CORONARY ARTERY DISEASE :
Coronary artery disease (CAD) affects almost more than 2 million worldwide, making it the most common form of
heart disease. CAD and its complications, like arrhythmia, angina pectoris, and myocardial infarction (MI), are the
leading causes of death. It is estimated that in South Asia and China in which over half the world's population live,
death from coronary heart disease will rise by 11.5-12.7% for Indian and 811-10% for Chinese women and men,
respectively, from the level in 1990 to 2020 [Yip GWKetal, 1999; Murray CJLIet all 996].
Coronary artery disease (CAD) rates in urban areas in India are now 4-fold higher than in the United States (US)
although the rates were similar in 1968. Both overseas and resident Indians have the highest rates of CAD,
although almost half of them are life-long vegetarians.
When compared to Whites, Blacks, Hispanics and other Asians, CAD rates among Indians worldwide are two to
four times higher at all ages and five to ten times higher in those < 40 years of age.
Although CAD is a fatal disease with no known cure, it is also highly predictable, preventable, and treatable.
During the past 30 years, CAD rates halved in the US, Australia, Canada, France, Japan, and Finland. These vast
reductions in CAD mortality are attributed to nationwide changes in specific risk factors that were identified
through epidemiological research and addressed through population-based interventions, rather than extensive
use of expensive technology. Reduction in risk factors explains most of the decline with modest contributions from
advances in treatment.
Ironically, the CAD rates doubled in India during the same period, primarily due to dietary changes associated with
epidemiological transition from a rural sustenance economy to an urban market oriented economy [Enas EA et al,
2000].
Studies on the prevalence of coronary artery disease (CAD) in India reveal some disturbing trends.
BP & CVD
The relationship between BP and risk of cardiovascular disease (CVD) events is continuous, consistent, and
independent of other risk factors. The higher the BP, the greater the chance of myocardial infarction, heart failure
(HF), stroke, and kidney disease. For individuals aged 40 to 70 years, each increment of 20 mm Hg in systolic BP
or 10 mm Hg in diastolic BP doubles the risk of CVD across the entire BP range from 115/75 to 185/115 mm Hg
[VasanRSetal, 2002].
IMPACT OF BP CONTROL ON CLINICAL OUTCOMES
In clinical trials, antihypertensive therapy has been associated with reductions in stroke incidence averaging 35-40
percent; myocardial infarction, 20-25 percent; and heart failure, more than 50 percent [Neal B, 2000].
It is estimated that in patients with stage 1 hypertension (SBP 140/159 mmHg and or DBP 90/99 mmHg) and
additional cardiovascular risk factors, achieving a sustained 12mmHg reduction in SBP over 10 years will prevent
1 death for every 11 patients treated. In the presence of CVD or target organ damage, only 9 patients would require
such BP reduction to prevent a death [Ogden LG etal, 2000].
DRAWBACKS OF EXISTING DRUGS
Introduction
Keeping in view of Atenolol as an example of a typical Beta-blocker, it is easily evident that the following traits
are obvious:
Avoid in Bronchospastic disease.
Impotence/loss of libido documented.
Avoid in diabetics
Cold hands and feet. Raynaud's phenomena. Vasoconstriction.
Avoid in peripheral vascular disease (PVD).
May worsen lipid profile and have increased atherosclerotic effect.
Atenolol (also Celiprolol) are the most water-soluble; the kidneys excrete them; they accumulate in renal
impairment and dosage reduction is therefore often necessary.
Suppress the normal exercise induced tachycardia, hence avoid in active or young [at heart]
Orthostatic Hypotension; hence, avoid in older patients
Reduced cardiac out put; Fatigue.
Atenolol & Metoprolol
Commonly used Beta Blockers (BBs), atenolol and metoprolol are cardio selective i.e. they block only the Beta-1
receptors found predominantly in the heart and do not block the Beta-2 receptors (found predominantly in the
bronchi and peripheral blood vessels). Neither of these drugs have intrinsic sympathomimetic activity and both
may produce substantial slowing of the pulse.
PROPRANOLOL
Propranolol is a non-selective Beta-blocking drug whose place in medicine has been largely overtaken by other
selective Beta Blocker. In the treatment of migraine, its Beta-2 blocking properties may be useful in assisting
vasoconstriction. However, it is unsuited for use in individuals with any degree of asthma (because it blocks the
action of Beta-2 agonists such as salbutamol or terbutaline) and is unsuited for use in diabetics prone to
hypoglycemia because it delays recovery of the blood sugar level.
CARVEDILOL
Carvedilol is a minimally Beta-1 receptor-selective Beta-blocking agent that also has high affinity for alpha-1
receptors. At low doses (6.25 mg twice daily) Carvedilol may exhibit some Beta-1 selectivity in humans with HF. At
higher target doses, Carvedilol blocks all three adrenergic receptors coupled to hypertrophy and other adverse
biological effects. Carvedilol's side effect profile on initiation of therapy and during up titration is different from that of highly Beta-1 -selective second-generation agents, with orthostatic symptoms being more prominent.
