1. Drugs for Treatment of Congestive Heart Failure

2. Contents Overview ACE inhibitors (ACEI) AT1 receptor blockers(ARB)
mineralocorticoid receptor blockers(MRB)
Diuretics
 receptor blockers
Cardiac glycoside
Others

3. A. Overview
1. Pathophysiological changes of congestive heart failure (CHF)
(1) Function and structure changes
(2) Neuroendocrine changes
(3) Changes of  receptor signal transduction

6. Changes of hemodynamics in CHF
Cardiac failure
Cardiac output
Blood supply
Venous pressure
Renal blood flow
Renin - angiotension Ⅱ
Venous hyperemia
Aldosterone
Pulmonary circulation:
cough, emptysis, dyspnea
Systemic circulation hyperemia :
jugular vein distension, edema
Sodium and water
retention
Changes of hemodynamics in CHF

7. Changes of -adrenergic receptors
A. Overview
Changes of -adrenergic receptors
1-receptor down-regulation
uncoupling of 1-adrenergic receptors
increased activity of the inhibitory G-protein(Gi)
increased activity of G-protein receptor kinase

8. A. Overview 2. Grades of CHF Ⅰ(A): no symptoms
Ⅱ(B): physical activities were limited and symptoms could be induced by general activity
Ⅲ(C): physical activities were markedly limited
Ⅳ(D): symptoms appear even at rest

9. A. Overview 3. Therapeutic strategies in CHF
(1) Increasing contractility of the cardiac muscles
(2) Inhibiting RAAS
(3) Decrease sympathetic activity
(4) Dilating vessels
(5) Diuresis
 Cardiac
remodeling
Decrease
overload

12. B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers(ARB)
captopril 卡托普利
enalapril 依那普利
ARB:
losartan 氯沙坦
irbesartan 厄贝沙坦

14. B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists
1. Pharmacological effects
Inhibiting the production of Ang II
vasoconstriction ; sodium retention ;
cardiac remodeling (myocardial hypertrophy) 
Inhibiting the degradation of bradykinin
vasodilatation 
Increasing ANP and scavenge free radicals

15. Actions of ACEI B2 receptor Angiotensin II Inactive peptide
brandykinin
Angiotensin I
ACEI
(—)
B2 receptor
ACEI
(—)
ACE
Circulation and local tissues
PGI2 NO
ACE
Circulation and local tissues
Vasodilatation
Anti-proliferation, anti-hypertrophy

16. Box Actions of angiotensin II
Constricting vessels, increase peripheral resistance and returned blood volume.
Increasing sympathetic tension, promote release of sympathetic transmitter.
Stimulating release of aldosterone.
Inducing expression of c-fos、c-myc、c-jun rapidly.
Activating MAPK and PTK pathway

17. AngII
AngII

18. B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists
Cardiovascular effects
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

19. B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists
2. Clinical uses
(1) CHF
increase motor tolerance
decrease mortality
(2) Hypertension

20. B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists
3. Adverse effects
Hypotension
Cough and angioedema
Hyperpotassemia
Contraindications: pregnancy and stenosis of renal artery

21. AT1 receptor blockers(ARB)
B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists
AT1 receptor blockers(ARB)
Compared with ACEI:
Blocking actions of angiotensin II directly
Not influencing bradykinin metabolism
Protecting renal function
Used for CHF and hypertension

23. 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.

24. C. mineralocorticoid receptor blockers(MRB)or aldosterone blocker
Spironolactone (螺内酯)
a nonselective aldosterone blocker
Eplerenone (依普利酮)
a selective aldosterone blocker
either alone or in combination with other agents, and for the first-line treatment of heart failure secondary to myocardial infarction
Aldosterone action
MR (in nonepithelial tissues such as the brain and heart )activates transcription of target genes upon aldosterone binding
Formation of reactive interstitial fibrosis, a maladaptation that contributes to left ventricular (LV) remodeling

25. Fig1. The renin-angiotensin-aldosterone (RAA) system and aldosterone blockade and renin-angiotensin inhibitors (ACE inhibitors and ARBs). * RALES, the Randomized Aldactone Evaluation Study; EPHESUS, the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study.

26. Fig. 2. mineralocorticoid receptor signal transduction.
MR, mineralocorticoid receptor;
HRE, hormone responsive element.

