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The management of asthma has been the focus of intense research of late, owing to controversies regarding the safety of beta2 agonist use. Asthma is a chronic condition, which causes structural changes to the small airways, making efficient exhalation of air difficult. This results in symptoms such as: shortness of breath, crackling and wheezing, most commonly experienced during the night.
Although the treatments of asthma are not aimed at curing the disease, substantial progress has been made over the past few decades towards the development of 'on-demand' drugs, exemplified by short acting beta2 agonists, which alleviate the symptoms of sudden onset attacks. Whilst some believe that the benefits of beta2 agonist use outweigh the possible drawbacks, there is concern with regards to their side effect profile, in addition to other more fatal adverse events, experienced by patients. Particular worries are aimed towards the long term use of beta2 agonists, with theories that the body may eventually build up tolerance, being in circulation. More serious concerns surround long acting beta2 agonists, which are believed by some, to be responsible for an increase in the rates of morbidity and mortality, contrary to their supposed therapeutic effects.
Despite the lack of clinical evidence regarding the anti-inflammatory properties of long acting beta2 agonists, a shift in their role from 'on-demand' to maintenace drugs has been observed during the last few decades. In moderate-severe cases of asthma, their use alongside prophylactic treatments such as glucocorticosteroids is advised, and lack of adherence to the latter is likely to worsen the condition of such patients. This is mainly because beta2 agonists alone are not as effective in countering effects of the underlying pathology.
This essay discusses the plethora of opinions surrounding the role of beta2 agonists in asthma treatment. Here, a balanced view with regards to the pharmacokinetics of both, short, and long acting beta2 agonists will be presented, as well as possible side effects and the extent of damage caused by adverse events of prolonged use of this class of drug.
Asthma is an inflammatory disease, caused by a combination of environmental and genetic predisposing factors characterised by 'underlying' bronchial hyper-responsiveness (Allen JE et. al, 2009). For example, an asthmatic subject runs a greater risk of irritant receptor stimulation by smaller amounts of allergen, eliciting a more negative response on airway function and airflow, than in a normal subject (Quanjer P, 2010). Predisposing host factors bear great importance on genetic make up, atopy (IgE dependent asthma) and airway hyperresponsiveness; whilst environmental factors that contribute to asthma in an already predisposed individual largely revolve around exposure to allergens. Such allergens are substances which may not be noxious in themselves; however, due to over-expression of IgE antibodies and their binding to eosinophils, inflammatory mediators released from the degranulation of mast cells, lead to bronchoconstriction amongst other effects. (Ward J et. al, 2006) A list includes dust mite, exposure to pets, pollen, irritants in the work place, pollution and drugs such as NSAIDS.
The pathophysiological series of events that occur leads to variable and widespread narrowing of the airways, which may be reversed by treatment with various drugs, including beta2 agonists; the drug of interest in this study. It is worthy of note that such drugs can relieve symptoms and airway obstruction but cannot reverse the underlying airway hyperresponsiveness or abnormal function.
In order to understand the pathophysiology of asthma and the reversal mechanisms deployed by beta2 agonists, it is essential to examine the basics of airway structure and the different cell types in situ.
A normal airway has a very uniform structure, with outer C-shaped cartilages, lined with inner smooth muscle rings as illustrated by the diagram above (left). Deeper layers which contain blood vessels, carrying the required nutrients and oxygen, are lined with a distinct basement membrane which separates outer layers from the innermost layer of mucosa, which in turn consist of epithelial cells and mucus producing goblet cells. In chronic progression of the disease, airway remodelling occurs presenting various crucial changes in the structure:
A greatly thickened smooth muscle layer which elicits a thicker bronchial wall (Paganin F et. al, 1992). This justifies the greater bronchoconstriction following exposure to an allergen in the asthmatic patient: the larger the muscle mass, the greater the constriction, leading to higher airway obstruction. Not only is there hypertrophy of the smooth muscle layer, but hyperplasia of smooth muscle cells also contributes to the same outcome of reduced function.
