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  3. 3. ROLE OF BETA-BLOCKER IN HYPERTENSION INTRODUCTION Beta blockers (β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists) are a class of drugs that target the beta receptor found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stimulated by epinephrine(adrenaline). Beta blockers interfere with the binding to the receptor of epinephrine and other stress hormones, and weaken the effects of stress hormones. They are particularly used for the management of cardiac arrhythmias, protecting the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention) and hypertension. In addition, β-blockers reduce plasma rennin activity, reduce norepinephrine release, and prevent the pressure response to exercise or stress catecholamine release. β -blockers are effective antihypertensive agents, particularly for young white patients, and have been proven to reduce mortality in randomized clinical trials . Beta blockers block the action of endogenous catecholamine's epinephrine (adrenaline) and norepinephrine (noradrenalin) in particular, on β-adrenergic receptors, part of the sympathetic nervous system, which mediates the fight-or-flight response. Three types of beta receptors are known, designated β1, β2 and β3 receptors. β1-adrenergic receptors are located mainly in the heart and in the kidneys. β2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-adrenergic receptors are located in fat cells CLASSIFICATION OF BETA-BLOCKER Beta blockers differ in the type of beta receptors they block and, therefore, their effects. Non-selective beta blockers, for example, propranalol (Inderal), block β1 and β2 receptors and, therefore, affect the heart, blood vessels, and air passages. Selective beta blockers, for example, metoprolol (Lopressor, Toprol XL) primarily block β1 receptors and, therefore, mostly affect the heart and do not affect air passages. Some beta blockers, for example, pindolol (Visken) have intrinsic sympathomimetic activity (ISA), which means they mimic the effects of epinephrine and norepinephrine and can cause an increase in blood pressure and heart rate. Beta blockers with ISA have smaller effects on heart rate than agents that do not have ISA.
  4. 4. Labetalol (Normodyne, Trandate) and carvedilol (Coreg) block beta and alpha-1 receptors. Blocking alpha receptors adds to the blood vessel dilating effect of labetalol and carvedilol. Presently beta-blockers are classified into three, they are: First Generation ( β1 & β2 , Cardioselective) Propranalol  Second Generation ( β1, Non-Cardioselective) Atenolol, Metaprolol, Acebutolol, Bisoprolol, Betaxolol, Celiprolol  Third Generation ( Vasodilatory Properties) Carvedilol, Bucindolol, Nebivolol PROPERTIES OF BETA-BLOCKERS Many beta-blockers have ancillary properties which influence choice in hypertensive individuals. Selectivity : Since the desired effects of beta-blockers are mediated by blockade of beta1-receptors which predominate on the heart, “cardioselective” agents with relative selectivity for this receptor are generally preferred. However, receptor selectivity is not absolute and is lost at high doses. Examples of “cardioselective” beta-blockers include atenolol, bisoprolol and metoprolol. Beta-blockers with selectivity rates > 50, e.g. bisoprolol and nebivolol, are least likely to lose selectivity at high doses. Partial agonist activity (intrinsic sympathomimetic activity) : This manifests as a beta-stimulant effect when background adrenergic activity is low (e.g. during sleep) but beta-blockade occurs when adrenergic activity is increased (e.g. during exercise). Beta-blockers with partial agonist activity include pindolol. Membrane-stabilising activity : This e.g. sotalol. mostly confers a local anaesthetic and anti-arrhythmic effect Other properties : Some beta-blockers also block effects mediated at peripheral alpha-adrenoreceptors, e.g.:(carvedilol and labetalol), stimulate beta2-adrenoceptors (e.g. celiprolol) or have direct vasodilator activity (e.g. nebivolol)
  5. 5. MECHANISM OF ACTION Beta blockers, also known as beta-adrenergic blocking agents, are drugs that block norepinephrine and epinephrine (adrenaline) from binding to beta receptors on nerves. Norephinephrine and epinephrine are produced by nerves thorough out the body as well as by the adrenal gland. They serve as neurotransmitters (chemicals that nerves use to communicate with one another ), and also are released into the blood. There are three types of beta receptors and they control several different functions based on their location in the body. Beta-1 (β1) receptors are located in the heart, brain, and kidneys; Kidney: Blockade of beta1-receptors inhibit the release of rennin from juxta-glomerular cells and reduce the activity of the renin-angiotensin-aldosterone system. thereby
