Beta blockers were first introduced in the 1960s and have since been shown to be effective for treating several cardiovascular conditions like hypertension, angina, heart failure, and arrhythmias. Key events included the development of propranolol in 1962 and the differentiation of beta receptors into subtypes. Large clinical trials demonstrated beta blockers reduce mortality in acute myocardial infarction, hypertension, and heart failure. While earlier non-selective beta blockers had more side effects, later trials showed cardioselective beta blockers are well tolerated and do not negatively impact patients with mild to moderate asthma.

1. Journey of Beta
blockers
From hypertension to heart failure

2. Beta Blockers – Historical Background
Year Scientist Research
1948 Ahlquist Introduced the concept of alpha &
beta receptors
Lands Subdivided beta receptors into
beta1 and beta2 subtypes
1958 Powell and
Slater
Described anti-adrenergic
properties of a new compound,
Dichloroisoproterenol
1962 Sir James W.
Black
Developed Propranolol
Earned the Nobel prize for Medicine
in 1989
1964 First clinical studies of the
treatment of angina, arterial rhythm
and hypertension disorders

3. Beta Blockers – Historical Background
• Remarks by the Nobel Committee in 1988 about
the research of Sir James W. Black “the greatest
breakthrough when it comes to pharmaceuticals
against heart illness since the discovery of
digitalis 200 years ago”.
Radford et.al. NEJM, 1998, Vol. 339:551-553

4. Beta Blockers
Drugs
Nonselective beta1 &
beta2 adrenergic
antagonists
Propranolol
Sotalol
Selective beta1
adrenergic antagonists
Atenolol
Bisoprolol
Celoprolol
Nebivolol
Metoprolol
Alpha1 & beta1
adrenergic antagonists
Carvediol
Labetolol

5. Beta Blockers
Lipid
solubility
Peripheral
vasodilation
Average daily
dosage
Propranolol High 40-80 mg
Sotalol Low 160-320 mg
Atenolol Low 25-100 mg
Bisoprolol Moderate 2.5-10 mg
Celoprolol Moderate + 200-600 mg
Nebivolol Moderate + 2.5-5 mg
Metoprolol High 50-100 mg
Carvediol Moderate + 3.125-50 mg
Labetolol Low + 200-800 mg

6. Beta blockers
Indications
• Hypertension
• Angina pectoris
• Post-myocardial infarction
• Tachyarrhythmias
• Congestive heart failure

7. Beta blockers in hypertension
• Atenolol has been most extensively studied in
patients with essential hypertension
• Reductions in blood pressure in patients with
mild to severe hypertension have been
associated with reduced mortality from both
stroke and myocardial ischaemia.
Sethi KK et al, Cardiology Today, 2002
Recommended as first line treatment in Hypertension by
•European Society of Hypertension Guidelines
•British Hypertensive Society Guidelines

9. Beta-blockers in Hypertension
• Established long term mortality and morbidity
benefits
• Beta blockers significantly reduce:
 Sudden cardiac death
 Overall coronary events
 Incidence of stroke

10. Beta Blockers
The Cornerstone Of IHD Therapy
• Beta blockade is a standard therapy for effort angina,
mixed effort and rest angina and unstable angina.
• Beta blockers decrease mortality in acute MI and in post
MI period.
• Beta blockers retain their position among basic therapies
of numerous other conditions including hypertension,
arrhythmia and cardiomyopathy.
Opie.L.H., Drugs for Heart, 2001

11. Beta Blockers
In acute coronary syndromes
• A summary analysis of randomized trials
with threatened or evolving MI showed
lower rates of progression to MI with
beta-blocker treatment.
www.acc.org/clinical/practice_advisory/
pdfs/COMMITBetaBlockerFACTSheet.pdf

