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 [email_address]
16. β -Blockers- Antihypertensive Effects 1 st line drugs for management of hypertension [email_address] Parameters Effects of SNS Effects of beta blockers HR Force of contraction CO Renin release BP
17. β -Blockers- Anti anginal action [email_address] Reduces Myocardial Oxygen Demand (MOD) ↓ Heart Rate ↓ Force Of Contraction Increases Coronary Filling ↑ Diastolic Time
20. Properties of -blockers [email_address] Name β -1 Selective α -blockade Lipophilic Increases ISA Other ancillary properties Atenolol Yes No No No No Bisoprolol Yes No Weak No No Carvedilol No Yes Yes No Antioxidant, effects on endothelial function Celiprolol Yes No No b-2 only No Metoprolol Yes No Yes No No Nebivolol Yes No ? No Vasodilation through nitric oxide Propranolol No No Yes No Membrane stabilizing Effect
51. Comparison with other Beta blockers [email_address] Parameters Other beta blockers (Atenolol Metoprolol) Nebivolol Clinical significance Selectivity Comparatively lower β 1 selectivity Highly β 1 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
52. [email_address] 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- Atenolol 100 – 200 mg BID-Metoprolol 2.5 – 5 mg once daily Highly effective at low dose Patient Compliance
The endothelium: A living organ Content Points: Healthy endothelial cells have multiple functions. They form a barrier between the blood and the tissues. As shown in this transmission electron micrograph, endothelial cells compose the innermost layer of blood vessels. The cells tightly interlock so that passage from the blood into the tissue occurs through the endothelial cell. The endothelium, however, is much more than a passive filter. Endothelial cells actively transport substances into and out of the blood. They also secrete active substances that regulate the local milieu.
Similarly, as illustrated in Figure 62-3 , a delicate balance exists in the capability of endothelial cells to modulate vascular tone. An important physiological vasodilator released by endothelial cells is nitric oxide (NO), a simple diatomic gas synthesized from the terminal guanidino nitrogen atoms of L-arginine by the action of a group of enzymes known as nitric oxide synthases (NOSs ).[15] [16] [17] [18] [159A] [173A] The major isoform of NOS present in endothelial cells, eNOS, is constitutively active and is further activated by stimuli that increase intracellular calcium, including several receptor-dependent agonists (e.g., Thrombin) and hemodynamic forces (shear stress and cyclic stretch).[19] NO acts as a potent vasodilator as well as an inhibitor of platelet adhesion and platelet aggregation by stimulating soluble guanylate cyclase and thereby elevating intracellular levels of cyclic guanosine monophosphate in vascular smooth muscle cells and platelets. Prostaglandin I2 (PGI2 , prostacyclin) is a major endothelium-derived oxygenation product of arachidonic acid, synthesized by the sequential actions of cyclooxygenase (COX) and prostacyclin synthase.[4] [20] [21] Prostacyclin, like NO, is both a vasodilator and inhibitor of platelet aggregation (but not adhesion), exerting these actions by stimulating adenylate cyclase and thereby elevating intracellular cyclic adenosine monophosphate (AMP) in target vascular smooth muscle and platelets. Endothelium-derived hyperpolarizing factor (EDHF)[21] [22] [23] and carbon monoxide (CO), a byproduct of heme metabolism to biliverdin by heme oxygenases,[24] are also direct vasodilators elaborated by endothelial cells. Endothelial ecto-adenosine diphosphatase (ADPase), recently identified as CD39,[25] is a membrane-associated platelet inhibitor but may also indirectly promote vasodilation by generating adenosine .[5] These vasodilator properties of endothelium are counterbalanced by endothelium-derived vasoconstrictors, including platelet-activating 2101 factor,[26] [27] Endothelin-1,[28] [29] [30] and thromboxane A2 (TXA2 ).[31] In many cases, endothelium-derived vasodilators are also platelet inhibitors and, conversely, endothelium-derived vasoconstrictors can also be platelet activators. The net effect of vasodilation and inhibition of platelet function is to promote blood fluidity, whereas the net effect of vasoconstriction and platelet activation is to promote hemostasis. Thus, as indicated in Figures 62-2 and 62-3 , blood fluidity and hemostasis can be exquisitely regulated by the balance of antithrombotic/prothrombotic and vasodilatory/vasoconstrictor properties of endothelial cells, which are often coordinately modulated by their relative states of quiescence and activation.[5]
Main Factors Contributing to Heterogeneity Within the β -blocker Class A number of important pharmacologic factors influence heterogeneity within the β -blocker class, as illustrated on this slide. In addition to the factors illustrated on this slide, other factors contributing to heterogeneity of the β -blocker class include intrinsic sympathomimetic activity (ISA); membrane stabilizing activity; and the cross antagonism with other receptors, such as α receptors. β -blockers can be classified as nonselective or selective β -blockers based on their affinity for β -adrenergic receptors. Older, nonselective β -blockers (eg, propranolol) produce competitive blockade of both β 1 - and β 2 -receptors. Those with higher affinity for the β 1 -receptors than the β 2 -receptors are termed cardioselective β -blockers. Traditional β -blockers have well-known side effects that have limited their use in some patients; these side effects include fatigue, dyspnea, bradycardia, erectile dysfunction, and depression. Newer β -blockers have been distinguished by ancillary pharmacologic properties, in particular their ability to cause vasodilation.
