Whale, Christopher Ian
(2009)
Safety aspect of β2-agonists in chronic obstructive pulmonary diesease.
DM thesis, University of Nottingham.
Abstract
Chronic Obstructive Pulmonary Disease (COPD) presents an enormous public health challenge. Cigarette smoking remains the most important aetiological factor and although legislation to reduce smoking has been introduced in parts of the more developed world, consumption is increasing in many of the poorest parts of the world. With the predicted rise in disease prevalence, COPD is expected to become the worlds third largest cause of death by 2020.
COPD is a disease state characterised by airflow limitation that is not fully reversible. Inhaled bronchodilators can only produce a small improvement in the airflow obstruction, but despite this, patients with COPD frequently use high doses of beta-2-agonists as the disease progresses and they develop breathlessness and exercise limitation.
Short-acting beta-2-agonists are generally used as required to reduce breathlessness and reduce airflow obstruction whereas long-acting beta-2-agonists are prescribed on a regular twice-daily basis to reduce symptoms and rescue medication use and because of a potential beneficial effect on quality of life and exacerbation rates.
Although generally well tolerated, the safety of inhaled beta-2-agonists has been a source of some concern since the late 1960s, when an epidemic of asthma deaths was associated with the use of a high dose formulation of isoprenaline. Further controversy has followed and questions have extended to long-acting beta-2-agonists, most notably after a recent large-scale post marketing surveillance study identified an association between the regular use of inhaled salmeterol and asthma-related deaths.
The safety of inhaled beta-2-agonists is also an important consideration for patients with COPD. Being older and likely to have a history of cigarette consumption means that they are at risk of having symptomatic, or subclinical, ischaemic heart disease. Beta-2-agonists cause a number of systemic effects including an increase in heart rate, transient hypoxaemia and hypokalaemia. Since many patients with COPD are already hypoxaemic and may be taking other drugs that stimulate the myocardium and cause hypokalaemia, the additional systemic effects from beta-2-agonists may be more likely to produce adverse cardiac events including dysrhythmia and ischaemia.
This thesis is concerned with the safety of inhaled beta-2-agonists in the management of COPD. The introduction consists of an overview of the epidemiology, natural history and pathology of COPD (Chapter 1) and a review of human beta-2-adrenoceptor function and inhaled beta-2-agonist pharmacology (Chapter 2). This is followed by a systematic literature review of the results from long-term clinical studies of inhaled beta-2-agonists in subjects with COPD (Chapter 3). The original work consists of three clinical studies that have examined aspects of the effect of high dose inhaled beta-2-agonists in subjects with COPD and a discussion to place these findings in context.
Most published studies of inhaled beta-2-agonists in subjects with COPD have focused on their efficacy, rather than safety. We were concerned that some individuals with COPD and limited bronchodilator reversibility may experience an increase in adverse systemic effects after inhaling high doses of beta-2-agonists, which could lead to detrimental outcomes in certain clinical situations.
Apart from the cardiac effects mentioned above, beta-2-agonists increase tremor, which causes CO2 production, and cardiac output and tissue perfuson, which increases the transport of CO2 to the lungs. The increase in CO2 flux to the lungs will normally increase ventilation. We were concerned however that some subjects with severe COPD would not be able to increase ventilation appropriately in response to the beta-2-agonist and this would lead to an increase in PaCO2. Our hypothesis was that high dose inhaled beta-2-agonists could worsen respiratory failure in some subjects with severe COPD.
The first two studies in the thesis examined the effect of high dose inhaled salbutamol on the partial pressure of arterial oxygen and carbon dioxide in subjects with severe COPD.
We initially conducted a double blind, randomised study on subjects within 48 hours of being admitted to hospital with an acute exacerbation of COPD (Chapter 4). The study was designed to determine whether high dose salbutamol caused an increase in the partial pressure of arterial carbon dioxide. We randomised subjects at a ratio of 3:1 to receive either salbutamol or ipratropium bromide and studied the pharmacodynamic effect on heart rate, PaO2 and PaCO2 over five hours. Over eighteen months and despite extensive efforts I was only able to recruit ten subjects, of whom five completed the study. I found that subjects who required hospital admission with an acute exacerbation of COPD were either too unwell for the study, had co-morbidities that precluded participation or the individuals were unwilling to participate. Although the study was terminated prematurely and we were unable to perform statistical analysis, I have presented the findings from the five subjects who completed the study, of whom four were randomised to receive salbutamol. We used ascending doses of salbutamol (1.25mg, 1.25mg, 25mg, 5mg, 5mg) and found no consistent effect on PaCO2 or PaO2 and no dose response relationship. The subject with the highest baseline PaCO2 did however have a rise in PaCO2 with the highest 5mg doses of salbutamol.
To test the hypothesis further we conducted a randomised, double blind, crossover study and examined the effect of salbutamol on the arterial blood gas tensions of fourteen patients with stable severe COPD and a history of chronic or intermittent hypercapnia. The study was designed to determine whether high dose salbutamol causes a rise in PaCO2 when inhaled by subjects with severe COPD and a history of alveolar hypoventilation. We compared the effect of two 5mg doses with two 200 microgram doses of salbutamol on PaO2 and PaCO2 and heart rate. The subjects had severe COPD with a mean FEV1 of 0.71 L (27% predicted) and a mean smoking history of 53 pack years. The mean baseline PaO2 was 7.9 kPa and the mean baseline PaCO2 was 7.0 kPa. The high dose of salbutamol caused a mean fall in both PaO2 and PaCO2 and a small increase in heart rate. There was some support for our hypothesis however as three subjects had a small rise in PaCO2 after high dose nebulised salbutamol (Chapter 5).
The third study was a double blind, crossover, dose-response examination of the bronchodilator and systemic effects of inhaled formoterol in subjects with COPD (Chapter 6). The rapid onset and prolonged duration of action of formoterol offers potential for the drug to be used as rescue medication in addition to twice daily maintenance therapy, as is the case in the management of asthma. Our hypothesis was that high doses of formoterol would produce adverse systemic effects that would outweigh the beneficial bronchodilator effects in subjects with COPD and limited bronchodilator response to salbutamol. We studied 20 subjects, with a mean FEV1 of 1.32 L (47% predicted) and a mean smoking history of 42 pack years. Each subject was studied on five days and after receiving placebo, formoterol 6, 12, 24 and 48 mg in a random sequence, we examined the effect of each dose on FEV1, tremor, dyspnoea, heart rate, blood pressure, SpO2, walk distance, potassium and satisfaction. We found that all doses were well tolerated and although there was a small dose related increase in FEV1 and the mean satisfaction scores were higher with each dose of formoterol than placebo, there was no dose related improvement in measures that are important to the patient, including breathlessness and walk distance. Apart from a dose related increase in tremor, other systemic effects were limited.
All three studies found that high dose inhaled beta-2-agonists produced relatively modest systemic effects in subjects with COPD. This probably reflects the fact that almost all subjects were taking beta-2-agonists on a regular basis and had developed tolerance to the systemic effects of an inhaled beta-2-agonist. Although the results from the three studies were generally reassuring, questions still remain about the balance between beneficial and adverse effects with high dose inhaled beta-2-agonists in subjects with COPD. The results may have been different if subjects had more severe disease, were exposed to higher doses of beta-2-agonists, had certain beta-2-adrenoceptor polymorphisms or were beta-2-agonist naive.
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