SLIDES TO GIVE A COMPREHENSIVE REVIEW OF BETA BLOCKER USE IN CARDIOVASCULAR DISEASES

1. CURRENT STATUS OF BETA
BLOCKER USE IN
CARDIOVASCULAR DISEASES

2. History
• Beta-blockers were first developed by Sir James
Black at the imperial chemical industries in the
United Kingdom in 1962.
• They are considered one of the most important
contributions to clinical medicine and
pharmacology in the 20th century.
• Sir James Black was awarded the Nobel prize in
1988 for advances in medicine.

3. Today’s talk will include
• The pertinent clinical
pharmacology of beta-blockers
• Their clinical use in cardiovascular
medicine.

4. CLASSIFICATION

5. Actions of beta receptor stimulation

6. Beta 1 VS Beta 2 Selectivity

7. 30 0:1
1:35 1:35
1:75
increasing
ß 1
-selectivity
increasing
ß 2
-selectivity
ICI
11 8.55 1
1 .8 :1
Propranolol
Atenolol Betaxolol
Bisoprolol
no
selectivity
Ratio of constants of inhibition
1:20
M etoprolol
1-selectivity of various -blockers
Wellstein A et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 36-40
Wellstein A et al. Eur Heart J 1987; 8 (Suppl. M): 3–8

8. Summary of use of beta blockers in
cardiovascular diseases

9. ACTIONS OF BETA BLOCKERS

10. Mechanism of β-blocker benefits
in ischemic heart disease
• Reduction in myocardial oxygen
requirements via a decrease in
heart rate, blood pressure and
ventricular contractility.
• Slowing of the heart rate
prolongs coronary diastolic
filling period.
• Redistribution of coronary

11. Mechanism of β-blocker benefits
in ischemic heart disease
• Increases threshold to
ventricular fibrillation.
• Reduction in infarct size and
reduction in the risk of cardiac
rupture.
• Reduction in the rate of
reinfarction.
• Regression of the atheromatous

12. β-Blockers and atheromatous plaque
regression/progression/vulnerabilit
y stability
Decrease in coronary atheromatous plaque
volume by BB
(as assessed by intracoronary ultrasound) over 1 year
(independent of statins, ACE inhibitors, other drugs, low-
density lipoprotein concentration, and heart rate). ns, not
significant; sig, significant.
Sipahi I, Tuzcu EM, Woski KE, et al. Ann Intern Med 2007;147:10–18

15. MECHANISM OF BETA BLOCKERS IN
HEART FAILURE
• Upregulation of β receptors and improved β adrenergic
signaling.
• Reducing the hyperphosphorylation of calcium release
channels of sarcoplasmic reticulum and normalizing their
function
• Bradycardia (↑ coronary blood flow and decreased
myocardial oxygen demand).
• Protection from catecholamine myocyte toxicity.
• Suppression of ventricular arrhythmias.
• Anti-apoptosis. β2 receptors, which are relatively increased,
are coupled to inhibitory G protein & block apoptosis.
• Inhibition of RAAS. When added to prior ACE-I or ARB,
metoprolol augments RAAS inhibitors

16. β-Blockers and the
inflammatory process
The effect of monotherapy
antihypertensive treatments upon plasma
C-reactive protein levels. ACE/ARB,
angiotensin-converting enzyme/ ACE
receptor blocker; CCB, calcium channel
blocker.
Palmas W, Ma S, Psaty B, et al. Am J Hypertens 2007;20:233–41
Reduction
in Vascular
markers
with BB

17. JNC 7 recommendations

18. Beta blockers for hypertension
• In the 1980s, beta-adrenergic receptor blockers
(beta blockers) became the most popular form of
antihypertensive therapy after diuretics,
reflecting their relative effectiveness and freedom
from many bothersome side effects
• Because beta blockers reduce mortality in
patients post–myocardial infarction or heart
failure (i.e., secondary prevention), it was
assumed they would also provide special
protection against initial cardiac events (i.e.,
primary prevention).

19. Beta blockers for hypertension….any
benefit in primary prevention??? NO
• In multiple large RCTs, the use of a beta blocker
(particularly atenolol) provided no more
protection against the first myocardial infarction
(MI) than other drugs and was associated with a
statistically significant 16% increase in the
incidence of stroke.
• rationale—beta blockers lower brachial systolic
BP equally but do not lower aortic pressure as
well as other drugs. They reduce heart rate and
increase peripheral resistance, so that the arterial
wave reflection from the periphery returns during
systole rather than during diastole.