There is an increase in collagen types III and IV (Beasley R et. al, 1989), just beneath the basement membrane, attributed to an increase in the number of myofibroblasts (Brewster EP et. al, 1990) which produces collagen for the basement membrane under normal circumstances and produces an excess in pathology. It is unclear whether the basement membrane itself is thickened or if there is merely an increase in the number of proteins lying beneath it; however, recent studies show that the submucosal layer is also significantly thickened in airway remodelling. (Wilson JW and Li X, 1997) and (Ward J et. al, 2006)
Epithelial cell damage can also be observed allowing for several inferences to be drawn: shedding of epithelial cells is likely to expose irritant receptors and cholinergic nerve endings, meaning greater sensitivity to irritants and allergens and quicker stimulation of the parasympathetic pathway. Consequently, this leads to rapid bronchonconstriction.
Mucus Hypersecretion- is attributed to submucosal gland hypertrophy and hyperplasia. The increased number and thickness of glands results in increased secretion of mucus, which clogs the airways and reduces airflow significantly (Zhou Zhu et.al, 1998).
Despite the several studies conducted on airway remodelling, scientists have been unable to establish a link between the degree of airway remodelling and the severity of disease (Lloyd CM and Robinson DS, 2007): what is certain is that airway remodelling contributes to airway hyperresponsiveness, which makes asthmatics more susceptible to bouts of bronchoconstriction and airflow obstruction with exposure to a bronchoconstrictor agonist. Researchers have argued that, due to the extensive involvement of eosinophils, chemokines and cytokines as part of the TH2 response, airway hyperresponsiveness should be viewed 'as an independent factor rather than an outcome of airway remodelling'(Lloyd CM and Robinson DS, 2007). In my opinion, due to the nature of airway remodelling, epithelial cell shedding and smooth muscle cell hypertrophy, there is an explicit link between one event leading to another: the exposure of irritant receptors leads to a reduced threshold for allergens to induce a parasympathetic pathway, or to activate mast cell degranulation. The hypertrophy of smooth muscles, leads to a greater level of constriction than in a normal subject, as a result of histamine and other inflammatory mediator action.
Beta2 agonists are a class of drugs that acts on the beta2-adrenergic receptors, which are found predominantly in skeletal muscle and in the airway. Their proficiency as the first line of symptomatic relief in asthma stems from their bronchodilating properties, as well as their inhibition of mast cell degranulation. These properties make them a class of drugs difficult to accurately classify: on one hand it relieves the acute symptoms of asthma, and on the other it can also interfere with the inflammatory pathway involved in the disease. Here, it important to appreciate that asthma attacks may present in two ways:
An acute, early asthmatic response: This is largely a type 1 hypersensitive reaction, which lasts for no longer than 5-15 minutes. Allergens, some of which are listed above, bind to IgE antibodies which are cross binded onto mast cells via their FC receptors. Binding leads to 'immediate degranulation' (Metzger WJ et. al, 1987) of mast cells, and the release of histamine, which leads to severe bronchonconstriction and subsequent airway obstruction. Relief of airflow obstruction can be brought about with inhalation of a beta two agonist, which relaxes airway smooth muscles causing bronchodilation. Mast cell degranulation may also be interrupted preventing the breakout of events that lead to an attack.
A late asthmatic response (takes place within 2-8 hours of the initial attack): This is largely a TH2 response, whereby the allergen is broken down by an antigen presenting cell such as a macrophage, and presented to a CD4+ T helper cell, which produced cytokines IL-4; IL-5; and IL-13 (Romagnani S, 1991). This in turn leads to a huge inflammatory response , attracting more macrophages, neutrophils and eosinophils, culminating in mucus hypersecretion, a mucus plug and an element of bronchoconstriction, the latter which can be alleviated with beta2 agonist use. The inflammatory nature of this type of attack, means that a prophylactic drug such as an oral corticosteroid is necessary to act as a background anti-inflammatory in conjunction with the on demand beta2 agonist treatment, given to relieve acute attacks.
Controversy surrounds the use of beta2 agonists, used as primary treatment for early asthmatic responses. This is not only down to the possibility of side effects that patients may endure, but also owing to the advocated hampering effects of long term beta2 agonist use on the airway. One theory hypothesises that prolonged use of beta2 agonists does more harm than good, since the pharmacokinetics of the drug are not concerned with curing the underlying pathology of asthma, but merely alleviating symptoms and returning lung function to normal on the short-term when required.
As previously mentioned, beta2 agonists are a difficult class of drugs to classify, since though in the main they are used as an on demand drug to alleviate the symptoms of an acute bout of asthma, some anti-inflammatory properties have recently been discovered of salmeterol, a long acting beta2 agonist. Although such properties have been proven in vitro, studies have been inconclusive in providing in vivo evidence of this phenomenon due to practical difficulties of exploring the pharmacological action of a drug on a live subject (Rees J, 1991).
