CONTENTS

• Heart Failure
Classification
Etiology of heart failure
Pathophysiology
Changes accompanying
Diagnosis
Signs and symptoms
• Management of heart failure
Prognosis
• Beta blockers
Classes
Structures
Examples
Mechanism of action
Ancillary properties
Cardiovascular effects
• Clinical effects of beta blockers
• The clinical importance of differences between beta blockers
• Differences between beta-blocking drugs
Beneficial actions
• Stereochemical aspects and SAR
• Indications for beta blockers
• Clinical evidence of benefit from beta blockers
• Side effects of beta blockers
• Contraindications
• Effectiveness of beta-blockers
Safety of beta-blockers
• Guidelines for use of beta blockers
Suggested counseling during beta blockers use

1
 INTRODUCTION
Heart failure (HF) currently represents one of the most prevalent
diseases of the cardiovascular system, resulting in elevated social and
economic costs. In India, there are currently 5 million people with the
disease; with 550,000 new cases diagnosed every year. It also corresponds to
19.6% of hospital admissions due to cardiovascular causes, which
comprehends 11.7% of all hospital admissions in the country.
In the last two decades there has been remarkable progress in the
treatment of HF. The introduction of beta blockers and the rennin-
angiotensin-aldosteron system (RAAS) has caused a noticeable change in
the patients’ clinical behavior, as well as brought a perspective of more
promising survival rates. Large studies have shown important reductions in
mortality, as never before seen in the treatment of Heart Failure.[1]

HEART FAILURE

Heart failure is a complex syndrome that can result from any

structural or functional cardiac disorder that impairs the ability of the heart
to function as a pump to support a physiological circulation. The syndrome
of heart failure is characterized by symptoms such as breathlessness and
fatigue, and signs such as fluid retention [2].

CLASSIFICATIONS OF HEART FAILURE

The Indian Heart Association developed a system that has been used
for many” years to provide a standardized set of criteria for the classification
of heart failure based on the severity of the condition. This is evaluated by
symptoms and ability to function.

Class I: no undue symptoms associated with ordinary activity and no

limitation of physical activity
Class II: slight limitation of physical activity; patient comfortable at rest
Class III: marked limitation of physical activity; patient comfortable at rest
Class IV: inability to carry on any physical activity without discomfort;
symptoms of cardiac insufficiency or chest pain possible even at rest [3]

2
 ETIOLOGY OF HEART FAILURE

A. Causative Factors:

• Coronary Artery Disease

• Hypertension
• Valvular Heart Disease
• Infections
• Cardiomyopathies (including alcoholic and idiopathic)
• Endocrine disorders (especially Thyrotoxicosis)
• Genetic Conditions
• Congenital Heart Disease
• Inflammatory/immunological
• Chronic arrhythmias eg complete heart block or incessant tachycardia

B. Precipitating or Exacerbating Factors:

It is important to identify and treat any reversible factors, which may be

exacerbating the symptoms of heart failure. These factors include:
• Anemia
• Infection
• Arrhythmias, especially atrial fibrillation
• Drugs, e.g. non-steroidal anti-inflammatory drugs, calcium channel
blockers, corticosteroids and liquorices
• Renal dysfunction / renal artery stenosis
• Pulmonary embolism
• Silent myocardial infarction
• Excess salt intake [4]

3
 PATHOPHYSIOLOGY

Left ventricular dysfunction results in neurohormonal activation

(renin-angiotensin-aldosterone system, sympathetic system, cytokine
release), which, although beneficial in acute cases, is responsible for a
gradual deterioration in myocardial function. For instance, in response
to a decrease in cardiac output, an increase in circulating norepinephrine
(NE) can be seen, which acts on the sympathetic myocardial receptors—
particularly beta-1—thus increasing myocardial contractility. In addition, by
stimulating peripheral alpha receptors, NE induces peripheral
vasoconstriction, which helps maintain blood pressure. This effect is
counterbalanced by peripheral beta-2 stimulation, and consequent
vasodilation. Prolonged exposure of the heart to alpha- and beta-receptor
stimulation unfortunately promotes left ventricular modeling, cell death due
to necrosis or apoptosis, and water/salt retention. The roles played by beta-1
and beta-2 myocardial receptors in cardiovascular homeostasis differ
in normal and heart failure patients. In normal cases, there is little expression
of beta-2 receptors at the myocardium, but they retain their full importance
peripherally where they mediate vasodilation. In heart failure, however,
beta-2 receptors can represent up to 40% of total adrenergic receptors,
because of the greatly diminished density of beta-1 receptors (down-
regulation).

Fig. Pathophysiology of heart failure

4
 There have been recent reports of the presence of beta-3 receptors,
responsible for a negatively inotropic effect, and their density would appear
to increase in heart failure.4 currently; no specific treatment involving these
receptors is available.
Finally, an inter-relationship also exists between the sympathetic and
renin-angiotensinaldosterone systems. Activation of the sympathetic
system stimulates the release of renin, and thus angiotensin 2. This
accentuates left ventricular remodeling and peripheral vasodilation,
aggravating the heart failure [5]

CHANGES ACCOMPANYING HEART FAILURE

Cardiac
Decreased stroke volume and cardiac output
Increased stroke volume and diastolic pressure
Ventricular dilation or hypertrophy
Impaired filling (Diastolic Dysfunction)
Reduced ejection fraction (Systolic Dysfunction)

Vascular
Increased systolic vascular resistance
Decreased arterial pressure
Impaired organ perfusion
Decrease venous compliance
Increase venous pressure
Increase blood volume

Neurohumoral
Activation of sympathetic nerves
Activation of renin-angiotensin system,
Increased release of antidiuretic hormone , atrial natriuretic peptide
Produce arterial vasoconstriction
Increased blood volume.
Aggravate heart failure by increasing ventricular afterload
Increasing preload to the point where pulmonary or systemic
congestion .