20. This is how braunwald’s textbook summarizes
the use of betablockers in hypertension
• “Beta blockers are specifically recommended for
hypertensive patients with concomitant coronary
disease, particularly after a myocardial infarction,
congestive heart failure, or tachyarrhythmias.”
• “If a beta blocker is chosen, the agents that are more
cardioselective offer the likelihood of fewer
perturbations of lipid and carbohydrate metabolism
and, because of fewer side effects (except for
bradycardia), better adherence to therapy.”
• “Long-acting formulations are better for once-daily
dosing.”
Page 945 braunwald’s textbook of medicine 9th edition

21. Copyright © The American College of Cardiology.
All rights reserved.
From: Cardiovascular Protection Using Beta-Blockers: A Critical Review of the Evidence
J Am Coll Cardiol. 2007;50(7):563-572. doi:10.1016/j.jacc.2007.04.060
Proposed Use of Beta-Blockers for Hypertension
In patients with uncomplicated hypertension, beta-blockers should not be used as first-line
agents. However, in patients with uncontrolled hypertension on various other antihypertensive
agents and in those with complicated hypertension, beta-blockers should be considered in the
armamentarium of treatment. CHF = chronic heart failure; MI = myocardial infarction.
Figure Legend:

22. Changing patterns of betablocker use

23. BISOPROLOL…. THE MOST
CARDIOSELECTIVE BETA BLOCKER

24. Bisoprolol experience in
Indian patients
Mar
2012

25. Objectives:
This study was aimed to evaluate the
efficacy and tolerability of
bisoprolol, in Indian patients
diagnosed with stage I essential
hypertension as first line drug.
Primary and secondary outcomes
measures:
• The primary outcome measure was
percentage of patients achieving
blood pressure (BP) <140/90 mm Hg at
Bisoprolol in hypertension
Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683

26. • Results:
– 2131 (96.44%) patients achieved
BP control.
– There was significant
reduction in systolic blood
pressure (25.29; SD: 13.22 mm
Hg), diastolic blood pressure
(14.14; SD: 7.67 mm Hg) and
heart rate (12/min; SD: 6.15)
compared with baseline (all
p values <0.05).
– The median dose of
bisoprolol and average
period required for the
response were 5 mg/day and
33 days,
0
20
40
60
80
100
120
140
160
180
Baseline 2 4 8 12
SBP
DBP
66
68
70
72
74
76
78
80
82
84
86
88
HR
HR
Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open

27. Bisoprolol: Pharmacology
• Pharmacology
–Bisoprolol is a highly potent ß1
adrenoceptor blocking agent
–No ISA
–No pronounced negative inotropic
effects
–Low affinity for ß2-receptors
involved with metabolic
regulation
• does not influence airways
resistance

28. Modified from: Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Su
Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8
Highly β1-selective
1:35
1:75
Increasing β1-
selectivity
Increasing β2-selectivity
1.8:1Propranolol
Atenolol
Bisoprolol
No
selecti
vity
Ratio of constants of inhibition
1:20
Metoprolol
ß1-selectivity of bisoprolol compared with other
ß-blockers

29. Selectivity at clinical dose
β1-adrenoceptor occupancy, as achieved in a dosage interval of 24 h equivalent to a
single dose
ß1- and ß2-receptor occupancy in relation to plasma
concentrations
Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):41–54
Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8
Atenolol
Occupancy Ration = 80% : 20%
Bisoprolol
Occupancy Ration = 100% : 0%

30. Bisoprolol in HTN with COPD 2013
•Cardioselective beta-1 blockers such as
metoprolol, bisoprolol, or nebivolol may be
beneficial in COPD.
•Atenolol does not reduce cardiovascular
events in patients with hypertension.
•Nonselective beta blockers such as
propranolol may induce bronchospasm and
should not be used in patients with COPD
Dipak Chandy1, Wilbert S Aronow2, Maciej Banach3, 1Division of
Pulmonary, Critical Care and Sleep, 2Division of Cardiology, Department of
Medicine, New York Medical College, Valhalla, NY, USA; 3Department of

