Beta-blockers in cardiovascular diseases


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  • Coronary plaque disruption was closely related to a high heart rate, which was reversed by the presence of β-blockade; β-blockadealso reduces coronary artery wall stress. Thus, β-blockers appear to stabilize the vulnerable plaque. β-Blockers can also decrease the coronary artery atheromatous plaque volume as assessed directly by intravascular ultra sonography. In patients with known coronary artery disease (80% of whom had hypertension) followed up for 1 year, those on β-blockers (n = 1154, nonrandomized) experienced a signifi cant regression ofplaque volume compared with those who were not on β-blockers (n = 361); the effect of statins is included for comparison.
  • Many factors underlie the infl ammatory process, a major component being high sympathetic nerve (β1) activity/noradrenaline levels. Thus, in patients with ischemic heart disease and hypertensives, β-blockers were more effective than diuretics, calcium blockers, ACEinhibitors, and angiotensin receptor I blockers in reducing CRP levels.
  • Bisoprolol 5-10 mg will have little, or no, effect on metabolic parameters such as lipids, blood sugar/haemoglobin A1c (HbA1c),23 and post-insulin blood sugar and lactate changes.
  • ABPM: BP Control beyond traditional BP control. Superior 24 hour BP control as compared to atenolol. Ensures more than 82% of patients with Stage II HTn achieve BP goals.
  • Beta-blockers in cardiovascular diseases

    2. 2. History • Beta-blockers were first developed by Sir James Black at the imperial chemical industries in the United Kingdom in 1962. • They are considered one of the most important contributions to clinical medicine and pharmacology in the 20th century. • Sir James Black was awarded the Nobel prize in 1988 for advances in medicine.
    3. 3. Today’s talk will include • The pertinent clinical pharmacology of beta-blockers • Their clinical use in cardiovascular medicine.
    5. 5. Actions of beta receptor stimulation
    6. 6. Beta 1 VS Beta 2 Selectivity
    7. 7. 30 0:1 1:35 1:35 1:75 increasing ß 1 -selectivity increasing ß 2 -selectivity ICI 11 8.55 1 1 .8 :1 Propranolol Atenolol Betaxolol Bisoprolol no selectivity Ratio of constants of inhibition 1:20 M etoprolol 1-selectivity of various -blockers Wellstein A et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 36-40 Wellstein A et al. Eur Heart J 1987; 8 (Suppl. M): 3–8
    8. 8. Summary of use of beta blockers in cardiovascular diseases
    10. 10. Mechanism of β-blocker benefits in ischemic heart disease • Reduction in myocardial oxygen requirements via a decrease in heart rate, blood pressure and ventricular contractility. • Slowing of the heart rate prolongs coronary diastolic filling period. • Redistribution of coronary
    11. 11. Mechanism of β-blocker benefits in ischemic heart disease • Increases threshold to ventricular fibrillation. • Reduction in infarct size and reduction in the risk of cardiac rupture. • Reduction in the rate of reinfarction. • Regression of the atheromatous
    12. 12. β-Blockers and atheromatous plaque regression/progression/vulnerabilit y stability Decrease in coronary atheromatous plaque volume by BB (as assessed by intracoronary ultrasound) over 1 year (independent of statins, ACE inhibitors, other drugs, low- density lipoprotein concentration, and heart rate). ns, not significant; sig, significant. Sipahi I, Tuzcu EM, Woski KE, et al. Ann Intern Med 2007;147:10–18
    13. 13. MECHANISM OF BETA BLOCKERS IN HEART FAILURE • Upregulation of β receptors and improved β adrenergic signaling. • Reducing the hyperphosphorylation of calcium release channels of sarcoplasmic reticulum and normalizing their function • Bradycardia (↑ coronary blood flow and decreased myocardial oxygen demand). • Protection from catecholamine myocyte toxicity. • Suppression of ventricular arrhythmias. • Anti-apoptosis. β2 receptors, which are relatively increased, are coupled to inhibitory G protein & block apoptosis. • Inhibition of RAAS. When added to prior ACE-I or ARB, metoprolol augments RAAS inhibitors
    14. 14. β-Blockers and the inflammatory process The effect of monotherapy antihypertensive treatments upon plasma C-reactive protein levels. ACE/ARB, angiotensin-converting enzyme/ ACE receptor blocker; CCB, calcium channel blocker. Palmas W, Ma S, Psaty B, et al. Am J Hypertens 2007;20:233–41 Reduction in Vascular markers with BB
    15. 15. JNC 7 recommendations
    16. 16. Beta blockers for hypertension • In the 1980s, beta-adrenergic receptor blockers (beta blockers) became the most popular form of antihypertensive therapy after diuretics, reflecting their relative effectiveness and freedom from many bothersome side effects • Because beta blockers reduce mortality in patients post–myocardial infarction or heart failure (i.e., secondary prevention), it was assumed they would also provide special protection against initial cardiac events (i.e., primary prevention).
