sympatheticoverdriveinhypertension ppt.pptx

contents
1. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of β-blocker therapy. J Clin Hypertens. 2005;7(7):409–16.
Sympathetic nervous activity
 Heart rate1
 Heart rate variability1
 Contractility1
 Renin release1
 Angiotensin1
 Blood pressure1
 Left ventricular hypertrophy1
 Heart failure1
Beta1 receptor stimulation
1
Beta1 receptor stimulation
1
Sympathetic overdrive plays a key role in the pathophysiology of
cardiovascular disease1
Mechanical/
vascular damage
• Pulsatile stress on
vascular system1
• Augment atherosclerosis1
• Plaque rupture1
• Risk of cardiac ischemia1
Neural release of norepinephrine1
Graph according to reference 1
0
Cardiovascular Risk : Heart failure, Coronary event, and SCD

contents
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011; Fig. 3-8
2. Cruickshank JM. Beta-blockers and diabetes: the bad guys come good. Cardiovasc Drugs Ther. 2002;16(5):457–70.
3. Poitras VJ, Pyke KE. The impact of acute stress on vascular endothelial function: Evidence, mechanisms and importance. Int J Psychophysiol. 2013;88(2):124–35
4. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011
5. Klein LW, Pichard AD, Holt J et al. Effects of chronic tobacco smoking on the coronary circulation. J Am Coll Cardiol. 1983;1(2 Pt 2):421–26
6. Huggett RJ, Scott EM, Gilbey SG et al. Circulation. 2003;108:3097–101.
1
What can trigger for sympathetic overdrive?
 Diabetes1,2
 Mental stress3
 Obesity4  insulin resistance, endothelial dysfunction and increased NE
 Smoking5  increased 2 to 3 fold increased NE
 Hypertension6

contents
Underlying causes of hypertension differ between
The Young VS Old – Framingham Heart Study1
Blood pressure (BP); Diastolic BP (DBP); Systolic BP (SBP); Diastolic hypertension (DH); Systolic/diastolic hypertension (SDH); Isolated systolic hypertension (ISH); Pulse pressure (P-P)
1. Franklin SS, Pio JR, Wong ND et al. Predictors of new-onset diastolic and systolic hypertension. Circulation. 2005;111:1121–7.
2. Cruickshank JM. Are we misunderstanding beta-blockers? Int J Cardiol. 2007;120:10–27.
3. Grassi G. Assessment of sympathetic cardiovascular drive in human hypertension: achievements and perspectives. Hypertension. 2009;54(4):690–97.
Sympathetic overdrive is the main cause of hypertension in young or middle-aged patients2,3
Predictors of diastolic hypertension
(± systolic hypertension)
= DBP ≥90 mmHg ( SBP ≥140 mmHg)
1 Young age
2 Male sex
3 High BMI at baseline
4 Increasing BMI during follow-up
Main mechanism of DH and SDH
is raised peripheral resistance
Predictors of isolated systolic hypertension
= SBP ≥140 mmHg + DBP <90 mmHg (wide P-P)
1 Older age
2 Female sex
3
Increasing BMI during follow-up
(but weaker than in young)
4
ISH arises more commonly from normal
and high normal BP
5
Only 18% with new-onset ISH
had a previous DBP ≥ 95 mmHg
Main mechanism of ISH is
increased arterial stiffness = aging of arteries
2

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Increased heart rate is a long-term predictor of cardiovascular events in
patients with hypertension1
 Increased cardiovascular mortality rate, suddden cardiac death
53 %
difference in
incidence of
endpoints1
The incidence of primary
endpoints in the highest in-
trial HR group compared to
the pooled 4 lower quintiles
was 53% greater in patients
with well-controlled blood
pressure (p<0.001)1
1. Julius S, Palatini P, Kjeldsen SE et al. Usefulness of heart rate to predict future cardiac events in treated patients with high-risk systemic hypertension.
Am J Cardiol. 2012;109:685–92.
14 %
12 %
10 %
8 %
6 %
4 %
2 %
0 %
250 750 1250 1500
1000
500
Days since year 1 and patients at risk
Cumulative
primary
event
rate
High HR, BP uncontrolled
High HR, BP controlled
Low HR, BP uncontrolled
Low HR, BP controlled
Graph adapted from reference 1
3