5
 DIAGNOSIS

Indian Society of Cardiology guidelines for the diagnosis

Of heart failure

1. Essential features
• Symptoms of heart failure (breathlessness, fatigue, ankle
Swelling) and
• Objective evidence of cardiac dysfunction (at rest)
2. Non-essential features
In cases where the diagnosis is in doubt, there is a response
to treatment directed towards heart failure [6]

(Table no. I) RECOMMANDED TESTS [7]

Test Recommendations Findings

Chest x-ray Cardiomegaly
Pulmonary venous congestion
Interstitial fluid
Pulmonary disease
Electrocardiogram Acute ST-T wave changes Atrial
fibrillation, other tachyarrhythmia
Bradyarrhythmias
Previous MI (e.g. Q waves)
Echocardiogram LV systolic dysfunction
LV hypertrophy clues
LV diastolic dysfunction
Valve disease
Complete blood count Anemia
Urinalysis Proteinuria Red blood cells or
cellular casts
Serum creatinine Elevated
Serum albumin Decreased
T4 and TSH Abnormal T4 or TSH
Brain natriuretic peptide Elevated BNP

6
ABNORMAL PHYSICAL FINDINGS IN HEART FAILURE

• Tachycardia, irregular pulse

• Elevated jugular venous pressure or positive hepato-jugular reflux
• A third heart sound
• Laterally displaced apical impulse
• Pulmonary rales that do not clear with coughing
• Peripheral oedema

SIGNS AND SYMPTOMS

• Biventricular failure
• Cardiac decompensation
• Cardiac failure
• Congestive heart failure (CHF)
• Edema described as alveolar, diffuse interstitial, diffuse interstitial
pulmonary, interstitial, pulmonary, or pulmonary interstitial
• Edema of the lungs
• Edema not described as pulmonary in nature, if referenced as chest x-ray
finding (e.g., “cxr shows mild edema”)
• Fluid overload
• Heart failure described as left, right, or unspecified
• Perihilar congestion
• Pulmonary congestion
• pump failure
• Vascular congestion
• Venous congestion
• Ventricular failure
• Volume overload
• Wet lungs [8]

7
SIGNS OF HEART FAILURE DURING AN EXAMINATION

In the heart

• Heart enlargement
• Increased heart rate (tachycardia)

In the lungs

• Crackling noises (rales) heard through a stethoscope indicating a

buildup of fluid in the lungs
• Leakage of fluid from the lungs (pleural Effusion) into the chest
cavity

In other areas

• Swelling (edema) of the skin and soft tissues, usually noted in the feet
and ankles Edema of the lower back (sacral edema)
• Buildup of fluid of the abdominal cavity (ascites)
• increased size of liver (hepatomegaly), Ascites [9]

MANAGEMENT OF HEART FAILURE

Objectives:

• Increase cardiac contractility

• Decrease preload (left ventricular filling pressure)
• Decrease afterload (systemic vascular resistance)
• Normalize heart rate and rhythym

APPROACHES

1. Reduce workload of heart

• limit activity level

8
 • reduce weight
• control hypertension

2. Restrict sodium (low salt diet)

3. Give diuretics (removal of retained salt and water)
4. Give angiotensin-converting enzyme inhibitors
(decreases afterload and retained salt and water)
5. Give digitalis (positive inotropic effect on depressed heart)
6. Give vasodilators (decreases preload & afterload)

The management of heart failure includes pharmacological and non-

pharmacological modes of management. These are discussed below

A) Non-pharmacological Lifestyle Management

Suggestions for the following lifestyle changes should be offered and
reviewed at each visit:

• Smoking cessation
Recommend complete cessation of smoking and exposure to second hand
smoke. .

• Physical activity
Prescribe 30-60 minutes of moderate intensity dynamic activity (such as
walking 2 miles in 30 minutes once per day, or 1 mile in 15 minutes two
times per day, jogging, cycling or swimming) 4-7 days per week.
Recommend getting a pedometer for immediate positive feedback.

• Weight reduction
All overweight patients with hypertension should be advised to lose weight.
Weight loss strategies should be long-term and employ a multidisciplinary
approach that includes dietary education, increased physical activity, and
behavioral intervention. Target: body mass index (BMI) 18.5-24.9 kg/m2,
waist circumference <102 cm for men and <88 cm for women.

• Dietary recommendations
Advise a diet high in fruits, vegetables, low-fat dairy products, dietary and
soluble fibre, whole grains and protein sources reduced in saturated fats and
cholesterol (Dietary Approaches to Stop Hypertension (DASH) diet).

9
Reduce consumption of trans-fats and increase intake of fish that is high in
omega 3 fatty acids.

• Reduce salt intake

Recommend reduced dietary sodium intake of ≤ 1,500 milligrams per day
(approximately 1 tsp of table salt).

• Alcohol consumption
Limit to two drinks or less per day, and consumption should not exceed 14
standard drinks per week for men and 9 standard drinks per week for
women.

• Potassium, calcium and magnesium intake

Supplementation of potassium, calcium and magnesium is not recommended
for the prevention or treatment of hypertension.

B) Pharmacological Management
• Angiotensin-converting enzyme (ACE) inhibitors
• Diuretics
• Beta-blockers
• Spironolactone
• Digoxin
• Angiotensin II antagonists
• Anticoagulation
• Aspirin
• Co-prescribing
• Concomitant conditions
• Atrial fibrillation
• Ischaemic heart disease

10
 CO-PRESCRIBING

Certain drugs interact adversely with the primary therapeutic agents

for congestive heart failure or are poorly tolerated. Vigilance should
be exercised in all prescribing. The following groups of drugs should be
used cautiously or avoided altogether:

• NSAIDS
• Calcium channel blockers (with the exception of amlodipine and
felodipine)
• Corticosteroids
• Tricyclic Antidepressants
• Carbenoxolone
• Urinary alkalinisers (high sodium content)

PROGNOSIS

The outlook for most people with heart failure is dependent upon the
cause of the heart failure and the overall degree of cardiac dysfunction. An
estimated 50 percent survive more than five years after diagnosis.
That figure, however, is an average of all patients with varying levels of
severity of the disease.
The prognosis for a specific person with heart failure depends to a
large degree on effects of the disease, such as the level of blood output of the
left ventricle, or his or her ability to exercise, as well as other factors,
Including age, overall health, and other medical conditions. The sooner heart
failure is diagnosed and action is taken to control the problem, the better.
In many cases, heart failure can be effectively treated to prevent or
slow the progression of the disease and to alleviate its symptoms. Therapy
can achieve several goals: It can improve the performance of the left
ventricle, prevent further deterioration of heart function, improve a patient’s
ability to exercise, and improve quality of life.
In addition, it is possible that in selected instances, early, effective
treatment may increase a person’s likelihood of improved survival. [10]

