Download Digitalis

Drugs for Treatment of
Congestive Heart Failure （CHF）
1
OVERVIEW---Types of heart failure
(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).
2
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.
3
1. OVERVIEW--Pathophysiological changes of CHF
Fall in cardiac output
Myocardial injury
Activation of SNS, RAAS and
others
Myocardial toxicity
Morbidity and mortality
ANP
BNP
Remodeling and
progressive
worsening of
LV function
Fonarow GC. Rev Cardiovasc Med..2001;2:7–12.
Peripheral vasoconstriction
Hemodynamic alterations
Heart failure symptoms
4
Actions of angiotensin II
• 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、cjun rapidly, promotes proliferation and
remodeling.
5
Changes of  receptor signal transduction in CHF
---Uncoupling of 1receptors and Gs protein
---Density of 1 receptors 
---Amount and/or activity of Gs protein 
6
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 decrease circulation volume: diuretics
E To dilate vessels: vasodilators
F To retard or reverse remodeling: ACEIs, amlodipine
7
ACEIs and ARBs
Angiotensin II
Angiotensin I
Inactive peptide
Brandykinin
B2
receptor
ACEIs
(—)
ACE
Circulation and
local tissues
PGI2
NO
ACEIs
(—)
ACE
Circulation and
local tissues
Vasodilatation
Anti-proliferation, anti-hypertrophy
8
ACEIs and ARBs
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
9
ACEIs and ARBs
ACEIs
Clinical uses:
CHF
- increase motor tolerance
- decrease mortality
Hypertension
10
ACEIs and ARBs
ACEIs
Adverse effects:
Hypotension
Cough and angioedema
Hyperpotassemia: aldosterone inhibition
Contraindication: Pregnant or lactation
women, stenosis of renal artery
11
ACEIs and ARBs
ARBS
Compared with ACEIs:
Block actions of angiotensin II directly
No influence on bradykinin metabolism
Protect renal function
Used for CHF and hypertension
12
ACEIs and ARBs
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.
13
Probability of Survival (%)
RALES: Aldosterone Antagonist Reduces
All-Cause Mortality in Chronic HF
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
Spironolactone (25 mg) + standard care (n = 822)
Placebo + standard care (n = 841)
HR = 0.70 (95% CI, 0.60 to 0.82)
P<.001
0
0
3
6
9
12
HR = hazard ratio; RR = risk reduction.
15
18
21
24
27
30
33
36
Months
*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.
Pitt B et al. N Engl J Med. 1999;341:709-717.
14
Cumulative Incidence (%)
EPHESUS Co-Primary Endpoint:
Total Mortality
22
20
18
(16.7%)
Eplerenone + standard care
(n = 3319)
(14.4%)
Placebo + standard care
(n = 3313)
16
14
12
10
8
6
HR = 0.85 (95% CI, 0.75 to 0.96)
P = .008
4
2
0
0
3
6
9
12
15
18
21
24
27
Months Since Randomization
HR = hazard ratio.
Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.
15
 blockers
metoprolol, carvedilol, bisoprolol
Actions
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
16
 blockers
Clinical uses:
CHF
-Ⅱ ~ Ⅲ
- decrease mortality
Hypertension, arrhythmias, angina, etc
17
The Use of Beta Adrenergic Blocking
Agents in Heart Failure
LVEF % change
15
10
5
0
-5
-10
0
6
12
18
24
Time (weeks)
Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV
and ESV) with improved ventricular function over time (increased LVEF)
18
-Blockers Differ in Their LongTerm Effects on Mortality in HF
Bisoprolol1
Bucindolol2
Carvedilol3-5
Metoprolol tartrate6
Metoprolol succinate7
Nebivolol8
Xamoterol9
Propranolol10
1CIBIS
Beneficial
No effect
Beneficial
Not well studied
Beneficial
Minor effect
Harmful
Harmful+Beneficial
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;344:16511658. 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.
