1. Vasodilating Versus First- Generation β-blockers for Cardiovascular Protection Scott Morgan MSIII November 2012

2. Introduction Hypertension (HTN) Defined as BP >140/90 mmHg Prevalence in US adults is 29% or approximately 59 million Risk factor for several diseases: Cardiovascular (CV) Cerebrovascular Renovascular β-blockers Discovered in mid 1960s Were first-line HTN treatment previously Currently falling out of favor due to side effects

3. β-blocker Classes GenerationPropertiesExamples FirstNonselective w/o VasodilationPropanolol, pindolol, nadolol, tindolol, sotalol Secondβ1-selective w/o VasodilationAtenolol, bisoprolol, metoprolol ThirdNonselective w/ Vasodilation β1-selective w/ Vasodilation Carvedilol, bucindolol, labetalol Nebivolol

4. Vasodilating Effects First and Second-Generation (older generation) No vasodilation Third-Generation Nonselective w/ Vasodilation Block vascular α-receptors Carvedilol, bucindolol, labetalol β1-selective w/ Vasodilation Increase NO Nebivolol

5. 1 st Generation Pharmacology Inhibits catecholamines acting on β1-receptors in heart Decreases HR and contractility Leads to decrease CO (SV x HR) and BP Decreases cardiac work and oxygen demand Inhibits β1-receptors on juxtaglomerular apparatus in kidneys Decreases renin release Leads to decreased activation of renin angiotensin aldosterone system (RAAS) Inhibits presynaptic transmission in CNS Decreases catecholamine release

7. Older Gen Clinical Indications Coronary heart disease Heart failure Reduce mortality by 30% in HF w/o preserved ejection fraction Post-myocardial infarction Prevent catecholamine arrhythmogenic effects such as ventricular tachyarrhymias Chronic stable angina Reduction in cardiovascular events PTs with advanced age LV dysfunction Anterior MI

8. Older Gen for Blood Pressure Deceased CO Rebound peripheral vasoconstriction to maintain BP Leads to chronic HTN Decreased skeletal muscle perfusion Adverse effects on lipid and glucose metabolism Less effective in elderly and black populations Tend to have low plasma renin HTN Diuretics are more effective Contraindicated in asthmatics β2 effects cause bronchoconstriction Failed to show reduction in myocardium remodeling LVH still occurs similarly to uncontrolled HTN

9. Compliance Issues Lethargy Drowsiness Depression Peripheral vascular effects Cold extremities Sexual side effects Erectile dysfunction Orgasmic dysfunction Can worsen Diabetes mellitus Decreased insulin release by block β2 receptors in pancreas COPD PVD

10. Nonselective 3 rd Gen β-blockers Carvedilol, bucindolol, metoprolol Block vascular α-receptors Decreased PVR and increased glucose delivery to muscles Increases insulin sensitivity Normally vasodilates by NO, but vasoconstricts by SNS Diabetes and HTN blunt NO effects allowing SNS to increase PVR Can raise HDL and lower LDL levels Increases renal blood flow Less activation of RAAS Reduces microalbuminuria No negative BUN/creatinine effects

11. Carvedilol Better tolerated in elderly Body already has β-blocker like effects Decreased β-adrenergic response and increased catecholamine levels Less β-blocking effects and more vasodilation Less sympathetic activation Fewer adverse effects More compliance Most common side effects HA Dizziness Orthostatic hypotension

12. Nebivolol Highest cardioselectivity of the β blockers Vasodilates Inhibits NADPH oxidase decreased oxygen radical development Produces lower peroxynitrite levels Prevents endothelial cell NO synthesis (eNOS) Increased levels of NO Inhibits platelet aggregation NO normally inhibits aggregation Inhibits atherosclerosis Inhibits edothelin-1 which normally promotes cell growth Increased exercise tolerance compared to traditional β-blockers

13. β-blocker Properties

14. Summary Third generation β-blockers are more effective at controlling HTN than traditional More favorable metabolic effects Better choice with multiple comorbid conditions Safer in elderly and black populations Fewer side effects Older generation β-blockers are still useful for treatment of other cardiovascular diseases

15. Citation Fares, Hassan et al. Vasodilating Versus First-Generation β- blockers for Cardiovascular Protection. Postgraduate Medicine. Volume 124; Issue 2: 7-14. March, 2011.