11
 BETA BLOCKERS
Introduction of Beta Blockers

Hormones known as catecholamine (norepinephrine, epinephrine)

activate or stimulate specific receptors on cell surfaces, known as adrenergic
receptors. A receptor has a specific structure that allows a drug or hormone
to bind to it, similar to a key fitting in a lock.
The catecholamines are released from nerve endings of the
sympathetic nervous system, an involuntary nerve network that enables the
body to withstand stress, anxiety, and exercise. Adrenergic receptors are
found in the heart, blood vessels, and the lungs, and can be stimulated by
catecholamine binding, thus increasing the activity of cells in the body. Beta
adrenergic receptor stimulation causes an increase in heart rate, heart muscle
contraction, blood pressure, and relaxation of smooth muscle in the
bronchial tubes in the lung, making it easier to exercise and expand the
lungs.
When beta blocking drugs are given to patients through a vein or by
mouth, they will block the access of catecholamine to their receptors so that
the heart rate and blood pressure are reduced, and the heart will pump with
less intensity.
This, in turn, will reduce the oxygen needs of the heart. The effects of
beta blockers are greatest when catecholamine levels and receptor numbers
are high, as would occur during intense exercise, and are lessened when
catecholamine levels are reduced, as during sleep. Beta Blockers usually do
not completely diminish the ability of the heart to respond to stress, but
instead modify the heart’s response to stress. [11, 12]

(Table no II) CLASSES OF BETA BLOCKERS: [13]

ACTION ADRENERGIC EXAMPLE

SELECTIVITY
Non-selective Beta1 > beta2 Propranolol
Sotalol
Selective Beta1 and beta2 atenolol
metoprolol succinate
metoprolol tartrate

12
 (sustained release)
bisoprolol
Non-selective and Beta1, beta2 and alpha1 Carvedilol
Vasodialating labetalol
Non-selective and Beta1 and beta2 Nebivolol
vasodialating (nitric
acid pathway)

STRUCTURES OF BETA BLCKERS: [14]

Labetalol

Propranolol

Atenolol

13
 Oxprenolol

Alprenolol

Timolol

Acebutolol

Sotalol

14
(Table no III) Examples of Some Beta Blockers [15]

Beta blocker Usual dosage Daily maximum

propranolol 40 - 80 mg bid 320 mg
atenolol lOO mg qd-bid 400 mg
oxprenolol 1 00 mg daily 200 mg
alprenolol 100- 200 mg bid 1200 mg
300 mg tids
prindolol 5 - 20 mg tds 60 mg
timolol 5- lO mg tids 45 mg
acebutolol 80 mg daily 240 mg
metoprolol 80- 160 mg bid 320 mg
nadolol 20 mg tid 320 mg
160 mg daily 320 mg
bisprolol 1.25 mg q.d. 10.0 mg q.d.
metoprolol 12.5 mg q.d. 20 mg q.d.
carvediol 3.125 mg b.i.d. 6.5 mgb.i.d.

MECHANISM OF ACTION OF BETA-BLOCKING AGENTS

Beta-blockers cause a competitive inhibition of beta-adrenergic

receptors. Most of the myocardial beta-receptors are of the beta1-subtype;
just a few are of the beta2-subtype. Sympathetic nervous system activation is
prolonged in patients with heart failure. There is a down regulation of beta1-
receptors in the failing heart. They are reduced in number and density,
whereas the number of beta2-receptors remains unchanged. The percentage

15
of beta2-receptors increases from 20 % up to 40 %. The plasma levels of
norepinephrine are elevated.
Catecholamines have a direct toxic effect on cardiac myocytes. Beta
stimulation leads to an elevation of cAMP and, therefore, to an increase in
intracellular calcium. Prolonged activation in heart failure may be the reason
for calcium overload and myocytes death. This is considered to be one of the
key points of the beneficial effects of beta-blockers. Reduction of the heart
rate prolongs diastole and, due to this, increases coronary perfusion time. A
low heart rate is also associated with a lower myocardial oxygen demand
and, therefore, myocardiac ischemia is reduced.
Other possible effects of beta-blockers on the myocardium are a
reduction of cardiac arrhythmias, prevention of coronary plaque ruptures by
modifying the atherosclerotic process even when no effect on platelet
aggregation could be demonstrated.
Concerning the hemodynamic effects of beta-blockers, one must
distinguish between acute and chronic changes .Beta-blockers act as
negative inotropic and negative chronotropic agents because of their
reduction of cardiac index in the short term.
Activation of beta1-adrenoceptors in the kidney leads to release of
renin, which stimulates angiotensin II consecutively. Angiotensin II
represents a potent vasoconstrictor which increases vascular peripheral
resistance. It also leads to renal vasoconstriction, to the release of aldosteron
and, therefore, to salt and water retention. Catecholamines as well as
angiotensin II have additional direct toxic effects on cardiomyocytes. Beta-
blockers can interrupt these neurohumoral activation pathways.

Cardio Protective Mechanisms of Beta-Blockers

• Antiischaemic effect
• Prevention of catecholamine toxicity
• Antiarrhythmic effect
• Reduction of neurohumoral activity
• Reduction of plasma norepinephrine
• Hemodynamic effects
• Modification of the atherosclerotic process [16]

BETA-BLOCKERS: ANCILLARY PROPERTIES

16
 Ancillary properties of beta-blockers include level of lipophilicity,
intrinsic sympathomimetic activity (ISA), high receptor affinity, selectivity,
and vasodilatory property. So far compounds with different ancillary
properties have been considered equally effective. Based on current
literature it seems no longer appropriate that this be done so. A subgroup
analysis of the HAPPHY hypertension trial found that the lipophilic
compound, metoprolol, was more effective than the lipophobic, atenolol, in
reducing the combined risks of cardiac failure.
Because of their excellent record of effectiveness and safety, beta-
blockers have become one of the commonly prescribed classes of drugs to
be used in the treatment of hypertension and angina pectoris, for the
prevention of recurrent angina pectoris, and possibly also in specific cases of
cardiac failure

Lipophilicity

In the past year Soriano et al. performed a meta-analysis involving no

less than 69 secondary prevention trials myocardial infarction and,
surprisingly, the best performance was displayed by the lipophilic beta-
blocker metoprolol: 17% overall risk reduction of myocardial infarction,
compared to 15% with the some what less lipophilic, propranolol, and only
5% with the hydrophilic, atenolol.

Intrinsic sympathyomimetic activity (ISA)

Beta-blockers with ISA are partially blocker and partially agonist.

Their effect on cardiac output is smaller, but so is their effect on peripheral
resistance. Even though such hemodynamic effects are interesting by
definition clinical relevance has been very limited so far. ISA beneficial
blockers seem to be beneficial in patients with hypo-adrenergic orthostatic
hypotension.

