
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Effect of Digoxin on Mortality in Heart Effect of Digoxin on Mortality in Heart FailureFailure
DIG (Digitalis Investigation Group): 6,800 patients with LVEF 45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months.
The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.
Digoxin
Placebo
00 4 8 12 16 20 24 28 32 36 40 44 48 52
10
20
30
40
50
Relative Risk 0.9995% CI 0.91–1.07
P=.80
All-cause mortality rates: Placebo 35.1%; Digoxin 34.8%
Mo
rtal
ity
Fro
m A
ny
Cau
se (
%)
Months
CV Mortality 0%
Hospitalizations 28%
Total Hospitalizations 6%
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Digoxin
Adverse effects :Gastrointestinal responses
- severe nausea, vomit, diarrhea
Symptoms of the central nervous system : - alteration of color perception
(chromatopsia ,色视 )
- headache, fatigue, confusion
Digitalis
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Digoxin
Adverse effects :Cardiac effects
- arrhythmias : tachycardia
atrioventricular block
sinus bradycardia
Digitalis
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Symptoms to stop digitalis administration :
- Severe vomit
- Chromatopsia
- Ventricular premature
- Heart rate < 60 /min
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Digoxin
Adverse effects :Treatments :
- KCl, phenytoin sodium or lidocaine, iv.
- Bradycardia : Atropine, isoprenaline (NO supplement of K+)
- Fab segment of digoxin antibody, iv.
Digitalis
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Digitoxin (洋地黄毒苷 ) : long-term actions
digitalization + maintaining dose
Deslanoside (Cedilanid ,西地兰,毛花苷 C(丙))
i.v., acute attack of CHF
Digitalis
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Actions:
Reduce plasma volume
Reduce Na+-Ca2+ exchange in vascular smooth muscle cells
Diuretics
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Clinical uses:
CHF
- CHF
- used alone or combined with other drugs
Edema, hypertension, etc
Diuretics
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Adverse effects:
plasma level of renin (combined with ACEIs to minimize)
hypokalemia ( 低钾血症 )
hyperuricemia ( 高尿酸血症 )
hyperglycemia ( 高血糖 )
hyperlipidemia ( 高脂血症 )
Diuretics
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Reduction in preload (through venous dilation), or reduction in afterload (through arteriolar dilation), or both.
Long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart.
Vasodilators
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J Cardiac Fail 2007;13:331-339
I/H: isosorbide dinitrate/hydralazine
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PDE-III inhibitors (milrinone, vesnarinone)
Catecholamines (dopamine)
Calcium channel blockers Amlodipine
Felodipine
Calcium sensitizers (pimobendan, levosimendan, thiadizinone)
Other drugs
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病 例 回 顾入院医嘱:第一天 2pm :心内科护理常规、 I 级护理、低盐普食、吸氧必要时速尿(呋塞米) 20mg qd
安体舒通(螺内酯) 20mg qd
欣康(单硝酸异山梨酯) 40mg qd
FDP( 果糖二磷酸钠 ) 10g qd
来立信(左氧氟沙星) 0.3g ,静滴, bid
……( 各种检查 )
53
病 例 回 顾
第二天 1am :计 24 小时尿量米力农 10mg ,静滴, qd
地高辛 0.125g qd
洛汀新(贝那普利) 10mg qd
吉诺通(粘痰溶解药) 1 tid
第三天…………… . (利尿药)
第七天出院达力全(卡维洛尔) 3.125mg qd
倍他乐克(美托洛尔) 120mg bid
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ⅣⅢⅡgrades
strategies
Low Na+
thiazides Loop diuretics combined
Dilator
Positive inotropic drugs
Limit Na+
Digitalis
Limit activity
blockers
ACEIs
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