Targets and Benefits of Blood Pressure

Lowering Through Nitric Oxide and

B3 Agonism ; Focus on NEBIVOLOL
 Algorithm for Treatment of Hypertension
Lifestyle Modifications

Not at Goal Blood Pressure (<140/90 mmHg)

(<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling With Compelling

Indications Indications

Stage 1 HTN (SBP 140–159 or
DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB,
CCB, or combination.
Stage 2 HTN (SBP >160 or DBP
>100 mmHg)
2-drug combination for most
(usually thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.

Not at Goal
Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
JNC 7 Express. JAMA. 2003 Sep 10; 290(10):1314
 -blockers:
Compelling Indications

ACE Angiotensin Calcium Aldosterone

Diuretic -blocker
Inhibitor II Blocker Antagonists Antagonist

Heart Failure     
Post Heart Attack    
High CAD Risk     
Diabetes Mellitus     
Chronic Renal
Disease  
Recurrent Stroke   

 New studies

Modified from Chobanian AV, et al. JAMA 2003;289:2560-2572.

 -blockers:
Targets and Receptor Selectivity

Heart Blood Vessel

a2 a2
_ _
+ b1 a2 Vasoconstriction
Inotropy
+ b Vasoconstriction
Chronotropy 2
NE NE NE a1
+ Vasodilation
Dromotropy _ a – + b2 Vasodilation
1
M2 b2
M2 M2
Sympathetic
• 1-selective blocker Nerve Terminal
• -nonselective blocker

• -nonselective blocker with 1- ACh

blocking activity

Parasympathetic Sympathetic Cholinergic Nerve

Nerve Terminal Terminal

a=alpha receptor, Ach=acetylcholine, b=beta receptor, M=muscarinic receptor, NE=Norepinephrine

Klabunde RE (ed). Cardiovascular Physiology Concepts LWW 2001

 Effects Mediated by
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 T4T3 conversion
Fat cells 1 ,3 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

López-Sendón J, et al. Eur Heart J 2004;25:1341-1362.

 ß-blockers:
Heterogenous Drug Class

-blockers

ß1/ß2 Vasodilatory
Selectivity Properties
Which One?

ß-blockers

Side Metabolic Outcomes

Effects Profile Trials
 -blocker History

First Generation
Nonselective
Propranolol
Timolol

Second Generation
Selective
Atenolol
Metoprolol
Bisoprolol

Third Generation
Vasodilatory
Labetalol
Carvedilol
Nebivolol
 -blockers Approved in the
United States
Date of New Drug Application Approval

Acebutolol
1984

Penbutolol
1987
Pindolol
Bisoprolol
1982
Metoprolol 1992
Tartrate
1978 Nebivolol
Propranolol Atenolol Esmolol Metoprolol
1967 2007
1981 1986 Succinate
1992

1960 1970 1980 1990 2000 2010

Nadolol
1979
Carteolol
1988 Sotalol Propranolol XL
Timolol 1992 2003
1981

Propranolol LA Carvedilol 1995

1983 Betaxolol Carvedilol CR
1989 2006
Labetalol
1984
Vasodilating -blockers are yellow LM Prisant 2008
Source: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Reports.ReportsMenu
 Characteristics
-adrenoceptor Blockers

Nonselective 1-blocker Selective

ISA- ISA+ ISA+ ISA-

Nadolol Pindolol Acebutolol* Atenolol
Propranolol* Carteolol Esmolol
Timolol Penbutolol Labetalol 1:4-7* Metoprolol
Sotalol¶ Carvedilol 1:10*† Nebivolol‡
Bisoprolol
Betaxolol*

No -blocker is cardioselective in large doses

2-blockade is needed for tremor and migraines
1-blockers are better for bronchospasm & insulin-requiring diabetes

* Membrane Stabilizing Activity

† Antioxidant
‡ Nitric oxide-mediated vasodilation
¶ Class III antiarrhythmic

Modified from Kaplan NM. Clinical Hypertension (8ed). 2002;262.