  6. 6. Heart: Blockade of beta1-receptors in the sino-atrial node reduces heart rate (negative chronotropic effect) and blockade of beta1-receptors in the myocardium decrease cardiac contractility (negative inotropic effect). Central and Peripheral Nervous System: Blockade of beta-receptors in the brainstem and of prejunctional beta-receptors in the periphery inhibits the release of neurotransmitters and decreases sympathetic nervous system activity. Beta (β2) receptors are found in the lungs, gastrointestinal tract, liver, uterus, blood vessels, and skeletal muscles. Activation of β2 receptors induces smooth muscle relaxation in the lungs, gastrointestinal tract, uterus, and various blood vessels. Increased heart rate and heart muscle contraction is also associated with the β2 receptors. β3 receptors are mainly located in adipose tissue. Beta (β3) receptors are located in fat cells. Activation of the β3 receptors induces the metabolism of lipids PHARMACOKINETICS Beta-blockers vary in the degree of elimination by the kidney or the liver, usually with extensive first-pass metabolism. Lipid-soluble beta-blockers, e.g. labetalol, metoprolol, pindolol and propranolol, typically depend upon hepatic metabolism for clearance, whereas water soluble beta-blockers e.g. atenolol are cleared by the kidney. Drugs eliminated by the liver tend to exhibit wide inter-individual variability in bioavailability. The half-life of most beta-blockers is relatively short; those eliminated by the kidney tend to have longer half-life. Beta-blockers are first-line drugs for the management of systemic hypertension, used alone and in combination with other antihypertensive agents. Drugs in the beta-blocking class have the common property of blocking the binding of catecholamine to beta-adrenergic receptor sites; however, there are significant pharmacodynamic and pharmacokinetic differences between the individual agents that are of clinical importance. Among these differences are the completeness of gastrointestinal absorption, the degree of hepatic first-pass metabolism, lipid solubility, protein binding, brain penetration, concentration within the cardiac tissue, rate of hepatic biotransformation, and renal clearance of drug and/or metabolites. Long-acting formulations of existing beta-blockers are currently in use, and ultra-short-acting agents are also available. Age, race, cigarette smoking and concomitant drug therapy can also influence the
  7. 7. pharmacokinetics of beta-blocking drugs. The wide interpatient variability in plasma drug concentrations observed with beta-blockers makes this parameter unreliable in routine patient management. Despite the pharmacokinetic differences among beta-blockers, these drugs should always be titrated to achieve the desired individual patient response. TRIALS WITH BETA-BLOCKER IN HYPERTENSION For more than 3 decades, beta-blockers have been widely used in the treatment of hypertension and are still recommended as first-line agents by national and international guidelines. However, ever since the Veterans Administration study in the 1970s multiple, prospective randomized trials have documented that diureticbased antihypertensive therapy reduces risk of stroke and, to a lesser extent, the risk of myocardial infarction and cardiovascular morbidity and mortality. However, the data are much less convincing for beta-blockers. The benefit of β-blockers compared with that of other anti-hypersensitive agents has recently been questioned on the basis of the result of two randomized trials LIFE STUDY & ASCOT STUDY LIFE STUDY The most important result of the study is that treatment based on once‐daily administration of losartan reduced LVMI during up to 5 years of treatment significantly more than conventional atenolol‐based treatment, confirming previous suggestions of superior regression of hypertensive LVH by AT1 receptor antagonism. In the Treatment of Mild Hypertension Study(TOMHS), no difference was observed between the ACE inhibitor and B‐blocker arms Atenolol as a comparator in outcome trials in hypertension OBJECTIVE Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we
