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0

Nebilet BERLIN-CHEMIE MENARINI


1
2

N=O

Sve je poelo 1970.

POZNATO:
Nitroglycerin i nitroprusside
veoma potentni vazodilatatori

PITANJA:
Da li postoji neki endogeni
nitro vazodilatator ?
Nebilet BERLIN-CHEMIE MENARINI
3
EDRF
4

Do you know what EDRF is?

NO
Molekul godine
N=O
Science 1992
5

Nebilet
6

Activation of purified soluble guanylate cyclase by


EDRF from Intrapulmonary artery and vein.
Stimulation by acetylcholine and bradykinin

Ignarro, L.J., Harbison, R.G., Wood, K.S.


Kadowitz, P.J.
J. Pharmacol. Exp. Ther. 230: 602-610, 1986

Nebilet BERLIN-CHEMIE MENARINI


PERIFERNA VAZODILATACIJA
7

Nebilet Klasini
-bloker

NO

Azot oksidom posredovana Nema vazodilatacije


vazodilatacija
Tzemos et al; Circulation 104, 511-514 (2001)

Nebilet BERLIN-CHEMIE MENARINI


II. NO Nitric oxide

4. The endothelium

INTIMA MEDIA ADVENTITIA

smooth
muscle cells

endothelium
fibroblasts

vasomotor nerve
8
II. NO Nitric oxide

4. The endothelium

Largest organ in the body


5x heart in mass
6x tennis courts in area

The vessel wall is an active, integrated organ composed of


endothelial, smooth muscle and fibroblast cells. The endothelium
is capable of release numerous vaso-active substances

Lscher TF, Vanhoutte PM; The Endothelium, CRC Press (1990)


9
ROLE OF ENDOTHELIUM-DERIVED VASOACTIVE SUBSTANCES
FROM PHYSIOLOGY TO ATHEROSCLEROTIC VASCULAR DISEASE
11

Relaxing factors Contracting


NO factors
PGI2 Endothelin
TXA2
EDHF
PGH2
O 2-
ATII

Growth
promoters
Endothelin
Growth inhibitors O 2-
NO ATII
II. NO Nitric oxide

5. Principle of NO stimulation

endothelium shear stress agonist


basal stimulated
NO-synthase R
NO-synthase

cGMP
smooth muscle cells
relaxation

13
II. NO Nitric oxide

6. Vascular effects of NO

Vasodilation
Inhibition of platelet aggregation
Inhibition of SMC proliferation
Inhibition of monocyte migration
Inhibition of adhesion molecules expression
Inhibition of endothelin-1 synthesis

Lscher TF, Vanhoutte PM; The Endothelium, CRC Press (1990)


14
II. NO Nitric oxide

7. Summary

The endothelium plays a primary role in the local control


of vascular function and structure
The most important endothelium-derived relaxing factor
is nitric oxide
Cardiovascular risk factors are associated to endothelial
dysfunction caused by oxidative stress
Endothelial dysfunction is an early promoter of the
development of atherosclerosis

15
16
III. Characteristics of a modern antihypertensive drug

Characteristics of a modern antihypertensive drug

effectiveness

safety of therapy

reliable 24 h action

no impairment to quality of live

prevention of delayed complications

17
IV. Nebivolol

Nebilet: two enantiomers for a new approach to


hypertensive patients

l-nebivolol d-nebivolol
F
O
O
F
O O
O
O
O
O

F
O F

Nitric-Oxide (NO) mediated vasodilation Nitric-Oxide (NO) mediated vasodilation


Moderate reduction in heart rate

18
IV. Nebivolol

2. Nebilet: two mechanisms of action

Nebilet Nebilet
acts at peripheral level acts at cardiac level

19
IV. Nebivolol

Nebilet increases endothelial NO-production in vivo

%
0.265

0.215
NO increase

0.165 NO

0.115

0.065
Nebilet metoprolol control

Broeders et al; Circulation 102, 677-684 (2000)

20
IV. Nebivolol

Nebilet stimulates endothelial NO release in


hypertensive patients
NO-mediated
vasodilation
Nebilet classical under Nebilet
therapy
-blocker

NO

Tzemos et al; Circulation 104, 511-514 (2001)

21
IV. Nebivolol

NO-mediated vasodilation by Nebilet

Lowering of peripheral resistance under Nebilet (Periphal resistance* after 4 weeks)

