presentation with trials............favours Pharm-D Students.........

1. PHARMACOTHERAPEUTICS
PRESENTATION ON :
ROLE OF BETA-BLOCKER IN HYPERTENSION
BY
AAROMAL SATHEESH
II PHARM-D
JSS UNIVERSITY,MYSORE

2. ROLE OF BETA-BLOCKER
IN
HYPERTENSION

3. ROLE OF BETA-BLOCKER IN HYPERTENSION
INTRODUCTION
Beta blockers (β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists,
beta-adrenoreceptor antagonists) are a class of drugs that target the beta receptor found on cells of
the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of
the sympathetic nervous system and lead to stress responses, especially when they are stimulated
by epinephrine(adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other
stress hormones, and weaken the effects of stress hormones.
They are particularly used for the management of cardiac arrhythmias, protecting the heart from a second
heart attack (myocardial infarction) after a first heart attack (secondary prevention) and hypertension. In
addition, β-blockers reduce plasma rennin activity, reduce norepinephrine release, and
prevent the pressure response to exercise or stress catecholamine release. β -blockers are
effective antihypertensive agents, particularly for young white patients, and have been
proven to reduce mortality in randomized clinical trials .
Beta
blockers
block
the
action
of endogenous catecholamine's epinephrine
(adrenaline)
and norepinephrine (noradrenalin) in particular, on β-adrenergic receptors, part of the sympathetic nervous
system, which mediates the fight-or-flight response. Three types of beta receptors are known, designated β1,
β2 and β3 receptors. β1-adrenergic receptors are located mainly in the heart and in the kidneys. β2-adrenergic
receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and
skeletal muscle. β3-adrenergic receptors are located in fat cells
CLASSIFICATION OF BETA-BLOCKER
Beta blockers differ in the type of beta receptors they block and, therefore, their effects.
Non-selective beta blockers, for example, propranalol (Inderal), block β1 and β2 receptors and,
therefore, affect the heart, blood vessels, and air passages.
Selective beta blockers, for example, metoprolol (Lopressor, Toprol XL) primarily block β1 receptors
and, therefore, mostly affect the heart and do not affect air passages.
Some beta blockers, for example, pindolol (Visken) have intrinsic sympathomimetic activity (ISA),
which means they mimic the effects of epinephrine and norepinephrine and can cause an increase in
blood pressure and heart rate.
Beta blockers with ISA have smaller effects on heart rate than agents that do not have ISA.

4. Labetalol (Normodyne, Trandate) and carvedilol (Coreg) block beta and alpha-1 receptors. Blocking
alpha receptors adds to the blood vessel dilating effect of labetalol and carvedilol.
Presently beta-blockers are classified into three, they are: First Generation ( β1 & β2 , Cardioselective)
Propranalol
 Second Generation ( β1, Non-Cardioselective)
Atenolol, Metaprolol, Acebutolol, Bisoprolol, Betaxolol, Celiprolol
 Third Generation ( Vasodilatory Properties)
Carvedilol, Bucindolol, Nebivolol
PROPERTIES OF BETA-BLOCKERS
Many beta-blockers have ancillary properties which influence choice in hypertensive individuals.
Selectivity : Since the desired effects of beta-blockers are mediated by blockade of beta1-receptors which
predominate on the heart, “cardioselective” agents with relative selectivity for this receptor are generally
preferred. However, receptor selectivity is not absolute and is lost at high doses. Examples of
“cardioselective” beta-blockers include atenolol, bisoprolol and metoprolol. Beta-blockers with selectivity
rates > 50, e.g. bisoprolol and nebivolol, are least likely to lose selectivity at high doses.
Partial agonist activity (intrinsic sympathomimetic activity) : This manifests as a beta-stimulant effect
when background adrenergic activity is low (e.g. during sleep) but beta-blockade occurs when adrenergic
activity is increased (e.g. during exercise). Beta-blockers with partial agonist activity include pindolol.
Membrane-stabilising activity : This
e.g. sotalol.
mostly
confers a local anaesthetic and anti-arrhythmic effect
Other properties : Some beta-blockers also block effects mediated at peripheral alpha-adrenoreceptors,
e.g.:(carvedilol and labetalol), stimulate beta2-adrenoceptors (e.g. celiprolol) or have direct vasodilator
activity (e.g. nebivolol)

5. MECHANISM OF ACTION
Beta blockers, also known as beta-adrenergic blocking agents, are drugs that block norepinephrine and
epinephrine (adrenaline) from binding to beta receptors on nerves. Norephinephrine and epinephrine are
produced by nerves thorough out the body as well as by the adrenal gland. They serve as neurotransmitters
(chemicals that nerves use to communicate with one another ), and also are released into the blood. There
are three types of beta receptors and they control several different functions based on their location in the
body.
Beta-1 (β1) receptors are located in the heart, brain, and kidneys;
Kidney: Blockade of beta1-receptors inhibit the release of rennin from juxta-glomerular cells and
reduce the activity of the renin-angiotensin-aldosterone system.
thereby