The Beta2 receptor:
There is more than one type of beta receptor in the body, thus increasing the side effect profile of these bronchodilators. Manufacturing beta-adrenergic drugs targeting a specific type of receptor; in this case the beta-2-adrenergic receptors, has proven difficult, resulting in the increased likelihood of multi-receptor stimulation.
Salbutamol, a beta2 selective agonist, may therefore stimulate beta1 receptors in the heart, leading to cardiac arrhythmias which, albeit rare, may be fatal. Note the use of 'selective' rather than 'specific', where attempts have been made to alter the chemical structure of beta2 stimulants in order to make them more selective for their desired target receptor, amongst attempts to alter their duration of action, both which will be examined later. Complete specificity of the drug is yet to be achieved, which would probably result in the eradication of the drug's unwanted effects.
Beta-adrenergic receptors are metabotrophic, seven transmembrane G-protein linked receptors (Fraser CM et. al, 1993). When the beta2 agonist; whether it is an endogenous catecholamine, e.g. adrenaline, or an exogenous agent, e.g. salbutamol, binds the receptor, the guanosine diphosphate molecule on the the Gas subunit is exchanged with a guanosine triphosphate molecule leading to the dissociation of the Gas subunit. This triggers a sequence of events which activates the enzyme adenylate cyclase, which cleaves cAMP from adenosine triphosphate, more commonly known as ATP (Nelson H.S, 1995). Cyclic AMP is the secondary messenger responsible for amplifying the signal intracellularly, and bringing about the physiological response, which in the case of beta2 agonists, is bronchodilation and inhibition of mast cell degranulation.
Development of beta2 agonists:
The endogenous catecholamine, adrenaline, has been observed to provide relief from asthmatic symptoms and systemic anaphylaxis for over 90 years. However, many of its effects were achieved by stimulation of both alpha and beta receptors, bringing about undesirable effects, such as hyperglycaemia in already diabetic patients, as well as cardiac arrhythmias and muscular tremors. In a bid to improve selectivity of the drug, with emphasis on its bronchodilating properties, the side chain of adrenaline was extended, cleaving isoprenaline (aka isoproterenol), a short acting beta agonist; despite, not being entirely beta2 specific, one of it's main advantages over adrenaline, was the fact that it was only beta selective and did not stimulate alpha receptors, discounting fears over an asthma drug aggravating the state of hyperglycaemia in an already diabetic patient.
In order to bring about improved beta2 selectivity and exhibit a longer duration of action than that of isoprenaline, intermediate acting beta2 agonists were developed, albuterol; more commonly known as salbutamol, being the most notable example of which. This type of beta2 agonist has a duration of action between 4-6 hours. It is often used in moderate cases of asthma, which is not completely controlled by inhaled corticosteroids, necessitating use of the former more than once daily to alleviate the symptoms of the early asthmatic response. Altering the pharmacokinetic profile of the drug was achieved by 'changing the configuration of catechol groups on adjacent hydroxyl groups on carbons 3 and 4 on the benzene ring,' bringing about a longer duration of action (Nelson HS, 1993). Moreover, in order to achieve a degree of beta2 selectivity, a methyl group was added onto the nitrogenous end of the carbon chain.
Furthermore, intermediate acting beta2 agonists did not provide a solution to the late asthmatic response reaction, more commonly experienced in moderate-severe cases of asthma, nor were they useful for treatment of nocturnal asthma attacks. This led to the development of long acting beta2 agonists, with salmeterol and formetorol being the most notable examples. Although they both have a much lengthened duration of action, extending above twelve hours each, 'the mechanism by which they achieve this differs' (Anderson GP, 1993).
Whereas salmeterol side chains play a part in the selective binding to beta2 adrenergic receptors, formoterol works by entering the lipid bilayer of plasma membranes and, by getting broken down slowly, achieves a longer stimulation of the receptor. It is worthy of note that salmeterol is '10,000 times more lipophillic than salbutamol', (Johnson M et. al, 1993) as well as having a higher efficacy for beta2 receptors, possibly explaining the differences in duration of action between the two drugs.