12. Beta blockers in post MI
• In post MI patients, beta blockers limit infarct
size, reduce angina episodes, reinfarction,
suppress tachyarrhythmias and sudden
cardiac death and improve survival
Roy CP et al, Cardiology Today, 2002
•Life saving potentials of the drugs in IHD are:
-blockers : 33%
Statins : 30%
Aspirin : 23%
Cardiac Drug Therapy, M. Gabriel Khan, Saunder; 1999

13. Beta blockers in MI
• Reduce mortality during both acute and long-term
management of myocardial infarction.
Howard et al., American Family Physician, 2000
• Benefit occurred regardless of the patient's age or
sex, infarct location and initial heart rate, or the
presence or absence of ventricular arrhythmias.
Lamb RK et al, Eur Heart J. 1988 Jan;9(1):32-6
• Studies indicate that the most marked reduction in
mortality (25 percent) occurs in the first two days
after infarction.
Yusuf S. et al., JAMA. 1988 Oct 14;260(14):2088-93

14. Beta blockers in MI
As per ACC/AHA guidelines:
- Recommends beta blocker therapy early during an
ongoing MI
- Treatment is recommended in all patients so long
as contraindications does not exist, irrespective of
whether the patient receives concomitant
thrombolytic therapy or primary angioplasty
http://circ.ahajournals.org/cgi/reprint/100/9/1016.pdf

15. “Beta blockers continue to surprise us”
Cruikshank, Eur. Heart J., 2000

16. Use of beta-blockers in
hypertensive diabetic
CLINICAL EVIDENCE

17. UKPDS
THE UK PROSPECTIVE DIABETES STUDY
LANDMARK STUDY
• Multi-center randomized controlled trial of
different therapies of type II diabetes
• Clinical centers: 23
• Type II diabetic patients: 5102
• Person years follow up: 53000

18. UKPDS
BLOOD PRESSURE CONTROL STUDY
To determine whether
• Tight blood pressure control policy can reduce
the morbidity and mortality in type II diabetes
patients
• ACE inhibitor(Captopril) or beta blocker
(Atenolol) is advantageous in reducing the risk of
development of clinical complications.

19. ukpds
Blood Pressure : ACE inhibitor vs Beta blocker
Blood Pressure : ACE inhibitor vs Beta blocker
60
80
100
140
160
180
0 2 4 6 8
mm
Hg
Years from randomisation
cohort, median values
Less tight control ACE inhibitor Beta blocker

20. ukpds
Any Diabetes Related Endpoint (cumulative)
Any Diabetes Related Endpoint (cumulative)
429 of 1148 patients (37%)
0%
10%
20%
30%
40%
50%
0 3 6 9
%
of
patients
with
an
event
Years from randomisation
ACE inhibitor (n=400)
Beta blocker (n=358)
Less tight BP control (n=390)
ACE vs Beta blocker p=0.43
Less tight vs Tight
p=0.0046

21. ukpds
Diabetes Related Deaths (cumulative)
Diabetes Related Deaths (cumulative)
144 of 1148 patients (13%)
0%
5%
10%
15%
20%
0 3 6 9
%
of
patients
with
an
event
Years from randomisation
ACE inhibitor (n=400)
Beta blocker (n=358)
Less tight BP control (n=390)
ACE vs Beta blocker p=0.28
Less tight vs Tight
p=0.019

22. ukpds
Microvascular Endpoints (cumulative)
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or photocoagulation
122 of 1148 patients (11%)
0%
5%
10%
15%
20%
0 3 6 9
%
of
patients
with
an
event
Years from randomisation
ACE inhibitor
Beta blocker
Less tight BP control
ACE vs Beta blocker p=0.30
Less tight vs Tight
p=0.0092

23. Clinical end point Absolute risk
(events per 1000
patient years)
Captopril
Absolute risk
(events per 1000
patient years)
Atenolol
p value
Any diabetes related
end-point
53.3 48·4 0·43
Deaths related to
diabetes
15.2 12·0 0·28
All-cause mortality 23·8 20·8 0·44
Myocardial infarction 20·2 16·9 0·35
Stroke 6·8 6·1 0·74
Peripheral vascular
disease
1·6 1·1 0·59
Microvascular disease 13·5 10·4 0·30