Receptor affinity

Timolol is in the dose-response curves 10 times more potent than

metoprolol is. Of course high potency is relevant. However, it may at the
same time give rise to certain hazards some patients treated with Timoptol
eye-drops swallowed the compound and subsequently developed a fatal
attack of bronchial asthma.

17
Selectivity

Fundamentally, beta-1 activity is the capability of a beta-blocker to

antagonize isoproterenol-induced tachycardia. Beta-2 activity is the
capability to antagonize isoproterenol-induced bronchial constriction or
peripheral vasoconstriction. The problems with beta-2 blockade follows
immediately from these definitions. For non-selective beta-blockade
otherwise called beta-1+2 blockades causes vasoconstriction, or, at least,
reduces vasodilation of major resistance vessels. In addition, beta-1+2
blockade involve negative metabolic effects simply because they are
predominantly beta-2 receptor mediated.

Vasodilatory property

In the past few years a new generation of beta-blockers, with

vasodilatory properties, has entered the market. Carvedilol, a component of
the former labetalol, is an alpha-1-selective alpha-blocker and non-selective
beta-blocker. [17]

CARDIOVASCULAR EFFECTS OF BETA BLOCKADE

Beta blockers are antiischemic agents and they decrease myocardial

oxygen consumption by reducing heart rate, blood pressure and myocardial
contractility. Heart rate is reduced at rest and more importantly during
exercise and excitement, when sympathetic tone is increased. Maximal
double product of heart rate and systolic blood pressure during exercise,
measure of myocardial oxygen consumption, may be reduced up to 20%
under influence of the beta blockers.

18
 By decreasing surges of the systolic arterial pressure, beta blockers
may prevent the rupture of the coronary atherosclerotic plaque and the
development of the acute coronary syndrome. Prolonged diastole due to
reduced heart rate, which is caused by beta blockers, enables better perfusion
of the jeopardized subendocardial myocardium. Beta blockers manifest
antiarrhythmic effects, decrease automatism of sinus node and ectopic focus
and suppress calcium influenced after depolarization. These agents represent
a treatment of choice for sympathetic mediated rhythm disorders such as
arrhythmias during exercise or an emotional excitement.

The Effects of Beta Blockers in Patients After Acute Myocardial

Infarction

Randomized double blind, placebo controlled studies of patients after an

acute myocardial infarction have shown favorable effects on mortality and
morbidity of the beta blockers. Well known BHAT study (Beta blockers in
Heart Attack Trial) has shown that post myocardial infarction patients with
chronic Propranolol (60 – 80 mg three times per day) treatment had lower
degree of the total mortality and lower sudden cardiac death frequency. Beta
blockers have shown better effects in improving survival in patients with Q
wave myocardial infarction than in patients with non-Q infarction.
Also, patients with more extensive myocardial infarction and lower left
ventricular ejection fraction have achieved better results while treated with
beta blockers in improving prognosis. Norwegian multicenter Study has
shown a reduction of 26% in sudden cardiac death and nonfatal reinfarction
in post infarction patients who had received Timolol. This study has also
shown better effects of beta blocker in Q wave myocardial infarction
patients in relation to patients with non Q wave infarction. . [18]

CLINICAL EFFECTS OF BETA BLOCKERS

Swedish authors were the first to show, in 1975, the beneficial effects
of beta-blockade in HF patients. Further studies from the same group
showed that long term beta-blocker therapy may improve LV systolic and
diastolic function and, even more importantly, may improve survival. It is
impressive how this last study, including only 36 patients, could show such
an effect and predict the results of trials concluded almost 20 years later.
Concomitant analyses of the major post-infarction trials showed that beta-

19
blockade had its greatest effects among the patients with signs of HF or of
LV dysfunction.
In the following years, controlled trials showed the beneficial effects
of beta-blockers on LV function and the clinical course of patients with
chronic HF. Beta-blockers were more effective than angiotensin-converting
enzyme (ACE) inhibitors at reversing LV remodeling, with an improvement
in LV ejection fraction (EF), a decline in LV volumes, reduced severity of
mitral regurgitation and a less spherical LV shape. These changes are
secondary to the beneficial effects of beta-blockade on the intrinsic
mechanisms leading to progressive myocardial degeneration. They include
changes in myocardial metabolism, myocardial contractile protein isoforms,
sarcoplasmic reticulum calcium dependent ATPase (SERCA) activity and
gene expression, and ryanodine receptor phosphorylation. In turn, LV
inverse remodeling by beta blocker therapy may further contribute to the
overall improvement in LV function.
Large multicenter controlled clinical trials showed the beneficial
effects of beta-blocker treatment on prognosis. All-cause and cardiovascular
(CV) mortality, as well as all-cause, CV and worsening HF hospitalizations,
were reduced by beta-blocker treatment, compared with placebo, in
landmark trials. The effects on survival were additive to that of ACE
inhibitors and were of greater magnitude compared with those previously
found with them. The first mortality trials included patients with LV systolic
dysfunction, shown by a low EF and mild to moderate HF. This was shown
by the relatively low annual mortality of the placebo-treated patients (13.2%
in the Cardiac Insufficiency Bisprolol Study II (CIBIS-II) and 11% in
Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart
Failure (MERIT-HF)). The Carvedilol Prospective Randomized Cumulative
Survival COPERNICUS) broadened the indications to beta-blocker therapy.
It included patients with symptoms at rest or minimal exertion and
severe LV dysfunction (EF of less than 25%). Accordingly, the mortality of
the placebo treated patients was higher (18.5%). Carvedilol was associated
with a significant 35% reduction in all-cause mortality (relative risk (RR),
0.65; 95% confidence interval (CI), 0.81–0.52; p=0.0014) and with a 24%
reduction in the combined end-point of death and hospitalizations (RR, 0.76;
95% CI, 0.67–0.87). Carvedilol was associated with an excellent tolerability
With a similar incidence of side effects and early (two weeks after study
initiation) beneficial effects on prognosis, compared with placebo.
Carvedilol was also associated with a reduction in mortality,
compared with placebo, in patients with early post-infarction LV

20
dysfunction, with or without symptoms, in the Carvedilol Post-Infarct
Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial.