With controversy surrounding their anti-inflammatory properties, due to the lack of clinical evidence to prove this, long acting beta2 agonists are well known for their potent bronchodilating capabilities, as well as their inhibition of inflammatory mediators. They also facilitate the beating of cilia in airways to clear mucus plugs, demonstrating beneficial steps necessary to treat both early and late asthmatic responses, as well as potentiating the anti-inflammatory role of glucocorticosteroids, which should be taken in conjunction for the more severe cases.
Potentiation of glucocorticosteroid action is demonstrated through, both mechanisms of action shared by the short/intermediate acting beta2 agonists, namely mast cells stabilistation, and others which are just unique to long acting beta2 agonists, for example inhibition of inflammatory mediators, such as chemokines. Salmeterol also 'inhibits the recruitment and infiltration of inflammatory cells' (Whelan CJ and Johnson M, 1992), as demonstrated in a guinea pig's lung. This again reiterates the possibility of anti-inflammatory effects, drawing light to another advantage of long-acting beta2 agonist use over their short-acting counterparts, other than the obvious convenience factor provided by their longer duration of action.
Above: a table showing the main beta2 agonists in use today (Nelson HS, 1993)
It is clear that the use of beta2 agonists in the treatment of asthma is, nowadays, imperative, paving the way for more effective symptom control. Without control of the disease, both, in terms of prophylaxis and in terms of an 'on demand' drug which may be resorted to, levels of severe morbidity and mortality are likely to have been increased. As is the case with most other chronic diseases, it is difficult to truly appreciate the detrimental effects of a disease which is latent in many cases, before triggering a brutal, acute attack.
If such attacks are not treated quickly and aggressively, they are capable of reducing air flow to dangerous extents. It is for these reasons and based on the evidence provided so far, that both, short-, and long-acting beta2 agonists seem to provide the solutions needed to deal with the serious immediate consequences of asthma, with the latter more generally preserved for long term management when used in conjunction with glucocorticosteroids. The role of long-acting beta2 agonists has now shifted from being an 'on-demand' drug, to a 'maintenance' drug; however, it is important that emphasise that they are not to be used as a substitute for steroids (Nelson HS, 1993).
The importance of patient adherence to prophylactic treatment should be acknowledged, bearing in mind issues discussed above which inadvertently lead to reluctance for sticking to the treatment plan. Moreover, the inconvenience of taking a number of drugs at different times, many of which may seem to have no beneficial effect to the average patient, may lead to lower rates of patient adherence to treatment. In the overall evaluation of the drug, it is important to bear in mind that beta2 agonists cannot be totally effective when used alone, raising issues which are to be explored in detail later.
On the contrary, are side effects of the drug serious enough to undermine the many benefits that the use of beta2 agonists can provide? The answer can be derived from clinical study figures showing the probability of patients suffering from theoretically proven side effects of this drug class. The main side effects are detailed below:
Muscular Tremors- as mentioned previously, beta receptors are present across the whole body, and unless the drug given is beta2 selective, there is a likelihood of stimulating receptors in an undesired target. Beta receptors in muscle are also beta2 receptors, and, despite the selectivity of the drug, stimulation of the beta2 receptors in muscle leads to tremors (Nizet TAC et.al, 2004). These may progress to muscular cramps.
Cardiac Adverse effects- Arrhythmias are the most serious concern; however, they are fortunately very rare. The more likely palpitations and sinus tachycardias (Teule GJ and Majid PA, 1980) may result from vasodilation of blood vessels, a direct effect of beta2 receptor stimulation across the body. The dilation of blood vessels reduces blood pressure upstream, leading to a reflex sympathetic reaction by the heart, to increase the number and force of beats, ultimately restoring blood pressure. Direct stimulation of cardiac beta receptors is now much less common, as they are mostly of the beta1 type, and unlike isoproterenol, most drugs are beta2 selective, as already mentioned. Some studies, however, have shown the presence of beta2 receptors in both 'the left ventricle and the right atrium of the heart' (Stiles GL et. al, 1983 ), suggesting that use of beta2 agonists can infact exhibit a direct chrontropic effect, other than that induced as a result of vasodilation.
Metabolic effects- Hyperglycaemia and hypokalaemia are two major metabolic effects; however, such events become less common with increased use of the drug because receptor sensitivity to the drug becomes reduced. This is ' the clinical correlate of beta2 receptor down-regulation' (Nelson HS, 1993). On the one hand, this is beneficial for reduction of such side effects, but on the other raises a doubt over the long term use of beta2 bronchodilators. There is reduced bronchodilation with use of beta2 agonists, due to this sub-sensitivity which develops over time (Weber RW, 1982), possibly lowering the long term effectiveness of the drug.