 Nebivolol:
Ultraselective, Vasodilating 1-blocker

A Nitric-oxide-donating, vasodilating, lipophilic 3rd generation

highly selective Beta-1- adrenoceptor Blocker
Racemic mixture of 2 enantiomers d & l-Nebivolol

d- Nebivolol l- Nebivolol
• involved in the nitric oxide (NO)-mediated
• responsible for selective β-1-
endothelium-dependent dilatation,
antagonism
through L-arginine / NO pathway †
• highly selective β1-receptor
• responsible for the vasodilatory,
antagonist and a β3-receptor
antioxidant, antiproliferative and anti-
agonist.
platelet actions of the drug.
 Structure of Nebivolol Compared With Other {beta}-Blockers

Munzel, T. et al. J Am Coll Cardiol 2009;54:1491-1499

Copyright ©2009 American College of Cardiology Foundation. Restrictions may apply.

NEBIVOLOL : β3 Receptor Agonist
NEBIVOLOL : β3 Receptor Agonist
 1-Selectivity

50
45 40.7
40
35
Ki 2/Ki 1

30
25
20 15.6
15
10
4.23
5 0.73 0.49
0
Nebivolol Bisoprolol Carvedilol Metoprolol Bucindolol

Brixius K, et al. Br J Pharmacol 2002;133:1330-1338.

 What is Nitric Oxide?

► First described in 1979 as a potent relaxant

of peripheral vascular smooth muscle.
► Used by the body as a signaling molecule.
► Serves different functions depending on
body system. i.e. neurotransmitter,
vasodilator, bactericide.
► Environmental Pollutant
► First gas known to act as a biological
messenger
 The structure and nature of Nitric Oxide

N O
► Nitric oxide is a diatomic free radical consisting of one
atom of nitrogen and one atom of oxygen
► Lipid soluble and very small for easy passage between
cell membranes
► Short lived, usually degraded or reacted within a few
seconds
► The natural form is a gas
 Synthesis of Nitric Oxide

• Nitric oxide is synthesized from L-arginine

 Activation of NOS

► Glutamate neurotransmitter binds to NMDA receptors

► Ca++ channels open causing Ca influx into cell
► Activation of calmodulin, which activates NOS
► Mechanism for start of synthesis dependent on body
system
► NO synthesis takes place in endothelial cells, lung cells,
and neuronal cells
Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.ht
Contd…
Nitric Oxide Synthase (NOS)
 Types of NOS

► NOS I
● Central and peripheral neuronal cells
● Ca+2 dependent, used for neuronal communication
► NOS II
● Most nucleated cells, particularly macrophages
● Independent of intracellular Ca+2
● Inducible in presence of inflammatory cytokines
► NOS III
● Vascular endothelial cells
● Ca+2 dependent
● Vascular regulation
 Nitric Oxide Signaling

Enzyme Gene No. of No. of Subcellular Regulation

exons residues location

nNOS NOS1 29 1429-1433 Mainly

soluble Ca2+/CaM
(brain);
iNOS NOS2 27 1144-1153 Mainly Ca2+
soluble independent

eNOS NOS3 26 1203-1205 Mainly Ca2+/CaM

particulate
Neuronal Nitric Oxide Synthase (nNOS)
Epithelial Nitric Oxide Synthase (eNOS)
Inducible Nitric Oxide Synthase (iNOS)
 Mechanism of Action of NO

Various stimuli 5’- HT

Acetylcholine
Thrombin
Calcium ionophore A23187
Changes in AP &ES Arachidonic Acid

NO Release

Prostacyclin

Platelet antiaggregation &

Vasorelaxation effect
 Mechanism of Action of NO
NO

NO bind to Fe 2+ haem group Active Guanylate Cyclase

of Guanylyl Cyclase

Increased cGMP

Increased intracellular Ca 2+

Relaxes muscle

Dilating the vessel &

lowering B.P.
 Mechanism of Action of NO

NO inhibitor of platelet activation

Alteration in formation of NO

Vasoconstriction, Platelet adhesion and Aggregation

 Nitric Oxide Signaling
Relaxation of smooth muscle
1) Stimulated nerve releases
Acetylcholine(ACh) at Nerve
terminal