Robert F. Furchgott – Banquet Speech Robert F. Furchgott's speech at the Nobel Banquet, December 10, 1998 Your Majesties, Your Royal Highness, Ladies and Gentlemen, It is indeed an honor for me to address you on behalf of Professor Ferid Murad, Professor Louis Ignarro and myself, co-winners of the Nobel Prize for Physiology or Medicine. It is of special interest that the prize this year is being awarded to us for "discoveries concerning NO 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. As you may be aware, Alfred Nobel in the last ten years of his life suffered from attacks of angina pectoris, the chest pain resulting from an insufficient flow of oxygenated blood in the coronary vessels of the heart. By that time, tablets containing nitroglycerin, a potent dilator of blood vessels, had been introduced as the drug of choice for alleviating anginal pains or for preventing such pains during physical exertion. 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." Today it seems like fate, but not an irony of fate, that some ninety years after Nobel wrote that letter, my two co-winners would present evidence that the vasodilating effect of nitroglycerin on coronary and other blood vessels is due to the nitric oxide released from it when it is enzymatically metabolized in the blood vessel wall, and that I would discover the endothelium-derived relaxing factor, a signalling molecule which would turn out to be nitric oxide. So the seemingly fated progression was from nitroglycerin as Nobel's active ingredient in dynamite, to nitroglycerin for treating angina pectoris, to nitric oxide as the metabolic product of nitroglycerin responsible for its vasodilating action, to nitric oxide as an important endogenous signalling molecule in the cardiovascular system, to the award of the Nobel Prize in Physiology or Medicine to the three of us for our discoveries concerning this unique signalling molecule. The three of us wish to extend our sincere thanks to the members of the Nobel Committee of the Karolinska Institute for the great honor they have bestowed upon us. And finally, for the three of us, NOBEL means NO is beautiful! From Les Prix Nobel 1998.
36: Schweiz Rundsch Med Prax. 2001 Mar 15;90(11):435-41. Related Articles, Links [Nebivolol, a beta blocker of the 3rd generation: modern therapy of arterial hypertension. Results of a multicenter observation study] [Article in German] von Fallois J, Faulhaber HD. Franz-Volhard-Klinik am Max-Delbruck-Centrum fur molekulare Medizin, Berlin-Buch. BACKGROUND: Nebivolol represents a therapeutic class of beta blockers with high beta 1 selectivity and modulatory effect on vascular reactions by releasing nitric oxide (NO) from endothelial cells. Its antihypertensive effect by once a day application is established. The aim of the study was to investigate the acceptability and the antihypertensive efficacy of Nebivolol in hypertensives with and without concomitant diseases. METHODS AND RESULTS: An observational study was carried out in 6376 patients with arterial hypertension in 1529 centres in a period of time of six weeks. The initial dosage was 5 mg daily resp. 2.5 mg daily in patients over 65 years. The systolic blood pressure (BP) decreased during treatment from initial values of 173 +/- 18 mm Hg (mean +/- standard deviation) by 29 mm Hg to 144 +/- 14 mm Hg at the end of the observational period. The diastolic BP decreased from 101 +/- 9 mm Hg initially by 16 mm Hg to 85 +/- 8 mm Hg at the last examination of the patients. The normalization of the diastolic BP (< 90 mm Hg) was achieved in 62.2% of the patients. The mean heart rate (HR) was 84 +/- 12 beats/minute at the beginning of the study and decreased by 11 to 73 +/- 8 beats/minute. During the observational period cholesterol, triglycerides and blood glucose showed a significant decrease (p < 0.001). Triglycerides were diminished by 13%, cholesterol by 8%. In diabetic patients the most favourable effect was observed (decrease of triglycerides by 18% and cholesterol by 9%); glucose decreased in diabetics by 16%. CONCLUSIONS: In this multicentre observational study Nebivolol was proved as a safe and well-tolerated antihypertensive drug. The results of the analysis of metabolic parameters during Nebivolol treatment are of interest as a contribution to the preventive effect of this beta blocker on coronary heart disease. Publication Types: Evaluation Studies Multicenter Study PMID: 11293936 [PubMed - indexed for MEDLINE]
Nebivolol 5 or 10mg plus Hydrochlorothiazide 25mg reduced sitting DBP more than monotherapy ( Nebivolol 1 to 10mg or Hydrochlorothiazide 12.5 and 25mg) after 12 weeks in patients with mild to moderate hypertension. 81 Combination therapy produced an additive dose-related reduction in mean sitting DBP ranging from 9.4mm Hg for Nebivolol 1mg/Hydrochlorothiazide 1.5mg to 15.3 mm Hg for Nebivolol 10mg/hygrochlorothiazide 25mg (p=0.0001 vs. baseline for all) After 12 weeks, monotherapy with either agent produced significant, dose related reductions in mean sitting DBP from baseline (by 5.5 to 13.8mm Hg with 1 to 10mg Nebivolol and 4.6 and 5.8mm Hg with 12.5 and 25mg Hydrochlorothiazide; p<0.001 for all). Compared with placebo, only monotherapy with Nebivolol 5 or 10mg or Hydrochlorothiazide 25mg produced statistically significant reductions in mean sitting DBP; combination therapy was not compared with placebo.