LIMITATIONS OF CURRENT BETA BLOCKER THERAPY IN HEART
FAILURE
Despite their proven efficacy in mild to moderate Heart Failure (HF) in patients with primary or secondary dilated
cardiomyopathy, it is important to emphasize that Beta blockers have limitations to general application in HF
populations.
First and foremost is that many HF patients have contraindications to Beta blockade, such as reactive airway
disease, sinus node or conduction system disease with bradycardia, and advanced HF with hemodynamic
decompensation.
Another problem is that even in mild to moderate HF, initiation of therapy and up titration of Beta-blocking agents
can be difficult and require both persistence and a knowledge of management maneuvers that allow target doses
to be achieved.
A third problem is that for reasons that are not yet clear, some patients do not respond to Beta blockade in terms of
favorable effects on myocardial function, and these individuals may have a worse outcome than patients treated
with placebo.
Some, but not all of these problems might be overcome by the development of more efficacious or better-tolerated
compounds, the use of other, more effective types of antiadrenergic therapy, or the use of a combination of Beta
blockers with positive inotropic agents.
The importance of the Beta blocker data set is not that it demonstrates a "cure" for chronic HF, but rather that it has
now been shown that in some patients, the prognosis can be substantially improved by medical therapy. This
observation should provide an impetus to develop further types of treatment that improve the biological properties
of the failing heart.
Heart failure is a common syndrome with disabling symptoms and a poor prognosis. Heart failure is usually
associated with impaired systolic ventricular function (heart failure with a large heart and decreased ejection
fraction) but may also present with preserved systolic ventricular function (normal sized heart and near-normal
ejection fraction). This latter entity is more common in the elderly [Vasan RSetal, 1995; PernenkilRetal, 1997].
The average age of patients in these previous placebo controlled mortality and morbidity studies of betablockers
in heart failure has been 63 years, and patients with an ejection fraction >0.40% were excluded [ShibataMCetal,
2001]
In a community-based study, the average age of new incident cases of heart failure was 76 years. The lack of
evidence from a representative sample of elderly patients with heart failure has raised doubts about extrapolating
the current evidence for beta-blockers to patients in the community. More relevant evidence from randomized
trials is needed to clarify the balance of risk and benefit of beta-blockers in elderly patients with a broad range of
ventricular function. The SENIORS Study (Study of the Effects of Nebivolol Intervention on Outcomes and
Re-hospitalization in Seniors with Heart Failure) was undertaken to determine the effect of Nebivolol on
mortality and morbidity in elderly patients with heart failure, regardless of ejection fraction [Flather MD et al 2005].
HOW SENIORS COMPARED WITH OTHER TRIALS DATA :
A CRITICAL ANALYSIS
The estimated hazards ratio (HR) for the primary outcome in SENIORS was 0.86, which suggests a lesser degree
of risk reduction compared with previous large trials.
Nevertheless both components of the primary outcome (all cause mortality and CV hospital admission) show a
similar and consistent effect indicating that the results are robust with a 15% proportional and 4% absolute
reduction in risk. Furthermore, when a sub analysis was undertaken in order to determine the result for patients
most similar to those recruited in previous trials, the findings were similar to the results from previous trials, with a
significant 27% and 38% reductions in the primary composite endpoint and all cause mortality, respectively. This
indicates that Nebivolol has beneficial effects of a magnitude similar if not more to those of other beta-blockers
proved to have major outcome benefits in heart failure. In addition, analysis by subgroups clearly shows that
Nebivolol is particularly effective in patients with preserved ejection fraction, women and those <75 yrs .
DRUG OF CHOICE IN ASSOCIATED CO MORBIDITY WITH HT
The patient with hypertension and certain co morbidities requires special attention and follow-up by the clinician.
Coronary artery Disease (CAD)
CAD is the most common form of target organ damage associated with hypertension. In patients with
hypertension and stable angina pectoris, the first drug of choice is usually a BB; alternatively, long-acting CCBs
can be used [JNC, 1997].
In patients with acute coronary syndromes (unstable angina or myocardial infarction), hypertension should be
treated initially with BBs and ACEIs, with addition of other drugs as needed for BP control [Cleophas TJ, 2001].
In patients with post myocardial infarction, ACEIs, BBs, and Aldosterone antagonists have proven to be most
beneficial [Braunwald E et al, 2002].
Diabetic Hypertension.
Combinations of 2 or more drugs are usually needed to achieve the target BP goal of less than 130/80 mm Hg
[ADA, 2003].
Thiazide diuretics, BBs, ACEIs, ARBs, and CCBs are beneficial in reducing CVD and stroke incidence in patients
with diabetes.
Pregnancy and lactation
Women with hypertension who become pregnant should be followed carefully because of increased risks to
mother and fetus. Methyldopa, beta-blockers, and vasodilators are preferred medications for the safety of the
fetus[122].
Angiotensin-converting enzyme inhibitors and ARBs should not be used during pregnancy because of the
potential for fetal defects and should be avoided in women who are likely to become pregnant [NHBPEP, 2000].