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Pharmacotherapy options for elevated heart rate:1-5
Beta blockers
(without ISA)3
HR control via
actions on
Sympathetic
overdrive3
If channel inhibitor
(ivabradine)
Specific action on
the If channel that
controls in sinoatrial
node
Non-
dihydropyridine CCBs
(verapamil, diltiazem)1
Action is not related to
Sympathetic overdrive
Elevated heart rate
Calcium channel blockers(CCBs) Sympathetic overdrive(SO) Intrinsic sympathomimetic activity(ISA) Coronary heart disease(CHD)
1. Palatini P, Benetos A, Julius S. Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Drugs. 2006;66(2):133–44.
2. Gupta D. A review on calcium channel & its blockers. Int J Pharm Pharm Sci. 2012;4:3842.
3. Egan BM, Basile J, Chilton RJ et al. Cardioprotection: the role of beta-blocker therapy. J Clin Hypertens. 2005;7(7):409–16.
4. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective I(f) current inhibition with ivabradine. Drugs. 2004;64:1757–65.
5. Sulfi S, Timmis AD. Ivabradine: the first selective sinus node I(f) channel inhibitor in the treatment of stable angina. Int J Clin Pract. 2006;60:222–28.
6. Procoralan (ivabradine) Summary of Product Characteristics, revision dated 7 June 2016.
7. Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of stable coronary artery disease. Eur Heart J. 2013;34:2949-3003.
4,5
4

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Modulation of sympathetic activation is an important goal of
antihypertensive treatment: effect of different drug classes1
Drug class Effects on peripheral SNS Effects on cardiac SNS
Central sympatholytics Marked reduction Reduction
Alpha-blockers Marked reduction No change
Thiazide diuretics Marked increase No change
Anti-aldosterone agents Reduction No change
Beta-blockers Reduction Marked reduction
Short-acting CA Marked increase Marked increase
Long-acting CA Reduction or no change No change or increase
ACE inhibitors Reduction or no change No change
Angiotensin II receptor blockers* Reduction or no change No change
*Although laboratory studies suggest that angiotensin II receptor blockers may inhibit the SNS, they have been shown to increase sympathetic activity in young
men with normal or slightly high blood pressure2
1. Grassi G. Sympathetic overdrive in hypertension: clinical and therapeutic relevance. J Cardiol Pract. 2015;13(24):24 November 2015.
2. Heusser K, Vitkovsky J, Raasch W et al. Elevation of sympathetic activity by eprosartan in young male subjects. Am J Hypertens. 2003;16(8):658–64.
Angiotensin-converting enzyme (ACE) CA: Calcium antagonists(CA) Sympathetic nervous system(SNS)
5

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Myocardial
infarction
Neurohormonal
activation
Arrhythmias
and loss of muscle
Remodelling
Ventricular
enlargement
CHF
Death
Risk factors
• Hyperlipidemia
• Hypertension
• Diabetes
• Smoking
Atherosclerosis
LVH
CHD
Myocardial
ischemia
Coronary
thrombosis
Left ventricular hypertrophy (LVH)
Coronary heart disease (CHD)
Chronic heart failure (CHF)
Beta-blockers can intervene at many points in the
cardiovascular continuum1
1. Adapted from Willenheimer R, Erdmann E. Beta-blockade across the cardiovascular continuum – when and where to use? Eur Heart J Suppls. 2009;11(Suppl A):A1–2.
Sudden
death
Beta-
blockers
6

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Why beta1-selectivity is important in the treatment of hypertension
associated with sympathetic overdrive1,2
Beta1 receptors Beta2 receptors
Myocardium
 Contractility and heart rate1
 Myocardial necrosis/apoptosis1
Bronchial smooth muscle  Bronchodilation1
Blood vessel smooth
muscle
 Vasodilation1
Kidney  Renin release1
Primary distribution of beta-receptors and effects of stimulation1
 Highly selective beta1-blockers inhibit sympathetic activity in the heart and kidney
 reduce the risk of adverse effects mediated by blockade of beta2 receptors in the lungs
and peripheral tissues2
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011
7

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Beta-blockers offer additional protection to BP reductions in preventing
recurrent events in patients with a history of CHD1
1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in
the context of expectations from prospective epidemiological studies. BMJ. 2009;338:b1665. doi:10.1136/bmj.b1665.
Trials of beta-blockers
People with history of CHD
Entry after acute myocardial infarction
Entry after long term coronary heart disease
People with no history of CHD
Trials other than beta-blocker
People with history of CHD
People with no history of CHD
All trials except ones of beta-blockers in people
with history of CHD
37
27
11
6
37
24
64
2524
2155
369
851
5834
3217
9417
0.71 (0.66 to 0.78)
0.69 (0.62 to 0.76)
0.87 (0.71 to 1.06)
0.89 (0.78 to 1.02)
0.85 (0.79 to 0.91)
0.84 (0.79 to 0.90)
0.85 (0.81 to 0.89)
No of
trials
No of
events
Relative risk
(95% CI)
Relative risk
(95% CI)
p<0.001
Treatment better Placebo better
0.5 0.7 1 1.4 2
Blood pressure(BP) Coronary heart disease(CHD)
8