6. Heart: Blockade of beta1-receptors in the sino-atrial node reduces heart rate (negative chronotropic effect)
and blockade of beta1-receptors in the myocardium decrease cardiac contractility (negative inotropic effect).
Central and Peripheral Nervous System: Blockade of beta-receptors in the brainstem and of prejunctional
beta-receptors in the periphery inhibits the release of neurotransmitters and decreases sympathetic nervous
system activity.
Beta (β2) receptors are found in the lungs, gastrointestinal tract, liver, uterus, blood vessels,
and skeletal muscles.
Activation of β2 receptors induces smooth muscle relaxation in the lungs, gastrointestinal tract,
uterus, and various blood vessels. Increased heart rate and heart muscle contraction is also
associated with the β2 receptors. β3 receptors are mainly located in adipose tissue.
Beta (β3) receptors are located in fat cells.
Activation of the β3 receptors induces the metabolism of lipids
PHARMACOKINETICS
Beta-blockers vary in the degree of elimination by the kidney or the liver, usually with extensive
first-pass metabolism. Lipid-soluble beta-blockers, e.g. labetalol, metoprolol, pindolol and
propranolol, typically depend upon hepatic metabolism for clearance, whereas water soluble
beta-blockers e.g. atenolol are cleared by the kidney. Drugs eliminated by the liver tend to exhibit
wide inter-individual variability in bioavailability. The half-life of most beta-blockers is relatively
short; those eliminated by the kidney tend to have longer half-life. Beta-blockers are first-line drugs
for the management of systemic hypertension, used alone and in combination with other
antihypertensive agents. Drugs in the beta-blocking class have the common property of blocking the
binding of catecholamine to beta-adrenergic receptor sites; however, there are significant
pharmacodynamic and pharmacokinetic differences between the individual agents that are of clinical
importance.
Among these differences are the completeness of gastrointestinal absorption, the degree of hepatic
first-pass metabolism, lipid solubility, protein binding, brain penetration, concentration within the
cardiac tissue, rate of hepatic biotransformation, and renal clearance of drug and/or metabolites.
Long-acting formulations of existing beta-blockers are currently in use, and ultra-short-acting agents
are also available. Age, race, cigarette smoking and concomitant drug therapy can also influence the

7. pharmacokinetics of beta-blocking drugs. The wide interpatient variability in plasma drug
concentrations observed with beta-blockers makes this parameter unreliable in routine patient
management. Despite the pharmacokinetic differences among beta-blockers, these drugs should
always be titrated to achieve the desired individual patient response.
TRIALS WITH BETA-BLOCKER IN HYPERTENSION
For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still
recommended as first-line agents by national and international guidelines. However, ever since the Veterans
Administration study in the 1970s multiple, prospective randomized trials have documented that diureticbased antihypertensive therapy reduces risk of stroke and, to a lesser extent, the risk of myocardial infarction
and cardiovascular morbidity and mortality. However, the data are much less convincing for beta-blockers.
The benefit of β-blockers compared with that of other anti-hypersensitive agents has recently
been questioned on the basis of the result of two randomized trials
LIFE STUDY
&
ASCOT STUDY
LIFE STUDY
The most important result of the study is that treatment based on once‐daily administration of
losartan reduced LVMI during up to 5 years of treatment significantly more than conventional
atenolol‐based treatment, confirming previous suggestions of superior regression of hypertensive
LVH by AT1 receptor antagonism. In the Treatment of Mild Hypertension Study(TOMHS), no difference
was observed between the ACE inhibitor and B‐blocker arms
Atenolol as a comparator in outcome trials in hypertension
OBJECTIVE
Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE)
study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we

8. reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on
reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study.
METHODS:
A literature search was conducted in September 2006 for randomized, controlled trials comparing betablockers with/without diuretics with placebo or no treatment in patients with hypertension and without
recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events,
cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all
beta-blockers first-line.
RESULTS:
Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in
groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all betablocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were
19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.730.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p =
0.146).
CONCLUSIONS:
Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension
compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the
results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this
agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension.
ASCOT STUDY
A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol
lowering in a factorial study design