CURRENT GUIDELINES TO TREAT THE MAJOR CARDIVASCULAR DISEASE
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure (JNC-VII) recommended that clinicians reduce blood pressure below 140/90 mm Hg or even
lower if tolerated. In high-risk populations such as those with DN or renal disease a treatment goal of <130/80 mm
Hg is recommended. The primary goal in the treatment of hypertension is to reduce morbidity and mortality by
lowering blood pressure and by modifying other cardiovascular risk factors.
The few key messages while treating the HT:
Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension,
either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for
the initial use of other antihypertensive drug classes (Angiotensin converting enzyme inhibitors, Angiotensin
receptor blockers, beta-blockers, calcium channel blockers).
Most patients with hypertension will require two or more antihypertensive medications to achieve goal blood
pressure (<140/90 mmHg, or <130/80 mmHg for patients with diabetes or chronic kidney disease).
If blood pressure is >20/10 mmHg above goal blood pressure, consideration should be given to initiating therapy
with two agents, one of which usually should be a Thiazide-type diuretic.
WHO:
Unlike the current US hypertension guidelines (JNC 7) and European guidelines, the WHO/ISH guidelines are
aimed at a global audience and are intended to serve as a template for the development of national, regional, and
local guidelines [WHO, 2003]. However, they resemble the European guidelines more closely than they do JNC 7.
Blood Pressure Classification
The WHO/ISH blood pressure classification includes 3 grades of hypertension
Unlike JNC 7, in the WHO/ISH statement, there is no "prehypertension" classification. Observational studies,
limited randomized clinical trial data, and extrapolation from randomized trial data are in agreement that the
primary goal is to lower SBP to < 140 mm Hg and in high-risk patients to < 130/80 mm Hg.
Initial Therapy (after lifestyle modifications):
The WHO/ISH statement cites multiple randomized clinical trials showing reductions in morbidity/mortality
compared with placebo for diuretics/BBs and CCBs. Meta-analyses of randomized clinical trials comparing ACEIs
or CCBs against older drugs have shown no convincing differences (but they do not exclude the possibility of small
differences in specific outcomes).
The WHO/ISH agree that the aggregate trial data suggest the morbidity/mortality benefits of antihypertensive
treatment derive largely from blood pressure reduction: at the same time, strong evidence that specific agents
benefit patients with compelling indications is cited as the basis for recommending certain classes of drugs in such patients.
For patients without compelling indications, the comparative trial data indicate that, on the basis of availability and
cost, a (low-dose) diuretic should be considered for first-line therapy.
Subsequent Therapy
The WHO/ISH guidelines point out that monotherapy will be inadequate for the majority of patients. They note that
no available comparative randomized clinical trial data on morbidity/mortality are available to guide selection of
optimal combinations, but point out that diuretics enhance the efficacy of other classes and will most often be a
component of combination therapy. Fixed-dose combination formulations have advantages in patient adherence
and efficacy, and are not more expensive than monotherapy.
Cost-effectiveness:
In many settings, Thiazide diuretics are cheapest and hence most cost-effective, but for compelling indications
classes that provide additional benefits, even if more expensive, may be more cost-effective. In high-risk patient;
with large benefits from treatment, even expensive drugs may be cost-effective, whereas in low-risk patients
treatment may not be cost-effective unless the drugs are cheap.
ESH/ESC:
The new European Society of Hypertension (ESH)/European Society of Cardiology (ESC) guidelines for the
management of arterial hypertension were presented at the 2003 ESH meeting in Milan and published
simultaneously in the Journal of Hypertension [ESH/ESC, 2003]. Prior to the publication of the new ESH
guidelines, both the ESH and the ESC had simply endorsed the guidelines formulated by the International Society
of Hypertension (ISH) and the World Health Organization (WHO). However, the Europeans had come to believe
that they needed to issue their own guidelines, because the WHO/ISH guidelines, last published in 1999, were
concerned with a global vision and dealt largely with issues concerning the developing world, where the health
problems are different from those pertaining only to Europe.
No European "Prehypertensives"
According to JNC 7, the category of prehypertensive pools all subjects with SBP 120-139 mm Hg and DBP 80-89
mm Hg together. But to date, there is evidence of therapeutic benefit in this so-called high normal range only if the
patient has a high or a very high additional risk. If a patient has a blood pressure of 122/82 mm Hg, for example,
there is no evidence that the patient should get any form of pharmacologic treatment. However, if there is evidence
that a patient with blood pressure 120/80 mm Hg is at high risk (e.g., has diabetes and family history of
hypertension), then this patient should in fact be assigned to drug treatment. So, They object the word
"Prehypertensive"
Combination Therapy
The importance of combination treatment is emphasized in both the European and the JNC 7 guidelines.
However, the ESH/ESC guidelines have a new element, in that they say that since combination treatment is so
important and so prevalent, physicians should be given the option to start with combination treatment. So one of
the flow charts in the guidelines gives 2 options, monotherapy or low-dose combination.