650 p < 0.05


Nitric oxide stimulation
600
leads to
550
500 better perfusion of
Units [mmHg x min/ml]

450 extremities
400
lowering of preload
350 and afterload
300
Nebilet

placebo
250 *The periphal resistance was
200 calculated by diving the mean arterial
150 blood pressure by the measure blood
100 flow.
50
0

According to Himmelmann A et al; European J Clin Pharmacol 51, 159 ff. (1996)

22
IV. Nebivolol

NO-mediated vasodilation by Nebilet

Influence of Nebilet on arterial blood flow


Nebilet causes vasodilation in the forearm
vascular bed in individuals with essential
80
hypertension.
Since the response is antagonized by
Increase in bloodflow in %

L-NMMA ( an inhibitor of the L-arginine/NO


60
pathway) the vasodilation is mediated by
activation of the NO pathway.
40 NO-synthase
stimulated,
p = 0.0003

20
NO-synthase
inhibited
p < 0.05
0

Dawes M et al; BR J Clin Pharmacol 48, 460-463 (1999)

23
IV. Nebivolol

Nebilet: highest 1 selectivity in the human heart

%
45
40.7
40
35
30
B1/B2 ratio

25
20
15.6
15
10
5 4.23
0.73 0.49
0
Nebilet bisoprolol metoprolol carvedilol bucindolol

Brixius K et al; Br J Pharmacol 133, 1330-1338 (2001)

25
IV. Nebivolol

Hemodynamic profile of anti-hypertensive drugs

Reduction of peripheral resistance Increase of cardiac output


% % (1)
(1)
15 15 nebivolol
atenolol
10 10
(2)
5 5 amlodipine

0 0

-5 -5

-10 -10 lisinopril


(2)
-15 lisinopril -15
(2) nebivolol
-20 (1) -20 atenolol
amlodipine
(1)
(2)

1. De Cree J; Drug Investigation 3, 40-50 (1991)


2. Omvik; Cardiovascular Drugs Therapy 7, 193-206 (1993)

26
IV. Nebivolol

Distinctive hemodynamic features of Nebilet

increase in stroke volume


reduction in peripheral resistance
and cardiac output

-25% +25% -25% +25%


peripheral resistance stroke volume
-15,7 +25
+11,7
+2

cardiac output
+12
-18

moderate reduction in heart rate


nebivolol 5mg

atenolol 100mg -25% +25%


heart rate
-10
-18

De Cree J; Drug Investigation 3, 40-50 (1991)

27
IV. Nebivolol

Effective lowering of blood pressure under Nebilet

systolic blood pressure


mmHg

diastolic blood pressure


180
175
170
165 5 mg nebivolol oral
160 638 patients with essential
155 hypertension (diastolic values between
150
145 95 and 115 mmHg)
140
135
130
125
120
115
110
105
100
95
90
85
80 weeks

0 2 4 6 8 52
Van Nueten L et al; nebivolol documentation unpublished (1994)

28
IV. Nebivolol

Nebilet: effective 24 h action

RR Diastolic Plasma levels: trough peak


110

105

100
mmHg

95

90

85

80

start 2 4 8 12 weeks

Van Nueten L et al; American Journal of Therapeutics 5, 237-243 (1998)

29
IV. Nebivolol

Nebilet: 24 h full control of blood pressure for all


patients
Nebilet has high
% trough-to-peak ratio
100 compared to existing
antihypertensive
agents
90
trough-to-peak ratio

80 Nebilet 1-2
bisoprolol 3
71 enalapril 2
60 nifedipine 3
62 63
60 lacidipine 4
57
amlodipine 4
40

1. Korlipara K et al; Multicenter int nebivolol trial. JFR Clinical Research Report on NEB-INT (5. July 1994)
2. Schelling A et al; Multicenter int nebivolol trial. JFR Clinical Research Report on NEB-INT (3. July 1994)
3. Meredith PA; Archives des maladias du coeur et des vaiessaux 87 (11), 1423-1429 (1994)
4. Zannad F et al; Am J Hypertension 9, 633-643 (1996)

30
IV. Nebivolol

Nebilet: circadian rhythm

130
placebo
120

110
mmHg

Nebilet 5 mg

100

90

80
start 6 12 18 24 hours after last dose
7.00 13.00 19.00 01.00 07.00
Lacourciere Y et al; J Clin Pharmacol 32, 660-660 (1992)
Lohmann FW et al; Hochdruckkrankheiten 12, 622-624 (2000)