9. ASCOT
Launched in 1997, ASCOT was an independent, investigator-led study designed to evaluate different
treatment strategies for preventing cardiovascular disease in hypertensive patients not considered
conventionally dyslipidemic. It was conducted in more than 650 general practices and 32 regional medical
centres across the United Kingdom, Ireland, and the 5 Scandinavian countries (Denmark, Finland, Iceland,
Norway, and Sweden). ASCOT also included a lipid-lowering arm, ASCOT-LLA, that was stopped early as
well, due to a significant reduction of cardiovascular events in the patients treated with atorvastatin. The full
results of ASCOT-LLA were published in 2003.
The primary objective of the trial was to compare the effects of the 2 treatment strategies on nonfatal
myocardial infarction (MI) and fatal coronary heart disease (CHD). In addition to assessing a number of
secondary and tertiary endpoints, the trial also was designed to examine the interaction between statins and
antihypertensive treatment.
STUDY DESIGN
ASCOT-BPL ( stopped after 5.5. years)
19,257 hypertensive
patients
atenolol ±
bendroflumethiazide
amlodipine ± perindopril
Investigator-led, multinational randomised controlled trial conducted in hypertensive patients,
40 -79 yrs, with no prior history of CHD, but with 3 additional cardiovascular risk factors
(male sex, > 55 yrs, smoking etc )

10. Treatment algorithm to BP targets < 140/90 mmHg or < 130/80 mmHg in patients with
diabetes
Amlodipine 5-10 mg
Atenolol 50-100 mg
Perindopril 4-8 mg
Bendroflumethiazide-K
1.25-2.5 mg
Doxazosin GITS 4-8 mg
Additional drugs, e.g., moxonidine/spironolactone
(Median follow up was for 5.5 years)
Baseline Characteristics
Demographic and clinical
characteristics
Amlodipine ± perindopril
n = 9639
Atenolol ± thiazide
n = 9618
Male
7381 (76.6%)
7361 (76.5%)
White
9187 (95.3%)
9170 (95.3%)
Current smoker
3168 (32.9%)
3110 (32.3%)

11. Age (years)
63.0 (8.5)
63.0 (8.5)
SBP (mmHg)
164.1 (18.1)
163.9 (18.0)
DBP (mmHg)
94.8 (10.4)
94.5 (10.4)
Heart rate (bpm)
71.9 (12.7)
71.8 (12.6)
BMI (kg/m2)
28.7 (4.6)
28.7 (4.5)
Diabetes
2567 (27%)
2578 (27%)
Other vascular disease
2169 (23%)
2162 (22%)
Total cholesterol (mmol/L)
5.9 (1.1)
5.9 (1.1)
1841 (19.1%)
1825 (19.0%)
1
4280 (44.4%)
4283 (44.5%)
≥2
3518 (36.5%)
3510 (36.5%)
Lipid-lowering therapy
1046 (10.9%)
1004 (10.4%)
Aspirin
1851 (19.2%)
1837 (19.1%)
Drug therapy
Previous antihypertensive treatments
0
Values are number of patients (%), or mean (SD)
TRIAL:- CONCLUSION
•
Amlodipine
perindopril-based therapy conferred an advantage over atenolol
thiazide-based
therapy on all major CV endpoints, all-cause mortality and new-onset diabetes
•
Additional statistical analyses demonstrated that adjusting for blood pressure differences between
treatment groups early on in the trial, did not account for the observed differences in cardiovascular
outcomes
•
•
Mean BP in trial has minimal effect on stroke outcome and no effect on CHD outcome
Various measures of visit-to-visit BP variability (SD, coefficient of variation and variation
independent of mean BP) are powerful predictors of both stroke and CHD outcomes
•
Other measures of variability (within-visit variability and variability assessed by ABPM) also
predict cardiovascular outcomes but less than visit-to-visit variability
•
Amlodipine reduces variability compared with atenolol
•
Variability increased with age, diabetes, smoking, and in those with established vascular disease

12. 2004 Meta Analysis of Outcomes: Atenolol vs. Other Antihypertensive
Treatments
 Analysis of 5 studies: Atenolol versus other antihypertensive therapy
 17,671 patients included, with a mean follow up of 4.6 years
 No differences in BP lowering
Risk Reduction
( 95% CL )
All cause-Mortality
1.13 (1.02-1.25)
CV Mortality
1.16 (1.00-1.34 )
Myocardial Infraction
1.04 (0.89-1.20 )
Stroke
1.30 (1.12-1.50 )
β-Blocker V/S Other Anti-hypertensive Agents
The graph shows the trial on a patient with hypertension and renal disease.