An obvious disadvantage of starting with a low-dose combination is that some patients may be on two drugs even
though they could get their blood pressure under control with one. The advantage is faster blood pressure control,
which has favorable psychological reflection on both the patient and the physician. Low dose means probably less
chance of side effects and better compliance.
The new guidelines also outline the criteria for when the doctor may want to start with a low-dose combination or
with monotherapy-for example, the blood pressure level. If the blood pressure is quite high, the patient is going to
require 2 or 3 drugs eventually, and it may seem like a waste of time to start the patient on a single drug. Then
again, if the patient is at high risk (even with a more moderate blood pressure), he/she needs blood pressure
control quickly, and it seems unnecessary to wait 3-5 months before achieving control.
The guidelines mention that fixed-dose combinations could increase compliance by simplifying treatment.
Avoid Switching
Both the European and JNC 7 guidelines discourage switching from one drug regimen to another. This practice
which used to be known as sequential monotherapy, takes a very long time and has a negative impact on the
patient. In addition, the chance of achieving blood pressure control is not high. As a result, switchers are patients
whose blood pressure is not controlled, and they are the ones who tend to become noncompliant.
Blood pressure is a multiregulated variable and it takes several points of attack to control it and also to prevent
compensating mechanisms. As a result, combination treatment is probably going to be more effective
There are instances in which sequential monotherapy is inevitable. For example, if a drug is not effective at all
then it is useless to keep it on board; or if the patient develops a side effect, then the drug must be changed, ln
other words, switching cannot be prevented completely, but it should not be the regular strategy, as this is
a bad policy.
According to ESH/ES the following two-drug combinations have been found to be effective and well tolerated
Diuretic and Beta-blocker;
Diuretic and ACE inhibitor or angiotensin receptor antagonist;
Calcium antagonist (dihydropyridine) and Beta-blocker;
Calcium antagonist and ACE inhibitor or Angiotensin receptor antagonist;
Calcium antagonist and diuretic;
Alfa-blocker and Beta-blocker;
Other combinations (e.g. with central agents, including Alfa -adrenoreceptor agonists and imidazoline 12 receptor
modulators, or between ACE inhibitors and Angiotensin receptor antagonists) can be used if necessary, and three
or four drugs may be required in many cases.
Rationale Of Combination Of Drugs
Physicians often have a misguided belief that blood pressure can be controlled with a single drug and
demonstrate reluctance to change or to add pills in those patients whose blood pressures are not at
recommended goals. Many physicians are inclined to practice sequential monotherapy with individual agents as
opposed to recognizing the additive benefits of agents in combination.
It is well recognized that no more than 50% of a hypertensive population will be controlled by a single drug, even
when used in maximal recommended dosages. On the other hand, the skillful use of two or more agents in
combination can improve hypertension control rates to well above 80% [Lloyd-Jones DM, 2000].
The JNC 7 states that persons with blood pressure (BP) more than 20/10 mm Hg above goal should be started on
combination drug therapy. This criterion includes patients with BP >160/100 mm Hg and diabetics with
hypertension. The goal BP for persons with diabetes mellitus is <130/80 mm Hg [Jonathan C et al, 2003].
Because of the lower dose of each agent in a combination antihypertensive drug, metabolic and clinical adverse
events are decreased.
The rationale for using fixed-dose combination therapy is to obtain increased blood pressure control by employing
two antihypertensive agents with different modes of action and to enhance compliance by using a single tablet that
is taken once or twice daily [EisenSA, 1990].
Using low doses of two different agents can also minimize the clinical and metabolic effects that occur with
maximal dosages of the individual components of the combined tablet [Sica DA. 1994]. These potential
advantages are such that some investigators have recommended using combination antihypertensive therapy as
initial treatment, particularly in patients with target-organ damage or more severe initial levels of hypertension
[MoserM, 1997; MoserM, 1998]
Rationale Of Combination Beta Blocker And Thiazide Diuretics
As per JNC 7, thiazide-type diuretics should be used as initial therapy for most patients with hypertension, either
alone or in combination with 1 of the other classes (ACE inhibitors, ARBs, -blockers, CCBs) demonstrated to be
beneficial in randomized controlled outcome trials.
Thiazide-type diuretics have been the basis of antihypertensive therapy in most outcome trials [Psaty BM et al
1997]. Diuretics enhance the antihypertensive efficacy of multi drug regimens, can be useful in achieving BP
control, and are more affordable than other antihypertensive agents. Despite these findings, diuretics remain
underused [Psaty BM, 2002].
The combination of a beta-blocker and a diuretic produces additive effects compared with monotherapy using
either agent alone. A recent study assessed the safety and efficacy of antihypertensive therapy using the cardio
selective beta-blocker alone and in combination with low dosages of Hydrochlorothiazide. The study showed that
monotherapy with either agent was more effective than placebo, but that when combination therapy was used, the
beneficial effects were greater than when either agent was used alone [Frishman WH et al, 1995]. In the same
study combination therapy was associated with a low incidence of adverse effects.