31
IV. Nebivolol

Nebilet: high percentage of responders

3-month double-blind
study in 419 patients
with essential hyper-
tension
nebivolol
5mg
once daily
Nebilet 70%
(n=208)
Patients with
DBP 90 mmHg
or reduction
enalapril of 10 mmHg
10mg
once daily
enalapril 55%
(n=211)

% patients
0 20 40 60 80 100

Van Nueten L; Journal of Human Hypertension 11, 813-819 (1997)


32
IV. Nebivolol

Nebilet: high percentage of normalized patients

3-month double-blind
study in 420 patients
60 with essential hyper-
tension

nebivolol
40
54% nifedipine normalized BP defined
% patients

(retard) as
p = 0.007
diastolic 90 mmHg
42%
20

5mg once daily (n=211) 20 mg bd (n=209)

Van Nueten L; American Journal of Therapeutics 5, 237-243 (1998)

33
IV. Nebivolol

Comparison of Nebilet to losartan

Nebivolol: greater reduction of diastolic blood pressure after 6 and 12 weeks

6 weeks 12 weeks
0

losartan

losartan
nebivolol

nebivolol
-2

-4
Reduction (mmHg)

-6

-8 -8,3

-10 * -10,4
-12,5
-12 -13,0 *
-14
* p < 0.05 Nebivolol vs losartan

Van Bortel LA; Menarini Data on File (2002)

34
IV. Nebivolol

Comparison of Nebilet to losartan

Nebivolol: higher responder rate compared to losartan

70

60
63,3
50 56,5
% responders

40 45,7
30 39,8
nebivolol

nebivolol
losartan

losartan
20

10

0
3 weeks 6 weeks

Van Bortel LA; Menarini Data on File (2002)

35
IV. Nebivolol

Nebilet: antiproliferative effect

Inhibition of the
90 proliferation of human
*p < 0.05 nebivolol coronary artery smooth
80 muscle cells
*
70 (BrdU-ELISA) by
Nebilet comparison
60 * with beta-blockers
50
carvedilol
per cent

40 *
30
*
20 *
10
control metoprolol
0
-10
* * propanolol
-20 * * *
-30

Brehm et al; J Cardiovascul Pharmacol 36 (suppl 1), 401-403 (2000)


36
IV. Nebivolol

Nebilet: improved physical performance

Effect on exercise
endurance time in
70 healthy volunteers

60
p < 0.01 vs placebo
Time (min.)

50

40

30

20
placebo atenolol 50mg nebivolol 5mg

Van Bortel LMAB; Cardiovascular Drugs and Therapy 6, 239-247 (1992)

37
IV. Nebivolol

Nebilet: exercise performance in physically active


hypertensive patients
Risk reduction during maximal exercise test Exercise performance under day-to-day conditions

n = 18 n = 18
180
165

risk reduction
160
160 140

Work load in watt


120
Heart rate

155
100
150
80

145 60
40
140
20
0
placebo Nebilet placebo Nebilet
Predel et al; Journal of Human Hypertension 15, 715-721 (2001)

38
IV. Nebivolol

Respiratory effects of nebivolol and celiprolol in


patients with mild asthma
placebo nebivolol celiprolol
4

n = 12; *p < 0.05 vs baseline

3
FEV1/l

0
baseline after 2 hrs after 5 hrs

Cazzola M et al; Chest 118, 1322-1326 (2000)

39
IV. Nebivolol

Nebilet does not affect airway function

3
FEV1/l

0
placebo Nebilet

Mattheys et al; Z Kardiol 90, (Oct. 2002)

41
IV. Nebivolol

Nebilet in patients with hypertension and diabetes


mellitus
No change in HbA1c
serum glucose HbA1c under Nebilet
therapy
8 8
No change in blood
glucose values
under therapy
7 7
Marked increase in

per cent
safety of therapy
mm/l

Follow-up values of
6 6 HbA1c and serum glucose
under Nebilet in 15
patients with hypertension
and diabetes mellitus
(NIDDM)
5 5
0 6 12 24 weeks 6 12 24 weeks
According to Fogari R; J Human Hypertension 11, 753-757 (1997)