13. Beta Beta-Blockers V/s Other Antihypertensive Drugs: Composite Outcome
*
(* Death Stroke or MI )
Study Population
Beta-blocker
n/N
Other Drugs
n/N
RR
(95% CL)
Participants
<60 years
745/15136
770/15276
0.97
(0.88-1.07)
Participants
>60 years
3588/39010
3817/40765
1.06
(1.01-1.10)
Nebivolol : The 3rd Generation Beta-Blocker
Nebivolol is a β1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment
of hypertension and also for left ventricular failure. It is highly cardioselective under certain
circumstances. Nebivolol slows down the activity of your heart by stopping messages sent by some
nerves to your heart. It does this by blocking tiny areas (called beta-adrenergic receptors) where the
messages are received by your heart. Nebivolol also relaxes (widens) some blood vessels. Along with
their useful effects, The most common side-effects of nebivolol are tiredness, cold fingers or toes,
disturbed sleep, and stomach upset. Treatment with nebivolol is usually long-term. Do not stop taking
these tablets without speaking to your doctor first as this can cause problems.
Insulin Resistance: Effect of Nebivolol V/s Atenolol

14. CONTRAINDICATIONS OF BETA-BLOCKER
COMPELLING CONTRAINDICATION
Second or Third Degree Heart Block
In the heart condition called second degree block, some electrical impulses from the heart chambers called
the atria do not reach the chambers called the ventricles. When this occurs, there will be missed beats--the
normal heart beat will be interrupted with these intermittent missed beats. Patients with second or third
degree heart block should not take beta blockers because there is a risk that the heart block will worsen and
result in abnormal, potentially fatal heart rhythms.
Asthma
A 2007 study of over 11,000 patients, published in the journal "Pharmacotherapy," found that patients with
asthma who were on beta blockers had higher rates of hospitalization and more visits to the emergency
department, when compared with asthma patients not on beta blockers. This is because one of the actions of
beta blockers is to constrict the airways; patients with asthma already have constricted airways, so the beta
blockers make the problem worse. Asthma medicine works to relax the airways beta blockers constrict them.
Bradycardia
Bradycardia is the medical term for a heart rate that is fewer than 60 beats per minute. Patients with
bradycardia should not take beta blockers. This is because one of the effects of beta blockers is to decrease
the heart rate. So a patient with bradycardia who takes beta blockers is at risk for a dangerously low heart
rate. Patients may feel no symptoms related to their abnormally slow heart rate. Alternatively, patients may
experience symptoms such as light-headedness, chest pain, fatigue and weakness. Worsening of alreadyexisting
heart
failure
may
also
POSSIBLE CONTRAINDICATION
Atrial fibrillation
Tachycardia
Idiopathic hypertrophic subaortic stenosis
Migraine prophylaxis
Myocardial infarction prophylaxis
Hypertension
Pheochromocytoma
Thyrotoxicosis
Tremor
Ventricular arrhythmia
Atrial flutter
Myocardial Infraction
occur.

15. CONCLUSION
 Advice the use of β-blocker as a fourth
line anti-hypertensive agent
 Recent meta-analysis have shown that β-blocker
do not provide benefit for the endpoint of all
cause MI and mortality even when compared
with a placebo, both in elderly and younger
population
β-blocker's
 The β-blocker/diuretic combination favours
development of diabetes and should thus be
avoided, unless required for other reasons
ARB's
 β-blockers are not only less efficacious at reducing
peripheral blood pressure but also have a lesser
effect on perhaps the more important central
aortic pressure when compared with RAAS
blockers, diuretics &calcium antagonist

In patients with uncomplicated hypertension, there is paucity of data or absence of evidence
to support use of beta-blockers as monotherapy or as first-line agents. Risk of stroke, lack of
cardiovascular morbidity and mortality benefit, numerous adverse effects, lack of regression
of target end-organ effects of hypertension like LVH, and endothelial dysfunction, the risk
benefit ratio for beta-blockers is not acceptable for this indication
 All outcomes studies showing no benefit in hypertension were conducted with traditional
beta-blockers such as atenolol and metoprolol. Whether the newer vasodilating agents such as
nebivolol and carvedilol, which have a more favourable hemodynamic and metabolic profile,
will be more efficacious in reducing morbidity and mortality, remains to be determined.

16. REFERENCE
1. Wikipedia (www.wikipedia.com)
 Definition, Classification, Properties , Pharmacological Action , Nebivolol etc
(Date of Reference :- 25/10/13)
2. Medscape (www.medscape.com)
 Current Analysis of Beta-blocker, When to use beta-blocker etc
(Date of Reference:- 25/10/13)
3. Jaac (www.onlinejaac.org)
 Meta Analysis of Beta-Blocker, Trials-Life Study etc
(Date of Reference:-25/10/13)
4. WebMD (www.webmd.com)
 Contraindication, Present beta-blockers, Adverse effects etc
(Date of Reference:-27/10/13)
5. www.cardiosource.org , www.ncbi.gov.com
 Atenolol, Amilodipine, Mechanism of action etc
(Date of Reference;-27/10/13)
6. MedicineNet Search (www.medicinenetsearch.com)
 Trials :- ASCOT , Meta-analysis of Beta-blocker, Study Design , Treatment Algorithm etc
(Date of Reference:-27/10/13)