nebivolol
DESCRIPTION
TRANSCRIPT
Road Map
Section-I- Introduction to Endothelium & Nitric Oxide
Section-II- Beta Blockers
Section-III- Pharmacology & Salient features of Nebivolol
Section-IV- Comparison with other Beta blockers
Section-V - Summary2 [email protected]
Robert F. Furchgott's speech
Alfred Nobel in the last ten years of his life suffered from attacks of angina pectoris
By that time, tablets containing nitroglycerin, had been introduced as the drug of choice
When Nobel's doctor prescribed nitroglycerin for him, Nobel wrote to a friend, "It sounds like the irony of fate that I should be ordered by my doctor to take nitroglycerin internally."
om
Robert F.Furchgott's Speech at the Nobel Banquet, December 10, 1998
Prize this year is being awarded to us for "discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system,"
For there is a fascinating relationship between these discoveries and the chemical that Alfred Nobel tamed for use in dynamite and other explosives, namely Nitroglycerin.
The Endothelium: The largest living organ
1 ½ kg.
Semi-permeable
5medicalquery@torrentpharma
.com
5
Regulation of vascular tone by the balance of endothelium-derived vasodilators and vasoconstrictors
ADPase=adenosinediphosphatase; EDHF=endothelium-derived hyperpolarizing factor; PAF=platelet-activating factor; TXA2 =thromboxane A2
6medicalquery@torrentpharma
.com
What is NO?
• L-arginine
L-citrulline + NO (g)
NOS
•1980:
Incubation of endothelial cells in absence of L-arginine
EDRF
When N-O means Yes
Stimulates guanylate cyclase
↓
↑ In Conc. of cyclic guanosine monophosphate
(cGMP)
↓
Decrease in intracellular Ca++ Conc.
↓
Vasorelaxation
Nitric Oxide
Vasodilator - Most important intrinsic dilator Anti-thrombotic - Prevents cell adhesion & Platelet
aggregation Anti-atherogenic - Inhibits lipid oxidation Actions :
monocyte migration Growth inhibitor - inhibits cellular growth & migration Antioxidant- Scavenges superoxide anions Anti inflammatory - Prevents generation of thrombosis
NO :In disease Hypertension = endothelial dysfunction!
Normotensive offsprings of hypertensive parents who are more at risk of developing hypertension in the future have been reported to have impaired endothelial function.
This finding would support the notion that endothelial dysfunction precedes hypertension
“ NO· may be an important anti-inflammatory mediator and regulator of microvascular blood flow in sepsis.
10medicalquery@torrentpharma
.com
Editorial in Critical Care Medicine, Volume 31 • Number 3 • March 2003
When NO production impaired [when vascular endothelium dysfunctional], result:
Vasoconstriction
Platelet aggregation
Vascular stenosis, or restenosis e.g. foll. balloon angioplasty and stent placement
Increased inflammation and tissue damage mediated by reactive oxygen species
Conditions have endothelial dysfunction and reduced NO production and/or bioavailability:
Hypertension
Obesity
Dyslipidemias (particularly hypercholesterolemia and hypertriglyceridemia)
Diabetes (both type I and II)
Heart failure
Atherosclerosis, cigarette smoking, aging, and vascular injury
[email protected] 13 13
[email protected] 14 14
15
Q: What class of drugs is missing here?
A: Beta Blockers…
This means that the benefits we will show with Nebivolol are NOT A CLASS EFFECT
β-Blockers- Antihypertensive Effects
1st line drugs for management of hypertension
Parameters Effects of SNS Effects of beta blockers
HRHR
Force of Force of contractioncontraction
COCO
Renin releaseRenin release
BPBP
β-Blockers- Anti anginal action
Reduces Myocardial Oxygen Demand (MOD)
↓ Heart Rate ↓ Force Of Contraction
Increases Coronary Filling ↑ Diastolic Time
1st gen= Vasoconstrictor to 3rd = Vasodilator
1st – Gen: Non-selectiveEnhance alpha
receptor-mediated vaso-constriction
2nd – Gen
Beta,-selective
Less vaso-constrictor
3rd – GenVasodilatory effects
on the resistance arteries.