2) ACh binds to receptors

on endothelial cells
Smooth muscle cell
blood vessel wall

4) NO diffuses
across membranes GTP cGMP

Arg NO
NO
3) Activate NO synthase
5) NO binds to Guanylyl cyclase
 Role of NO in the human body

► Nitric Oxide in the human body has many

uses which are best summarized under five
categories.
● NO in the nervous system

● NO in the circulatory system

● NO in the muscular system

● NO in the immune system

● NO in the digestive system

 Nitric Oxide in the Nervous System

► Nitric oxide as a neurotransmitter

● NO is a signaling molecule, but not necessarily a neurotransmitter

● NO signals inhibition of smooth muscle contraction, adaptive

relaxation, and localized vasodilation
► Nitric oxide believed to play a role in long term memory
● Memory mechanism proposed is a retrograde messenger that
facilitates long term potentiation of neurons (memory)
● Synthesis mechanism involving Ca/Calmodulin activates NOS-I

● NO travels from postsynaptic neuron back to presynaptic neuron

which activates guanylyl cyclase, the enzyme that catalyzes cGMP
production
● This starts a cycle of nerve action potentials driven by NO
 Nitric Oxide in the Circulatory System

► NO serves as a vasodilator
● Released in response to high blood flow rate and
signaling molecules (Ach and bradykinin)
● Highly localized and effects are brief

● If NO synthesis is inhibited, blood pressure

skyrockets
 Nitric Oxide in the Muscular System

► NO was orginally called EDRF (endothelium

derived relaxation factor)
► NO signals inhibition of smooth muscle
contraction
● Ca+2 is released from the vascular lumen
activating NOS
● NO is synthesized from NOS III in vascular
endothelial cells
● This causes guanylyl cyclase to produce cGMP
● A rise in cGMP causes Ca+2 pumps to be
activated, thus reducing Ca+2 concentration in
the cell
● This causes muscle relaxation
Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htm
 Mechanism Underlying Endothelial Dysfunction

An unbalanced production of nitric oxide (NO) and superoxide (O2 –) leads to inappropriate formation of peroxynitrite
(ONOO–). Peroxynitrite and superoxide cause vascular dysfunction through several mechanisms (reviewed in
Forstermann and Munzel [1]). Peroxynitrite is a strong inhibitor of NO and prostacyclin (PGI2) signaling, and it may cause
eNOS uncoupling, causing this enzyme to produce superoxide instead of NO. ADMA = asymmetrical dimethylarginine;
cGMP = guanosine 3',5'-cyclic monophosphate; cGK = cGMP-dependent kinase; eNOS = endothelial nitric oxide
synthase; ET = endothelin; sGC = soluble guanylate cyclase; TXA = thromboxane.
 Oxygen Free Radicals in CV Pathophysiology

Munzel, T. et al. J Am Coll Cardiol 2009;54:1491-1499

(Left) Kaplan-Meier analysis demonstrating cumulative proportion of patients without cardiovascular events during follow-up.
Effect of vitamin C on acetylcholine-induced vasodilation is divided into values below and above the median. Interestingly, patients
who responded well to vitamin C treatment had a worse prognosis compared with patients with a weak response to vitamin C.
Thus, a strong vitamin C-induced improvement of endothelial dysfunction may point to increased oxidative stress in coronary
arteries as well. (Right) Mechanistic hypothesis: vitamin C may restore eNOS function by either direct scavenging of superoxide
(red) or by recoupling of the eNOS. Details in Forstermann and Munzel (1). NOS = nitric oxide synthase; Vit = vitamin; other
abbreviations as in Figure 1.
 Nebivolol: Potential Benefits
of Nitric Oxide Potentiation

► Endothelial dysfunction is:

 A key marker of atherosclerosis

 Characterized by impaired nitric oxide

bioactivity
► Nebivolol has been shown to enhance nitric
oxide bioactivity and improve endothelial
function
► This effect may explain the cardioprotective
benefits of the vasodilating β-blocker nebivolol

Mason RP, et al. J Clin Hypertens. 2006;8 (suppl 2):31-40

 NEBIVOLOL : Vascular Relaxation via the
L-arginine–NO Pathway

L-arginine

Endothelial
NOS

Nitric oxide
(diffuses into smooth muscle)

Guanylyl Cyclase

Activated Guanylyl Cyclase

GTP cGMP

Vascular Smooth Muscle Relaxation

Veverka A, et al. Am Pharmacother 2006;40:1353-1360.