31. Comparison of PK properties of
BB

32. Metabolic Disturbance
Change in plasma triglyceride and high-density
lipoprotein (HDL) levels in
normocholesterolemic hypertensive patients
after long-term therapy with propranolol
(nonselective), atenolol (moderately β1-
selective), mepindolol (nonselective with
ISA), and bisoprolol (highly β1-selective).
Fogari R, Zoppi A. Rev Contemp Pharmacother 1997;8:45–54.
** **
** **
**
**
** **
**
*
6 12 18 24 30 36 months
Bisoprolol 10 mg/day (n=17)
Propranolol 160 mg/day (n=15)
Atenolol 100 mg/day (n=22)
vs baseline
*p<0.05
**p<0.01
%HDL-cholesterol
+10
0
-10
-20
-30
-40
Difference in
effect on
lipid profile
– Beta-1
selectivity is
the key.

33. Different beta blockers and sexual
dysfunction versus placebo

34. Elimination routes of various beta
blockers from body

35. Product Information for Bisoprolol

36. Product Information for Bisoprolol
Use in Pregnancy: not labeled; though used by many

37. COMPARISONS

38. Atenolol Bisoprolol
Moderately β1-selective Highly β1-selective
No first-pass effect Little first-pass effect (10%)
Bioavailability: 40-50% Bioavailability: 90%
Unchanged renal elimination
=> dose reduction in renal
impairment
Balanced clearance: no dose
adjustment in mild-to-moderate renal
impairment. Do not exceed 10 mg in
severe cases
Once-daily administration (SPC!)
BUT: twice daily necessary
Once-daily administration sufficient and
clinically proven
24 h Peak-trough BP control ratio 31% 24 h Peak-trough BP control ratio 78%
No CHF indication CHF indication
Competitor ß-blocker Pharmacology:
atenolol

39. Bisoprolol Vs Atenolol: ABPM
study results
• Multi-centric, double-
blind, randomized ABPM study.
• Bisoprolol (10 – 20 mg/OD) Vs
Atenolol (50 – 100mg/OD) for 8
weeks.
• N = 659.
• Efficacy Variables –
–Average 24 hour fall in BP
–Night time 4 hour fall in BP
Neutal J et al. Am J Med,1993;94(2):181-187

40. Bisoprolol Vs Atenolol: Change
in night time BP
Neutal J et al. Am J Med,1993;94(2):181-187

41. Bisoprolol Vs Atenolol:
Conclusion
• Conventional BP measurement
fails to detect difference
between bisoprolol and
atenolol.
• Bisoprolol –
–Greater fall in DBP from
baseline than atenolol.
–Greater fall in SBP and DBP in
night time BP than atenolol.Neutal J et al. Am J Med,1993;94(2):181-187

42. Competitor ß-blocker Pharmacology:
metoprolol succinate
Metoprolol (succinate) Bisoprolol
β1-selective (due to ZOK formulation) Highly β1-selective
50% bioavailability due to first-pass
elimination (CYP2D6)
High bioavailability, small first-pass-
effect
Dose-reduction in hepatic
impairment required
Balanced clearance: no dose
adjustment in mild-to-moderate
hepatic impairment. Do not exceed
10 mg in severe cases
Once-daily administration (due to ZOK
formulation)
Once-daily administration
CHF indication proven (MERIT-HF) CHF indication proven (CIBIS II)

43. Competitor ß-blocker Pharmacology:
metoprolol tartrate
Metoprolol (tartrate) Bisoprolol
Moderately β1-selective, reliable
selectivity only in lower dose range
Highly β1-selective
Bioavailability: 50% High bioavailability, small first-pass-
effect
Predominantly hepatic clearance:
Dose-reduction in hepatic
impairment required (CYP2D6)
Balanced clearance: no dose
adjustment in mild-to-moderate
hepatic impairment. 10 mg in severe
cases not to be exceeded
Short half-life of 3–4 h, no once daily
administration
Once-daily administration
No CHF indication proven CHF indication proven

44. 180
160
140
120
100
80
90
80
70
60
50
mm Hg SBP
n.s.
DBP
2-4 weeks
0 + 2 + 4 weeks
placebo ß-blocker
p < 0.01
p < 0.05
HRbeats/min
Bisoprolol (n = 44)
Metoprolol (n = 43)
B vs. M
n.s.= not significant
*
** **
* **
**
*
Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113
± SDx
_
Bisoprolol Vs Metoprolol :
Change in
BP & HR (at rest)