19
Circulation. 1986;73(3):503-10.
 blockers
Adverse effects:
Inhibition of cardiac function
Contraindications: severe heart failure
severe AV block
hypotension
bronchial asthma
20
Digitalis
毛地黄
21
Digitalis
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
22
Mechanism of digitalis
3 Na+
2 K+
Digitalis
Na+-K+-ATPase
NKA
[Na+]i
[K+]i
AP
[Ca2+]i
NCE
Na+-Ca2+ exchange
23
Digitalis
Digoxin
Actions:
Negative chronotropic action
- inhibits sympathetic activities
- improves vagal activities (accelerate K+
efflux)
24
Digitalis
Digoxin
Actions
Actions on cardiac electrophysiology
- decreases automaticity of sinoatrial node
- slows conduction
- increases automaticity of Pukinje fibres
- shortens ERP of fast reaction cells
25
Digitalis
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)
26
Digitalis
Digoxin
Actions
Actions on kidney (diuretic effect）
- increases blood supply of the kidney
- decreases Na+ resorption (inhibition of
Na+-K+ ATP ase)
27
Digitalis
Digoxin
Clinical uses：
CHF
Especially associated with atrial fibrillation
and ventricular tachycardia
28
Digitalis
Digoxin
Clinical uses：
Some arrhythmias
- atrial fibrillation
- atrial flutter
- paroxysmal surpraventricular tachycardia
29
Effect of Digoxin on Mortality in Heart Failure
CV Mortality
 0%
Hospitalizations
 28%
Total Hospitalizations
 6%
Mortality From Any Cause (%)
50
Relative Risk 0.99
95% CI 0.91–1.07
P=.80
40
Placebo
Digoxin
30
20
10
All-cause mortality rates: Placebo 35.1%; Digoxin 34.8%
0
0
4
8
12
16 20 24 28 32 36 40
44
48 52
Months
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.
30
The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.
Digitalis
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
31
Digitalis
Digoxin
Adverse effects：
Cardiac effects
- arrhythmias：tachycardia
atrioventricular block
sinus bradycardia
32
Digitalis
Digoxin
Adverse effects：
Treatments：
- KCl, phenytoin sodium or lidocaine, iv.
- Bradycardia：Atropine, isoprenaline (NO
supplement of K+)
- Fab segment of digoxin antibody, iv.
33
34
Diuretics
Actions:
Reduce plasma volume
Reduce Na+-Ca2+ exchange in vascular
smooth muscle cells
Clinical uses:
CHF
- CHF, used alone or combined with other
drugs
Edema, hypertension, etc
35
Vasodilators
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.
36
I/H: isosorbide dinitrate/hydralazine
J Cardiac Fail 2007;13:331-339
37
Other drugs
PDE-III inhibitors (milrinone, vesnarinone)
Catecholamines (dopamine)
Calcium channel blockers
Amlodipine
Felodipine
Calcium sensitizers (pimobendan,
levosimendan, thiadizinone)
38
Limit
activity
Limit Na+
Low Na+
ACEIs
Digitalis
strategies
 blockers
thiazides
combined
Loop diuretics
Dilator
Positive inotropic drugs
grades
Ⅱ
Ⅲ
Ⅳ
39
Part 1
Lipid regulating agents
Part 3 Agents Used in Hyperlipidemia
调血脂药
40
Classification of Dyslipidemia
I
Elevated lipoprotein
CM
IIa
LDL
++
/
High
IIb
LDL+VLDL
++
++
High
III
βVLDL
++
++
Moderate
IV
VLDL
+
++
Moderate
V
CM+VLDL
+
++
/
Type
Ch
TG
Risk of CHD
+
+++
/
Ch: cholesterol; TG: triglyceride; /: no change
41
HDL (high density lipoprotein)
•
•
•
•
HDL: secreted by the liver and intestine
Lipids of HDL come from CM and VLDL
during lipolysis, or acquires cholesterol
from peripheral tissues.
The role of HDL is keeping the cholesterol
homeostasis of cells
Low HDL is an independent risk factor for
CHD.