 Mechanisms Underlying Release of NO
in Response to Acute Nebivolol Challenges

Munzel, T. et al. J Am Coll Cardiol 2009;54:1491-1499

In renal glomeruli, nebivolol activates mechanosensitive ion channels, which subsequently release adenosine triphosphate (ATP) and
stimulate P2Y receptors, causing calcium-dependent eNOS activation (24). Nebivolol or its metabolite may also activate β2 (in
conduit arteries) (22) or β3-receptors (in resistance arteries) (23), which also increase intracellular calcium, thereby activating eNOS.
cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; ERβ = estrogen receptor beta; other
abbreviations as in Figure 1.
 Impact of Nebivolol on Endothelial Responses
and Free Radicals Production

Effects of intra-arterial infusion of nebivolol on forearm blood flow in healthy control subjects (A) and patients with essential
hypertension (B) (26,27). In both groups, nebivolol but not atenolol caused vasodilation, an effect that was antagonized by
endothelial nitric oxide synthase (eNOS) inhibition. (C) Percent change in forearm blood flow in response to the endothelium-
dependent vasodilator acetylcholine after treatment with atenolol or nebivolol, respectively. Nebivolol alone markedly improved
endothelial function in hypertensive patients (30). (D) Nebivolol, but not other β-blockers, inhibits phorbolester (PDBu)-induced
superoxide production in neutrophils from hypercholesterolemic rabbits (34). EPR = electron paramagnetic resonance.
 Nebivolol: Nitric Oxide Mediates Stimulation of
Endothelium-Dependent Venodilation

100 Without NO Inhibitor

80
Venodilation (%)

60

40
With NO Inhibitor

20

-20
10-12 10-11 10-10 10-9 10-8 10-7

Nebivolol Dose (mol min-1)

Bowman AJ, et al. Br J Clin Pharmacol 1994;38:199-204.

 Release of Nitric Oxide from
Human Endothelium: White vs Blacks
Nitric Oxide: NO
Superoxide Anion: O2-
Peroxynitrite: ONOO-
African American
White African American + Nebivolol
30 mM

300 mM
30 mM

Time (s) Time (s) Time (s)

Calcium ionophore Calcium ionophore Calcium ionophore

Mason RP, et al. Circulation 2005;112:3795-3801.

Nebivolol : Vasodilation
Nebivolol : Vasodilation
Nebivolol reduces arterial stiffness
Nebivolol Hemodynamic Effect
Nebivolol Hemodynamic Effect
Nebivolol Hemodynamic Effect
 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.

Clinical Study of Nebivolol
 Efficacy of Nebivolol in Black Patients:
Diastolic and Systolic BP
N 47 46 51 49
Baseline DBP (mm Hg) 100.6 99.9 100.3 101.4
Baseline SBP (mm Hg) 151.4 151.7 154.2 156.4
Dose Placebo 5 mg 10 mg 20 mg
0
Mean Δ in BP vs baseline (mm Hg)

-2
-4 -3.6
-4.4
-6
-5.9
-8
-10 -9.1
-10.3 -10.2 -10.6
-12
-12
-14

DBP SBP
Placebo DBP Placebo SBP
Saunders E et al. J Clin Hypertens. 2007;9:866-875
 Efficacy of Nebivolol in Obese* Patients:
Diastolic and Systolic BP
N 92 189 188 196
Baseline DBP (mm Hg) 100.6 99.9 100.3 101.4
Baseline SBP (mm Hg) 151.4 151.7 154.2 156.4
Dose Placebo 5 mg 10 mg 20 mg
0
Mean Δ in BP vs baseline (mm Hg)

