Not All Beta Blocker Are The Same

Out with the Old, In with the New

Rochmad Romdoni

Department of Cardiology and Vascular Medicine

Airlangga School of Medicine - Dr. Soetomo Teaching
Hospital Surabaya
 OBJECTIVES

Identify limitation of traditional (non-

vasodilating Beta Blockers).
Identify the advantages of the newest Beta
Blocker: Nebivolol
Prevalence of Hypertension in
the Asia-Pacific Region
 BP Reductions as Small as 2 mmHg Reduce
the Risk of CV Events by Up to 10%

Meta-analysis of 61 prospective, observational

studies
1 million adults
12.7 million person-years
7% reduction in
risk of ischemic
heart disease
2 mmHg
mortality
decrease in
mean SBP
10% reduction in
risk of stroke
mortality

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913

 ESH-ESC guidelines 2013 25

Thiazide Diuretics

-Bs ARBs

Other Calcium
Antihypertensives Antagonists

preferred combinations;
useful combination (with some limitations);
possible but less well tested combinations; ACEIs
not recommended combination

The Task Force for the Management of Arterial Hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013;
34:2159-2219.
 HYSTORY OF BETA BLOCKER

Beta-blockers were first

developed by Sir James Black
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
 THE JOURNEY OF BETA BLOCKERS
Nonselective Penbutolol
Selective
Vasodilating Acebutolol Carvedilol Nebivolol
Pindolol
Metoprolol
Atenolol Succinate
Propanolol
Metoprolol
tartrate

1960 1970 1980 1990 2000 2010

Nadolol
Timolol
Labetalol Bisoprolol
Carteolol
Betaxolol
- Blockers: Mode of Action
Heart Vessels

Beta-blockers are drugs that bind to

beta-adrenoceptors and thereby block
the binding of norepinephrine and
epinephrine to these receptors.
This inhibits normal sympathetic
effects that act through these
receptors
 1- and 2-adrenoceptors
Tissue Receptor Effect
Heart
SA node 1, 2 heart rate
AV node 1, 2 conduction velocity
Atria 1, 2 contractility
Ventricles 1, 2 contractility, conduction velocity &
automaticity of idioventricular pacemakers
Arteries 2 Vasodilation
Veins 2 Vasodilation

Skeletal muscle 2 Vasodilation, contractility

Glycogenolysis, K+ uptake

Liver 2 Glycogenolysis and gluconeogenesis

Pancreas ( cells) 2 Insulin and glucagon secretion

Parathyroid glands 1, 2 Parathormone secretion
Thyroid gland 2 T4T3 conversion
Fat cells 1 Lipolysis

Bronchi 2 Bronchodilation

Kidney 1 Renin release

Urinary bladder detrusor 2 Relaxation

Gallbladder and ducts 2 Relaxation

Gastrointestinal 2 Relaxation

Uterus 2 Relaxation

Nerve terminals 2 Promotes noradrenaline release

Lpez-Sendn J, et al. Eur Heart J 2004;25:1341-1362.

 Beta blocker Evidence in CVD
Summary of Secondary Prevention Trials of b-blocker Therapy

Phase of Total #
Treatment Patients RR (95% CI)

Acute 28,970 0.87 (0.77-0.98)

treatment

Secondary 24,298 0.77 (0.70-0.84)

prevention

Overall 53,268 0.81 (0.75-0.87)

0.5 1.0 2.0

RR of death
b-blocker better Placebo better
CI=Confidence interval, RR=Relative risk

Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A
textbook of Cardiovascular Medicine, 6th ed., Philadelphia, PA: W.B. Sanders, 2001, 1168.
 3 Generations of -Blockers
Properties Drugs

1st Generation Non-selective Propranolol

No vasodilation Timolol
(block 1 and 2 Rec) Pindolol
Nadolol
Sotalol
2nd Generation 1- selective without Atenolol
vasodilation Bisoprolol Metoprolol
(1 >>>2) Esmolol
Betaxolol

3rd Generation Periphearal vasodilation Carvedilol

Non-1 selective Via antagonism a1 Rec
1 selective plus NO release Nebivolol
 -BLOCKERS:
HETEROGENEOUS DRUG CLASS
-blockers

1/2 Vasodilatory
Selectivity Properties
Which One?

-blockers

Side Metabolic Outcomes

Effects Profile Trials
Side Effects of Beta Blockers

Sexual Dysfunction
Decrease Exercise Tolerance
Metabolic side effects
ARE ALL BETA BLOCKERS
THE SAME
???
Nebivolol is a Racemic Mixture Of Two Enantiomers

L - Nebivolol D - Nebivolol
NO-mediated High selective 1
vasodilation Blockade
 Nebivolol: 1 Receptor Selectivity
Human Myocardium
50
40,7
40
1 selectivity

30

20 15,6

10
4,23
0,49 0,73
0
Bucindolol Carvedilol Metoprolol Bisoprolol Nebivolol

1 Selectivity = K1 (2)/K1(1).
In extensive metabolizers and at doses less than or equal to 10 mg, nebivolol is preferentially 1 selective.
Brixius K et al. Br J Pharmacol. 2001;133:1330-1338
 Nebivolol and Metoprolol:
Effect on BP at 3 Months
DBP SBP
N 73 67 73 67
Baseline BP (mmHg) 106 107 160 157