Nebivolol 5mg once daily produced through to peak ratios of about 0.9 for sitting or supine diastolic blood pressure, 163 199 which is the same as for Nifedepine sustained release 20mg twice daily. 199 but higher than that for Enalapril 10mg once daily(0.84 vs. 0.6; p=0.02). 165 These data suggest that Nebivolol 5mg once daily is a suitable dosage to provide adequate antihypertensive control throughout a 24-hour period. However, there is debate regarding the importance of this parameter as a relative or absolute measure of sustained antihypertensive efficacy after once daily drug administration. 200 201 59
Overall response rates to treatment with Nebivolol 5mg once daily ranged from 58% after 4 weeks’ therapy 163 to 81% after 52 weeks’ therapy 40 in patients without comorbidities. One study demonstrated a dose-related increase in response rate (31 to 58%) over the dosage range 0.5 to 10mg once daily but there was no difference between the 5 and 10mg doses. 163 In comparative trials, there was no difference in response rates between patients treated with Nebivolol and Atenolol for 4 166 and 24 weeks or Nifedepine for 12 weeks. 81 164 However, compared with Nifedepine , more Nebivolol that Nifedepine recipients responded to treatment after the first 2 weeks of therapy (65.8 vs. 50% for Nebivolol and Nifedepine ; p=0.001)[table IV] . 199 In addition, a greater proportion of Nebivolol than Nifedepine recipients had a trough sitting DBP of <=90mm Hg after 12 weeks (54 vs. 42%, p=0.007). 164 Although response rates in Nebivolol 5mg once daily recipients were greater than in those receiving Enalapril 10mg once daily for 4(65 vs. 40%, no p value given) 196 and 12 weeks (70 vs. 55%; p<0.01), 165 there were no significant differences between the 2 drugs at 7 months. 198 . Response rates were higher with Nebivolol plus Enalapril 10mg daily (81%) than with Enalapril alone after 4 weeks (p<0.008). 196 Nebivolol was reported to normalize DBP (to <=90mm Hg) in more patients than Metoprolol 100mg twice daily for 12 weeks (79.5 vs. 65.6%, p=0.04). 195 The number of partial responders (DBP reduced by 10% but not normalized) was greater with Metoprolol (17.2 vs. 2.7%, p=-0.01) and about 17% of patients in each group did not respond to treatment. Race had no significant effect on response rates in 1 study, 163 . Older age and Cigarette smoking did not influence the antihypertensive effects of Nebivolol .
When compared to baseline, maximal exercise duration increased by 7 and 13 seconds with placebo and Atenolol, respectively (both NS vs. baseline), and increased by 44 seconds with Nebivolol (P = .0077 vs. baseline). Both Atenolol and Nebivolol decreased maximal exercise heart rate; the reduction was more pronounced with Atenolol . Prolonged beta 1-adrenoceptor blockade leads to a significant increase in LV ejection fraction in patients with ischemic LV dysfunction. The dissociation between the changes in resting LV function and the changes in exercise duration suggests that in this clinical setting, the changes in systolic function may have less impact on functional capacity than an improvement in diastolic distensibility during the rapid filling phase.