42
Therapeutic Strategies
1. Identify patients at risk
- Routine screening of serum cholesterol
- Assessment of contributing risk factors
2. Non-pharmacologic therapy
- Diet modification
- Lifestyle modification
3. Pharmacological therapy
43
44
Drugs used for dyslipidemia
 HMG CoA reductase inhibitors (他汀类): lovastatin, etc.
 Cholesterol absorption inhibitors: ezetimide,
Bile acid binding resins (树脂类, colestryramine, colestipol)
 Nicotinic acids (烟酸类): nicotinic acid, acipimox
 Fibates (贝特类): gimfibrozil, feinofibrate
 Antioxidants (抗氧化剂): probucol
 Polyunsaturated fatty acids (多烯不饱和脂肪酸): EPA, DHA,
linoleic acid
45
Action sites of drugs for hypercholesterolemia
46
HMG-CoA Reductase Inhibitors (Statins)
Lovastatin（洛伐他汀）
Simvastatin（辛伐他汀）
Pravastatin （普伐他汀）
Atovastatin（阿伐他汀）
Fluvastatin（氟伐他汀）
Rosuvastatin（瑞舒伐他汀）
47
Statins
Mechanisms:
• Structural analogs of
the HMG-CoA, inhibit
synthesis of Ch.
• Increase high-affinity
LDL receptors
甲羟戊酸
（异戊二烯 ）
• Increase catabolic
rate of VLDL
48
Statins
Pharmacological effects:
• Lipid regulating effects: reduce LDL, TC, TG,
increase HDL.
49
Statins
Pharmacological effects:
• Lipid regulating effects: reduce LDL, TC, TG,
increase HDL.
• Pleiotropic effects: ameliorate the functions of
vascular endothelial cells, inhibit the
proliferation and migration of VSMCs, inhibit
platelet aggregation, antioxidant effect
• Renal protection
50
Statins
Indications:
– Hypercholesterolemia
– Renal syndrome
– Prevention of acute cardiocerebrovascular attack
– Reduce restenosis after PTCA
– Reduce rejection rate after organ transplantation
51
Statins
– Due to the first pass hepatic extraction, the major
effect is in the liver
– Enhanced if taken with food (except for pravastatin –
taken without food)
– Taken in the evening (Why?)
– May need to increase the dosage during the
treatment period (Why?)
52
Statins
Adverse effects
–
Statins are pregnancy category X
–
Rash, GI disturbances (dyspepsia, cramps,
flatulence, constipation, abdominal pain)
–
Myopathy (0.5% of pts)
»Risk highest with lovastatin and especially in
combination with fibrates (贝特类降脂药)
–
CYP3A4 or CYP2C9 drug interactions with many
statins
–
Hepatotoxicity
53
Cholesterol absorption inhibitors
• Ezetimibe (依折麦布)
• Resins (cholestyramine, 考来烯胺；colestipol，考来替泊)
54
Ezetimibe
• Mechanisms and effects:
– Blocks cholesterol absorption at the intestinal brush border
– Reduces LDL
Drug class
LDL-C
(% ∆)
HDL-C
(% ∆)
TG
(% ∆)
Ezetimibe
 18
 1
8
Resins
 15-30
 3-5
/Neutral
Fibrates
 5-20
 10-35
 20-50
Statins
 18-60
 5-15
 7-30
Niacin
 5-25
 15-35
 20-50
Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.
JAMA. 2001;285:2486-2497.
55
Ezetimibe
• Mechanisms and effects:
– No effect on absorption of lipid-soluble vitamins
– Interruption of enterohepatic circulation (肝肠循环)
– Minimal systemic exposure and very well tolerated
– Additive in combination with statins
5%-6%
Statin – starting dose
5%-6%
1st
5%-6%
2nd
3rd
3-STEP TITRATION
Doubling
15%-18%
Statin – starting dose
+ Zetia10 mg
% Reduction in LDL-C
1-STEP
COADMINISTRATION
56
Resins
• Mechanisms:
- Binds to bile acid in the intestines, interrupting
enterohepatic circulation and increasing fecal
excretion
-  LDL receptors
• Efficacy:
LDL  15-30%
57
Resins
Indications:
- High LDL
- Can be used to relieve pruritis in patients who have
cholestasis and bile salt accumulation; and/or to relieve
diarrhea in post-cholecystectomy patients
- May be useful in digitalis toxicity.