THE CLINICAL IMPORTANCE OF DIFFERENCES

BETWEEN BETA BLOCKERS

Previous studies have already showed that the pharmacological

characteristics of antiadrenergic agents may influence their effects on
survival. Both agents with intrinsic sympathomimetic activity and agents
decreasing norepinephrine release are associated with untoward effects on
survival – the first because of excessive sympathetic stimulation, the others,
likely, because they blunt sympathetic response when an increase in
myocardial contractility and blood pressure would be necessary, such as
during exercise, stress or arrhythmias.
It remained uncertain whether there could be differences in the
magnitude of the effects on mortality between beta-blockers that are both
associated with favorable effects on outcome. This hypothesis was tested in
the Carvedilol or Metoprolol European trial (COMET). Three thousand and
twenty-nine patients with II–IV New York Heart Association (NYHA) class
HF, an LV EF less than 35%, a CV hospitalizations in the previous two years
and on standard treatment with diuretics and ACE inhibitors, were
randomized to either Carvedilol, titrated up to 25mg bid, or Metoprolol
tartrate, titrated to up to 50mg bid. COMET was an event-driven trial
designed to end when 1,020 deaths had occurred. The average follow-up was
long (57.9 months) making it one of the largest and longest trials of CHF
patients.
In COMET, Carvedilol treatment was associated with a significant
17% reduction in all-cause mortality (RR, 0.83; 95% CI 0.74–0.93;
p=0.0017), compared with metoprolol tartrate. The annual mortality rate was
reduced from 10% to 8.3% and calculated median survival was prolonged by
1.4 years with Carvedilol. The distribution of the mode of death was similar
with both treatments. The reduction of sudden death rate was significant
with Carvedilol compared with metoprolol (RR, 0.81; 95% CI, 0.68–0.97;
p=0.022).
The reduction of circulatory failure death was of similar magnitude
although it did not reach statistical significance because of the lower number
of events (RR, 0.83; 95% CI, 0.67–1.02; p=0.07). Significant differences
were found in other end points including those related to vascular events
such as MI and stroke. The other co-primary end-point of all-cause mortality

21
and all-cause-hospitalizations was reached by 73.9% of patients on
Carvedilol and 76.4% on metoprolol with no difference between the two
groups (HR, 0.937; 95% CI, 0.863–1.017; p=0.1219).
The incidence of hospitalizations was, in fact, similar between the
patients on Carvedilol and those on metoprolol tartrate. (The explanation of
this finding is that the lower mortality of the patients on Carvedilol exposed
them to an increased risk of hospitalizations. [19]

DIFFERENCES BETWEEN BETA-BLOCKING DRUGS

Beta-blockers differ in various pharmacologic qualities like selectivity

for beta1 and beta2-receptors, their intrinsic activity (ISA), their action on
other adrenergic receptors, their ability of vasodilatation as well as their
antioxdative and antiproliferative effects. In comparison to the normal
myocardium, the portion of beta2-receptors rises from 20 % to 40 % in the
failing heart. So, non-selective agents that block both types of receptors may
be more effective.
Beta-blockers with intrinsic sympathomimetic activity (ISA) such as
labetalol may block or stimulate sympathetic effects in order to achieve a
high or low level of norepinephrine. However, the use of such agents in
patients with severe left ventricular dysfunction has been associated with
increased mortality. Therefore beta-blockers with ISA should not be
prescribed to patients with heart failure. Beta-blockers can induce
vasodilatation by alpha1-receptor- blockade (Carvedilol), by an agonistic
effect to peripheral beta-receptors (Celiprolol) or by direct effects
(Bucindolol).
The reduction of preload and afterload is responsible for the
Hemodynamic benefits of these drugs. Antiproliferative and antioxidant
effects have been shown for Carvedilol in vitro and in vivo in hypertensive
patients. Clinical significance is not yet proven.

(Table no.IV) Various beta-blocking agents and their differentiation

with respect to beta1-selectivity, ISA and vasodilatation

Agent Beta1-selective ISA Vasodilatation

Atenolol Yes No No
Bisoprolol Yes No No
Bucindolol No Yes Yes
Carvedilol No No Yes

22
Celiprolol Yes Yes No
Labetalol No Yes Yes
Metoprolol Yes No No
Oxprenolol No Yes No
Pindolol No Yes No
Propranolol No No No
Sotalol No No No

BENEFICIAL ACTIONS OF BETA-BLOCKERS

• Reduce sympathetic tone

• Normalize high phosphorus energetic imbalance
• Increase vagal tone
• Reduce renin release
• Improve force-frequency relationship
• Reduce endothelin production and release
• Improve myocardial work/oxygen consumption ratio
• Increase norepinephrine re-uptake
• Reduce subendocardial ischaemia
• Upregulate beta-adrenergic receptors
• Increase heart rate variability
• Reduce inflammatory cytokines
• Reduce QT-dispersion
• Antagonize autoantibodies against beta1-receptors
• Reverse deterioration in heart rate Variability
• Antioxidant effect [20]

STEREOCHEMICAL ASPECTS AND SAR

MODELING BIOLOGICAL ACTIVITY

Discovering new drugs takes lots of time. Proving to FDA that a new
drug works and is reasonably safe takes even more time. By the time a new
drug is brought to market, most of the patent has expired and millions of

23
dollars have been spent with no return on investment. One of the reasons
pharmaceuticals are so expensive is the current drug development
methodologies create a lot of false leads. Similarly, it costs an outrageous
amount to do animal testing for toxic compounds. All drugs have side effects
and some are potentially toxic.
In order to more clearly understand the process for modeling
biological activity and predicting the interaction between molecules and
biological systems, it will be helpful if we use a common problem and
follow the process through for a real life example. We will assume for this
discussion that we are looking for new molecules that will act as blood
pressure lowering drugs and are active biologically as beta-blockers. For this
example, let’s assume we have thirty known molecules that show varying
effectiveness as beta-blockers and lower blood pressure (i.e. the existing
drugs used for this purpose today).

QSAR:
The most common technique for modeling chemical/biological
interactions is called Quantitative Structure Activity Relationships (QSARs).
The first task for the researcher is to identify a set of chemical structural
parameters that define the biological activity of known beta-blocker drugs.
Often this results in as many as two hundred or more parameters for each
molecule evaluated. In our example, where we have thirty known molecules
that are classified as beta-blockers, that can typically take up to a month to
perform these calculations. The calculated data is then entered into a
computer program and a statistical analysis is performed to define a model
that predicts whether a new molecule of interest might be an effective beta-
blocker.
At this point the researcher is ready to evaluate new molecules. Let’s
say the researcher picks thirty new molecules for evaluation. Each molecule
must go through the same procedure and all the required parameters must
calculate for each new molecule. This will take more time. At this point each
new molecule is analyzed against the model, which predicts the biological
interactions.

