This document summarizes beta-blockers, which were discovered in 1962 and are inverse agonists of β1- and β2-adrenoceptors. It discusses their mechanism of action, structure-activity relationships, clinical uses including hypertension and angina, adverse effects, drug interactions, and current research on their effects on cancer survival, platelet aggregation, fractures, and traumatic brain injury outcomes. The summary reviews key points about beta-blockers' chemical structures, mechanisms in different tissues, clinical applications, and cited references.
2. ⦁ Background
⦁ Mechanism of action
⦁ Structure-activity relationship
⦁ Clinical information
⦁ Current research
⦁ Summary
⦁ References
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3. ⦁ Discovered by Sir James Black in 1962
⦁ Awarded the Nobel Prize for Medicine in 1988
⦁ Propranolol and pronethalol were the first
clinically significant beta-blockers (van der Vring et
al., 1999)
⦁ All beta-blockers end in ‘-lol’, e.g. labetalol,
timolol, bisoprolol, etc.
Nobel Media,
2014
3
4. ⦁ β1- and β2-adrenoceptor inverse agonists
⦁ Drugs vary in inverse agonist activity
⦁ Selectivity vs. specificity
Panesar and
Guzman,
2009
4
5. ⦁ Part of the sympathetic nervous system
⦁ Metabotropic, G-protein-coupled receptors
⦁ Linked to the Gs protein
⦁ β1-adrenoceptors
◦ Heart, kidneys
⦁ β2-adrenoceptors
◦ Bladder detrusor muscle, eye ciliary muscle, GI
tract, liver, pancreas, smooth muscle, skeletal
muscle (Lechat, 2008)
5
8. ⦁ Essential for binding to receptors (Lechat, 2008)
◦ Oxymethylene
⦁ Essential for activity (Gorre and Vanderkerckhove, 2010)
◦ Aromatic ring
◦ β-ethanolamine
Adapted from Mehvar and Brocks, 2001
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11. ⦁ Second- or third-degree heart block
⦁ Worsening unstable heart failure
⦁ Renal impairment
◦ Dose reduction of water-soluble beta-blockers, e.g.
atenolol and sotalol
⦁ Asthma or COPD
◦ Treatment should be initiated by a specialist
⦁ Diabetes
◦ Cardioselective beta-blockers are preferred
◦ Avoid altogether if hypoglycaemia occurs frequently
(Joint Formulary Committee, 2014)
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12. ⦁ Adrenaline and noradrenaline
⦁ Antihypertensives, e.g. ACE inhibitors,
angiotensin-II-receptor antagonists, alpha-
blockers, calcium-channel blockers, diuretics
⦁ Anti-arrhythmics, e.g. amiodarone, flecainide
⦁ Anti-psychotics
◦ Increased risk of arrhythmias with sotalol
⦁ Insulins
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13. ⦁ Conflicting research on use of beta-blockers
in cancers
◦ Use of beta-blockers pre-mastectomy in breast
cancer patients was associated with improved
recurrence-free survival (Melhem-Bertrand et al., 2011)
◦ Increased survival time of patients with melanoma
receiving beta-blockers (Lemeshow et al., 2011)
◦ No association between exposure to beta-blockers
and improved survival for breast, lung, or colorectal
cancer in hypertensive patients (Musselman et al. 2014)
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14. ⦁ Beta-blockers reduce platelet aggregation
◦ Non-selective lipophilic beta-blockers cause a
greater reduction than selective hydrophilic beta-
blockers (Bonten et al., 2014)
⦁ Beta-blockers reduced risk of fractures (Toulis et
al., 2014)
⦁ Mortality reduced post-acute traumatic brain
injury by beta-blockers (Alali et al., 2014)
14
15. ⦁ All beta-blocker drug names end in ‘-lol’
⦁ β1- and β2-adrenoceptor inverse agonists
⦁ Decrease cAMP concentration
⦁ Different mechanisms of action in different
muscle types
⦁ Importance of chemical structure
⦁ Indications, adverse effects, cautions,
contraindications, drug interactions
⦁ Current research
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16. ⦁ Alali AS, McCredie VA, Golan E, Shah PS, and Nathens AB. (2014) Beta Blockers for Acute
Traumatic Brain Injury: A Systematic Review and Meta-analysis. Neurocrit Care 20 (3):
514-523.
⦁ Bonten TN, Plaizier CEI, Snoep JJD, Stijnen T, Dekkers OM, and van der Bom JG. (2014)
Effect of β-blockers on platelet aggregation: a systematic review and meta-analysis. Br J
Clin Pharmacol 78 (5): 940-949.
⦁ Gorre F, Vanderkerckhove H. (2010) Beta-blockers: focus on mechanism of action. Which
beta-blocker, when and why? Acta Cardiol 65 (5):565–570.
⦁ Joint Formulary Committee. (2014) Beta-adrenoceptor blocking drugs. In: Joint
Formulary Committee. British National Formulary. 68th ed. London: BMJ Group and
Pharmaceutical Press.
⦁ Klabunde RE. (2013) Beta-Adrenoceptor Antagonists (Beta-Blockers). Available:
http://cvpharmacology.com/cardioinhibitory/beta-blockers.htm. Last accessed 24th Oct
2014.
⦁ Lechat P. (2008) Clinical pharmacology of beta-blockers in cardiology: trial results and
clinical applications. Hot Topics in Cardiology 10 (7):7-44.
⦁ Lemeshow S, Sørensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, Lesinski GB, Jackson
R, and Glaser R. (2011) β-Blockers and survival among Danish patients with malignant
melanoma: a population-based cohort study. Cancer Epidemiol Biomarkers Prev 20 (10):
2273-2279.
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17. ⦁ Mehvar R, Brocks DR. (2001) Stereospecific Pharmacokinetics and Pharmacodynamics of
Beta-Adrenergic Blockers in Humans. J Pharm Pharmaceutical Sci 4 (2):185-200.
⦁ Musselman RP, Li W, Gomes T, Mamdani M, Haggar F, Mollo H, Boushey RP, Al-Omran M,
Al-Obeed O, VanWalraven C, and Auer RC. (2014) Association Between Beta Blocker
Usage and Cancer Survival in a Large, Matched Population Study Among Hypertensive
Patients. JSurg Res 186 (2): 639-640.
⦁ Nobel Media AB. (2014) Sir James W. Black – Facts. Available:
http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/black-facts.html.
Last accessed 10th Nov 2014.
⦁ Toulis KA, Hemming S, Stergianos S, Nirantharakumar K, and Bilezikian JP. (2014) β-
adrenergic receptor antagonists and fracture risk: a meta-analysis of selectivity, gender,
and site-specific effects. Osteoporos Int 25 (1): 121-129.
⦁ van der Vring JAFM, Daniëls MCG, Holwerda NJH, Withagen PJAM, Schelling A, Cleophas
TJ, Hendriks MGC. (1999) Combination of Calcium Channel Blockers and Beta Blockers
for Patients with Exercise-Induced Angina Pectoris: A Double-Blind Parallel-Group
Comparison of Different Classes of Calcium Channel Blockers. Angiology 50 (6):447-
454.
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