27. Eplerenone(依普利酮) Pharmacology/ pharmacokinetics
C. mineralocorticoid receptor blockers(MRB)or aldosterone blocker
Eplerenone(依普利酮) Pharmacology/ pharmacokinetics
Eplerenone selectively binds to the mineralocorticoid receptor, thereby blocking the binding of aldosterone and thus inhibiting sodium reabsorption and other deleterious aldosterone-mediated mechanisms.
Eplerenone is metabolized via the cytochrome P450 (CYP) 3A4 pathway. No active metabolites are known to exist. The elimination half-life is 4 to 6 hours. Steady state is achieved within 2 days. Blood levels are potentiated and increased with concomitant use of inhibitors of the CYP3 A4 pathway (e.g., ketoconazole, saquinavir, erythromycin). The pharmacokinetics of eplerenone did not differ between men and women or between whites and blacks. Steady-state area under the curve and maximum concentration are increased with renal and hepatic insufficiency. Hemodialysis does not remove eplerenone.

28. C. mineralocorticoid receptor blockers(MRB)or aldosterone blocker
Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis.
In humans, eplerenone appears to be effective for the treatment of hypertension.

29. Adverse events reported most frequently with eplerenone
Adverse event Rate (%) of adverse event Hyperkalemia (K+ >5.5 mEq/L) 33% (eplerenone alone) 
38% (eplerenone and enalapril) Hypertriglyceridemia %
Hyponatremia %
Mastodynia % (men)
Abnormal vaginal bleeding % (women)
Gynecomastia % (men)
Proc (Bayl Univ Med Cent) April; 17(2): 217–22

30. D. Diuretics 1. Pharmacological effects Reduce plasma volume
Reduce Na+-Ca2+ exchange in vessel smooth muscle cells
2. Clinical uses
CHF: grand I – IV (mainly used in II –III), alone or combined with other drugs
Edema, hypertension, etc.
3. Adverse effects
plasma level of renin  hypokalemia
hyperuricemia hyperglycemia
hyperlipidemia

31. D. Diuretics

32. Therapeutic effects of diuretics in CHF

33. D. Diuretics Loop agents: Thiazides &analogue:
furosemide(呋塞米)
Bumetanide(布美他尼)
torasemide(托拉塞米)
Piretanide(吡咯他尼)
Furosemide 40mg= Bumetanide1mg= Piretanide 6mg= torasemide 20mg
Thiazides &analogue:
Hydrochlorothiazide(氢氯噻嗪)
Chlorthalidone(氯肽酮)
Indapamide(吲达帕胺)
metolazone (美托拉宗)
Aldosterone antagonists：
Spironolactone (螺内酯)
Amiloride(阿米洛利)

34. E.  receptor blockers Conmmonly used: Carvedilol 卡维地洛, labetalol 拉贝洛尔
1. Pharmacological effects
(1) Blocking effects of catecholamines on myocardium: decreasing heart rate and cardiac oxygen demand
(2) Up-regulating  receptor
(3) Inhibiting RAAS and VP (vosopressin, 加压素): anti- myocardial hypertrophy and remodeling
(4) Blocking -receptor and anti- free radical
(5) Anti-arrhythmic and anti-hypertensive effects

35. E.  receptor blockers
Inverse agonist activity: The ability of β blockers to reduce this basal β-AR activity is termed "inverse agonist activity." Thus, a β blocker does not simply "block" the receptor, but further inactivates receptor activity beyond its baseline value, depending on its degree of inverse agonist activity.
Metoprolol>bisoprolol=nebivolol>carvedilol

36. Significance of inverse agonist activity
β-AR regulation
Activated β-ARs are a substrate for receptor phosphorylation by β-AR kinase. Beta-AR phosphorylation leads to uncoupling of the receptor from the stimulatory G protein ("desensitization") or even internalization of the receptor ("down-regulation").
Inactivation of β-ARs by inverse agonists inhibits phosphorylation of receptors and thus desensitization and down-regulation.
In chronic heart failure, where β-ARs are down-regulated due to chronic sympathetic activation, only the strong inverse agonist metoprolol, but not the weak inverse agonist carvedilol, leads to up-regulation of ventricular β-AR density.

37. E.  receptor blockers 2. Clinical uses (1) CHF: NYHA grand II - III
decrease of mortality
(2) Other uses:
hypertension, arrhythmias, angina, etc.

