Comprehensive Study Of Beta Blockers

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

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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 renninangiotensin-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]

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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]

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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 (downregulation).

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 .

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DIAGNOSIS Indian Society of Cardiology guidelines for the diagnosis Of heart failure 1.

2.

Essential features • Symptoms of heart failure (breathlessness, fatigue, ankle Swelling) and • Objective evidence of cardiac dysfunction (at rest) 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 Chest x-ray

Electrocardiogram

Echocardiogram

Complete blood count Urinalysis Serum creatinine Serum albumin T4 and TSH Brain natriuretic peptide

Findings Cardiomegaly Pulmonary venous congestion Interstitial fluid Pulmonary disease Acute ST-T wave changes Atrial fibrillation, other tachyarrhythmia Bradyarrhythmias Previous MI (e.g. Q waves) LV systolic dysfunction LV hypertrophy clues LV diastolic dysfunction Valve disease Anemia Proteinuria Red blood cells or cellular casts Elevated Decreased Abnormal T4 or TSH Elevated BNP

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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]

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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 nonpharmacological 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). •

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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

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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]

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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 Non-selective

ADRENERGIC SELECTIVITY Beta1 > beta2

Selective

Beta1 and beta2

EXAMPLE Propranolol Sotalol atenolol metoprolol succinate metoprolol tartrate 12

Non-selective and Vasodialating Non-selective and vasodialating (nitric acid pathway)

Beta1, beta2 and alpha1 Beta1 and beta2

(sustained release) bisoprolol Carvedilol labetalol Nebivolol

STRUCTURES OF BETA BLCKERS: [14]

Labetalol

Propranolol

Atenolol

13

Oxprenolol

Alprenolol

Timolol

Acebutolol

Sotalol

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(Table no III) Examples of Some Beta Blockers [15] Beta blocker propranolol atenolol oxprenolol alprenolol prindolol timolol acebutolol metoprolol nadolol bisprolol metoprolol carvediol

Usual dosage 40 - 80 mg bid lOO mg qd-bid 1 00 mg daily 100- 200 mg bid 300 mg tids 5 - 20 mg tds 5- lO mg tids 80 mg daily 80- 160 mg bid 20 mg tid 160 mg daily 1.25 mg q.d. 12.5 mg q.d. 3.125 mg b.i.d.

Daily maximum 320 mg 400 mg 200 mg 1200 mg 60 mg 45 mg 240 mg 320 mg 320 mg 320 mg 10.0 mg q.d. 20 mg q.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 beta1receptors 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. Betablockers 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

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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, betablockers 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 betablocker 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.

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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.

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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 beta19

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

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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 Atenolol Bisoprolol Bucindolol Carvedilol

Beta1-selective Yes Yes No No

ISA No No Yes No

Vasodilatation No No Yes Yes 22

Celiprolol Labetalol Metoprolol Oxprenolol Pindolol Propranolol Sotalol

Yes No Yes No No No No

Yes Yes No Yes Yes No No

No Yes No No 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

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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 betablocker. 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 betablockers 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

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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.

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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 betablocking 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 betablocking 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 lpropafenone 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 dpropranolol 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,lcarvedilol. 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, betablockers 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 lenantiomers 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 placebocontrolled 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.

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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 Carvediol Timolol Acebutalol Labitalol Bucindolol Metoprolol

No. of patients 56 345 278 415 2708 383

Changes in EF(%) Beta blocker Placebo 6.5 -0.4 6.3 2.0 8.0 3.0 5.1 -0.2 7.3 3.3 12.0 6.0

Duration (mo) 3.5 6 6 12 12 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.

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• • • • •

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 betablockers. 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 betablockers 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, betablockers 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 betablockers. 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 betablockers is quite unacceptable to some people but tolerable to others. [25]

Guidelines for Use of Beta Blockers

35

NO

MYOCARDIAL INFARCTION IN PAST 5 YEARS YES

No need to commence beta blockers unless other indicated eg. angina

Contraindications eg. Asthma, COPD, uncontrolled heart failure , bradycardia, hypotension , heart block , peripheral arterial disease , drug interaction with beta blockers eg. verampil

Yes

Consider verampamil, unless contraindicated. Diltiazem may also be used if concurrent angina and no contraindications

NO Heart failure present ? No

Yes

Consider metoprolol or reduced dose of atenolol

Yes

Consider referral to cardiologists , if abnormal ECG , AF or mumur , for assessment of suitability for bisprolol or carvediol