How common are the side effects?
In a qualitative study conducted in a clinical setting to examine the adverse effects of long-acting beta2 agonists, 158 patients were interviewed regarding the intensity and frequency of predictable pharmacological side effects suffered as a result of drug use by inhalation. The criteria for inclusion in the study included a consistent use of the drug for at least 3 months prior to the start of the investigation. Frequency was measured in terms of the number of days per month that the patient suffered from a certain side effect, and intensity was measured on an arbitrary scale from 1-10, with 10 being very significant and 1 being very insignificant. The patients were then interviewed 3 months after cessation of drug use, to observe whether side effects had disappeared, and to evaluate whether or not they were in fact caused by the drug, in cases where they had not resolved after cessation (Korsgaard J and Ledet M, 2008). The results of this study are shown below:
From the table above, it seems like a large proportion of patients had experienced the main side effects of beta2 agonists over the period of treatment with the drug. Based on such evidence, the side effects of beta2 agonists may be thought of as a common theme when weighing up treatment options. However, it is appreciated that this is a relatively small scale study, and so results may not be representative of the population and as is proven by a further larger scale clinical study, it shows a rather superficial representation of drug-related adverse events comparative to the latter. This larger clinical study shows that incidence of tremors due to use of long acting beta2 agonists is much reduced comparative to the small scale clinical study conducted by Korsgaard and Ledet, down from 34% to 2% (O'Byrne PB, 2005), with many other studies, including O'Byrne's data, showing a similar frequency for heart palpitations down from 34% again (Rabe KF et. al, 2006 and Scicchitano R et. al, 2004).
An explanation for such large differences between the two studies may be that such side effects occur normally in life, and that patients have linked them with drug use. This explanation seems to be backed up by results obtained 3 months after cessation of drug use, which show a 10% persistence of adverse events, demonstrating that perhaps such side effects were not caused by beta agonist drug treatment. In qualitative studies, which are based on subjective data, the incidence of adverse effects is made to seem higher by the patient, who recalls and links any negative event to exacerbations of their chronic disease.
Meanwhile, in quantitative studies, based on objective findings this cannot be the case, as results are statistically evaluated and conclusions drawn (Korsgaard J and Ledet M, 2008). My personal interpretation of the large discrepancy in findings, is based on a psychological phenomenon, known as top-down processing. In the table above, it is evident that a significant number of patients were aware of the possible side effects prior to the start of the investigation. This may have led to over-analysis of one's self, leading them into thinking that they had suffered a side effect, whereas in reality they may have not experienced any such altered sensations.
Overall, it seems more reasonable to rely on the findings of the many quantitative large scale studies conducted, rather than on the one isolated study which despite showing some element of truth, seems to over-exaggerate the significance of beta2 agonist related side effects. There is a portion of patients who are troubled by side effects, the majority of which are neither fatal nor life threatening. Here, dose reductions should be considered, where a strongly positive correlation between dose and intensity of side effects has been reported (Nizet TAC, 2004), rather than maintaining a state of laissez-faire regarding beta agonist drug treatment.
How significant are the side effects?
In context of other dangers linked to beta2 agonist use e.g. loss of protection from bronchoconstrictor stimuli and an increase in adverse events linked to use of long acting beta2 agonists, the side effects remain the least of the concerns, especially considering how rare and unfatal they may be. The use of beta2 agonists has lately come under a lot of scrutiny, raising controversy over the setbacks concerned with long term use in particular, with scientists divided over the benefits: adverse effects ratio of the drug. This has led to the conduction of various studies, many of which show contradicting evidence over the pros and cons of beta2 agonist use.