  8. 8. reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study. METHODS: A literature search was conducted in September 2006 for randomized, controlled trials comparing betablockers with/without diuretics with placebo or no treatment in patients with hypertension and without recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events, cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all beta-blockers first-line. RESULTS: Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all betablocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were 19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.730.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p = 0.146). CONCLUSIONS: Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension. ASCOT STUDY A randomised controlled trial of the prevention of CHD and other vascular events by BP and cholesterol lowering in a factorial study design
  9. 9. ASCOT Launched in 1997, ASCOT was an independent, investigator-led study designed to evaluate different treatment strategies for preventing cardiovascular disease in hypertensive patients not considered conventionally dyslipidemic. It was conducted in more than 650 general practices and 32 regional medical centres across the United Kingdom, Ireland, and the 5 Scandinavian countries (Denmark, Finland, Iceland, Norway, and Sweden). ASCOT also included a lipid-lowering arm, ASCOT-LLA, that was stopped early as well, due to a significant reduction of cardiovascular events in the patients treated with atorvastatin. The full results of ASCOT-LLA were published in 2003. The primary objective of the trial was to compare the effects of the 2 treatment strategies on nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD). In addition to assessing a number of secondary and tertiary endpoints, the trial also was designed to examine the interaction between statins and antihypertensive treatment. STUDY DESIGN ASCOT-BPL ( stopped after 5.5. years) 19,257 hypertensive patients atenolol ± bendroflumethiazide amlodipine ± perindopril Investigator-led, multinational randomised controlled trial conducted in hypertensive patients, 40 -79 yrs, with no prior history of CHD, but with 3 additional cardiovascular risk factors (male sex, > 55 yrs, smoking etc )
  10. 10. Treatment algorithm to BP targets < 140/90 mmHg or < 130/80 mmHg in patients with diabetes Amlodipine 5-10 mg Atenolol 50-100 mg Perindopril 4-8 mg Bendroflumethiazide-K 1.25-2.5 mg Doxazosin GITS 4-8 mg Additional drugs, e.g., moxonidine/spironolactone (Median follow up was for 5.5 years) Baseline Characteristics Demographic and clinical characteristics Amlodipine ± perindopril n = 9639 Atenolol ± thiazide n = 9618 Male 7381 (76.6%) 7361 (76.5%) White 9187 (95.3%) 9170 (95.3%) Current smoker 3168 (32.9%) 3110 (32.3%)
  11. 11. Age (years) 63.0 (8.5) 63.0 (8.5) SBP (mmHg) 164.1 (18.1) 163.9 (18.0) DBP (mmHg) 94.8 (10.4) 94.5 (10.4) Heart rate (bpm) 71.9 (12.7) 71.8 (12.6) BMI (kg/m2) 28.7 (4.6) 28.7 (4.5) Diabetes 2567 (27%) 2578 (27%) Other vascular disease 2169 (23%) 2162 (22%) Total cholesterol (mmol/L) 5.9 (1.1) 5.9 (1.1) 1841 (19.1%) 1825 (19.0%) 1 4280 (44.4%) 4283 (44.5%) ≥2 3518 (36.5%) 3510 (36.5%) Lipid-lowering therapy 1046 (10.9%) 1004 (10.4%) Aspirin 1851 (19.2%) 1837 (19.1%) Drug therapy Previous antihypertensive treatments 0 Values are number of patients (%), or mean (SD) TRIAL:- CONCLUSION • Amlodipine perindopril-based therapy conferred an advantage over atenolol thiazide-based therapy on all major CV endpoints, all-cause mortality and new-onset diabetes • Additional statistical analyses demonstrated that adjusting for blood pressure differences between treatment groups early on in the trial, did not account for the observed differences in cardiovascular outcomes • • Mean BP in trial has minimal effect on stroke outcome and no effect on CHD outcome Various measures of visit-to-visit BP variability (SD, coefficient of variation and variation independent of mean BP) are powerful predictors of both stroke and CHD outcomes • Other measures of variability (within-visit variability and variability assessed by ABPM) also predict cardiovascular outcomes but less than visit-to-visit variability • Amlodipine reduces variability compared with atenolol • Variability increased with age, diabetes, smoking, and in those with established vascular disease
  12. 12. 2004 Meta Analysis of Outcomes: Atenolol vs. Other Antihypertensive Treatments  Analysis of 5 studies: Atenolol versus other antihypertensive therapy  17,671 patients included, with a mean follow up of 4.6 years  No differences in BP lowering Risk Reduction ( 95% CL ) All cause-Mortality 1.13 (1.02-1.25) CV Mortality 1.16 (1.00-1.34 ) Myocardial Infraction 1.04 (0.89-1.20 ) Stroke 1.30 (1.12-1.50 ) β-Blocker V/S Other Anti-hypertensive Agents The graph shows the trial on a patient with hypertension and renal disease.