24. UKPDS
BLOOD PRESSURE CONTROL STUDY
Conclusion
ACE inhibitors and beta blockers were
equally effective in lowering mean blood
pressure in hypertensive patients with
type II diabetes and in reducing the risk of
– any diabetes related endpoints
– diabetes related deaths
– microvascular end-points

25. Use of beta-blockers in
heart failure

26. Use of beta-blockers in heart
failure
A Bayesian Meta-Analysis
• 22 trials
• 10 135 patients
James M. Brophy et al, Ann Intern Med. 2001;134:550-560.

27. Study Year Drug Duration NYHA class
Anderson et al 1985 Metoprolol 19 II–IV
Engelmeier et al. 1985 Metoprolol 12 II–IV
Pollock et al. 1990 Bucindolol 3 II–IV
Woodley et al. 1991 Bucindolol 3 II–III
Paolisso et al. 1992 Metoprolol 3 I–IV
Waagstein et al. 1993 Metoprolol 18 II–III
Wisenbaugh et al. 1993 Nebivelol 3 II–IV

28. Study Year Drug Duration NYHA class
Fisher et al 1994 Metoprolol 6 II–IV
Bristow et al. 1994 Bucindolol 3 I–IV
CIBIS-I 1994 Bucindolol 23 III–IV
Eichhorn et al. 1994 Metoprolol 3 II–III
Metra et al. 1994 Carvediol 3 II–III
Olsen et al. 1995 Carvediol 4 II–IV
Krum et al. 1995 Carvediol 4 II–IV

29. Study Year Drug Duration NYHA class
Bristow et al 1996 Carvediol 6 II–IV
Packer et al. 1996 Carvediol 6 II–IV
Colucci et al. 1996 Carvediol 15 II–III
Cohn et al. 1997 Carvediol 8 II–IV
Aust/Nz 1997 Carvediol 19 II–III
CIBIS-II 1999 Bisoprolol 15 III–IV
MERIT-HF 1999 Metoprolol 12 II–IV
RESOLVED 2000 Metoprolol 6 II–IV

30. Significantly less no. of deaths
Placebo Beta-blocker
therapy
Deaths 624/ 4862 444 /5273
% of deaths 12 8
4 lives saved per 100 patients
James M. Brophy et al, Ann Intern Med. 2001;134:550-560.

31. Significantly less hospitalization
Placebo Beta-blocker
therapy
Patients
requiring
hospitalization
754/ 4862 540 /5273
% Patients
requiring
hospitalization
15 11
4 fewer hospitazations per 100 patients
James M. Brophy et al, Ann Intern Med. 2001;134:550-560.

32. • Beta-Blocker therapy is associated with
clinically meaningful reductions in
mortality and morbidity in patients with
stable congestive heart failure and should
be routinely offered to all patients similar
to those included in trials.
The probability that beta-blocker therapy reduced
total mortality and hospitalizations for congestive
heart failure was almost 100%.
James M. Brophy et al, Ann Intern Med. 2001;134:550-560.

33. Tolerability of Beta Blockers
• In a meta-analysis of 90 comparative studies of
angina, beta blockers were found to be
associated with a lower incidence of adverse
effects than calcium antagonists.
(Heidenreich et al, JAMA. 1999 May 26;281(20):1927-36.
• 1-selective blockers such as atenolol appear to
be better tolerated than nonselective agents
(Dahlof et al, Circulation, 1991)

34. Tolerability of Beta Blockers
• 1-selective blockers are generally equivalent to
the ACE inhibitors and calcium antagonists in
terms of impact on quality of life.
(Landray MJ et al, J Clin Pharm Ther. 2002 Aug;27(4):233-42. Review)