Stereoisomers

The (R)- and (S)-nomenclature according to Cahn, Ingold and Prelog

(CIP) priority rules defines the absolute configuration of a stereogenic
centre, in the present case a tetracoordinated carbon atom substituted by four
different ligands. On the other hand, the prefixes d- and l- as well as the (+)–

24
and (–)-nomenclature give information according to the rotation of polarised
light to the right or to the left, and therefore, merely describe these
physicochemical properties of the enantiomers.
All beta-blockers that are currently used in clinical practice contain an
asymmetric carbon atom. In the aryloxypropanolamine type compounds the
d-enantiomers show the (R)-configuration, and the l-enantiomers show the
(S)-configuration. (S)-enantiomers usually are orders of magnitude more
potent in blocking adrenergic beta-adrenoceptors than the respective (R)-
forms. An exception is sotalol where the asymmetric carbon atom is located
in an ethanolamine type side chain. In this case, the priority of the four
substituents changes according to the CIP rules so that (R)-sotalol
(equivalent to l-sotalol) is much more effective as a beta-blocker than (S)-
sotalol (equivalent to d-sotalol)

Figure: Structural similarity of (S)-propranolol and (S)-propafenone.

Principles of Stereo selectivity in Beta-Adrenoceptor Antagonists

All beta-blockers that are currently used in research as well as in clinical

practice are structurally related to the beta-agonists epinephrine and
norepinephrine. As a common feature, these catecholamines and all beta-
blockers possess an asymmetric carbon atom. Effects of agonists as well as
of antagonists on adrenergic beta-receptors are highly stereoselective with
the l-enantiomers being markedly more potent than the respective d-forms.
Therefore, and in clear contrast to the racemic betablockers widely used in

25
therapeutics, the human organism stereoselectively synthesises and uses the
active enantiomers, ie, l-epinephrine and l-norepinephrine. Hence, it is not
surprising that the l-enantiomers of all beta-blockers are orders of magnitude
more potent in blocking beta-adrenoceptors than the respective d-forms.
Figure 4 shows the markedly different affinities of the d- and l-enantiomers
of propranolol, atenolol and propafenone to beta-adrenoceptors in vitro,
depicts the effects of d-, l- and d,l-atenolol and placebo on heart rate in
humans emphasising that half the dose of l-atenolol is equally as effective as
racemic d,l-atenolol suggesting that the full beta-blocking efficacy of the
racemic drug resides in its l-enantiomer . On the other hand, both d-atenolol
and placebo show no effect. However, it should be noted that propafenone,
which is mainly used as a class 1c antiarrhythmic agent, also exerts weak
beta-blocking effects due to its structural resemblance to beta-adrenoceptor
antagonists.

26
Figure: Structural formula of the (R)- and (S)-enantiomers of
propranolol which behave like mirror images. The asymmetric
carbon atom is marked by an asterisk.

Antiarrhythmic class-3 effects

Recently, a report was published as the first clinical trial to investigate

the influence of the d-enantiomer of a currently used racemic beta-blocker,
namely sotalol, on mortality. The results were disappointing: Bare of beta-
blocking effects that reside stereoselectively in the l-enantiomer, optically
pure dsotalol increased mortality by 65 % compared with placebo . In view
of these new data, an increase of fatal arrhythmias caused by d-sotalol might
presumably be the reason why d,lsotalol was the only beta-blocker that
failed to reduce mortality compared with placebo in a large trial in patients
with myocardial infarction whereas other beta-adrenoceptor antagonists
such as timolol , propranolol, metoprolol and atenolol markedly decreased
mortality.
Thus, it emphasised for the first time the potential hazard that might
be inhered in the d-enantiomer of a racemic betablocker. Bearing in mind
that beta-blockers are generally established as the most effective drugs for
the prevention of sudden cardiac death and that racemic d,l-sotalol was
shown to be more effective than other antiarrhythmic drugs in preventing
death from any cause although it consists of 50 % of a drug which is now
known to be potentially harmful, namely d-sotalol , one may assume that
optically pure l-sotalol might possibly be more effective in preventing death
after myocardial infarction than the racemic mixture d,l-sotalol .
Accordingly, it might appear more reasonable to investigate the beta-
blocking l-enantiomer rather than dsotalol which lacks a beta-blocking
effect. This might be true for all beta-adrenoceptor antagonists that are
marketed and used as racemates since their d-enantiomers have never been
shown not to cause harm in similar way to that of d-sotalol.

Antiarrhythmic Class-1 Effects

It is well known that propafenone is an effective class-1antiarrhythmic

agent although its chemical structure is that of a typical beta-adrenoceptor
antagonist . Although the antiarrhythmic class-1 effects of d- and l-
propafenone are quite similar a recent study revealed some mild differences

27
between the antiarrhythmic class-1 effects of propafenone . Similar to
propafenone, both enantiomers of the lipo-philic beta-adrenoceptor
antagonist propranolol exert antiarrhythmic class-1 effects to the same
extent.
According to our present knowledge, not only d-sotalol but also d-
propranolol might potentially put patients at risk since it possesses
antiarrhythmic class-1 effects similar to those of encainide and flecainide
which increased mortality in the CAST trial. This might also be true for all
other beta-blockers that are used as racemates since their d-enantiomers
have never been shown not to cause harm in similar way to that of d-sotalol.

Stereo selectivity in Pharmacokinetics

Although any racemic beta-blocker consists of its d- and lenantiomers

in a 1:1 ratio, plasma concentrations of these dand l-enantiomers usually
differ significantly and in wide ranges when the racemic mixture is
administered orally or intravenously. For example, plasma concentrations of
the lenantiomers are higher than those of the d-enantiomers following
administration of d,l-propranolol d,lmetoprolol (extensive metabolisers only)
or d,l-propafenone . In contrast, plasma concentrations of the d- are higher
than those of the l-enantiomers after administration of d,l-atenolol or d,l-
carvedilol. On the other hand, no significant differences between plasma
concentrations of the d- and l-enantiomers were found when d,l-celiprolol
or d,l-bisoprolol was given.
In addition, pharmacokinetic interactions between the dand
l-enantiomers have been described with propranolol, metoprolol and
propafenone which may influence plasma concentrations as well as the
effects of the respective drugs. Furthermore, plasma concentrations and
actions of beta-blockers may be influenced stereoselectively by a number
of different factors as emphasised by Walle and co-workers.
Due to their structural relationship to epinephrine and norepinephrine, beta-
blockers are taken up into, stored in and released from adrenergic nerves
together with these catecholamines . Recently, it has been shown that the
release of beta-blockers from adrenergic nerve endings may markedly
influence plasma concentrations of these drugs. However, substancial
stereoselective differences have been described.