  13. 13. Beta Beta-Blockers V/s Other Antihypertensive Drugs: Composite Outcome * (* Death Stroke or MI ) Study Population Beta-blocker n/N Other Drugs n/N RR (95% CL) Participants <60 years 745/15136 770/15276 0.97 (0.88-1.07) Participants >60 years 3588/39010 3817/40765 1.06 (1.01-1.10) Nebivolol : The 3rd Generation Beta-Blocker Nebivolol is a β1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment of hypertension and also for left ventricular failure. It is highly cardioselective under certain circumstances. Nebivolol slows down the activity of your heart by stopping messages sent by some nerves to your heart. It does this by blocking tiny areas (called beta-adrenergic receptors) where the messages are received by your heart. Nebivolol also relaxes (widens) some blood vessels. Along with their useful effects, The most common side-effects of nebivolol are tiredness, cold fingers or toes, disturbed sleep, and stomach upset. Treatment with nebivolol is usually long-term. Do not stop taking these tablets without speaking to your doctor first as this can cause problems. Insulin Resistance: Effect of Nebivolol V/s Atenolol
  14. 14. CONTRAINDICATIONS OF BETA-BLOCKER COMPELLING CONTRAINDICATION Second or Third Degree Heart Block In the heart condition called second degree block, some electrical impulses from the heart chambers called the atria do not reach the chambers called the ventricles. When this occurs, there will be missed beats--the normal heart beat will be interrupted with these intermittent missed beats. Patients with second or third degree heart block should not take beta blockers because there is a risk that the heart block will worsen and result in abnormal, potentially fatal heart rhythms. Asthma A 2007 study of over 11,000 patients, published in the journal "Pharmacotherapy," found that patients with asthma who were on beta blockers had higher rates of hospitalization and more visits to the emergency department, when compared with asthma patients not on beta blockers. This is because one of the actions of beta blockers is to constrict the airways; patients with asthma already have constricted airways, so the beta blockers make the problem worse. Asthma medicine works to relax the airways beta blockers constrict them. Bradycardia Bradycardia is the medical term for a heart rate that is fewer than 60 beats per minute. Patients with bradycardia should not take beta blockers. This is because one of the effects of beta blockers is to decrease the heart rate. So a patient with bradycardia who takes beta blockers is at risk for a dangerously low heart rate. Patients may feel no symptoms related to their abnormally slow heart rate. Alternatively, patients may experience symptoms such as light-headedness, chest pain, fatigue and weakness. Worsening of alreadyexisting heart failure may also POSSIBLE CONTRAINDICATION Atrial fibrillation Tachycardia Idiopathic hypertrophic subaortic stenosis Migraine prophylaxis Myocardial infarction prophylaxis Hypertension Pheochromocytoma Thyrotoxicosis Tremor Ventricular arrhythmia Atrial flutter Myocardial Infraction occur.
  15. 15. CONCLUSION  Advice the use of β-blocker as a fourth line anti-hypertensive agent  Recent meta-analysis have shown that β-blocker do not provide benefit for the endpoint of all cause MI and mortality even when compared with a placebo, both in elderly and younger population β-blocker's  The β-blocker/diuretic combination favours development of diabetes and should thus be avoided, unless required for other reasons ARB's  β-blockers are not only less efficacious at reducing peripheral blood pressure but also have a lesser effect on perhaps the more important central aortic pressure when compared with RAAS blockers, diuretics &calcium antagonist  In patients with uncomplicated hypertension, there is paucity of data or absence of evidence to support use of beta-blockers as monotherapy or as first-line agents. Risk of stroke, lack of cardiovascular morbidity and mortality benefit, numerous adverse effects, lack of regression of target end-organ effects of hypertension like LVH, and endothelial dysfunction, the risk benefit ratio for beta-blockers is not acceptable for this indication  All outcomes studies showing no benefit in hypertension were conducted with traditional beta-blockers such as atenolol and metoprolol. Whether the newer vasodilating agents such as nebivolol and carvedilol, which have a more favourable hemodynamic and metabolic profile, will be more efficacious in reducing morbidity and mortality, remains to be determined.
  16. 16. REFERENCE 1. Wikipedia (  Definition, Classification, Properties , Pharmacological Action , Nebivolol etc (Date of Reference :- 25/10/13) 2. Medscape (  Current Analysis of Beta-blocker, When to use beta-blocker etc (Date of Reference:- 25/10/13) 3. Jaac (  Meta Analysis of Beta-Blocker, Trials-Life Study etc (Date of Reference:-25/10/13) 4. WebMD (  Contraindication, Present beta-blockers, Adverse effects etc (Date of Reference:-27/10/13) 5. ,  Atenolol, Amilodipine, Mechanism of action etc (Date of Reference;-27/10/13) 6. MedicineNet Search (  Trials :- ASCOT , Meta-analysis of Beta-blocker, Study Design , Treatment Algorithm etc (Date of Reference:-27/10/13)