-2

-4 -3.6
-4.8
-6

-8

-10 -9.3
-9.9 -10.3 -9.9
-10.7 -10.9
-12

DBP SBP
Placebo DBP Placebo SBP
•Obesity defined as body mass index >30 kg/m2.
•Data on file, Forest Laboratories, Inc. New York, NY
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
NEBIVOLOL in Hypertension
 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 Δ 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
This study assessed blood pressure (BP) reductions and response rates following
addition of nebivolol to ongoing antihypertensive therapy in patients with uncontrolled
stage I–II hypertension despite antihypertensive treatment.

Study design: 12-week, randomized, double-blind, placebo-controlled, parallel-group

study conducted at 96 centres in the United States.
Effect of Nebivolol addition on blood pressure and heart rate

Addition of nebivolol to background antihypertensive therapy led

to significant additional BP and HR reductions compared with
placebo
Increased the BP responder rate
 Nebivolol Reduces Peripheral Vascular
Resistance in Patients with Hypertension

25 *
20.6 25
20
20
15
Percent change vs baseline

15

Beats per minute

10 7.1
10
5
5
0
0
-5
-5
-10
-10
-15 -13.2
* -15
Peripheral resistance Stroke volume Cardiac output Heart rate
(dyne/cm5) (mL) (L/min) (bpm)
*N=25; parameters at 2 weeks
At 2 weeks; *P<0.05 vs pretreatment. Change in SBP/DBP was -19/12 mm Hg for nebivolol
Adapted from Kamp O et al. Am J Cardiol. 2003;92:344-348
Nebivolol Safety and Tolerability Profile
 Nebivolol Analysis: Toleration

Flow chart of the selection of 85 clinical trials with NEB identified

clinical trials for a meta-analysis
of the comparative tolerability of
nebivolol (NEB) and other Head-to-head comparisons of NEB and other CSBs?
cardioselective ß-blocker drugs Yes No
(CSBs) in the treatment of
hypertension. 40 trials 45 trials excluded

Treatment of hypertension, duration ≥4 weeks and paper contains any evaluable tolerability data?
Yes No

10 trials (n = 569 for nebivolol; n = 553 for other CSBs) 30 trials excluded

Trial quality assessed according to pre-defined criteria (adequate reporting of

tolerability data, sample size ≥50 patients per study arm, and double-binding)

High quality (all criteria met) Low quality (violating one or more critera)
Three trials (n = 306 for nebivolol; Seven trials (263 treatment cycles with nebivolol; 259 treatment cycles
n = 294 for atenolol or metoprolol) with atenolol; bisoprolol or metroprolol [two studies had a crossover design])

Tolerability of Nebivolol in Head-To-Head Clinical Trials. Ettore Ambrosioni and Claudio Borghi.
High Blood Press Cardiovasc Prev 2005;12(1):27–35.
 Ratio of the Rates of Patients with AEs in Randomized
Clinical Trials of Nebivolol vs Other Cardiovascular
ß-Blockers in the Treatment of Hypertension

Tolerability of Nebivolol in Head-To-Head Clinical Trials. Ettore Ambrosioni and Claudio Borghi.
High Blood Press Cardiovasc Prev 2005;12(1):27–35.
Nebivolol Safety and Tolerability Profile
 Nebivolol Profile with Respect to Side Effects
Commonly Associated with ß-Blockers*

Incidence Rate (%) Discontinuation Rate (%)

Adverse Nebivolol Nebivolol

Placebo Placebo
Event (%) (n=205) 5mg-40mg (n=205) 5mg-40mg
(n=1597) (n=1597)

Fatigue 1.5 3.6 0.5 0.0

Dyspnea 0.5 1.0 0.0 0.1

Bradycardia 0.5 0.8 0.0 0.2

Erectile
0.9 0.6 0.0 0.0
Dysfunction†
Depression 0.0 0.3 0.0 0.0

*Pooled data from the three monotherapy US registration trials with nebivolol.
†For erectile dysfunction n=108 for placebo and n=853 for nebivolol. 5 mg to 40 mg
Registration trials. Data on file, Forest Laboratories, Inc. New York, NY
Nebivolol Safety and Tolerability Profile
 Insulin Resistance:
Effect of Nebivolol vs. Atenolol