28
 When single oral doses of the optically pure enantiomers of
propranolol or atenolol were given, plasma concentrations of the l-
enantiomers increased during exercise and returned to baseline after 15 min
of recovery whereas those of the denantiomers remained unaffected
. However, plasma concentrations of both the d- and lenantiomers increase
during exercise to the same extent and returned to baseline after 15 min of
recovery following oral administration of the racemic mixture. In patients
with long-term treatment with d,latenolol exercise stereoselectively
increased plasma concentrations of l-atenolol. In contrast, in patients
chronically treated with d,l-propranolol, exercise increased plasma
concentrations of both enantiomers to the same extent. Thus, plasma
concentrations obviously do not reflect the concentrations of the effective
parts of the racemic drugs, ie, the lenantiomers, at their sites of action in the
synaptic gaps. These findings might explain the poor correlation between
plasma concentrations and effects of beta-adrenoceptor antagonists
particularly during exercise, and why beta-blockers may still be effective
after withdrawal of therapy even when they are no longer detectable in
plasma. In addition, these data emphasise first that blood samples should be
taken strictly at rest whenever plasma concentrations of beta-blockers are to
be determined, and second that stereoselective aspects should not be
neglected.

INDICATIONS FOR BETA BLOCKERS

• Mild Asymptomatic Hypertension.

Beta blocker alone can be used as first drug for new case.
• Moderate or severe hypertension.
Beta blocker alone or in combination. Particularly good for young
males because of no side effect of impotence.
• Possibly high renin hypertension.
• To replace other anti-hypertensive drugs.
• When patients cannot tolerate the old drugs because of severe side
effects e.g. postural hypotension, impotence or tachycardia.
• Angina pectoris (insufficient blood to the heart)
• Heart Attack (injury to the heart muscle)
• Arrhythmias (heart rhythm irregularity)
• Dissection of an artery (torn blood vessel)
• Heart failure

29
 • Migraine headache
• Glaucoma (high pressure in eye)
• Muscle tremor (shaking of limbs)
• Ischaemic heart disease – angina (stable and unstable),
postmyocardial infarction
• Tachyarrhythmias – supraventricular and ventricular
tachycardia, atrial fibrillation, atrial flutter
• Chronic heart failure
• Palpitations
• Anxiety
• Essential tremor
• Migraine
• Glaucoma
• Thyrotoxicosis and Portal hypertension [21]
CLINICAL EVIDENCE OF BENEFIT FROM BETA
BLOCKERS [22]
Initial studies analyzing beta blocker utility were performed in the
1970s in Sweden in a small number of young patients with dilated
cardiomyopathy and moderate to severe heart failure and in the absence of
ACE inhibitors.
Findings showed significant symptomatic improvement, improved
exercise capacity, increased EF, and survival. Since then, many large
randomized, placebo-controlled trials have analyzed beta blockers in heart
failure of all etiologies of importance, these trials have been performed in
the modern arena of heart failure, seeking benefit in the setting of accepted
optimal medical management. Thus, in all clinical trials of beta blockers,
beta blocker therapy was added to standard therapy that included ACE
inhibition. Cleland et al summarized the mortality benefits of large placebo-
controlled trials as follows: beta blockers reduce the absolute risk of death
over an average 13-month follow-up by 4.5%, decreasing the 12.8% placebo
mortality rate to 8.3% in the treated group. This translates into 45 lives saved
for every 1000 persons treated. In analyzing the etiology of death, sudden
cardiac death and death due to progressive heart failure are both reduced
with beta blocker therapy. Hospitalization rates are significantly decreased
as well. Specifically, the number of patients hospitalized, total
hospitalizations, and duration of hospitalization were lower in patients
taking beta blockers.

30
 In addition to the dramatic effects on mortality and morbidity
numerous studies have investigated the effect of beta blockers on functional
status and quality of life. Most, but not all, studies using carvedilol,
metoprolol, bucindolol, and bisoprolol have shown an improvement in
New York Heart Association (NYHA) class with treatment. The effects of
beta blockers on quality of life have varied. Sub maximal and maximal
exercise performance, as assessed by the 6-minute walk and treadmill test,
respectively, has generally failed to improve with beta blocker therapy.
Exercise capacity may not be a useful measure of the efficacy of beta
blockers. With a lowering of the maximal achievable heart rate, the increase
in cardiac output with exercise may be blunted, thus limiting maximum
exertion.
The effect of beta blocker therapy on indices of systolic function such
as EF has also been studied. Early administration of a full dose of beta
blockade reduces EF. However, this effect is transient, and prolonged (>3-6
months) beta blockade has been consistently shown to improve EF. This
observation emphasizes the necessity of long-term maintenance therapy.
Other hemodynamic observations with therapy include lower pulmonary
wedge pressures, decreased systemic vascular resistance, and increased
stroke volume index.22,25,26.

(Table no.V) Various Beta Blocking Agents And Relative Benefits

Drug No. of Changes in EF(%) Duration

patients Beta blocker Placebo (mo)
Carvediol 56 6.5 -0.4 3.5
Timolol 345 6.3 2.0 6
Acebutalol 278 8.0 3.0 6
Labitalol 415 5.1 -0.2 12
Bucindolol 2708 7.3 3.3 12
Metoprolol 383 12.0 6.0 12

SIDE EFFECTS OF BETA BLOCKERS

A) Severe Side Effects

• Bronchospasm

31
 • Worsening claudication
• Cold extremities
• Indigestion
• Depression
• Vivid dreams and/or insomnia
• Neurological
• Fatigue
• Sexual activities impaired
• Diarrhoea
• Heart failure

B) Dose Limiting Side Effects

• Fatigue
• Cold extremities
• Indigestion
• Vivid dreams and/or insomnia
• Neurological
• Bronchospasm
• Heart failure
• Hallucinations
• Worsening claudication
• Depression
• Sexual activities impaired

CONTRAINDICATIONS

Contraindications to beta-blockers include:

• Cardiogenic shock or hypotension

• Bradycardia with a heart rate less than 50
• Any type of second-degree or third-degree atrioventricular block
• Active asthma
• Severe reactive airway disease.