There are various important adverse consequences to regular use of beta2 agonist use, which have come under the spotlight of late. These include the loss of tolerance to the protective effect of use, against bronchoconstriction. To explore how this occurs, it is important to review the early asthmatic response of asthma. In a predisposed individual, with the airway changes of asthma, the bronchus is likely to be more responsive to smaller doses of stimuli, which in normal circumstances may not at all be noxious. Such allergens bind to allergen-specific IgE antibodies found on mast cells, leading to their degranulation, releasing inflammatory mediators, the most important of which is histamine. With inflammatory consequences, such as mucus accumulation, playing a less significant role in this type of asthma attack, histamine exerts its detrimental effects by causing smooth muscle constriction in the airways, leading to obstruction of airflow and a notable decrease in FEV1 (forced expiratory volume in one second) (Fuhlbrigge A et. al, 2006). Intermediate acting beta2 agonists, such as salbutamol are believed to alleviate the acute symptoms of the attack, by carrying out various mechanims, the most notable of which are smooth muscle relaxation which leads to bronchodilation, and inhibition of mast cell degranulation which prevents histamine from exerting it's harmful effects on airways.
Theoretically and to a large extent clinically, salbutamol has been seen to cause such beneficial effects, leading to it's widespread use as the main 'on-demand' drug for treating early asthamtic responses. Despite such success, concerns have been raised over the long term safety of the drug, with concerns that it may in fact make asthma worse, and increase mortality and morbidity rate. (Spitzer WO et. al, 1992) The logic behind such arguments stems from the idea of beta receptor sensitivity. In a study comparing the regular use of salbutamol for two weeks, with placebo, the detrimental effects of beta2 agonists are demonstrated. The findings point to an increased sensitivity of airways to allergens as well as loss of the initial bronchodilating benefits of salbutamol (Cockcroft DW et al, 1993). In essence, both such consequences are highly linked. The increased sensitivity to allergens, means greater binding to allergen specific IgE antibodies on mast cells, leading to greater histamine release, allowing for greater smooth muscle constriction.
Below: a graph comparing sensitivity to allergen following cessation of treatment, in patients treated with placebo and those treated with salbutamol, for two weeks.
With reference to the bar on the far right, one can observe a reduction in the PC20 dose following use of salbutamol i.e. the concentration of allergen needed to exert a 20% reduction in the FEV1 value of the patient, is much reduced, suggesting increased bronchial reactivity.
So, why do the bronchodilating properties of salbutamol eventually wear off? With allergen levels kept constant and allergen specific IgE antibody levels unlikely to change, the most likely explanation is that excessive use of salbutamol down-regulates beta2 receptors present on mast cells (Cockcroft DW et al, 1993), and so this renders them free to respond to any allergen the patient is likely to be exposed to, exerting it's effects on smooth muscle by the action of histamine and other mediators ultimately reducing FEV1 to dangerous levels.
Larsson et. al describes that in five out of nine patients treated with terbutaline, there was also a marked increase in allergen sensitivity following the regular use of the beta agonist, with only one patient showing the same effect for placebo treatment (Larsson et. al, 1992), again bringing light to the great controversy surrounding use of this drug class in asthma treatment. Doubters of such theories argue that more extensive clinical research is required, since conclusions and inferences largely drawn from in vitro studies may not be enough to count off beta2 agonists. A possible argument is that allergens used in the laboratory may not be naturally available in the air patients are exposed to in their daily living, perhaps reducing reliability of such findings.
On a similar note, the findings of Wong et. al contradict those from the two studies mentioned above, with regards to bronchial reactivity to allergens following cessation of a regularly used beta2 agonist. In this study, terbutaline was used alongside a glucocorticosteroid, budesonide, to examine whether allergen response would be increased, therefore causing a reduction in FEV1 levels, more in patients inhaling terbutaline alone or in patients using the beta agonist concurrently with the glucocorticosteroid. Although patients in the latter showed more positive therapeutic protection against allergen sensitivity, allergen sensitivity had not increased in patients using terbutaline alone, disregarding theories concerning the long term safety of beta2 agonists (Wong et al, 1994).
Whilst much confusion surrounds the issue of regular treatment using beta2 agonists, my view is that such supposed increases in bronchial allergen sensitivity occur following the cessation of use of the drug. In patients prescribed beta2 agonists as an on demand drug, the chances are they will continue to use them to manage their condition on a long-term basis. Without ignoring the serious consequence of beta2 receptor down-regulation resulting from the regular use of beta2 agonists, leading to exacerbations of disease, my point of view is that with controlled doses and tight management of drug use only in patients who suffer from moderate-severe asthma, the bronchodilating benefits should outweigh the drawbacks. Certainly, this view is backed by Hancox et. al's study, which is sceptical of negative theories regarding regular use of beta2 agonists since the asthma is well controlled throughout the course of terbutaline use (Hancox RJ et. al, 2000).