Because higher doses of diuretics cause reflex activation of both the renin-angiotensin and sympathetic nervous
systems, preventing such activation with the addition of a a-blocker, ACE inhibitor, or an ARB produces synergistic
effects on blood pressure. With fixed-dose combinations, the dose of HCTZ should be 12.5 mg or, even better,
6.25mg. Unfortunately, many fixed-dose combinations contain 25 mg of HCTZ, which often is too high.
Thus, Combinations of two drugs offers:
Additive/synergistic efficacy-better efficacy
Low doses of individual drugs are required
Less adverse effects
Some of side effects of individual drug are counteracted
Clinical efficacy and safety of combination of Nebivolol and HCTZ
Nebivolol, compared with classical beta-blockers, exerts a high selectivity for beta-adrenergic receptors and also
reduces peripheral vascular resistance by modulating nitric oxide (NO) release. This dual mechanism of action
leads to effective control of blood pressure at a low degree of beta-blockade and explains the lack of any
interference with lipid metabolism. For the same reason, the tolerability profile of Nebivolol is highly favorable
compared with the classical beta-blockers, with less fatigue and dyspnea in hypertensive subjects, and with an
improvement of functional capacity and exercise tolerance in patients with left ventricular dysfunction.
Furthermore, contrary to atenolol and propranolol, Nebivolol does not diminish specific airway conductance.
Compared with other first-line antihypertensive agents, Nebivolol was shown to be better tolerated than nifedipine
and enalapril, and to have a positive effect on general wellbeing. Among the currently available antihypertensive
drugs, Nebivolol therefore appears to have a most attractive safety and tolerability profile, which can be attributed
to its NO-mediated effects allowing effective control of hypertension at a lower degree of beta-blockade than with
first-generation beta-blockers [Pessina AC et al, 2001].
Nebivolol has an additive effect in combination with Hydrochlorothiazide in management of essential
Hypertension [McNeely Wet al, 1999; lakushin SS et al, 2002].
In 30 hypertensive postmenopausal Nebivolol was given to women as monotherapy (5-10 mg/day) or in
combination with Hydrochlorothiazide and author found that clinical effect in terms of antihypertensive was
achieved in 76.6 and 86.7% of women on mono- and combination therapy, respectively. Blood pressure lowering
was not only associated with decrease of total peripheral resistance but also with regression of left ventricular
hypertrophy and Bart Bla et al concluded that Nebivolol appeared to be metabolically neutral and found to be
having only sporadic adverse effects. [Bart Blet al, 2002].
In one of the parallel 3 x 4 factorial placebo controlled study (n=240) the effects of Nebivolol, and
Hydrochlorothiazide (HCTZ) in combination on BP and plasma lipids, lipoproteins and apolipoproteins were
compared. Nebivolol 1, 5 or 10 mg, HCTZ 12.5 or 25 mg or one of the six possible combinations of Nebivolol and
HCTZ was found to be effective in significant dose-related reduction in BP among all active treatment groups.
Apart from a slight and isolated increase in triglycerides with HCTZ 12.5 mg, lipid, lipoprotein and
apolipoprotein levels as well as lipoprotein and apolipoprotein ratios were not significantly modified by
12-week active treatments when compared with placebo treatment. The results of this multifactorial study
with 12 small sample size groups, suggest that Nebivolol as monotherapy and in combination with HCTZ does not
cause deleterious effects on the lipid profile [Lacourciere Y et al, 1994].
Lacourciere Y et al assessed the antihypertensive efficacy of Nebivolol and Hydrochlorothiazide monotherapy
and in combination in placebo-controlled multifactorial design clinical study (n= 240) in white patients with a mean
daytime ambulatory blood pressure of > or = 90 mm Hg were randomized to receive either placebo, Nebivolol (1,
5, or 10 mg), Hydrochlorothiazide (12.5 or 25 mg), or one of the six possible combinations of Nebivolol and
Hydrochlorothiazide for 12 weeks. It was found that Nebivolol, given as monotherapy or in combination with low
dose of Hydrochlorothiazide, is effective in reducing clinic and 24-h ambulatory blood pressure in patients with
ambulatory hypertension. [Lacourciere Yet al, 1994].
INTRODUCTION TO NEBIVOLOL
Nebivolol is lipophilic, vasodilating highly selective beta 1 adrenoceptor blocker, which can be distinguished from
other Beta-blockers by its hemodynamic profile. It is the most Beta 1 -selective adrenoceptor antagonist currently
available for clinical use and has no alfa 1-blocking action [Van Bortel LMABetal, 1997; Van Nueten Let all 998].
It is devoid of intrinsic sympathomimetic or membrane stabilizing activity and Beta-adrenergic blocking activity
with a vasodilating effect mediated by the endothelial L-arginine NO pathway, the property not shared by other
beta-blockers [CockroftJR et, 1995, CleophasTJ, 2003]. Decreased bioavailability of NO has been demonstrated
in essential hypertension and other conditions associated with increased cardiovascular risk, such as diabetes
and hypercholesterolaemia. Nebivolol therefore, has considerable potential in cardiovascular therapy
In addition to its established antihypertensive effects, Nebivolol improves arterial compliance [Vanmerodet et i
1989] and left ventricular(LV) function in patients with heart failure [Uhuroetal, 1991]. Treatment with Nebivok
preserves LV function [De Cree J et al, 1991] and can reduce LV mass in hypertensive patients with L'
hypertrophy [Stolerul et al, 1993].
