Beta-blockers
For the past 50 years, beta blockers have been commonly used in cardiovascular medicine. Beta blockers play an important role in reducing mortality rates for patients following a myocardial infarction or those with heart failure, especially in individuals with reduced ejection fraction (this is known as secondary prevention).
A meta-analysis examining patients with hypertension as part of a primary prevention strategy found that the relative risk of stroke is 16% higher for individuals using beta blockers, particularly atenolol, compared to those using other medications. The 95% confidence interval for this finding ranges from 4% to 30%. The authors concluded that beta blockers should not be used as a first-line treatment for hypertension. We will explore this topic further below.
Type of betablocker
Without vasodilatory effect
With vasodilatory effect
Non-selective betablockers
propranolol, nadolol
carvedilol (with alpha-receptor blockage),
labetalol (with alpha-receptor blockage)
Selective betablockers
atonolol, metoprolol, bisoprolol, esmolol
nebivolol (nitric oxide mediated)
With intrinsic sympathomimetic activity
carteolol, pindolol, penbutolol
acebutolol
Cardioselectivity
Cardioselectivity refers to the preferential blocking effect on beta-1 adrenergic receptors in the heart compared to beta-2 receptors found in the bronchi, peripheral blood vessels, and other areas. This cardioselectivity can be clearly demonstrated using small doses. However, at the higher doses typically used to treat hypertension, much of this selectivity is diminished.
Comparison of the affinity ratio to the beta1 and beta2-adrenoreceptor for betablockers:
-
Nebivolol (40.6)
-
Bisoprolol (19.6)
-
Metoprolol (6.0)
-
Atenolol (5.7)
-
Carvedilol (0.6)
-
Propronolol (0.3)
This image depicts the signaling pathway of the β1 adrenergic receptor in the heart and its cardiac effects. The β1 adrenergic receptor, found on the cell membrane, is activated by epinephrine (E) or norepinephrine (NE).
It stimulates the G protein Gαs upon activation, which activates adenylate cyclase (AC). AC converts ATP to cyclic AMP (cAMP), activating protein kinase A (PKA). PKA phosphorylates key proteins such as Troponin-I, enhancing relaxation, and phospholamban, promoting calcium reuptake. It also activates ryanodine receptors (RyR) and calcium channels, increasing intracellular calcium and improving contractility.
Additionally, cAMP activates hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which increase heart rate. Activating the β1 adrenergic receptor increases heart rate, contractility, and myocardial relaxation.
This image illustrates the β2 adrenergic receptor signaling pathway in the airway, highlighting its vital role in smooth muscle relaxation, particularly in asthma and COPD. The β2 receptor, located on airway smooth muscle cells, is activated by epinephrine (E) and norepinephrine (NE).
When activated, the receptor stimulates the Gαs protein, which activates adenylate cyclase (AC). This enzyme converts ATP into cyclic AMP (cAMP), increasing its levels. The rise in cAMP inhibits myosin light chain kinase (MLCK), an enzyme that promotes contraction. At the same time, myosin light chain phosphatase remains active, aiding in dephosphorylation.
The inhibition of MLCK reduces actin-myosin interactions, resulting in smooth muscle relaxation. Additionally, β-arrestin may play a role in feedback or desensitization, although this is not detailed in the image. Overall, β2 receptor activation promotes bronchodilation by increasing cAMP levels and inhibiting MLCK activity.
Intrinsic Sympathomimetic Activity
Some drugs, like pindolol, exhibit intrinsic sympathomimetic activity and interact with beta receptors to produce a measurable agonist response while simultaneously blocking the more significant agonist effects of endogenous catecholamines.
The presence of intrinsic sympathomimetic activity (ISA) in beta blockers leads to less resting bradycardia and a smaller decrease in cardiac output compared to beta blockers that do not have ISA. This has created some controversy regarding the use of these beta blockers for secondary prevention after a myocardial infarction.
Beta blockers with intrinsic sympathomimetic activity are no longer available in Thailand.
Lipid Solubility
Atenolol and Nadolol are the least lipid-soluble beta blockers, which allows them to avoid hepatic metabolism and be excreted unchanged by the body.
