The document summarizes recent advances in understanding the endothelium and nitric oxide, with a focus on the beta blocker nebivolol. Nebivolol is a highly selective beta-1 receptor blocker that also stimulates nitric oxide production, giving it vasodilatory effects. Unlike other beta blockers, nebivolol has been shown to improve endothelial function, exercise capacity, and left ventricular function in heart failure and hypertension without impairing glucose or lipid metabolism.

1. Recent Advances in Endotheliology A focus on Nitric oxide [email_address]

2. 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 - Summary [email_address]

3. 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." [email_address]

4. 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 . [email_address]

5. The Endothelium: The largest living organ 1 ½ kg. Semi-permeable [email_address]

6. Regulation of vascular tone by the balance of endothelium-derived vasodilators and vasoconstrictors ADPase=adenosinediphosphatase; EDHF=endothelium-derived hyperpolarizing factor; PAF=platelet-activating factor; TXA 2 =thromboxane A 2 [email_address]

7. What is NO? [email_address] L-arginine L-citrulline + NO (g) NOS 1980: Incubation of endothelial cells in absence of L-arginine EDRF

8. When N-O means Yes Stimulates guanylate cyclase ↓ ↑ In Conc. of cyclic guanosine monophosphate (cGMP) ↓ Decrease in intracellular Ca ++ Conc. ↓ Vasorelaxation [email_address]

9. 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 [email_address]

10. 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. [email_address] Editorial in Critical Care Medicine, Volume 31 • Number 3 • March 2003

11. 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 [email_address]

12. 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_address]

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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

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19. 1 st gen= Vasoconstrictor to 3 rd = Vasodilator 1 st – Gen: Non-selective Enhance alpha receptor-mediated vaso-constriction 2 nd – Gen Beta,-selective Less vaso-constrictor [email_address] 3 rd – Gen Vasodilatory effects on the resistance arteries. Note: only Nebivolol dilates both arteries and veins and yet is cardio-selective * NS=Non selective Propranolol NS Atenolol Metoprolol Bisoprolol Carvedilol NS Celiprolol NS Nebivolol

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

21. Drawbacks of existing drugs Avoid in Bronchospastic disease. Avoid in Young patients Impotence/ loss of libido documented . Avoid in diabetics Impair Insulin Sensitivity Avoid in Obese & patients with impaired lipid profile Will worsen lipid profile and have increased atherosclerotic effect. [email_address] Beta 1/ Beta 2 Selectivity Nonselectivity Propranolol Carvedilol Atenolol

22. 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. [email_address] Vasoconstriction Class effect with 1 st , 2 nd gen. Water Soluble Atenolol, Celiprolol, Drawbacks of existing drugs

23. 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. [email_address] Plus, it should solve the problems mentioned earlier

24. Nebivolol [email_address]

25. Nebivolol A 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 [email_address]

26. Highest Beta-1 selectivity Cleophas et al, 2001, “Of the Beta-blockers, Nebivolol has the highest Beta 1-selective activity [email_address] Celiprolol selectivity is 5:1

27. Nebivolol- Pharmacokinetics T max 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% [email_address]

28. 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 [email_address]

29. Nebivolol- Indications Approved Mild to Moderate hypertension Promising results in Heart failure IHD [email_address]

30. 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 [email_address]

31. 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 [email_address]

32. 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 [email_address]

33. 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. [email_address] [Van Bortel LMAB, van Baak M et al]

34. 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 [email_address]

35. Trial 6376 patients Arterial hypertension Six weeks. The initial dosage was 5 mg daily Nebivolol in Hypertension [email_address] 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 von Fallois J, Faulhaber HD.Schweiz Rundsch Med Prax 2001 Mar 15; 90(11):435-41.

36. Nebivolol reverses endothelial dysfunction in Essential HT A Randomized, Double-Blind, Crossover Study [email_address] Circulation. 2001;104:511-514

37. 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 [email_address] Circulation. 2001;104:511-514 Thus, nebivolol may offer additional vascular protection in treating hypertension.

38. Combination therapy 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. [email_address]

39. Trough to peak ratios [email_address]

40. Response Rates [email_address]

41. 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 [email_address] (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.)

42. 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 [email_address]

43. 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 [email_address]

44. Nebivolol vs Atenolol : Nebivolol improves EF, CO [email_address] Nebivolol in CHF Unlike Atenolol, Nebivolol, shifted the diastolic pressure volume data, suggesting improved distensibility

45. 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 Atenolol Increased by 44 seconds with Nebivolol [email_address]

46. 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. [email_address]

47. Nebivolol vs Atenolol : E.F., C.O. Unlike Atenolol, Nebivolol shifted the diastolic pressure-volume data downward, suggesting improved LV distensibility [email_address]

48. 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, [email_address] 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.

49. 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 [email_address]

50. Comparison with other Beta blockers [email_address]

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

53. Summary Preferred 1 st line drug for management of hypertension Unlike conventional TREATMENT Nebivolol can be prescribed across all patients Most selective β 1 blocker, highly potent, Novel property of stimulating NO production from endothelium [email_address]

54. THANK YOU [email_address]