32
 • Heart failure.
• History of bronchospasm.
• After prolonged fasting.
• In metabolic acidosis (e.g. in diabetes).
• Peripheral vascular disease. [23]

EFFECTIVENESS OF BETA-BLOCKERS

Beta-blockers are potent, highly effective medicines. Studies show

them consistently better than placebo in treating high blood pressure and a
range of other heart conditions. There are important differences in how the
various beta-blockers work that will affect your doctor’s use of them. These
differences have affected our choice of best drugs as well — for the different
conditions specified. In effect, there are four subgroups among the 14 beta-
blockers.
A first group, called the nonselective beta-blockers, equally reduce
adrenaline’s impact on the heart muscle and on blood vessels, the lungs, the
bladder, and the eyes.
A second group, called the cardioselective beta-blockers, block
adrenaline’s impact on the heart more than tissues in the rest of the body.
A third group has less impact on the heart itself and more on blood
vessels and other tissues.
A fourth group works by affecting other nerve signals entirely,
primarily in blood vessels. For example, the six cardioselective beta-
blockers are acebutolol, atenolol, betaxolol, bisoprolol, metoprolol tartrate,
and metoprolol succinate. Your doctor should know about these differences.
And you should not hesitate to ask your doctor what kind of beta-blocker is

33
being prescribed — and how your doctor thinks it will act in your body. This
may help you understand why you need to continue taking the medicine
even though it won’t necessarily make you feel better — and could even
make you feel worse.
Overall, the strongest evidence on beta-blockers links them to a lower
risk of repeat heart attack and early death in the aftermath of a heart attack.
More than 60 studies have examined this, and all have found a marked
benefit for the pills. Almost everyone who has had a heart attack should be
taking a beta-blocker. There is also compelling evidence that some beta
blockers lower the risk of death in people with heart failure, preventing 3.8
deaths per 100 patients in the first year of treatment.
Against high blood pressure, beta-blockers are considered to be a
critical “second step" or additional drug — with strong evidence of
effectiveness when used in combination with other blood pressure drugs ,
most notably diuretics. In one landmark analysis published in 2003, beta-
blockers given to people with high blood pressure were better than placebo
in preventing stroke and cardiovascular disease events, including death. But,
when used alone, they were inferior to low-dose diuretics in reducing the
risk of these outcomes. [24]

SAFETY OF BETA-BLOCKERS

Beta-blockers are generally safe medicines, with more than 20 years

of widespread use around the world. They have not been shown to cause any
serious long-term or irreversible negative consequences, even after many
years of use. But side effects are common among people taking beta-
blockers. The majority of people can expect to experience at least one.
These include fatigue or drowsiness, dizziness or lightheadedness,
slow heartbeat, low blood pressure, difficulty breathing, numbness, tinkling
or coldness of fingers, toes or skin, weight gain, mental depression,
disturbing dreams, reduced libido, erectile dysfunction in men, or ability to
reach orgasm in both men and women. Any of these should prompt a call to
your doctor if it persists, especially breathing difficulties, dizziness, or
fatigue. Many of these side effects are related to the dose you take — with
the risk of side effects rising as the dose increases.
Your doctor may need to reduce your beta-blocker dose to see if that
solves the problem. Most side effects can be avoided or minimized by
starting with a low dose and increasing it gradually if that is necessary. Also,
some of these adverse effects go away or diminish in time, after your body

34
gets used to the drug. If one or more side effects persist with one beta
blocker, your doctor will likely suggest you try another one. There is no
evidence that any one beta-blocker produces more or less side effects than
any other, but people respond differently to the individual drugs.
Some people, however, have to stop taking any beta blocker because
they cannot tolerate the side effects. In one study of heart failure patients,
one in five could not tolerate the first beta-blocker they were given. About
half of that group was successfully switched to another beta-blocker. In other
studies the rate at which people had to stop taking a beta blocker
due to side effects was somewhat lower When used to treat high blood
pressure, beta-blocker side effects can be a problem because the condition
has no symptoms but the drug produces some.
People have widely varying tolerance for side effects and you should
talk to your doctor about their importance to you. In particular, the mild
mental depression or loss of sexual appetite that can occur with beta-
blockers is quite unacceptable to some people but tolerable to others. [25]
Guidelines for Use of Beta Blockers

35
 MYOCARDIAL INFARCTION IN PAST
NO
5 YEARS

YES

No need to Contraindications eg. Asthma,

commence beta COPD, uncontrolled heart failure , Yes
blockers unless other bradycardia, hypotension , heart
indicated eg. angina block , peripheral arterial disease ,
drug interaction with beta blockers
eg. verampil Consider verampamil,
unless contraindicated.
Diltiazem may also be
NO used if concurrent angina
and no contraindications

Heart failure Consider referral to

present ? Yes
cardiologists , if
abnormal ECG , AF or
mumur , for assessment
No of suitability for
bisprolol or carvediol

Renal
Yes
Impairment

Consider metoprolol No
or reduced dose of
atenolol

Consider atenolol , usual dose 50 mg

once daily (or 100 mg daily in 1 or 2
divided doses if angina)

Suggested Counseling During Beta Blockers Use [26]

36
1. General Counseling
• Explanation of heart failure and reasons for symptoms
•Cause of heart failure
• Expected symptoms
•Symptoms of worsening heart failure
•What to do if symptoms worsen
• Self-monitoring with daily weights
•Explanation of treatment/care plan
•Clarification of patient's responsibilities
2. Prognosis
• Life expectancy
• Advance directives regarding resuscitation
• Advice for family members in the
event of sudden death
3. Activity Recommendations
• Recreation, leisure, and work activity
• Exercise
• Sex, sexual difficulties,
and coping strategies
4. Dietary Recommendations
• Sodium restriction
•Avoidance of excessive fluid intake
• Fluid restriction (if required)
•Alcohol restriction
5. Medications
•Effects of medications on quality of
life and survival
•Dosing
• Likely side effects and what to do if
they occur
•Coping mechanisms for complicated
medical regimens
•Availability of lower cost medications or financial assistance
6. Importance of compliance with the Treatment / Care Plan

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37
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Paulo, SP – Brazil , 2005,419-22

2. Clinical Guideline 5, Developed by the National, Collaborating Centre for

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3. Robert Soufer, m.d. , Heart Failure, The New York Heart Association ,
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4. Lechat P, Packer M, Chalon S, Cusherat M, Arab T, Boissel J-P. Clinical

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13. Lindholm LH, Carlberg B, Samuelsson O., In, Should beta blockers
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20. Beta-blockade in CHF: pathophysiological considerations

Bernard Silke European Heart Journal Supplements (2006) 8 (Supplement
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24. Packer, M., G. V. Antonopoulos, et al. (2001). “Comparative effects of
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40