Adverse effects:
- Constipation, bloating, indigestion, nausea, large doses
may impair absorption of fats (脂肪痢) or fat soluble
vitamins (A, D, E, and K)
- Affect absorption of other drugs, should be given 1 hour
before the resin or 4 hours after.
58
Fibrates
Gemfibrozil（吉非贝齐）
Fenofibrate（非诺贝特）
Benzafibrates（苯扎贝特）
59
Fibrates
• Mechanisms
• Act as PPAR ligands (peroxisome proliferatoractivated receptor-, 过氧化物酶体增殖物激活受体)
• a nuclear receptor that regulates lipid metabolism and
glucose homeostasis
•  FA oxidation in muscle and liver
•  Apo CIII (key to  VLDL catabolism).
•  lipoprotein lipase, clearance of VLDL, VLDL
production
• Antioxidant, antiproliferation and antiinflammation
effects
60
Fibrates
• Efficacy:
TG  40-55%, HDL  10-25%, LDL + 10%
• Indications:
High TG and/or low HDL
• Adverse effects:
Rashes, GI upset, gallstones (increase biliary cholesterol
saturation)
Use with caution in pts with biliary tract disease hepatic or renal
dysfunction
Increase risk of statin-induced myopathy
Displaces warfarin from plasma albumin since drug is highly
protein bound.
61
Nicotinic acid and Acipimox
• Nicotinic acid (烟酸, Vitamin B3)
• Acipimox (阿昔莫司)
Nicotinic Acid
apo B-100
 VLDL
apo C
Liver
Other sites
apo E Decreased VLDL
Production
VLDL
Remnant
 LDL
Increased VLDL
clearance through LPL
62
Nicotinic acid and Acipimox
• Mechanisms
- Suppress synthesis of VLDL, IDL, & LDL in the liver.
- Increase clearance of VLDL via the LPL pathway,  TG
catabolism
- May  HDL catabolism
• Efficacy:
TC  25%, LDL  10-25%, HDL  10-40%, TG  20-50%
• Indications:
High LDL (and/or VLDL)
Combined hyperlipidemia (including low levels of HDL-Niaspan® , approved for elevating HDL levels)
63
Nicotinic acid and Acipimox
Adverse effects:
– Flushing (very uncomfortable, aspirin may helpful)
– Pruritis, rashes, dry skin
– Nausea and abdominal discomfort
– Rare hepatotoxicity
– Hyperuricemia (occurs in about 1/5 of pts, occasionally
precipitates gout)
– Reversible carbohydrate tolerance may be moderately
impaired (hyperglycemia)
64
Antioxidants
Probucol (普罗布考)
• Action: Taken up by LDL particles and endothelial cells,
inhibits oxidation of LDL and prevents ingestion by
macrophage foam cells, decreases HDL production.
• Effects: 1) decreases atherosclerotic plaque formation; 2)
small reduction in serum LDL; 3) greater reduction of serum
HDL.
• Clinical uses: may be used in combination therapy with
other drugs that lower serum LDL.
• Disadvantages: not effective in single drug therapy; no long
term clinical data.
65
Polyunsaturated fatty acids
EPA, DHA (-3 PUFAs)
• Reduce plasma TG
• Only highly purified preparation (>96%).
• Risk in increasing LDL-C (more strongly associated wih
coronary artery diseases)
• The effects on cardiac morbidity or mortality is unproven
(although there is epidemiological evidence that eating fish
regularly does reduce ischemic heart disease)
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http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a.s
hort?rss=1&amp%3bssource=mfr
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