    17. 17. Beta blockers for hypertension….any benefit in primary prevention??? NO • In multiple large RCTs, the use of a beta blocker (particularly atenolol) provided no more protection against the first myocardial infarction (MI) than other drugs and was associated with a statistically significant 16% increase in the incidence of stroke. • rationale—beta blockers lower brachial systolic BP equally but do not lower aortic pressure as well as other drugs. They reduce heart rate and increase peripheral resistance, so that the arterial wave reflection from the periphery returns during systole rather than during diastole.
    18. 18. This is how braunwald’s textbook summarizes the use of betablockers in hypertension • “Beta blockers are specifically recommended for hypertensive patients with concomitant coronary disease, particularly after a myocardial infarction, congestive heart failure, or tachyarrhythmias.” • “If a beta blocker is chosen, the agents that are more cardioselective offer the likelihood of fewer perturbations of lipid and carbohydrate metabolism and, because of fewer side effects (except for bradycardia), better adherence to therapy.” • “Long-acting formulations are better for once-daily dosing.” Page 945 braunwald’s textbook of medicine 9th edition
    19. 19. Copyright © The American College of Cardiology. All rights reserved. From: Cardiovascular Protection Using Beta-Blockers: A Critical Review of the Evidence J Am Coll Cardiol. 2007;50(7):563-572. doi:10.1016/j.jacc.2007.04.060 Proposed Use of Beta-Blockers for Hypertension In patients with uncomplicated hypertension, beta-blockers should not be used as first-line agents. However, in patients with uncontrolled hypertension on various other antihypertensive agents and in those with complicated hypertension, beta-blockers should be considered in the armamentarium of treatment. CHF = chronic heart failure; MI = myocardial infarction. Figure Legend:
    20. 20. Changing patterns of betablocker use
    22. 22. Bisoprolol experience in Indian patients Mar 2012
    23. 23. Objectives: This study was aimed to evaluate the efficacy and tolerability of bisoprolol, in Indian patients diagnosed with stage I essential hypertension as first line drug. Primary and secondary outcomes measures: • The primary outcome measure was percentage of patients achieving blood pressure (BP) <140/90 mm Hg at Bisoprolol in hypertension Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683
    24. 24. • Results: – 2131 (96.44%) patients achieved BP control. – There was significant reduction in systolic blood pressure (25.29; SD: 13.22 mm Hg), diastolic blood pressure (14.14; SD: 7.67 mm Hg) and heart rate (12/min; SD: 6.15) compared with baseline (all p values <0.05). – The median dose of bisoprolol and average period required for the response were 5 mg/day and 33 days, 0 20 40 60 80 100 120 140 160 180 Baseline 2 4 8 12 SBP DBP 66 68 70 72 74 76 78 80 82 84 86 88 HR HR Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open
    25. 25. Bisoprolol: Pharmacology • Pharmacology –Bisoprolol is a highly potent ß1 adrenoceptor blocking agent –No ISA –No pronounced negative inotropic effects –Low affinity for ß2-receptors involved with metabolic regulation • does not influence airways resistance
    26. 26. Modified from: Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Su Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8 Highly β1-selective 1:35 1:75 Increasing β1- selectivity Increasing β2-selectivity 1.8:1Propranolol Atenolol Bisoprolol No selecti vity Ratio of constants of inhibition 1:20 Metoprolol ß1-selectivity of bisoprolol compared with other ß-blockers
    27. 27. Selectivity at clinical dose β1-adrenoceptor occupancy, as achieved in a dosage interval of 24 h equivalent to a single dose ß1- and ß2-receptor occupancy in relation to plasma concentrations Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):41–54 Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8 Atenolol Occupancy Ration = 80% : 20% Bisoprolol Occupancy Ration = 100% : 0%
    28. 28. Bisoprolol in HTN with COPD 2013 •Cardioselective beta-1 blockers such as metoprolol, bisoprolol, or nebivolol may be beneficial in COPD. •Atenolol does not reduce cardiovascular events in patients with hypertension. •Nonselective beta blockers such as propranolol may induce bronchospasm and should not be used in patients with COPD Dipak Chandy1, Wilbert S Aronow2, Maciej Banach3, 1Division of Pulmonary, Critical Care and Sleep, 2Division of Cardiology, Department of Medicine, New York Medical College, Valhalla, NY, USA; 3Department of
    29. 29. Comparison of PK properties of BB
    30. 30. Metabolic Disturbance Change in plasma triglyceride and high-density lipoprotein (HDL) levels in normocholesterolemic hypertensive patients after long-term therapy with propranolol (nonselective), atenolol (moderately β1- selective), mepindolol (nonselective with ISA), and bisoprolol (highly β1-selective). Fogari R, Zoppi A. Rev Contemp Pharmacother 1997;8:45–54. ** ** ** ** ** ** ** ** ** * 6 12 18 24 30 36 months Bisoprolol 10 mg/day (n=17) Propranolol 160 mg/day (n=15) Atenolol 100 mg/day (n=22) vs baseline *p<0.05 **p<0.01 %HDL-cholesterol +10 0 -10 -20 -30 -40 Difference in effect on lipid profile – Beta-1 selectivity is the key.