Besides significant (p < 0.001 ) reduction in triglycerides (13 %) with Nebivolol cholesterol also found to b
decreased by 8% in hypertensives. In hypertensive with diabetic patients Nebivolol had the most
favorable effects in terms of decrease in triglyceride, cholesterol and glucose by 18%, 9% and 16°
respectively [von Fallois J et al, 2001]. In patients with essential hypertension hypotensive action of Nebivok
was associated with antiaggregation effect and improvement of blood flow in microvascular network
These properties of Nebivolol have considerable therapeutic potential especially in patients with
hypertension with coexisting coronary artery disease, a common cause of impaired cardiac function
Endothelial dysfunction occurs early in various forms of CVD and arterial endothelial damage may contribute to
the pathogenesis of atherosclerosis in hypertension [Moncada Set al, 1994]. A direct action of Nebivolol on the
vascular endothelium, together with its effectiveness as a Beta-blocker, may therefore be beneficial in patients
with endothelial dysfunction associated with hypertension, diabetes mellitus and hypercholesterolaemia. Thus
treatment with Nebivolol may slow, or even prevent some of the vascular complications of hypertension. Looking
to the above results of the studies and analysis of metabolic parameters are of interest as a contribution to the
preventive effect of Nebivolol on coronary heart disease also.
Nebivolol in complex therapy increases efficacy of treatment of patients with CHF due to IHD [Evdokimova AG et al, 2004].
Nebivolol (DL-Nebivolol) is a racemic mixture containing equal proportions of two enantiomers, L-Nebivolol
(RSSSS-Nebivolol) and D-Nebivolol (SRRRR-Nebivolol). The enantiomers have different pharmacological
properties as only the D-isomer provides the Beta-blocking component [Van PeerAetal, 1991] whilst both the D-
and L-isomers have an endothelial NO-dependent vasodilating effect. Coronary vasodilation induced by
stereoisomers of Nebivolol (D- and L) is mediated by endothelium-derived NO and does not depend on beta2,
beta3 adrenoceptors or 5 HT1A receptors [Chlopicki S et al, 2002]. The beneficial effects of Nebivolol on LV
systolic and diastolic function appears to require the presence of both D- and L-enantiomers [Stoleru L et al, 1993].
Thus, racemic Nebivolol is needed forthe drug to be most effective.
Pharmacokinetic and metabolism
Nebivolol is rapidly absorbed after oral administration of a standard 5 mg dose and reaches peak plasma levels
between 30 mins to 2 h after intake. It is extensively metabolized, partly to active hydroxy metabolites. Metabolism
by aromatic hydroxylation is subject to the cytochrome P450 (CYP) 2D6-dependent genetic oxidative
polymorphism and excretion is mainly in the faeces and urine. The absolute oral bioavailability of Nebivolol is -
12% in extensive metabolizes and almost complete (96%) in poor metabolizer. At steady state and at the same
dose level, the peak plasma concentration of unchanged Nebivolol is 23 times higher in poor metabolizer than in
extensive metabolizes. However, the plasma concentrations of unchanged Nebivolol plus the pharmacologically
active hydroxylated metabolites are comparable in both phenotypes, explaining the same clinical effects in poor
and extensive metabolizes. The fact that no measurable difference in hemodynamic effect between poor and
extensive metabolizes has been found suggests a similar hemodynamic effect of the parent molecule and its
active metabolizer, indicating that in poor metabolizes no dose adjustment is needed [Himmelman A et al, 1996,
Moncadasetal, 1993]. Thus, one dose fits all both in fast and poor metabolizers.
The pharmacokinetic of Nebivolol are not affected by age. However, the recommended starting dose for patients
> 65 years of age is 2.5 mg/day. This is in line with many other antihypertensive treatments where the dosage is
lowered in elderly patients.
Endothelial function and the role of nitric oxide
The pathophysiology involved in atherogenesis is not completely understood and therefore strategies for both
primary and secondary prevention have mainly focused on the modification of conventional risk factors in
isolation. Recently, however, attention has focused on the endothelial cells that line the blood vessels.
The vascular endothelium serves not only as a passive barrier to diffusion between the circulating blood and the
underlying vascular smooth muscle, but also regulates vessel tone, inhibits clot formation and impairs the
multiplication of cells involved in plaque formation. The endothelium synthesizes a potent endogenous smooth
muscle dilator NO, from the amino acid L-arginine, via the action of the constitutive enzyme NO synthase
[Moncadas et al, 1994]. NO regulates basal vascular tone and blood pressure and has powerful anti-atherogenic
properties. Abnormalities of the L-arginine/NO pathway resulting in decreased bioavailability of NO have been
demonstrated in a variety of conditions associated with increased cardiovascular risk including, diabetes,
hypercholesterolaemia and hypertension. As endothelial dysfunction often precedes the development of overt
CVD, it has been suggested that decreased bioavailability of NO may predispose to atherogenesis [Moncadas et
al, 1994].