38. E.  receptor blockers
Therapeutic effects of β receptor antagonists on cardiac function in CHF patients

39. E.  receptor blockers Carvedilol -- antioxidative effects in vitro
Hydroxyl radicals lead to systolic and diastolic dysfunction in human myocardium.
Carvedilol, but not metoprolol, reduces hydroxyl radical-induced cardiac contractile dysfunction in human myocardium.
In patients with heart failure, treatment with carvedilol reduces oxidative stress determined in myocardial biopsies.

40. E.  receptor blockers 3. Adverse effects
Inhibition of cardiac function
Contraindications:
severe heart failure
severe A-V block
hypotension
bronchial asthma

41. F. Cardiac glycosides
Digoxin 地高辛

42. F. Cardiac glycosides 1. Pharmacological effects
(1) Positive inotropic effects
inhibiting Na+-K+-ATPase, free Ca2+   excitation-contraction coupling 
cardiac output   organ blood supply 
Vmax   diastolic duration   venous return 
 coronary blood supply 
cardiac oxygen consumption 

43. Inhibition of Na+-K+-ATPase by digitalis and potentiation of cardiac muscle contraction

45. F. Cardiac glycosides (2) Negative chronotropic effects
Reflex inhibition of sympathetic activity
cardiac output   Sympathetic activity   HR 
Increasing vagal activity directly

46. F. Cardiac glycosides (3) Electrophysiological effects
decreasing automaticity of sinoatrial node
slow conduction
increasing automaticity of Purkinje fibres
shortening ERP of fast response cells
Mechanisms:
intracellular Na+, K+ , Ca2+  
MDP , afterdepolarization

47. F. Cardiac glycosides Electrophysiology SA node atrium AV node
Purkinje fibers
Automaticity  
Conductivity
ERP

48. Electrophysiological basis for digitalis overdose
Na+ , K+ , Ca2+  
 MDP 
 afterdepolarization
Electrophysiological basis for digitalis overdose

49. F. Cardiac glycosides (4) Other effects Nervous system
autonomic nervous system: NE 
central nervous system: CTZ D2 receptor
Neuroendocrine system
inhibiting RAAS
increasing ANP（心房钠尿肽）
Kidney
increase blood supply of kidney
diuretic effect: decrease Na+ resorption

50. F. Digitalis 2. Clinical uses
(1) CHF
especially associated with atrial fibrillation and sinus tachycardia
(2) Arrhythmias
atrial fibrillation
atrial flutter
paroxysmal surpraventricular tachycardia

51. F. Digitalis 3. Adverse effects (1) Gastrointestinal effects
nausea, vomiting, etc.
(2) CNS effects
alteration of color perception（色视, such as yellow vision 黄视）; headache, fatigue, confusion, etc.

52. F. Digitalis (3) Cardiac toxicity
arrhythmias：prematural beats, tachycardia， atrioventricular block, sinus bradycardia, etc.
Prevention：Dose individualization
Avoiding provocation factors: plasma K+ , and drug interactions, etc.
Treatment： KCl, phenytoin sodium or lidocaine, i.v.
Atropine: A-V block, sinus bradycardia
Fab segment of digoxin antibody, i.v.

53. Drug interactions that probably induce digitalis cardiotoxicity

54. F. Cardiac glycosides 4. Administration
(1) Loading + maintaining doses
full dose (digitalization) + maintaining doses
for severe patients
(2) Maintaining dose given daily
reaching steady state of plasma concentration with 1 week (digoxin)
for stable patients

55. F. Cardiac glycosides
5. ADME and properties of different digitalis drugs
(1) Moderate-acting: digoxin 地高辛
(2) Long-acting：digitoxin 洋地黄毒苷
digitalization + maintaining doses
(3) Short-acting：deslanoside 西地兰, 去乙酰毛花苷
acute attack of CHF

57. Different elimination modes of digoxin and digitoxin

58. G. Other drugs 1. PDE-III inhibitors milrinone 米力农, vesnarinone 维司力农，
amrinone 安力农
Positive inotropic drugs
Hypotension, thrombocytopenia, etc.
2.  receptor agonists
dobutamine 多巴酚丁胺
Arrhythmias, etc.

59. G. Other drugs
3. Vasodilators cardiac preload and afterload , output  4. Calcium channel blocker 5. Calcium sensitizers

60. Action modes of positive inotropic drugs