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Classification of beta-blockers according to their beta1-
selectivity1,2
Relative beta1-selectivity Non-selective Beta1-selective
• Bupranolol
• Propanolol
• Timolol
• Labetalol
• Carvedilol
• Atenolol
• Metoprolol
• Bisoprolol
• Betaxolol
• Esmolol
Intrinsic sympathomimetic
activity (ISA)
• Alprenolol
• Pindolol
• Oxprenolol
• Carteolol
• Bucindolol
• Acebutolol
• Celiprolol
• Nebivolol*
Hydrophilia
• Nadolol
• Sotalol
• Atenolol
• Celiprolol
2. López-Sendón J, Swedberg K, McMurray J et al. for the Task Force on Beta-blockers of the European Society of Cardiology. Expert consensus document on
beta-adrenergic receptor blockers. Eur Heart J. 2004;25:1341-62.
3. Cruickshank J. Nebivolol, a third generation beta-blocker. J Symptoms Signs. 2014;3(5):380-91
*Although nebivolol is often characterized as a beta1-selective beta-blocker without ISA, the nitric oxide release induced by nebivolol leading
to vasodilatation results from agonism at beta3-receptors, which is an ISA3
9

contents
1. Mancia G, Fagard R, Narkiewcz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial
hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.
European guidelines recommend beta-blockers for the initiation and
maintenance of antihypertensive treatment1
BP measurements SHOULD ALWAYS be associated with measurement of
heart rate, because resting heart rate values independently predict CV
morbid or fatal events in hypertension
Diuretics, beta-blockers, calcium antagonists, angiotensin converting
enzyme (ACE) inhibitors and angiotensin receptor blockers are all suitable
for the initiation and maintenance of antihypertensive treatment, either as
monotherapy or in some combinations
1
2
Class IA recommendations
Please refer to abbreviated product information in chapter 7 which may vary by country.
10

contents
Consider beta-blockers in younger people
with evidence of increased sympathetic drive
The NICE evidence review identified four studies that reported beta-blockers and
ACE inhibitors as being more effective at lowering blood pressure in younger
people than calcium channel blockers or thiazide-type-diuretics.
The guidelines do not generally recommend beta-blockers as a preferred initial
treatment option for hypertensive patients, but beta-blockers may be considered
for initial therapy of hypertension in younger people, particularly:
• those with an intolerance or contraindication to ACE inhibitors and
angiotensin II receptor antagonists or
• women of child-bearing potential or
• people with evidence of increased sympathetic drive.
1. NICE Guideline CG127. Hypertension: The clinical management of primary hypertension in adults. August 2011.
Available at: https://www.nice.org.uk/guidance/cg127/evidence/full-guideline-248588317. Last accessed March 2016.
NICE guidelines also recommend beta-blockers as initial therapy for
hypertension in younger people1
Please refer to abbreviated product information in chapter 7 which may vary by country.
11

contents
Bisoprolol (Concor®) indications*
Bisoprolol (Concor®) is indicated for the treatment of:
Reference to local prescribing information to be added here by speakers
Hypertension
Chronic heart failure
Coronary heart disease (angina pectoris)
12

contents
Overview of the pharmacokinetics of bisoprolol1-3
Bisoprolol
Absorption >90%3
Bioavailability ~90%1
Plasma protein binding 30%3
Metabolism 50% (inactive)2,3
Plasma elimination half-life 10–12 hours1
1. Leopold G, Kutz K. Bisoprolol: pharmacokinetic profile. Rev Contemp Pharmacother. 1997;8:35-43.
2. Leopold G, Pabst J, Ungethüm W, Bühring K-U. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
3. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16–20.
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contents
Bisoprolol has a 'balanced' clearance1,2,3
• 50% renal elimination of unchanged drug
• 50% hepatic metabolism to inactive metabolites – also renally excreted
Metabolism
• Only by oxidation – no subsequent conjugation4,5
• Primarily by CYP3A4 (~95%)4
• Only minor contribution of CYP2D64 ( metabolism not dependent
on CYP2D6 gene polymorphism, formerly debrisoquine-sparteine
polymorphism2)
 NO dose adjustment necessary in mild to moderate liver or kidney impairment6
 Daily dose to be limited to 10 mg in severe liver or kidney impairment6
Bisoprolol has a balanced clearance
1. Leopold G, Pabst J, Ungethüm W, Bühring K-U. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
2. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16–20.
3. Leopold G, Kutz K. Bisoprolol: pharmacokinetic profile. Rev Contemp Pharmacother. 1997;8:35-43.
4. Horikiri Y, Suzuki T, Mizobe M. Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63(13):1097-108.
5. Horikiri Y, Suzuki T, Mizobe M. Pharmacokinetics and metabolism of bisoprolol enantiomers in humans. J Pharm Sci. 1998;87(3):289-94.
6. Concor® / Concor® COR Product information (abbreviated prescribing information), Merck KGaA, Darmstadt, Germany; July 2017.
14