Note: only Nebivolol dilates both arteries and veins and yet is cardio-selective
* NS=Non selective
Propranolol NSAtenolol
MetoprololBisoprolol
Carvedilol NSCeliprolol NS
Nebivolol
Properties of -blockers
Name β-1 Selectiv
e
α -blockad
e
Lipophilic
Increases ISA
Other ancillary properties
Atenolol Yes No No No NoBisoprolo
lYes No Weak No No
Carvedilol
No Yes Yes No Antioxidant, effects on endothelial
functionCeliprolol Yes No No b-2 only NoMetoprol
olYes No Yes No No
Nebivolol Yes No ? No Vasodilation through nitric
oxidePropranol
olNo No Yes No Membrane
stabilizing Effect
Drawbacks of existing drugs
Avoid in Bronchospastic disease.
Avoid in Young patients Impotence/ loss of libido
documented.
Avoid in diabeticsImpair Insulin Sensitivity
Avoid in Obese & patients with impaired lipid profileWill worsen lipid profile and have
increased atherosclerotic effect.
Beta 1/ Beta 2 Selectivity
NonselectivityPropranolol CarvedilolAtenolol
Cold hands and feet. Raynaud’s phenomena.
Avoid in peripheral vascular disease.
Avoid in Heart Failure Reduced Cardiac Output No improvement in LV function
Accumulate in renal impairment and dosage reduction is therefore often necessary.
VasoconstrictionClass effect with 1st, 2nd gen.
Water SolubleAtenolol, Celiprolol,
Drawbacks of existing drugs
An ideal antihypertensive drug:
Effective as monotherapy in majority of patients.
Reduced PVR, preserves CO , blood flow and perfusion to vital organs both at rest and during exercise.
Favorable quality of life and side effect profile.
Reduces left ventricular hyper- trophy (LVH).
Reduces hypertensive end organ damage.
Drug compatibility with other drugs and can be given in co existing disorder
Once a day dosage.
Plus, it should solve the problems mentioned earlier
NebivololA Nitric-oxide-donating, vasodilating, lipophilic 3rd generation highly selective Beta-1- adrenoceptor Blocker
Racemic mixture of 2 enantiomers d & l-Nebivolol
d- Nebivolol
β-blockade
l- Nebivolol
Potent NO releaser
Highest Beta-1 selectivity
Beta1 /beta2 Selectivity
293.0
119.0
74.0
15.4
1.4
2.1
7.3
0 50 100 150 200 250 300 350
Nebivolol
Bisoprolol
Metoprolol
Atenolol
* Carvedilol
* Propranolol
* Bucindolol
Cleophas et al, 2001, “Of the Beta-blockers, Nebivolol has the highest Beta 1-selective activity 26medicalquery@torrentpharma.
com
Celiprolol selectivity is 5:1
Nebivolol- Pharmacokinetics
Tmax 0.5 - 2 hours
Food does not interfere with absorption
Nebivolol undergoes extensive first pass metabolism
Extensively metabolised in liver : metabolites are active
Dual mode of excretion - Urine 38% & Faeces 48%
Elimination ½ life - 10 hours
Plasma protein binding is near about 98%
Nebivolol- Dosage & Administration
Hypertension 5 mg OD with or without meals Elderly and renal dysfunction cases – 2.5 mg OD
CHF 2.5 mg was found to be better tolerated may be increased to 5 mg OD & Max up to 10 mg OD
Angina 5 mg OD
Nebivolol- Indications
Approved
Mild to Moderate hypertension
Promising results in
Heart failure
IHD
Effects on LV Function
Nebivolol appears to reduce preload & afterload
Left ventricular end-diastolic and systolic pressure is decreased in patients with left ventricular dysfunction
Nebivolol increased stroke volume or stroke index in health volunteers and patients with hypertension
Increased peak filling rate in hypertensive patients
Effects on LV Function
Cardiac output was not significantly affected is healthy volunteers
In hypertensive patients during exercise, however, only Atenolol , but not Nebivolol significantly reduced this parameter (p < 0.05)
In heart failure, ejection fraction was increased
Cardiac output and pulmonary artery and wedge pressures were maintained
Effects on exercise-induced changes in haemodynamic parameters and endurance time
Many patients taking Beta-blockers experience reduced exercise capacity
However, Nebivolol 2.5 to 10mg as a single dose reduces exercise-induced tachycardia to a lesser extent than equivalent therapeutic doses of Atenolol, Propranolol or pindolol in comparative studies for 4 months
Effects on exercise-induced changes in haemodynamic parameters and endurance time
Exercise-induced increases in systolic blood pressure (SBP) were also attenuated to a similar or lesser extent with Nebivolol than with the same comparator agents
Nebivolol and Atenolol increased stroke volume during exercise, and whereas Nebivolol tended to increase cardiac output and significantly reduced total peripheral resistance.