Serious concern has also arisen regarding the use of long acting beta2 agonists in asthma treatment. Whereas short/intermediate-acting beta2 agonists are used for early asthmatic response symptomatic relief, long acting beta2 agonists, such as salmeterol are used to alleviate symptoms of the late phase asthmatic response which follows. In addition to the standard bronchodilation, anti-inflammatory action of these drugs is also being advocated, based on in vitro studies (Twentyman O, 1991). Based on laboratory studies conducted on a human chopped lung, long-acting beta2 agonists have been shown to hamper the action of macrophages, as well as inhibiting the release of inflammatory mediators, in addition to boosting mucociliary beating (Lichtenstein LM and Margolis S 1968). Whilst the theory behind such mechanisms can be provided, clinical evidence of these occuring in reality is much more challenging to obtain, as it is hard to prove anything either related to or interfering with the normal physiology of the body, unless you can actually see it.
Long-acting beta2 agonists are also used for the convenience of their long duration of action, coupled with that they may be used to prevent nocturnal asthma attacks. The supposed anti-inflammatory actions of beta2 agonists means that they are prescribed to patients already taking oral corticosteroids. Since patients can obviously feel the long term symptomatic relief provided by long acting beta2 agonists, many of them choose to ignore taking their prophylactic treatment, which doesn't seem to be as immediately effective. This idea is put forward by those sceptical against the supposed adverse effects caused by long acting beta2 agonist use. The argument is that with the absence of conclusive evidence regarding the dangers of drugs like salmeterol and formeterol, it's safe to say that perhaps the lack of corticosteroid treatment is the main causative factor leading to increased adverse events, rather than regular treatment using long acting beta2 agonists (Rees J, 1991).
This is reiterated by a number of papers, namely by Martinez's, which examines a study comparing the adverse events suffered by patients on salbutamol with those on salmeterol. He observes that figures were almost three times as much for the latter group, where there was also one death. In his study, Martinez challenges the findings, which are not statistically significant, due to the lack of events occuring in either group, and raises the point that the study did not aim to examine whether or not patients using the long acting beta2 agonist had continued to use their oral corticosteroid treatment. The tendency is, of course, as mentioned previously, that patients prescribed salmeterol/formeterol would actually stop taking their prophylactic treatment, affecting the accuracy of results, raising the number of adverse events suffered by patients in such groups (Martinez F, 2005). This was not much of an issue for those prescribed salbutamol, because for those prescribed the long-acting beta2 agonist (salmeterol), the presumption was that their condition was more serious, requiring preventative treatment alongside the regular on-demand drug (Rees J, 1991).
On the other hand, a study comparing the adverse events experienced by patients taking a combination of inhaled corticosteroids and formeterol with those experienced by patients only prescribed the prophylactic treatment found that, whilst the asthma related adverse events were much decreased in the former group, the same could not be said about non-fatal all cause serious adverse events (Cates CJ et. al, 2009). This implies that, despite improvements in the management of asthma itself, the beta agonist was somehow causing setbacks, which were not generally related to asthma itself but more linked to the patients' overall health. The study expels theories, claiming that adverse events experienced by patients on regular treatment with long acting beta2 agonists are caused by their neglection of their preventative treatment, by designating a group of patients to concurrent treatment with both the beta agonist and the corticosteroid. Contrasting data gathered for this group with data gathered for patients soley on corticosteroids, demonstrates a net negative effect in the former, singling out the long acting beta2 agonist as the cause for such deficits.
Whilst small discrepancies in scientist findings are expected, the extent to which this particular subject has seen a plethora of contradicting views is reiterated by the interesting clash of views published by the same scientist (Cates CJ). A later study conducted by three scientists, one of which is Cates CJ, highlights the potential of long acting beta2 agonists (LABA) in the prevention of exacerbations, stating that for patients treated with inhaled corticosteroids, treatment with LABA is far more beneficial than treatment with anti-leukotrienes since it reduces the chance of exacerbations by one, for every thirty-eight patients (Ducharme FM et al, 2009).
It seems that this view is hugely backed by O'Connor GT, who dispels suspicions over the dangers of long acting beta2 agonist treatment in his review article, again reiterating early theories that adverse events experienced by patients were the result of poor patient adherence to their corticosteroid treatment. He states that the Salmeterol Multicentre Asthma Research Trial (SMART), which compared adverse events suffered by patients on salmeterol with those suffered by those on placebo, failed to examine whether or not patients were adhering to their corticosteroid treatment, meaning that adverse events experienced were probably caused by this rather than by the regular use of LABA (O'connor GT, 2006).
