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The Pharmacology of Beta-Blockers

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The Pharmacology of Beta-Blockers

  1. 1. Prijay Bakrania 1
  2. 2.  Background  Mechanism of action  Structure-activity relationship  Clinical information  Current research  Summary  References 2
  3. 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. 3 Nobel Media, 2014
  4. 4.  β1- and β2-adrenoceptor inverse agonists  Drugs vary in inverse agonist activity  Selectivity vs. specificity Panesar and Guzman, 2009 4
  5. 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
  6. 6. Klabunde, 2013 6
  7. 7. Klabunde, 2013 7
  8. 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 8
  9. 9.  Hypertension  Angina pectoris  Myocardial infarction  Cardiac arrhythmias  Congestive heart failure  Anxiety ◦ Reduced adverse effects, e.g. tremor  Glaucoma (Joint Formulary Committee, 2014) 9
  10. 10.  Bradycardia  Bronchospasm  Dyspnoea  Cold extremities  Hypoglycaemia  Hyponatraemia and hyperkalaemia  Insomnia / vivid dreams and nightmares (Joint Formulary Committee, 2014) 10
  11. 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) 11
  12. 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 12
  13. 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) 13
  14. 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. 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 15
  16. 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. 16
  17. 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. J Surg 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. 17

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