Atenolol had no such effects.
[Van Bortel LMAB, van Baak M et al]
Effective in mild-to-moderate hypertension.
Unlike Atenolol: No negative effect on LV function
in hypertensive patients; improves LV function.
Monotherapy
Effective alone or in combination with
other antihypertensive agents
Nebivolol in Hypertension
Trial• 6376 patients• Arterial
hypertension • Six weeks. • The initial
dosage was 5 mg daily
• SBP decreased by 29 mm Hg to 144 mm Hg
• DBP decreased by 16 mm Hg to 85mm Hg• Normalization of DBP (< 90 mm Hg)
achieved in 62.2% of patients• The most favourable effects observed in
Diabetic patients :—Decrease in triglycerides by 18% —Decrease in Cholesterol by 9% —Decrease in Glucose by 16%.
Nebivolol: therapy of arterial hypertension. Results of a multicenter study on 6376 patients
Nebivolol in Hypertension
von Fallois J, Faulhaber HD.Schweiz Rundsch Med Prax 2001 Mar 15; 90(11):435-41.
Nebivolol reverses endothelial dysfunction in Essential HTA Randomized, Double-Blind, Crossover Study
Circulation. 2001;104:511-514
Nebivolol reverses endothelial dysfunction in HT
The vasodilatory response to ACh significantly increased with Nebivolol/bendrofluazide [BFZ] but not with atenolol/ BFZ
Endothelium-dependent vasoconstrictive response to L-NMMA was significantly improved only with Nebivolol treatment but not with atenolol/ BFZ
Circulation. 2001;104:511-514
Thus, nebivolol may offer additional vascular protection in treating hypertension.
Combination Combination therapytherapy
sitting DBP(mm Hg)
HCTZ 12.5mg
HCTZ 25mg
Nebivolol 10mg/ HCTZ 25mg(p=0.0001 vs. baseline for all)
-15.3
-5.8-4.6
-16
-14
-12
-10
-8
-6
-4
-2
0
Nebivolol + HCTZHCTZ 12.5mg
HCTZ 25mg
Nebivolol 10mg/HCTZ 25mg(p=0.0001 vs.baseline for all)
May be used in an attempt to maintain or improve efficacy with lower dosages and/or
fewer associated adverse events of either or both drugs. Nebivolol has additive effects with Hydrochlorothiazide.
Trough to peak ratios
0.9 0.84
0.6
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
Nebivolol 5mg nifedipinesustained
release 20mgtwice daily
Enalapril 10mgonce daily
Trough to peak ratios [sitting or supine diastolic blood pressure]
Response Rates
65.80%50%
65%40%81%
70%55%
79.50%65.60%
81%
30% 40% 50% 60% 70% 80% 90%
2 weeks
4 weeks
12 weeks
52 weeks
Response Rates Metoprolol100mg BD
Nebivolol (p=0.04)
Nebivolol +Enalapril 10mgOD (p<0.008)Enalapril 10mgOD
Nebivolol(p<0.01)
Nifedepine
Nebivolol (p=0.001)
Nebivolol
41medicalquery@torrentpharma
.com
(Adapted from data in 208 Chae CU, Hennekens CH: Beta blockers. In Hennekens CH [ed]: Clinical Trials in Cardiovascular Disease: A Companion to Braunwald's Heart Disease. Philadelphia, WB Saunders, 1999, p 84.)
The relative risk of mortality is reduced with beta blockers both during the acute phase of treatment and when prescribed as secondary prevention after acute myocardial infarction.