    31. 31. Different beta blockers and sexual dysfunction versus placebo
    32. 32. Elimination routes of various beta blockers from body
    33. 33. Product Information for Bisoprolol
    34. 34. Product Information for Bisoprolol Use in Pregnancy: not labeled; though used by many
    35. 35. COMPARISONS
    36. 36. Atenolol Bisoprolol Moderately β1-selective Highly β1-selective No first-pass effect Little first-pass effect (10%) Bioavailability: 40-50% Bioavailability: 90% Unchanged renal elimination => dose reduction in renal impairment Balanced clearance: no dose adjustment in mild-to-moderate renal impairment. Do not exceed 10 mg in severe cases Once-daily administration (SPC!) BUT: twice daily necessary Once-daily administration sufficient and clinically proven 24 h Peak-trough BP control ratio 31% 24 h Peak-trough BP control ratio 78% No CHF indication CHF indication Competitor ß-blocker Pharmacology: atenolol
    37. 37. Bisoprolol Vs Atenolol: ABPM study results • Multi-centric, double- blind, randomized ABPM study. • Bisoprolol (10 – 20 mg/OD) Vs Atenolol (50 – 100mg/OD) for 8 weeks. • N = 659. • Efficacy Variables – –Average 24 hour fall in BP –Night time 4 hour fall in BP Neutal J et al. Am J Med,1993;94(2):181-187
    38. 38. Bisoprolol Vs Atenolol: Change in night time BP Neutal J et al. Am J Med,1993;94(2):181-187
    39. 39. Bisoprolol Vs Atenolol: Conclusion • Conventional BP measurement fails to detect difference between bisoprolol and atenolol. • Bisoprolol – –Greater fall in DBP from baseline than atenolol. –Greater fall in SBP and DBP in night time BP than atenolol.Neutal J et al. Am J Med,1993;94(2):181-187
    40. 40. Competitor ß-blocker Pharmacology: metoprolol succinate Metoprolol (succinate) Bisoprolol β1-selective (due to ZOK formulation) Highly β1-selective 50% bioavailability due to first-pass elimination (CYP2D6) High bioavailability, small first-pass- effect Dose-reduction in hepatic impairment required Balanced clearance: no dose adjustment in mild-to-moderate hepatic impairment. Do not exceed 10 mg in severe cases Once-daily administration (due to ZOK formulation) Once-daily administration CHF indication proven (MERIT-HF) CHF indication proven (CIBIS II)
    41. 41. Competitor ß-blocker Pharmacology: metoprolol tartrate Metoprolol (tartrate) Bisoprolol Moderately β1-selective, reliable selectivity only in lower dose range Highly β1-selective Bioavailability: 50% High bioavailability, small first-pass- effect Predominantly hepatic clearance: Dose-reduction in hepatic impairment required (CYP2D6) Balanced clearance: no dose adjustment in mild-to-moderate hepatic impairment. 10 mg in severe cases not to be exceeded Short half-life of 3–4 h, no once daily administration Once-daily administration No CHF indication proven CHF indication proven
    42. 42. 180 160 140 120 100 80 90 80 70 60 50 mm Hg SBP n.s. DBP 2-4 weeks 0 + 2 + 4 weeks placebo ß-blocker p < 0.01 p < 0.05 HRbeats/min Bisoprolol (n = 44) Metoprolol (n = 43) B vs. M n.s.= not significant * ** ** * ** ** * Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113 ± SDx _ Bisoprolol Vs Metoprolol : Change in BP & HR (at rest)
    43. 43. 0 20 40 60 80 100 % 90% SBP Bisoprolol 10 mg Metoprolol100 mg HR RPP 66% 93% 54% 92% 60% n = 87 Haasis R et al. Eur Heart J 1987; 8 (Suppl M): 103–113 Bisoprolol Vs Metoprolol : 24 hr Efficacy