35. In patients with reactive airway disease
Meta-analysis of 19 clinical studies
•Cardioselective beta-blockers do not produce
clinically significant adverse respiratory effects in
patients with mild to moderate reactive airway
disease. The results were similar for patients with
concomitant chronic airways obstruction.
•Given their demonstrated benefit in such conditions
as heart failure, cardiac arrhythmias, and
hypertension, cardioselective beta-blockers should
not be withheld from patients with mild to moderate
reactive airway disease.
Salpeter SR et al, Ann Intern Med. 2002 Nov 5;137(9):715-25

36. METOPROLOL
AT A GLANCE

37. METOPROLOL
• Metoprolol, a relatively selective beta1-
blocker, is devoid of intrinsic
sympathomimetic activity and
possesses weak membrane stabilising
activity.
Prakash A et al, Drugs. 2000 Sep;60(3):647-

38. METOPROLOL
• Well established in cardiovascular
medicine
• Particularly useful in the management
of hypertension and ischaemic heart
disease.
Plosker GL et al, Drugs. 1992 Mar;43(3):382-4

39. METOPROLOL
In hypertension, post-myocardial infarction and
idiopathic dilated cardiomyopathy
• Beneficial effects on morbidity and mortality,
or closely-related end-points.
• Improves quality of life
Peters DH SR et al, Pharmacoeconomics. 1994 Oct;6(4):370

40. METOPROLOL
Controlled release metoprolol
• Release the drug at a relatively constant
rate over a 24-hour period
• Producing sustained and consistent
metoprolol plasma concentrations and
beta 1-blockade while retaining the
convenience of once daily
administration.
Plosker GL et al, Drugs. 1992 Mar;43(3):382-4

41. METOPROLOL
Controlled release metoprolol
• Similar or lesser degree of adverse effects
related to the central nervous system
compared with atenolol or long acting
propranolol.
• Less pronounced beta 2-mediated
bronchoconstrictor effects than atenolol in
asthmatics, and less general fatigue and leg
fatigue in healthy subjects.
• These results are presumably due to the beta
1-selectivity of metoprolol in addition to the
the avoidance of high peak plasma
concentrations.
Plosker GL et al, Drugs. 1992 Mar;43(3):3

42. METOPROLOL
IN HEART FAILURE
• Trials in mild to moderate (NYHA functional
class II to III) chronic heart failure
MERIT-HF
• Metoprolol CR/XL Randomised Intervention
Trial in Congestive Heart Failure trial
RESOLVD
• Randomized Evaluation of Strategies for Left
Ventricular Dysfunction pilot study.
Prakash A et al, Drugs. 2000 Sep;60(3):647-78

43. METOPROLOL
IN HEART FAILURE
MERIT-HF
• Treatment with metoprolol CR/XL was initiated
at a low dosage of 12.5 to 25 mg once daily
and gradually increased at 2-weekly intervals
until the target dosage (200 mg once daily) or
maximal tolerated dosage had been attained in
patients receiving standard therapy for heart
failure.
Prakash A et al, Drugs. 2000 Sep;60(3):647-78

44. METOPROLOL
IN HEART FAILURE
MERIT-HF
• At 12 months, metoprolol CR/XL was
associated with a 34% reduction in relative risk
of all-cause mortality in patients with chronic
heart failure due to ischaemic or dilated
cardiomyopathy in the MERIT-HF trial.
• The incidence of sudden death and death due
to progressive heart failure were both
significantly decreased with metoprolol CR/XL.
Prakash A et al, Drugs. 2000 Sep;60(3):647-78

45. METOPROLOL
IN HEART FAILURE
MERIT-HF
• The drug is well tolerated when treatment is
initiated in low dosages and gradually
increased at intervals of 1 to 2 weeks.
• Conclusions of the study was Metoprolol
CR/XL effectively decreases mortality and
improves clinical status in patients with stable
mild to moderate (NYHA functional class II or
III) chronic heart failure due to left ventricular
systolic dysfunction, and the drug is effective
in patients with ischaemic or dilated
cardiomyopathy.
Prakash A et al, Drugs. 2000 Sep;60(3):647

46. THANK YOU