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Title: Evaluation of beta-blockers for the treatment of asthma and chronic obstructive pulmonary disease
Author: Short, Philip
ISNI:       0000 0004 5352 1504
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2014
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Beta-blockers are avoided in asthma and chronic obstructive pulmonary disease (COPD) due to the potential risk of drug induced bronchospasm. Despite these concerns, beta-adrenoceptor antagonism has recently been associated with potential therapeutics benefits in asthma. Furthermore the use of beta-blockers in COPD patients may potentially result in improved survival due to optimisation of treatment in those with concurrent cardiovascular disease. This thesis evaluates the role of beta-blocker use in asthma and COPD. The introduction outlines the pharmacological principles associated with the human beta-adrenoceptor and its therapeutic application in the management of asthma and COPD through established treatment strategies including inhaled beta-agonists. The historical literature documenting concerns with beta-blocker use in asthma and COPD is reviewed and critiqued. Finally the hypothesis, on which this thesis is based, that betablockers may have a therapeutic role in the asthma and COPD is discussed. Proof of concept studies and preliminary work suggesting potential putative effects of betablocker use in asthma, data highlighting the burden of cardiovascular disease in COPD patients and the potential role of beta-blockers are discussed. New data from two randomised double-blind placebo controlled trials evaluating betablocker use in asthma and an observational study investigating the effects of betablocker use on mortality in COPD are presented. The first randomised controlled trial, addresses the safety of beta-blocker use in asthma. Using the non-selective beta-blocker propranolol, the study investigated the safety of acute exposure to propranolol in asthmatics, sequentially challenged with histamine to mimic an asthma exacerbation and evaluated the role of intravenous hydrocortisone in potentiating salbutamol reversibility. The results of this study showed there was no significance difference in salbutamol recovery measured by change in FEV1 (ml) post histamine challenge following intravenous hydrocortisone verses placebo (mean difference 0.04 (95%CI - 0.07 to 0.15), p=0.417). The study also investigates the degree of bronchoconstriction attributable to oral propranolol in mild-to-moderate asthmatics and uses impulse oscillometry as an alternative method of assessing pulmonary function to conventional spirometry. Following 10 or 20mg of oral propranolol, a mean fall in FEV1 of 4.7% was observed (95%CI 1.8 to 7.5), p=0.008. Impulse oscillometry showed a greater response to propranolol with an increase of 31.3% (95%CI 15.6 to 47), p= 0.04, 2 hours post propranolol dosing. The second randomised controlled trial within this thesis, describes the first placebocontrolled trial to assess the effects of chronic dosing with oral propranolol as add-on to inhaled corticosteroids in patients with stable persistent asthma. The study investigated the hypothesis of potential therapeutic benefits of chronic beta-blocker use in asthma by improvements in airway hyper-responsiveness. This study evaluates the effects of oral propranolol on both methacholine and histamine bronchial challenges, in addition to spirometry, impulse oscillometry and inflammatory surrogates including exhaled nitric oxide. Furthermore the effects on asthma control and quality of life post chronic betablockade are described. Finally the safety and tolerability of acute cardio-selective beta-blockade with esmolol is compared to acute propranolol dosing and the protective effects of tiotropium are evaluated. The main result of this study showed chronic propranolol dosing did not affect airway hyper-responsiveness, with no significant difference observed in methacholine challenge PC20 following chronic propranolol exposure compared to placebo, geometric mean mg/ml: 2.57 (95%CI 1.13 to 5.85) versus 2.50 (95%CI 1.14 to 5.50), -i.e. a mean doubling dilution difference (DDD) of 0.04 (95%CI -0.56 to 0.63), p=0.89. Furthermore following chronic beta-blocker dosing, FEV1 showed a fall with propranolol versus placebo amounting to a 4.3% (95%CI -0.6 to 9.2) p=0.08. The final study within this thesis is a large observational cohort study using a disease specific dataset of COPD patients. By means of data linkage using pharmacy prescriptions, hospital admissions and mortality data, the potential effects of betablocker use on COPD exacerbations and mortality is examined. This study suggested a potential survival benefit with beta-blocker use amounting to a 22% reduction in mortality (HR 0.78 (95%CI 0.67 to 0.92). The discussion of this thesis evaluates the results of each study and describes their relevance in the management of patients with asthma and COPD.
Supervisor: Lipworth, Brian Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available