36-week Randomized, Double-blind Crossover Design

n = 25
Insulin Sensitivity Index
5
p<0.01
0
Percentage Change

-5

-10
-15 -12.2

-20

-25 -21.6
Nebivolol Atenolol
2.5-5 mg QD 50-100 mg QD

Poirer L, et al. J Hypertens 2001;19:1429-1435

 Effect of Nebivolol and Metoprolol
on Insulin Resistance
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
 Nebivolol: Effect on Glucose Levels
Pooled Analysis of the Three Monotherapy US Registration Trials
4 3.7
3.5
Mean Δ from baseline (mg/dL)

3 2.8
2.4
2.5
2 1.7
1.5
1
0.5
0
Placebo 5 mg 10 mg 20 mg
(n=196) (n=432) (n=435) (n=438)

Nebivolol
These laboratory parameters are among the 51 standard laboratory values that were collected from patients with mild to moderate
hypertension in three U.S Phase III, 3-month, placebo-controlled studies of nebivolol monotherapy.
Data on file, Forest Laboratories, New York, NY
 Nebivolol: Effect on Lipid Levels
Pooled Analysis of the Three Monotherapy US Registration Trials
200
Baseline Endpoint

150
mg/dL

100

50

0
LDL (mean) HDL (mean) Triglycerides
(median)
1. Registration trials. Data on file, Forest Laboratories, Inc. New York, NY
2. Nebivolol package insert. New York, NY. Forest Laboratories, Inc; 2007
Nebivolol Safety and Tolerability Profile
Effect of Nebivolol and Metroprolol on Sexual
Function: IIEF
Nebivolol 5 mg
Metoprolol succinate 95 mg
Nebivolol Safety and Tolerability Profile
 BIOEQUIVALEN STUDY - NEVODIO

BIOEQUIVALENCE = THERAPEUTIC EQUIVALENT

NEVODIO Bioekuivalen vs Originator artinya : KUALITAS,
KEAMANAN dan EFICACY NEVODIO SETARA dengan
ORIGINATORNYA
Aaroon S Kesselheim, JAMA 2008;300(21) 2514-2526
 BIOEKUIVALEN STUDY - NEVODIO

OBJECTIVE :
To find out whether the bioavailability of PT Dexa
Medica’s formulation 5 mg nebivolol tablets (NEVODIO
) is equivalent to the reference product (Nebilet® 5 mg
tablet, Berlin-Chemie A.G for Menarini International
Operations, Luxembourg S.A).

This study was carried out in accordance with the Declaration of

Helsinki and its amendment and to the relevant Good Clinical
Practice (GCP) standards and in agreement with the local Ethics
Committee
 BIOEKUIVALEN STUDY - NEVODIO
Mean plasma concentration-time profiles of nebivolol in human subjects (n = 17) after
a single dose oral administration of 5 mg nebivolol tablets produced by PT Dexa
Medica (Test drug) - NEVODIO and the reference (Reference drug = Nebilet® 5 mg
tablet) : COMPARABLE / SIMILAR  NEVODIO BIOEKUIVALEN vs ORIGINATOR

Vertical bars indicate standard deviation

 Conclusions

► Beta blockers are not all created equally

► NEBIVOLOL (NEVODIO) is a Novel third generation
β-Blocker with vasodilator properties, mediated by a direct
stimulatory effect on the endothelial nitric oxide synthase
( eNOS)
► NEBIVOLOL (NEVODIO) is a highly selective β1-receptor
antagonist and a β3-receptor agonist
► NEBIVOLOL (NEVODIO) may produce clinical outcomes
that differ from traditional beta-blockers because of its
efficacy, safety and tolerability profile
► NEVODIO BIOEKUIVALEN vs ORIGINATOR 
EFFICACY and QUALITY SIMILAR to its Originator
THANK YOU