Vasodilating Versus FirstGeneration β-blockers for
Cardiovascular Protection
Scott Morgan MSIII
November 2012
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
β-blocker Classes
Generation Properties
Examples
First
Nonselective w/o Vasodilation Propanolol, pindolol,
nadolol, tindolol, sotalol
Second
β1-selective w/o Vasodilation
Atenolol, bisoprolol,
metoprolol
Third
Nonselective w/ Vasodilation
Carvedilol, bucindolol,
labetalol
β1-selective w/ Vasodilation
Nebivolol
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
1st 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
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
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
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
rd
Nonselective 3 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
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
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
β-blocker Properties
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
Citation
• Fares, Hassan et al. Vasodilating Versus First-Generation βblockers for Cardiovascular Protection. Postgraduate
Medicine. Volume 124; Issue 2: 7-14. March, 2011.