Effects of Nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Brehm et al 15 of the Department of Cardiology, University of Tubingen, Germany proved a unique endothelin-lowering effect of Nebivolol . OBJECTIVE: Secondary failure due to late restenosis continues to occur in 30-50% of individuals after PTCA. The aim of this study was to investigate the effects of Nebivolol on cell proliferation of human coronary smooth muscle cells and endothelial cells in comparison to traditional Beta-blockers. RESULTS: added bullets Incubation for 1, 2, 4, 7 or 14 days resulted in a concentration- and time-dependent reduction of proliferation up to 80% in Human coronary smooth muscle cells and endothelial cells and Human coronary smooth muscle cells. Propranolol , Metoprolol or bisoprolol did not exert this effect. Nebivolol inhibited accelerated human coronary smooth muscle cell proliferation even in the presence of growth factors such as TGFBeta(1) and PDGF-BB. Human coronary smooth muscle cells and endothelial cells showed comparable results. During Nebivolol incubation NO formation of Human coronary smooth muscle cells and endothelial cells increased, while endothelin-1 transcription and secretion were suppressed. CONCLUSION: Whereas 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 . Furthermore, in Human coronary smooth muscle cells and endothelial cells NO formation increases and endothelin-1 secretion decreases suggesting that Nebivolol may represent a Beta-blocker with great promises in CAD therapy.
The Pharmacologic Treatment of Uncomplicated Arterial Hypertension in Patients With Airway Dysfunction* Mario Cazzola, MD, FCCP; Paolo Noschese, MD; Gennaro D’Amato, MD; and Maria Gabriella Matera, MD, PhD Because many antihypertensive drugs can affect airway function, the treatment of hypertension in patients with airway dysfunction is complex. For example, the worsening or precipitation of asthma by -adrenoceptor antagonists is well-recognized, but 1-adrenoceptor blockers that exert mild 2-agonist effects, and those that modulate the endogenous production of nitric oxide, affect airway function to a lesser extent. Therapy with selective 1-blockers is not contraindicated in cases of chronic airway obstruction. Conversely, 2-agonists must not be given to asthmatic subjects because they can adversely affect the bronchi. Calcium channel blockers do not exert severe side effects on the airways. Angiotensin-converting enzyme inhibitors may cause cough and exacerbate or even induce asthma; however, angiotensin II type I (AT1) antagonists do not cause cough. 5-Hydroxytryptamine modifiers such as urapidil are a treatment option for patients with chronic airway obstruction. In patients with airway dysfunction, we suggest treatment with thiazide diuretics as the initial drug choice, and calcium channel blockers if the response is poor. In the case of no response, calcium channel blockers alone must be used. However, there is no strict rule because individual patients may respond differently to individual drugs and drug combinations. Consequently, it is important to adopt a flexible approach. For patients who are unresponsive to the aforementioned drugs, AT1 receptor antagonists, newer 1-adrenoceptor-blocking agents with ancillary properties (eg, celiprolol or nebivolol), and/or vasodilators can be considered. (CHEST 2002; 121:230–241)
Robert F. Furchgott – Banquet Speech Robert F. Furchgott's speech at the Nobel Banquet, December 10, 1998 Your Majesties, Your Royal Highness, Ladies and Gentlemen, It is indeed an honor for me to address you on behalf of Professor Ferid Murad, Professor Louis Ignarro and myself, co-winners of the Nobel Prize for Physiology or Medicine. It is of special interest that the prize this year is being awarded to us for &quot;discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system,&quot; 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. As you may be aware, Alfred Nobel in the last ten years of his life suffered from attacks of angina pectoris, the chest pain resulting from an insufficient flow of oxygenated blood in the coronary vessels of the heart. By that time, tablets containing nitroglycerin, a potent dilator of blood vessels, had been introduced as the drug of choice for alleviating anginal pains or for preventing such pains during physical exertion. When Nobel's doctor prescribed nitroglycerin for him, Nobel wrote to a friend, &quot;It sounds like the irony of fate that I should be ordered by my doctor to take nitroglycerin internally.&quot; Today it seems like fate, but not an irony of fate, that some ninety years after Nobel wrote that letter, my two co-winners would present evidence that the vasodilating effect of nitroglycerin on coronary and other blood vessels is due to the nitric oxide released from it when it is enzymatically metabolized in the blood vessel wall, and that I would discover the endothelium-derived relaxing factor, a signalling molecule which would turn out to be nitric oxide. So the seemingly fated progression was from nitroglycerin as Nobel's active ingredient in dynamite, to nitroglycerin for treating angina pectoris, to nitric oxide as the metabolic product of nitroglycerin responsible for its vasodilating action, to nitric oxide as an important endogenous signalling molecule in the cardiovascular system, to the award of the Nobel Prize in Physiology or Medicine to the three of us for our discoveries concerning this unique signalling molecule. The three of us wish to extend our sincere thanks to the members of the Nobel Committee of the Karolinska Institute for the great honor they have bestowed upon us. And finally, for the three of us, NOBEL means NO is beautiful! From Les Prix Nobel 1998.
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