Studies in essential hypertension have demonstrated impaired endothelium-dependent vasodilation, although
this is not a universal finding [Panza JA et al, 1993;Shimokawa H, 1998]. Antihypertensive therapy can improve
endothelial function, either indirectly via adecrease in blood pressure or directly via an effect on the endothelial L-
aiginine/NO pathway [Taddeiset al, 1999; NapoliCetal,2002]
Nebivolol appears to interact with the endothelial NO pathway in two complementary ways: it increases NO
synthase (NOS) activity and reduces the NO-scavenging radical super oxide anion, by re-directing deranged
NOS activity, from super oxide to NO production [Ignarro LJ et al, 2004, Cominacini L et al, 2003]. The
vasorelaxation caused by Nebivolol is mediated via release of endothelium-derived NO [Gaoy Nagaot Bondra et
al, 1991]. Fig.9
These findings have been confirmed in a human vascular bed in vivo [Cockcroft JR et al, 1995]. Intra-arterial
infusion of Nebivolol produced vasodilatation and an increase in forearm blood flow whereas atenolol had no
effect. Co-infusion of L-NMMA blocks this effect and this inhibition can in turn be reversed by L-arginine, the
substrate for NO production. Similar effects of Nebivolol have also been demonstrated in patients with
hypertension [DAWES M et al, 1999]. Nebivolol, but not Atenolol, given orally improves both basal and
stimulated NO release relative to placebo in patients with essential hypertension [Tzemos Net al, 2001].
Evidence based medicines have shown that Nebivolol causes dose-dependent vasodilatation when infused into
superficial hand veins [Bowman AJet al, 1994], again this response can be inhibited by L-NMMA.
In addition to its positive effect on 24-hour BP profile and myocardial morphofunctional parameters,
Nebivolol restores the NO-ergic regulation of endothelial vasomotor function in patients with arterial
hypertension (AH), by potentiating NO expression, and modulates steady-state vasodilatation [Gel'tser Bl
etal, 2002].
Nebivolol appears also to possess a complementary antioxidant activity, through which the pathological
ROS-induced depression of intracellular NO levels can be prevented [Ignarro LJ et el, 2004]
Coronary Blood Flow And Other Hemodynamic Effects
Due to its vasodilator properties including a reduction in systemic vascular resistance and an increase in
cardiac output [83] the hemodynamic effects of Nebivolol differ from those of traditional Beta-blockers. In
healthy volunteers, Nebivolol 5 mg decreases systemic vascular resistance with no impairment of LV function
[Van De Water A et al 1988].
Nebivolol therapy induces not only a significant increase of the coronary flow rate (CFR) but also preserves
coronary flow at rest despite the reduction of metabolic {0, consumption) and hemodynamic (diastolic blood
pressure) determinants [Galderisi M et al 2004].
Chronic treatment with Nebivolol maintains/improves LV function in healthy volunteers and in patients with
hypertension [Ritter JM, 2001; Demiralp E et al 2004], acute myocardial infarction (MI) and congestive heart
failure [STOLERULet al, 1993].
Nebivolol demonstrated its high effectiveness and safety during prolonged therapy of patients with prior MI,
without cardio depressive activity and favorable impact on their Inequality [Bichan NA et al, 2004].
Nebivolol shares most of its effects with classical beta 1 -blockers but is devoid of the potentially harmful effects on
cardiac output (CO) and peripheral resistance apart from reduction in systemic vascular resistance (SVR), HR
and BP. After a week of treatment, acceleration of aortic flow velocity increased and isovolumic relaxation time
decreased with Nebivolol [Goldstein M et al, 1993].
In patients with essential hypertension hypotensive action of Nebivolol was associated with
antiaggregation effect and improvement of blood flow in microvascular networks [Zadionchenko VS et al,
Clinical efficacy &/Post marketing surveillance
A 6-week observational study has monitored the acceptability and antihypertensive efficacy of Nebivolol in 6376
hypertensive patients with and without concomitant diseases [Fallois JV et al, 2001]. Both systolic and
diastolic blood pressures were significantly reduced with Nebivolol treatment. Heart rate was also reduced.
..Nebivolol was well tolerated and adverse effects were markedly lower than those expected with other Beta-
blockers. Cholesterol,triglyceride,and blood sugarwere not adversely affected. Such findings are confirmed from
the results of double-blind randomized studies [Van BortellMabet al, 1993; Van Nuetenet al, 1998; Lacourcieryet
t;al, 1994].
By chronic administration to patients with left ventricular dysfunction Nebivolol increases myocardial contractility.
Nebivolol produced no significant changes in lipid levels, insulin sensitivity or glucose tolerance. These findings
make Nebivolol a promising therapeutic tool for the treatment of arterial hypertension and chronic heart failure
[KuroedovAetal, 2004].