Renal Impairment No

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]

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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

REFERENCES 1. Christiano Pereira Silva ,et al , Heart Failure Treatment Profile at the Beta Blockers Era, Hospital das Clínicas da Faculdade de 37

Medicina da Universidade de São Paulo (HC-FMUSP) – São Paulo, SP – Brazil , 2005,419-22 2. Clinical Guideline 5, Developed by the National, Collaborating Centre for Chronic conditions, UK, July 2003, 27-29 3. Robert Soufer, m.d. , Heart Failure, The New York Heart Association , Yale University of Medical Heart Book , USA, 2003, 177-178 4. Lechat P, Packer M, Chalon S, Cusherat M, Arab T, Boissel J-P. Clinical Effects of Beta Adrenergic Blockade In Chronic Heart Failure. Circulation 1998; 98: 1184–91. 5. Breaking Down Beta-Blockers and Heart Failure, By Michel Samson, MD , The Canadian Journal of CME / July 2001, pg no 65-67 6. Beta-blockers and heart failure , Laßnig E, Auer J, Berent R, Eber B, Mayr H , Journal of Clinical and Basic Cardiology 2001; 4 (Issue 1), 11-14 7. Comparative Effects of Two Beta-blockers on Cardiovascular Reactivity and Type A Behavior in Hypertensives by, david s. Krantz, richard j. Contrada, Et al, in Psychosomatic Medicine 50:615-626 (1988) 8. Fact Sheet - Beta-Blockers For Acute Myocardial Infarction Randomized Trial of Intravenous Atenolol Among 16,027 Cases of Suspected Acute Myocardial Infarction: ISIS-1. Lancet; (April 2005) 2(8498):57-66. 9. Taylor SH, Silke B. Haemodynamic Effects of Beta-Blockade in Ischaemic Heart Failure. Lancet 1981; I: 1441–8. 10. Hypertension Care Flow Sheet British Columbia Medical Association, ministry of health guidelines and protocols advisory committee, Great Britain 1997 (231-42) 11. Beta-Adrenergic Blockers, William H. Frishman published by the American Heart Association., Circulation 2003; 107;117-119 12. Antman EM, ed. , Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease.2nd ed. Philadelphia, Pa: WB Saunders Co;2002.

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13. Lindholm LH, Carlberg B, Samuelsson O., In, Should beta blockers remain first choice in the treatment of primary hypertension? A metaanalysis. Lancet 2005;366:1545-53. 14. Australian prescriber , volume 30 number 1 feb 2007 , pg -6-8 15. Beta adregenic blocking agents in treatment of hypertension , by Dr. Peter C. Y. Wong M.B..B.S., (H.K.) university of Stanford, 2006, 29-31 16. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985; 27: 335–71. 17. Beta-blockers: Ancillary Properties Important After all? Cleophas T.C., Van Der Meulen J. Department of Medicine, Merwede Hospital, Dordrecht, Netherlands Eastern Journal of Medicine 4 (1): 1-5, 1999. 18. Beta Blockers In Cardioprotection After Acute Myocardial Infarction , Milan Pavlović , University of Niš The Scientific Journal Facta Universitatis Uc: 612.17; 616.12 19. The Role of Beta Blockade in Hear t Failure , a report by Professor macro metra, savina Nordi and Livio Dei Cas Institute of cardiology, University of Brescia, 2004, 221-224 20. Beta-blockade in CHF: pathophysiological considerations Bernard Silke European Heart Journal Supplements (2006) 8 (Supplement C), C13–C18 doi:10.1093/eurheartj/sul009 21. Frishman WH, Sonnenblick EH, Sica D, eds. Cardiovascular Pharmacotherapeutics. 2nd ed. New York, NY: McGraw Hill; 2003. 22. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J. 1975;37:1022-1036. 23. Braunwald E, Antman E, Beasley J, et al. ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: executive summary and recommendations. Circulation 2000; 102:1193–1209. 39

24. Packer, M., G. V. Antonopoulos, et al. (2001). “Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: results of a meta-analysis.” American Heart Journal 141(6): 899-907. 25. Gottlieb, S. S., M. L. Fisher, et al. (2002). “Tolerability of beta-blocker initiation and titration in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF),” Circulation 105(10): 11828.. 26. Roberts R, Rogers WJ, Mueller HS, Lambrew CT, Diver DJ, Smith HC, Willerson JT, Knatterud GL, Forman S, Passamani E, . Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation 1991;83(2):422-37.

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