0
Mean vs baseline (mm Hg)

-5

-10

-15
-16 -15
-20 -17 *
* *
-20
-25 *

Nebivolol 5 mg qd (n=73)
Metoprolol 100 mg bid (n=67)

*P<0.05 vs. baseline

BP = sitting blood pressure; DBP=sitting diastolic blood pressure; SBP=sitting systolic blood pressure
Uhlir O et al. Drug Invest 1991;3(auppl 1):107-110
 Single Dose Control of Blood Pressure
over 24 hours with Nebivolol
130
Placebo
120
mmHg (MAP)

Nebivolol 5
mg o.d.
110

100

90
T/P ratio 89%
80
Start 6 hrs 12 hrs 18 hrs 24 hrs

Time from
last dose: 7 am Afternoon Evening Night Early morning

Van Nueten L. Clinical Research Report 1994.

 Hemodynamic Effects of Nebivolol:
Increase Exercise Tolerance
3.6
Stroke volume (mL)
20.6 Atenolol
(100 mg/qd)
-24.0
Cardiac output (L/min) Nebivolol
7.1 (5 mg/qd)
-2.1
Ejection fraction (%)
7.8
-28.2
Heart rate (beats/min)
-10.8
Peripheral resistance 5.8
(dyne/cm-5) -13.2

Left ventricular 5.7

end-diastolic volume (mL) 10.6
Left ventricular endsystolic 9.2
volume (mL) -1.4

-40 -30 -20 -10 0 10 20 30

*At 2 weeks
Percent change vs baseline

Kamp et al. Am J Cardiol. 2003;92:344

 Effect of Nebivolol on Insulin Resistance:
Good Metabolic Profile
P=0.003

P=0.008 P=NS
3 2,79 2,83
2,67
Mean insulin resistance by HOMA

2,5 2,29
(md/dL x IU/mL)

1,5

0,5

0
Baseline Month 6 Baseline Month 6
Nebivolol 5 mg (n=37) Metoprolol 100 mg (n=35)
Baseline SBP/BP was 153/92 mm Hg and 155/95 mm Hg in the nebivolol and metroprolol groups, respectively. Following 6 months
of therapy. BP was 131/79 mm Hg and 129/82 mm Hg in the nebivolol and metroprolol groups, respectively. HOMA=homeostasis
model assessment insulin resistance.
Celik T et al. J Hypertens 2006;24:591-596
 Effect on renal blood flow
Renal impairment is a common finding
in patients with heart failure and is
independently associated with an
increased risk of death

The use of beta-blockers in heart failure

patients with kidney disease is known
to improve outcomes, which may be
linked to reduction in activity of the
renin-angiotensin system, improvement
in renal blood flow, and improved
natriuresis in response to volume
loading

In a small double-blind crossover study

in hypertensive subjects, Nebilet
increased renal blood flow, whereas
atenolol decreased it1

Reference: 1. Mohri M, Egashira K, Tagawa T, et al. Hypertension 1997; 30:50-6. .

 Route of Elimination
100% 50% 0%

Liver Elimination

Renal Elimination

0% 20% 40% 60% 80% 100%

Propranolol Timolol Pindolol Diacetolol Atenolol
Metoprolol Acebutolol Nadolol
Labetalol Bisoprolol Sotalol *
Betaxolol Carteolol
Penbutolol
Carvedilol
Nebivolol
* Antiarrhythmic agent
No longer available in US for hypertension
Metabolite of acebutolol

Adapted from Meier J. Cardiology 1979;64 (Suppl 1):1-13.

Effect of Nebivolol and Metroprolol on
Sexual Function: IIEF
Nebivolol 5 mg
Metoprolol succinate 95 mg
 SENIORS Study
Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in
Seniors with Heart Failure

2128 patients 70 years heart failure history (admission < 1 year or known EF 35%) to
nebivolol, titrated to 10 mg QD, or placebo

All-cause Mortality or CV Hospital Admission All-cause Mortality

(Primary Outcome) (Main Secondary Outcome)
HR 0.86 (0.740.99) HR 0.88 (0.711.08)
P = 0.039 P = 0.214
100 Median 21 months 100
Nebivolol
90 Nebivolol 90
Event- 80 Placebo
80
free
survival 70 70
(%) Placebo
60 60
50 50
0 6 12 18 24 30 0 6 12 18 24 30
Time (months) Time (months)

Flather MD, et al. Eur Heart J 2005; 26:215-225.

 Conclusions

1. Beta blockers are not all created equally.

2. Nebilet (nebivolol) as the third generation,

cardioselective beta blockers with nitric
oxide release to mediate vasodilatation
may produce clinical outcomes that differ
from traditional beta-blockers and improve
patients Quality of Life.
THANK YOU
Achievement of Target Dose in
Beta-blocker Trials
Patients reaching
target dose

CIBIS II (bisoprolol 10 mg o.d.) 42%

MERIT-HF (metoprolol 200 mg o.d.) 64%
COPERNICUS (carvedilol 25 mg b.i.d.) 65%

SENIORS (nebivolol 10 mg o.d.) 68%

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group.
Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;
Flather MD. EHJ 2005; 26:215-5.