Effect of beta blockers on mortality in AMI
Nebivolol in CAD
Reduces Preload & Afterload
Reduces Heart Rate (HR)
Reduces LV end diastolic & systolic pressure
Reduced work done by heart
Increases Stroke Volume (SV)
Increases Peak filling rate
Nebivolol in CHF
Decreases arterial blood pressure and Heart Rate (HR) at rest and during exercise in patients in stable NYHA functional Class II or III
Increases Stroke Volume (SV)
Maintains Cardiac Output (CO)
Reduces LV End Diastolic Pressure (LVEDP)
Increase in Ejection Fraction from 23 to 33% (p< 0.01)
Improvement of the diastolic LV performance
Nebivolol vs Atenolol : Nebivolol improves EF, CO
Ejectionfraction (EF), p
< 0.05
Cardiac output[CO], p < 0.05
Nebivolol
Atenolol
-4%
-21%
4% 2%
-25%
-20%
-15%
-10%
-5%
0%
5%
Left ventricular systolic and diastolic function
Nebivolol
Atenolol
Nebivolol in CHF
Unlike Atenolol, Nebivolol, shifted the diastolic pressure volume data, suggesting improved distensibility
Nebivolol in Ischemic LV Dysfunction
In a comparison of Nebivolol vs Atenolol when compared to baseline, maximal exercise duration: increased by 7 with placebo increased by 13 secs with AtenololIncreased by 44 seconds with Nebivolol
Unique endothelin-lowering effect of Nebivolol
“Secondary failure due to late restenosis continues to occur in 30-50% of individuals after PTCA”
Classical Beta-blockers do not affect cell growth, only Nebivolol inhibits human coronary smooth muscle cell or human coronary smooth muscle cells and endothelial cell proliferation
Propranolol, Metoprolol or bisoprolol did not exert this effect.
Nebivolol may represent a Beta-blocker with great promises in CAD therapy.
Nebivolol vs Atenolol : E.F., C.O.
Ejection fraction(EF), p < 0.05
Cardiac output[CO], p < 0.05
Nebivolol
Atenolol
-4%
-21%
4% 2%
-25%
-20%
-15%
-10%
-5%
0%
5%
Left ventricular systolic and diastolic function
Nebivolol
Atenolol
Unlike Atenolol, Nebivolol shifted the diastolic pressure-volume data downward, suggesting improved LV distensibility
Nebivolol in Congestive heart failure
In CHF + CAD, decrease in arterial blood pressure and heart rate
at rest and during exercise, In patients in stable NYHA functional Class II or I11,
– significantly decreases heart rate,
– increases stroke volume,
– maintains cardiac output, and
– reduces left ventricular end-diastolic pressure
– increase in ejection fraction from 23 to 33% (p< 0.01), and an improvement of the diastolic left ventricular performance.
Nebivolol in Airway Conductance
Nebivolol does not impair Airway Conductance
“Beta blockers that modulate the endogenous production of nitric oxide, affect airway function to a lesser extent.
“Therapy with selective Beta1-blockers is not contraindicated in cases of chronic airway obstruction.
“Newer Beta1 adrenoceptor blocking agents with ancillary properties (eg nebivolol), and/or vasodilators can be considered.”
CHEST 2002; 121:230–241
Comparison with other Beta blockers
Parameters
Other beta blockers (AtenololMetoprolol)
Nebivolol Clinical significance
Selectivity Comparatively lower β1 selectivity
Highly β1 Selectivity
Preferred Antihypertensive
Airway parameters
Precipitates bronchospasm
No effect Preferred in COPD
Glucose metabolism
Impaired No effect Preferred in diabetic hypertensives
Lipid metabolism
Impaired No effect Preferred in Hypertensives with Hyperlipidemia
Endothelium No other effects Increases NO production and vasodilatation
Effective in patients of hypertension even with co-existing endothelial dysfunction
Platelet activation
Not significant Significantly decreased
May reduce thrombotic risk
Erectile dysfunction
Frequently Improvement in ED
Preferred in young active hypertensives
Exercise capacity
Decreased Not affected Preferred in young active hypertensives
Dose 50 – 100 mg OD- Atenolol100 – 200 mgBID-Metoprolol
2.5 – 5 mg once daily
Highly effective at low dosePatient Compliance
Summary
Preferred 1st line drug for management of hypertension
Unlike conventional TREATMENT Nebivolol can be prescribed across all patients
Most selective β1 blocker, highly potent, Novel property of stimulating NO production from endothelium