Patients treated for 3 months with up to Nebivolol 10 mg/day showed no changes in plasma total cholesterol,
triglycerides,lipoproteinsandapolipoproteins[VanNueten etal, 1997;LacourciereYetal, 1994; 1992].Thisisin
contrast with classical Beta-blockers, which can alter plasma lipids in a potentially adverse manner [Cruickshank
JM etal, 1987].
The antihypertensive effect of Beta-blockers increases during the first 6-8 weeks of treatment, but the effects of
chronic treatment have not been systematically assessed. Long-term efficacy of Nebivolol monotherapy has been
monitored by Cleophas et al and demonstrated greater reduction in blood pressure and a higher percentage of
responders after 6 months of Nebivolol treatment. Nebivolol was well tolerated and patients reported a better
feeling of general well being compared with any previous monotherapy [Cleophas TJ et,2001]..
Safety and Tolerability
Arterial stiffness and cardiovascular risk
Ii Direct assessment of aortic stiffness using measurement of the Pulse Wave Velocity (PWV) has shown that increased arterial stiffness not only predicts cardiovascular risk but also outcome in patients with hypertension,
diabetes, end stage renal failure and older individuals [Boutouyrie P et al, 2002; Cruickshank K et al, 2002;
Blacher Jet all 999; Meaumes et al 2001].
And as it is known that arterial stiffness is a major risk factor for CVD. Endothelial dysfunction, which is found in
patients with most cardiovascular risk factors, may explain why these conditions are also associated with
increased arterial stiffness at an early stage, before the development of manifest atheroma [Cockcroft JR, 1997]
Therefore, drugs that improve endothelial function may also be useful in these conditions.
Endothelium-derived NO is an important in the regulation of large arterial stiffness [Wilkinson IB etal, 2002; Kinlay
S et al 2001]. Moreover, in recent experiments it has been shown that Nebivolol, although not atenolol, at
equimolar doses is able to directly decrease large arterial stiffness, assessed by measuring iliac PW, without any effects on systemic blood pressure and that this beneficial effect of Nebivolol is due to the release of endothelium-
derived NO [Mceniery CM etal, 2002]. Such observations have importantimplicationsforthe management of the
increasing number of patients with conditions associated with arterial stiffening, such as ISH, diabetes and
hypercholesterolaemia. Nebivolol that decreases arterial stiffness and blood pressure may be of use both in terms
of reducing cardiovascular risk and outcome.
Nebivolol in Type 2 DM
Stringent control of blood pressure is more effective at reducing cardio-vascular events than tight control of blood
sugar as during the course of the diabetic mellitus, a high proportion of patients develop hypertension [Kannel WB
et, 1991; UKPDS Group, 1998]. Type 2 diabetes is associated with endothelial dysfunction characterized by a
decreased bioavailability of NO and Nebivolol restores the NO-ergic regulation of endothelial vasomotor function
in patients with AH, by potentiating NO expression, and modulates steady-state vasodilatation [Gel'tser Bl et al,
2002;]. Clinical studies had shown that Nebivolol is not linked with impairment of insulin sensitivity or glucose
tolerance, thus making it a good antihypertensive agent for use in diabetic patients [Fogari R et al, 1997].
Makolkin et al concluded in one of the study that "Nebivolol is effective and safe antianginal agents in
patients with IHD and hypertension combined with type 2 diabetes with more favorable metabolic and
hemodynamic effects" [Makolkin VI et al, 2003].
In Post menopausal women
Nebivolol was given for 8 weeks to 34 menopausal women with grade 1 and 2 hypertension The use of Nebivolol
was associated with decreased rate and severity of vasomotor reactions and thus with positive effect on
menopausal syndrome [Alekseeva NP et al, 2003].
In Elderly
Baroreflex sensitivity declines with age, creating a fall in systolic blood pressure and pulse pressure when
standing. If, in addition, blood pressure is reduced as a result of antihypertensive medication, compensatory
mechanisms may be inadequate and orthostatic problems may occur.
This may be less true in patients on beta-blockers. Effects of Nebivolol 5 mg daily on standing pulse pressures
in elderly subjects with mild hypertension was studied in 3741 patients with mild hypertension for 6 months.
The pattern of pulse pressure was unchanged in the younger subjects, but reversed into a steep and
significant rise of pulse pressure in the elderly group. In elderly patients with mild HT, a depressor trend of
pulse pressure while standing can be turned into a significant pressor response by treatment with Nebivolol
[Cleophas TJ et, 2002]. Several studies reported no signs of orthostatic hypotension with Nebivolol
[Ghiuru Ret al, 2001].
In COPD
Safety, tolerability and antihypertensive efficacy of a cardioselective beta-blocker Nebivolol was studied in 30
patients with mild and moderate hypertension and concomitant stage I chronic obstructive bronchitis.
Nebivolol (5 mg/day) was given for 1 month; in 5 patients complementary Hydrochlorothiazide (12.5 mg/day)
was required for sufficient antihypertensive effect. Nebivolol was well tolerated (only 1 patient complained of
head ache), did not cause worsening of bronchitis and spirometric parameters, exerted no cardio depressive
action, and did not induce apparent disturbances of metabolism [lakushin SS et al, 2002].