45. 0
20
40
60
80
100
%
90%
SBP
Bisoprolol 10 mg
Metoprolol100 mg
HR RPP
66%
93%
54%
92%
60%
n = 87
Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113
Bisoprolol Vs Metoprolol : 24
hr Efficacy

46. Competitor ß-blocker Pharmacology:
nebivolol (1)
Nebivolol Bisoprolol
Highly β1-selective Highly β1-selective
No adverse effects on lipid/glucose
metabolism
No adverse effects on lipid/glucose
metabolism
Vasodilatation via L-arginine/NO
pathway
Enhanced NO release due to ISA at
β2 or β3-receptors: stimulation β3=>
negative inotropic effects
No ancillary properties
Bioavailability: 90% (poor metabolisers)
Bioavailability: 12% (fast metabolisers)
Bioavailability: 90%
t½: 8 h (fast metabolisers) to 27 h (poor
metabolisers)
t½: 10–12 h
Figure 12: Bisoprolol compared with nebivolol (part 1 of 2)

47. Competitor ß-blocker Pharmacology:
nebivolol (2)
Nebivolol Bisoprolol
Increase in plasma concentration of
nebivolol and active metabolites in
patients with renal dysfunction
Balanced clearance: 2 independent
and equally effective routes
of clearance
High protein binding: ~98% Low plasma-protein binding: 30%
CHF indication (based on a composite
endpoint of all-cause mortality & CV
hospital admission)
No significant mortality reduction
Indication limited to elderly (70 years)
CHF indication with proven
signifcant mortality reduction
No CAD indication CAD indication approved
Figure 12: Bisoprolol compared with nebivolol (part 2 of 2)

48. BISOPROLOL
Vs
NEBIVOLOL

49. BISOPROLOL
Vs
NEBIVOLOL

50. BISOPROLOL
Vs
NEBIVOLOL

51. Indirect comparison 2013
STUDY BISOPROLOL NEBIOLOL
MAIN CHF II
At half dose, LVEF
increases
----
SENIORS ---- No significance on LVEF

52. Also,

53. NEBIVOLOL

54. Competitor ß-blocker Pharmacology:
carvedilol
Carvedilol Bisoprolol
Not β1-selective Highly β1-selective
Vasodilatation due to α1-blockade
(but may cause orthostatic disorders)
No α1-blocking activity
Metabolic effects (in some studies):
• No influence on carbohydrate
metabolism
• Positive effect on lipids (HDL  and
LDL)
• Negative lipid effect (cholesterol, TG,
VLDL )
No relevant influence on carbohydrate
metabolism
Lipid profile (almost) not affected
Antioxidative effect? No studies available
Antiproliferative effect? No studies available
Figure 13: Bisoprolol compared with carvedilol (part 1 of 2)

55. Competitor ß-blocker Pharmacology:
carvedilol
Carvedilol Bisoprolol
Bioavailability: 25% Bioavailability: 90%
Protein binding: >98% Protein binding: 30%
Oral bioavailability of digoxin increased No interaction with other CV drugs
known
Extensive metabolism in the liver
(CYP2D6)
Dose adjustment in patients with
hepatic impairment
Balanced clearance: 2 independent
and equally effective routes of clearance
No dose adjustment required (10 mg not
to be exceeded in terminal insufficiency)
Sensitive to liver enzyme induction Almost insensitive to liver enzyme
induction
t½ 610 h => b.i.d. administration
(extended release formulation available)
t½: 1012 h, once-daily administration
Figure 13: Bisoprolol compared with carvedilol (part 2 of 2)

56. 6. CIBIS–ELD
2011

57. CIBIS–ELD
2011

58. CIBIS–ELD
2011

59. CIBIS–ELD
2011

60. CIBIS–ELD
2011
• More pulmonary adverse events occurred
with Carvedilol.

61. 7. Bisoprolol
Vs
Carvedilol
in
CHF and COPD
2011

62. Bisoprolol
Vs
Carvedilol

63. Bisoprolol
Vs
Carvedilol

64. THANKYOU!

67. Cardiovascular contraindications

68. Classification of β-blockers
1st Generation Non-selective Propranolol
2nd Generation β1-selective
Atenolol
Metoprolol
Betaxolol
Bisoprolol
3rd Generation
Additional
properties, for
example
vasodilation
Carvedilol
Nebivolol
Table 6: Classification of ß-blockers