beta-blockers in cardiovascular diseases
DESCRIPTION
SLIDES TO GIVE A COMPREHENSIVE REVIEW OF BETA BLOCKER USE IN CARDIOVASCULAR DISEASESTRANSCRIPT
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CURRENT STATUS OF BETA BLOCKER USE IN CARDIOVASCULAR DISEASES
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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.
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Today’s talk will include
• The pertinent clinical pharmacology of beta-blockers
• Their clinical use in cardiovascular medicine.
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CLASSIFICATION
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Actions of beta receptor stimulation
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Beta 1 VS Beta 2 Selectivity
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300:1
1:35 1:35
1:75
increasing ß1-selectivity
increasing ß2-selectivity
ICI 118.551
1.8:1 Propranolol
Atenolol Betaxolol
Bisoprolol
no selectivity
Ratio of constants of inhibition
1:20
Metoprolol
1-selectivity of various -blockers
Wellstein A et al. J Cardiovasc Pharmacol 1986; 8 (Suppl. 11): 36-40Wellstein A et al. Eur Heart J 1987; 8 (Suppl. M): 3–8
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Summary of use of beta blockers in cardiovascular diseases
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ACTIONS OF BETA BLOCKERS
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Mechanism of β-blocker benefitsin 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 flow toward vulnerable sub-endocardial regions.
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Mechanism of β-blocker benefitsin 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 process.
• Atheromatous plaque stabilisation (rupture less likely).
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β-Blockers and atheromatous plaqueregression/progression/vulnerability 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
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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
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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
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JNC 7 recommendations
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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).
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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.
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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
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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:
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Changing patterns of betablocker use
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BISOPROLOL…. THE MOST CARDIOSELECTIVE BETA BLOCKER
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Bisoprolol experience in Indian patients
Mar 2012
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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 the end of 12 weeks, while multiple secondary outcome measures were assessed.
Bisoprolol in hypertension
Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683
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• 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,
Baseline 2 4 8 120
20
40
60
80
100
120
140
160
180
SBPDBP
65
70
75
80
85
90
HR
HR
Channaraya V, Marya RK, Somasundaram M, et al. BMJ Open 2012;2:e000683
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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• no adverse changes in lipid profile• no adverse changes in blood glucose levels
–Maximal antihypertensive effect reached in 2 weeks
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Modified from: Wellstein A et al. J Cardiovasc Pharmacol 1986;8(Suppl. 11):36–40Wellstein 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 1.8:1 Propranolol
Atenolol
Bisoprolol
No selectivity
Ratio of constants of inhibition
1:20Metoprolol
ß1-selectivity of bisoprolol compared with other ß-blockers
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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):41–54Wellstein A et al. Eur Heart J 1987;8(Suppl. M):3–8
AtenololOccupancy Ration = 80% : 20%
BisoprololOccupancy Ration = 100% : 0%
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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 Hypertension, Medical University of Lodz,Lodz, Poland) - Current perspectives on treatment of hypertensive patients with chronicobstructive pulmonary disease
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Comparison of PK properties of BB
True OD
administrat
ion
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Metabolic DisturbanceChange 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
%
HD
L-ch
ole
stero
l
+10
0
-10
-20
-30
-40
Difference in effect on lipid profile
– Beta-1 selectivity is the key.
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Different beta blockers and sexual dysfunction versus placebo
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Elimination routes of various beta blockers from body
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Product Information for Bisoprolol
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Product Information for Bisoprolol
Use in Pregnancy: not labeled; though used by many
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COMPARISONS
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Atenolol BisoprololModerately 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
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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–Fall in BP from BaselineNeutal J et al. Am J Med,1993;94(2):181-187
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Bisoprolol Vs Atenolol: Change in night time BP
|------------------------------------P value > 0.05------------------------|
|-----P<0.05----|Night Time Fall in BP
Neutal J et al. Am J Med,1993;94(2):181-187
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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
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Competitor ß-blocker Pharmacology: metoprolol succinate
Metoprolol (succinate) Bisoprololβ1-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)
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Competitor ß-blocker Pharmacology: metoprolol tartrate
Metoprolol (tartrate) BisoprololModerately 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
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180
160
140
120
100
80
9080706050
mm Hg SBPn.s.
DBP
2-4 weeks0 + 2 + 4weeks
placebo ß-blocker
p < 0.01p < 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)
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0
20
40
60
80
100
%
90%
SBP
Bisoprolol 10 mg
Metoprolol 100 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
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Competitor ß-blocker Pharmacology: nebivolol (1)
Nebivolol BisoprololHighly β1-selective Highly β1-selective
No adverse effects on lipid/glucose metabolism
No adverse effects on lipid/glucose metabolism
Vasodilatation via L-arginine/NO pathwayEnhanced 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)
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Competitor ß-blocker Pharmacology: nebivolol (2)
Nebivolol BisoprololIncrease 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 reductionIndication 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)
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BISOPROLOL Vs
NEBIVOLOL
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BISOPROLOL Vs
NEBIVOLOL
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BISOPROLOL Vs
NEBIVOLOL
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Indirect comparison 2013
STUDY BISOPROLOL NEBIOLOL
MAIN CHF II At half dose, LVEF increases ----
SENIORS ---- No significance on LVEF
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Also,
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NEBIVOLOL
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Competitor ß-blocker Pharmacology: carvedilol
Carvedilol BisoprololNot 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)
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Competitor ß-blocker Pharmacology: carvedilol
Carvedilol BisoprololBioavailability: 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 clearanceNo dose adjustment required (10 mg not to be exceeded in terminal insufficiency)
Sensitive to liver enzyme induction Almost insensitive to liver enzyme induction
t½ 610 h => b.i.d. administration (extended release formulation available)
t½: 1012 h, once-daily administration
Figure 13: Bisoprolol compared with carvedilol (part 2 of 2)
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6. CIBIS–ELD 2011
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CIBIS–ELD 2011
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CIBIS–ELD 2011
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CIBIS–ELD 2011
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CIBIS–ELD 2011
• More pulmonary adverse events occurred with Carvedilol.
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7. Bisoprolol Vs
Carvedilolin
CHF and COPD2011
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Bisoprolol Vs
Carvedilol
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Bisoprolol Vs
Carvedilol
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THANKYOU!
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Cardiovascular contraindications
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Classification of β-blockers
1st Generation Non-selective Propranolol
2nd Generation β1-selective
AtenololMetoprololBetaxololBisoprolol
3rd Generation
Additional properties, for
example vasodilation
CarvedilolNebivolol
Table 6: Classification of ß-blockers