42
IV. Nebivolol

Nebilet: blood lipid values in long-term therapy

HDL=High Density Lipoprotein


No relevant change
cholesterol triglycerides in lipid values in
mg/dl

mg/dl
LDL=Low Density Lipoprotein
280
therapy
160
Marked increase in
140
safety of the
120 therapy
220
100

80

60 160

40

20
weeks 100 weeks
0

0 2 12 24 0 2 12 24

According to Fogari R, J Human Hypertension 11, 753-757 (1997)

43
IV. Nebivolol

Effects of nebivolol on plasma triglycerides in


hypertensive patients
n = 51 baseline
2
week 8

week 12

1
nebivolol

nebivolol

nebivolol

nebivolol 5 mg o.d. nifedipine 20 mg bid

Lacourcire Y et al; J Clin Pharmacol 32, 660-666 (1992)

45
IV. Nebivolol

Effects of nebivolol on plasma triglycerides in


hypertensive patients
baseline week 8 week 12 baseline week 8 week 12
7 1
mmol/l

mmol/l
total cholestorol VLDL

6 * 0.5
*
nebivolol nebivolol
5 0
nebivolol 5 mg o.d. nifedipine SR 20 mg bid nebivolol 5 mg o.d. nifedipine SR 20 mg bid

4.5 2
mmol/l

mmol/l
LDL HDL

4 * 1.5

nebivolol
* nebivolol
4.5 1
nebivolol 5 mg o.d. nifedipine SR 20 mg bid nebivolol 5 mg o.d. nifedipine SR 20 mg bid

n=51; *p<0.05 vs baseline Lacourcire Y et al; J Clin Pharmacol 32, 660-666 (1992)

46
IV. Nebivolol

Profit from Nebilet therapy in patients with intermittent


claudication
Improvement of
m (1) (2) maximum walking
40 distance
(Fontaine Stad. II a/b)
35
20
Atenolol 50mg n = 15
0
n = 30 Nebilet 5mg
-20

-40 -50

Schweizer et al; Z Kardiol 85, (Nov. 1996) (1) / Altman et al; Perfusion 13, (2000) (2)

47
IV. Nebivolol

Nebilet: effective and safe in elderly patients (65 years)


in a 3 months therapy
% %
90 60
80
50
70 88% 86%

Patients with normalized BP


50%
60 47%
Responder patients

40
50
30
40

amlodipine
amlodipine

30 20

nebivlol
nebivlol

20
10
10
0 0
nebivolol amlodipine
2.5 - 5 mg per day 5 - 10 mg per day nebivolol amlodipine

13.8 % patients with oedema in the amlodipine groups ( 12 | 87 )


0% for Nebilet ( 0 | 81 )
Mazza A et al; Blood pressure 11, 182-188 (2002)

48
Nebivolol pokazuje izuzetnu tolerabilnost

49
V. Coronary heart disease

2. Nebilet: stress tolerance in comparison

Effect of 5 mg
nebivolol and 50 mg
atenolol on
endurance under
15 maximum stress in
patients with CHD,
p < 0.65 conditions after
p < 0.01 myocardial infarction
10 (Percentage rise
per cent

compared to initial
p < 0.38 values)

nebivolol atenolol placebo

Rousseau et al; J Cardiac Failure 2, 15-23 (1996)

50
V. Coronary heart disease

3. Nebilet influence on angina pectoris parameters

placebo
St-segment depression (mm) pectoris threshold (sec)

nebivolol
Time until angina

1000
p < 0.05 p < 0.05
800

600
4 h after administration 8 h after administration
0

-1

-2

-3 p < 0.05 p < 0.05

Cherchi A et al; Drug Invest 3 (suppl. 1), 86-98 (1991)

51
VII. Nebilet summary

1. Nebilet: get the optimal control of hypertension

Effectiveness
Safety of therapy
Reliable 24 h action
No impairment to quality of life
Prevention of delayed complications

53
VII. Nebilet summary

1. Nebilet: key features

Dual mechanism of action


- NO mediated vasodilation
- Moderate 1-adrenoceptor antagonism

High percentage of responders


High percentage of normalized patients
Preserves-improves cardiac hemodynamic
Increases exercise duration and endurance
Low incidence of side effects

54
VII. Nebilet summary

2. Nebilet: a solid promise

Nebivolol promises to be a unique drug for the


treatment of multiple cardiovascular disorders.
The uniqueness stems from the capacity of nebivolol to
eclicit various cardioprotective actions by mechanisms
involving nitric oxide.
Louis Ignarro