contents
Beta1-selectivity of different beta-blockers:
bisoprolol is a highly selective beta1-blocker1-5
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011, Fig. 1-5
2. Wellstein A, Palm D, Belz G. Affinity and selectivity of the β-adrenoceptor antagonists in vitro. J Cardiovasc Pharmacol. 1986; 8 (Suppl. 11): 36–40.
3. Wellstein A, Palm D, Betz GG et al. Reduction of exercise tachycardia in man after propranolol and bisoprolol in comparison to beta-adrenoceptor occupancy.
Eur Heart J. 1987; 8 (Suppl. M): 3–8.
4. Maack C, Tyroller S, Schnabel P et al. Characterization of beta1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium.
Br J Pharmacol. 2001;132:1817–26.
5. Brixius K, Bundkirchen A, Bölck B et al. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium.
Br J Pharmacol. 2001;133;1330–8.
Propranolol
Atenolol Betaxolol
Ratio of constants of inhibition (ci/β1 to ci/β2)
Metoprolol
300:1
1:35 1:35
1:75
1.8:1
1:20
ICI 118,551
Increasing beta1-selectivity
Increasing beta2-selectivity
No selectivity
Bisoprolol
Comparisons between the beta1-selectivity of bisoprolol
with that of nebivolol have reported inconsistent results.4,5
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Efficacy of bisoprolol compared with other antihypertensives (GENRES
Study): 24-hour ambulatory BP responses1,2
Systolic
-20
-15
-10
-5
0
5
Bisoprolol Losartan Amlodipine HCT
Systolic
BP
(mmHg)
p<0.001 p<0.01 p<0.001
-20
-15
-10
-5
0
5
Bisoprolol Losartan Amlodipine HCT
Diastolic
BP
(mmHg)
p<0.001 p<0.01 p<0.001
1. Cruickshank JM. Essential Hypertension. Shelton, CT: People's Medical Publishing House-USA;2013, Fig. 6-28
2. Hiltunen TP, Suonsyrjä T, Hannila-Handelberg T et al. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized,
cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007;20:311-8.
Prospective, randomized double-blind, cross-over, placebo-controlled study in 208 moderately hypertensive men (aged 35 to 60 years):
bisoprolol 5 mg/day, losartan 50 mg/day, amlodipine 5 mg/day, hydrochlorothiazide (HCT) 25 mg/day.
 Bisoprolol showed the best antihypertensive effect.
Diastolic
16

contents
Sympathetic overdrive in hypertension: the role of beta-blockers with a
focus on bisoprolol
Summary 1/2
• Sympathetic overdrive is associated with the development
of multiple cardiovascular risk factors and is the main cause
of hypertension in young and middle-aged men1,2
• The adverse cardiovascular outcomes associated with
sympathetic overdrive result from the neural release of
norepinephrine and stimulation of beta1 receptors in the
heart and kidneys4
• Beta1-blockade helps to prevent the adverse effects of
sympathetic overdrive and could protect the heart at every
stage of the cardiovascular continuum5
1. Cruickshank JM. Int J Cardiol. 2007;120:10–27; 2. Grassi G. Hypertension. 2009;54(4):690–97; 3. Gillman MW, Kannel WB, Belanger A et al. Am Heart J.
1993;125(4):1148–54; 4. Egan BM, Basile J, Chilton RJ et al. J Clin Hypertens. 2005;7(7):409–16; 5. Willenheimer R, Erdmann E. Eur Heart J Suppls. 2009;11(Suppl
A):A1–2; 6. Mancia G, Fagard R, Narkiewcz K et al. Eur Heart J. 2013;34:2159–219.
17

contents
Sympathetic overdrive in hypertension: the role of beta-blockers with a
focus on bisoprolol
Summary 2/2
• Bisoprolol is a highly beta1-selective beta-blocker1-3 , available
as Concor®
• Bisoprolol provides effective 24-hour BP control with once-
daily dosing4
• Bisoprolol is particularly useful for the treatment of young
hypertensive patients with additional risk factors for
sympathetic overdrive:
• Cigarette smoking8
• Overweight or obese9
• Diabetes 10
• High levels of stress11
1. Wellstein A, Palm D, Belz G. J Cardiovasc Pharmacol. 1986; 8 (Suppl. 11): 36–40; 2. Wellstein A, Palm D, Betz GG et al. Eur Heart J. 1987; 8 (Suppl. M): 3–8;
3. Smith C, Teitler M. Cardiovasc Drugs Ther. 1999;13:123–6; 4. References see slide 39; 5. References see slide 48; 6. References see slides 49, 50; 7. References see
slides 53-57; 8. References see slides 49, 13, 14; 9. References see slides 29, 11, 12; 10. References see slides 29, 30, 8; 11. References see slide 10.
18

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