    44. 44. Competitor ß-blocker Pharmacology: nebivolol (1) Nebivolol Bisoprolol Highly β1-selective Highly β1-selective No adverse effects on lipid/glucose metabolism No adverse effects on lipid/glucose metabolism Vasodilatation via L-arginine/NO pathway Enhanced NO release due to ISA at β2 or β3-receptors: stimulation β3=> negative inotropic effects No ancillary properties Bioavailability: 90% (poor metabolisers) Bioavailability: 12% (fast metabolisers) Bioavailability: 90% t½: 8 h (fast metabolisers) to 27 h (poor metabolisers) t½: 10–12 h Figure 12: Bisoprolol compared with nebivolol (part 1 of 2)
    45. 45. Competitor ß-blocker Pharmacology: nebivolol (2) Nebivolol Bisoprolol Increase in plasma concentration of nebivolol and active metabolites in patients with renal dysfunction Balanced clearance: 2 independent and equally effective routes of clearance High protein binding: ~98% Low plasma-protein binding: 30% CHF indication (based on a composite endpoint of all-cause mortality & CV hospital admission) No significant mortality reduction Indication limited to elderly (70 years) CHF indication with proven signifcant mortality reduction No CAD indication CAD indication approved Figure 12: Bisoprolol compared with nebivolol (part 2 of 2)
    49. 49. Indirect comparison 2013 STUDY BISOPROLOL NEBIOLOL MAIN CHF II At half dose, LVEF increases ---- SENIORS ---- No significance on LVEF
    50. 50. Also,
    51. 51. NEBIVOLOL
    52. 52. Competitor ß-blocker Pharmacology: carvedilol Carvedilol Bisoprolol Not β1-selective Highly β1-selective Vasodilatation due to α1-blockade (but may cause orthostatic disorders) No α1-blocking activity Metabolic effects (in some studies): • No influence on carbohydrate metabolism • Positive effect on lipids (HDL  and LDL) • Negative lipid effect (cholesterol, TG, VLDL ) No relevant influence on carbohydrate metabolism Lipid profile (almost) not affected Antioxidative effect? No studies available Antiproliferative effect? No studies available Figure 13: Bisoprolol compared with carvedilol (part 1 of 2)
    53. 53. Competitor ß-blocker Pharmacology: carvedilol Carvedilol Bisoprolol Bioavailability: 25% Bioavailability: 90% Protein binding: >98% Protein binding: 30% Oral bioavailability of digoxin increased No interaction with other CV drugs known Extensive metabolism in the liver (CYP2D6) Dose adjustment in patients with hepatic impairment Balanced clearance: 2 independent and equally effective routes of clearance No dose adjustment required (10 mg not to be exceeded in terminal insufficiency) Sensitive to liver enzyme induction Almost insensitive to liver enzyme induction t½ 610 h => b.i.d. administration (extended release formulation available) t½: 1012 h, once-daily administration Figure 13: Bisoprolol compared with carvedilol (part 2 of 2)
    54. 54. 6. CIBIS–ELD 2011
    55. 55. CIBIS–ELD 2011
    56. 56. CIBIS–ELD 2011
    57. 57. CIBIS–ELD 2011
    58. 58. CIBIS–ELD 2011 • More pulmonary adverse events occurred with Carvedilol.
    59. 59. 7. Bisoprolol Vs Carvedilol in CHF and COPD 2011
    60. 60. Bisoprolol Vs Carvedilol
    61. 61. Bisoprolol Vs Carvedilol
    62. 62. THANKYOU!
    63. 63. Cardiovascular contraindications
    64. 64. Classification of β-blockers 1st Generation Non-selective Propranolol 2nd Generation β1-selective Atenolol Metoprolol Betaxolol Bisoprolol 3rd Generation Additional properties, for example vasodilation Carvedilol Nebivolol Table 6: Classification of ß-blockers