Lipid-soluble agents like metoprolol and propranolol are absorbed and metabolized in the liver.
As a result, these lipid-soluble drugs have higher bioavailability when administered intravenously compared to oral administration.
Lipophilic
hepatic metabolized
propranolol
metoprolol
carvedilol
timolol
pindolol
bisoprolol
atenolol
nadolol
sotalol
Hydrophilic
renal excretion
Removal of Beta-blocker with dialysis
Percent removal with dialysis
Atenolol
Alebutolol
Bisoprolol
Propranolol
Carvedilol
Labetalol
Metoprolol
HD
75
70
55-60
<5
None
<1
High
PD
53
50
N/A
N/A
None
<1
unknown
Dializability
atenolol
metoprolol
bisoprolol
carvedilol
labetalol
Contraindication, caution and choice
Contraindications for the use of beta-blockers include severe bradycardia, second- to third-degree atrioventricular (AV) block, and asthma.
Caution is advised in patients with chronic obstructive pulmonary disease (COPD); in these cases, beta1-selective beta-blockers, such as atenolol, bisoprolol, metoprolol, and nebivolol, are preferred.
For patients with heart failure with reduced ejection fraction, evidence-based beta-blockers include bisoprolol, carvedilol, and metoprolol succinate.
Carvedilol and nebivolol are recommended for patients with diabetes mellitus. Numerous studies have shown that vasodilating beta-blockers have more favorable effects on glucose and lipid profiles compared to non-vasodilating beta-blockers. Cardioselective offer the likelihood of fewer perturbations of lipid metabolism.
Carvedilol is preferred for dialysis patients with end-stage kidney disease (ESKD) who also have cardiomyopathy. It is the only beta-blocker that has demonstrated a survival advantage in a randomized controlled trial (RCT) among dialysis patients with dilated cardiomyopathy.
Adverse effect
Blocking beta-adrenergic receptors may worsen concurrent problems like peripheral vascular disease and bronchospasm.
Fatigue is the most common side effect, likely due to decreased cardiac output. While beta blockers may increase sexual dysfunction, they probably do not contribute to depression.
Beta blockers may increase the risk of diabetes by decreasing insulin sensitivity, likely due to reduced skeletal muscle perfusion from peripheral vasoconstriction.
The body's responses to hypoglycemia— including symptoms (except sweating) and hormonal changes that raise blood glucose levels— are partially influenced by sympathetic nervous activity. Diabetic patients who are prone to hypoglycemia may not recognize the typical warning signs (also except sweating).
Beta-blocker use perturbs lipoprotein metabolism. Nonselective agents lead to increased triglyceride levels and decreased cardioprotective high-density lipoprotein cholesterol.
When a beta blocker is abruptly stopped, there is a risk of angina pectoris and myocardial infarction (MI). This is because the increased number of beta receptors that develop during beta blockade suddenly become exposed to sympathetic nervous system activity. Patients with hypertension, who are more prone to coronary artery disease, should have their beta blocker dosage reduced gradually and should receive appropriate treatment with coronary vasodilators.
Caution is advised in the use of beta blockers for patients suspected of harboring a pheochromocytoma because unopposed alpha-adrenergic agonist action may precipitate a severe hypertensive crisis if this disorder is present.
Scattered case reports of various fetal problems have clouded the use of beta blockers during pregnancy. Atenolol has been linked with reduced growth of the fetus (smaller in size and/or low birth weight).
Use of betablockers in hypertension
A meta-analysis involving patients with hypertension, which is considered a primary prevention strategy, found that the relative risk of stroke was 16% higher for those using beta blockers, particularly atenolol, compared to other medications (with a 95% confidence interval of 4–30%).
This could be attributed to the fact that while beta blockers lower brachial systolic blood pressure similarly to other drugs, they do not reduce aortic pressure as effectively. Additionally, beta blockers decrease heart rate and increase peripheral resistance, causing the arterial wave reflection from the periphery to return during systole rather than diastole.
