PHARMACOTHERAPEUTICS

PRESENTATION ON :

ROLE OF BETA-BLOCKER IN HYPERTENSION

BY

AAROMAL SATHEESH

II PHARM-D

JSS UNIVERSITY,MYSORE

ROLE OF BETA-BLOCKER

IN

HYPERTENSION

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.

 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 mostly confers a local anaesthetic and anti-arrhythmic

effect e.g. sotalol.

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)

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 thereby

reduce the activity of the renin-angiotensin-aldosterone system.

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

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 diuretic-

based 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

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 beta-

blockers 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 beta-

blocker 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 (0.73-

0.99, 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

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 )

Treatment algorithm to BP targets < 140/90 mmHg or < 130/80 mmHg in patients with

diabetes

(Median follow up was for 5.5 years)

Baseline Characteristics

Demographic and clinical characteristics

Amlodipine ± perindopriln = 9639

Atenolol ± thiaziden = 9618

Male 7381 (76.6%) 7361 (76.5%)

White 9187 (95.3%) 9170 (95.3%)

Current smoker 3168 (32.9%) 3110 (32.3%)

Amlodipine 5-10 mg

Perindopril 4-8 mg Bendroflumethiazide-K

1.25-2.5 mg

Atenolol 50-100 mg

Doxazosin GITS 4-8 mg

Additional drugs, e.g., moxonidine/spironolactone

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)

Drug therapy

Previous antihypertensive treatments 1841 (19.1%) 1825 (19.0%)

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%)

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

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.

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

CONTRAINDICATIONS OF BETA-BLOCKER

COMPELLING CONTRAINDICATION

Second or Third Degree Heart BlockIn 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.

AsthmaA 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.

BradycardiaBradycardia 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 already-

existing heart failure may also occur.

POSSIBLE CONTRAINDICATION

Atrial fibrillation

Tachycardia

Idiopathic hypertrophic subaortic stenosis

Migraine prophylaxis

Myocardial infarction prophylaxis

Hypertension

Pheochromocytoma

Thyrotoxicosis

Tremor

Ventricular arrhythmia

Atrial flutter

Myocardial Infraction

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

The β-blocker/diuretic combination favours

development of diabetes and should thus be

avoided, unless required for other reasons

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.

REFERENCE

1. Wikipedia (www.wikipedia.com)

ARB's

β-blocker's

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)