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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