55
Studied population, dose and The safety of nebivolol has been studied in a total of
duration of treatment 2871 patients at doses of 1-30 mg/day given for a
minimum of one month.
Safety Extremely low The incidence of the undesired effects typical of -
incidence of blockers is extremely low.
undesired effects The frequency of the appearance of undesired
effects is similar to that observed in patients treated
with placebo.
The only undesired effects observed more frequently
than in patients treated with placebo are dizziness,
fatigue and paresthesia (present in less than 5% of
patients).
Metabolic Nebivolol has a more favourable metabolic profile
neutrality than classical -adrenoceptor antagonists; it does
not interfere with glucose homeostasis in diabetic
patients and does not modify lipid metabolism.
Favourable The hemodynamics of nebivolol are favourable.
hemodynamic Unlike classical -antagonists, there is no worsening
profile in left ventricular function.
Exercise tolerance Exercise tolerance is not affected (and sometimes
even improved) by the administration of nebivolol.
Quality of life Nebivolol does not have a negative effect on the
quality of life of treated patients.
Comparison with These data have shown that nebivolol is well
other tolerated in comparison with traditional -blockers
antihypertensive and other antihypertensive agents, such as diuretics,
agents ACE-inhibitors and calcium channel blockers.
56
Summary diagram of the cardiovascular action of nebivolol

Nebivolol reduces
systemic vascular
resistance through an
endothelium dependent
NO-mediated
vasodilation, it also
achieves arterial
pressure reduction at Improved mechanics of
low levels of beta- diastolic filling (peak
blockade, improving filling rate and volume)
cardiac function. probably due to greater
distensibility

Longer diastolic time


intervals

Reduced end-diastolic
ventricular pressure
and end-diastolic wall
stress

Increased ejection
fraction, stroke volume
and cardiac output
Effects of
myocardial Increased distensibility
protection in and compliance of
ischemic diseases large vessels

Reduced peripheral
vascular resistance 57
Mechanism of action

Vasodilation through NO-mediated mechanism

Nebivolol

Highly selective 1-receptor antagonism

This dual mechanism of action gives nebivolol a unique hemodynamic, efficacy and safety profile. The drug controls
blood pressure in patients with essential hypertension by reducing vascular resistance through the NO-mechanism
and simultaneously improving left ventricular function.
Indications Its particular antihypertensive profile and tolerability at a dose of 5 mg/day make it a valid first-choice therapy in the
treatment of patients with essential hypertension.
Dose Nebivolol 5 mg in a single administration is the optimal efficacious dose. It does not require a multiple-dose titration
phase except in patients aged more than 65 years or with renal insufficiency (in whom the recommended starting dose
is 2.5 mg).
Studied population Nebivolol has so far been studied in 4500 patients.
Antihypertensiv Constant and long- Physiologically lowers systolic and diastolic pressure following circadian rhythms
e efficacy lasting Supports antihypertensive activity by means of an exceptional trough to peak ratio of 90% and a single daily dose
physiological blood Maintains its antihypertensive effect during long-term treatment without any rebound following its abrupt
pressure control discontinuation
High percentage of Administered alone, it is efficacious in 70% of patients
responders It is efficacious in both young and elderly patients
Hemodynamic Favourable Reduces peripheral vascular resistance (reduction in after-load)
profile hemodynamic Increases the ejection fraction, stroke volume and preserves cardiac output
profile in Increases the distensibility of large vessels
hypertensive Reduces heart rate
patients affected by Reduces end-diastolic ventricular pressure and end-diastolic wall stress (which indicates diastolic unloading and a
cardiac dysfunction, reduction in pre-load)
ischemic disease or Improves the mechanics of diastolic filling (peak filling rate and volume) probably because of improved distensibility
stable congestive Has myocardial protective effects in patients with ischemic disease
heart failure nebivolol therefore has an efficacious antihypertensive action, and simultaneously maintains or improves both the
systolic and diastolic function of the left ventricle.
Safety Metabolic neutrality Nebivolol does not have the typical metabolic interactions of -blockers in terms of glucose homeostasis (diabetes)
and lipid metabolism.
Optimum tolerability Nebivolol does not have the typical side effects of other antihypertensive agents, including -blockers, diuretics,
calcium channel blockers and ACE-inhibitors. This optimal tolerability means that patients do not have to suffer58
unpleasant side effects that may worsen their quality of life.