However, beta blockers are recommended explicitly for hypertensive patients with concomitant coronary disease, particularly after a myocardial infarction, congestive heart failure, or tachyarrhythmias.
Labetalol and carvedilol are newer beta-blockers with vasodilatory effects, acting as alpha- and beta-blockers. Intravenous labetalol is often used to treat hypertensive emergencies. The primary mechanism of blood pressure reduction is decreased peripheral resistance, which has a lesser effect on cardiac output.
Nebivolol is the most selective beta-1 blocker in its class. It generates and releases nitric oxide (NO) while providing complementary antioxidant effects. This medication may be especially beneficial for older patients with isolated systolic hypertension. Like other beta blockers, it reduces aortic stiffness and lowers the amplification of central systolic pressure by decreasing wave reflection from the periphery.
This image illustrates the β3 adrenergic receptor signaling pathway in endothelial cells, highlighting its role in vasodilation and antioxidant effects. The β3 adrenergic receptor, located on the endothelial cell membrane, is activated by agonists like Nebivolol, which acts as both a β3 agonist and a β1 blocker.
Activation of Gαs stimulates adenylate cyclase (AC), converting ATP to cyclic AMP (cAMP) and enhancing the calcium-mediated activation of endothelial nitric oxide synthase (eNOS). Gαi can also directly activate eNOS, which then converts L-arginine into nitric oxide (NO), a strong vasodilator. NO diffuses into nearby vascular smooth muscle cells, where it stimulates soluble guanylate cyclase (sGC) to produce cyclic GMP (cGMP), resulting in vasodilation.
While NO can react with superoxide to form the harmful oxidant peroxynitrite, Nebivolol demonstrates antioxidant properties that help counteract this process. Therefore, activation of the β3 receptor not only promotes vasodilation through the NO-cGMP pathway but also protects endothelial cells from oxidative stress.
References
Bonow, Robert O.; Mann, Douglas L. ; Zipes, Douglas P.; Libby, Peter. Braunwald's Heart Disease E-Book. Elsevier Health Sciences. Kindle Edition.
Lindholm LH, Carlberg B, Samuelsson O. Should β blockers remain first choice in the treatment of primary hypertension? A meta-analysis. The Lancet. 2005 Oct 29;366(9496):1545–53.
Ladage, D., Schwinger, R.H.G. and Brixius, K. (2013), Cardio-Selective Beta-Blocker: Pharmacological Evidence and Their Influence on Exercise Capacity. Cardiovascular Therapeutics, 31: 76-83.
Fonseca, V. A. (2010). Effects of β-blockers on glucose and lipid metabolism. Current Medical Research and Opinion, 26(3), 615–629.
Drygała, S., Radzikowski, M., & Maciejczyk, M. (2024). β-blockers and metabolic modulation: Unraveling the complex interplay with glucose metabolism, inflammation and oxidative stress. Frontiers in Pharmacology, 15, 1489657.
Shroff GR, Herzog CA. β-Blockers in dialysis patients: a nephrocardiology perspective. J Am Soc Nephrol. 2015 Apr;26(4):774-6.
Cice, G, Ferrara, L, D’Andrea, A. et al. Carvedilol increases two-year survivalin dialysis patients with dilated cardiomyopathy: A prospective, placebo-controlled trial. JACC. 2003 May, 41 (9) 1438–1444.
Inrig JK. Antihypertensive agents in hemodialysis patients: a current perspective. Semin Dial. 2010 May-Jun;23(3):290-7.
Bouchard, J., Shepherd, G., Hoffman, R.S. et al. Extracorporeal treatment for poisoning to beta-adrenergic antagonists: systematic review and recommendations from the EXTRIP workgroup. Crit Care 25, 201 (2021). https://doi.org/10.1186/s13054-021-03585-7
Tieu, Alvin; Velenosi, Thomas J.; Kucey, Andrew S.; Weir, Matthew A.; Urquhart, Bradley L.. β-Blocker Dialyzability in Maintenance Hemodialysis Patients: A Randomized Clinical Trial. Clinical Journal of the American Society of Nephrology 13(4):p 604-611, April 2018.