Bateman and his colleagues further scrutinize the SMART study: in their study, patients receiving both the corticosteroid and LABA did not suffer any more exacerbations than those treated with the former alone (Bateman et al, 2008). Although this seems to dispel fears over LABA dangers, it highlights how differences in sample types may result in copious contradictions. Whereas the SMART study examines outcomes in a realistic environment where patients may have neglected their prophylactic treatment, Bateman's study is based on a more idealised setting where patients were closely supervised and use of prophylactic treatment closely monitored (Weiss KB, 2008). LABA may not be harmful in itself; however, it is vital to consider a range of factors before prescribing treatment. Long-acting beta2 agonist use may not be harmful if used appropriately with a designated corticosteroid, but if there is no guarantee that the patient will adhere to their preventative treatment, then other considerations must be in place to prevent fatalities.
In summary, the dilemma regarding beta2 agonist use stems from balancing the pros and cons of this controversial drug class. For years, beta agonists have been used as effective on-demand reliever drugs, providing at the time of their discovery a breakthrough for asthma treatment. Mimicking the role of endogenous catecholamines, they bind to beta adrenoreceptors either on smooth muscle cells on the outer border of bronchi where they potentiate relaxation, or on mast cells where they prevent degranulation, hampering the release of inflammatory mediators, and providing quick relief against asthma attacks, whether they were early or late phase responses. The combination of both bronchodilating and non-bronchodilating properties make them efficacious when used concomitantly with oral/inhaled corticosteroids, which act as a preventative tool, as opposed to on demand reliever drugs as are the beta agonists.
Despite the clear benefits provided by beta agonists, the view is that a combination of side effects in addition to a number of potential adverse events goes strides in increasing the risk ratio of such a drug class perhaps rendering them unsafe for use. I am of the opinion that, particularly concerning the side effects, one should not rule out beta2 agonists based on such rare and distinctly non-fatal occurrences. Side effects are a common feature of many drugs, but for beta2 agonists in particular the only common side effect that seems to affect most of the using population is muscular tremor. Other side effects such as hyperglycaemia are relatively mild, whilst others such cardiac arrhythmias/ tachycardia are incredibly rare.
Whilst side effects seem the least of the worries surrounding beta2 agonist use, controversies surrounding adverse events experienced by patients chronically using beta2 agonists are not enough, in my opinion, to mask the many benefits provided by beta2 agonist treatment. Lack of conclusive evidence for the loss of protection against irritant stimuli with chronic use, or for the adverse events associated with long-term use of long acting beta2 agonists, demonstrates confusion over which most scientists and clinicians have based their criticism of the drug. In clinical science, with the life of patients at risk, one cannot be left to assume the consequences of taking grave decisions such as banning the use of beta2 agonist use, one which may prove fatal. As O'Connor states, it would be irresponsible to over-hype such supposed adversities since it would lead to use by patients of 'suboptimal therapy and noncompliance with regimens,' (O'Connor GT, 2006), leading to more serious consequences than if beta agonists were used.
In spite of this, one must not ignore warnings surrounding beta agonists completely. Albeit rare, adverse events do occur in some cases, and so certain measures must be implemented in order to prevent such negativities. It is a notable fact that despite regulations put in place to prevent over use of long acting beta agonists, doctors still over-prescribe them: there are more patients receiving long acting beta agonist treatment than there are patients diagnosed with moderate-severe asthma (Weiss KB, 2008), explaining the increasing number of adverse events in patients using this drug type. In light of Martinez's finding, I am fully supportive of the advocated treatment plan suggested in his review article. Glucocorticosteroids should be used as a background preventative measure. For mild-moderate cases of asthma, one should strictly use relievers such as leukotriene antagonists and sodium cromoglycate alongside the prophylactics. In progressive cases of the disease, i.e. moderate-severe cases, intermediate-acting beta-agonists should be introduced as relievers for the early asthmatic response. Should patients not respond to this treatment, one should dispel the following possibilities of: poor inhaler techniques and non-adherence to treatment, before which long acting beta2 agonists would become essential to asthma management (Martinez F, 2005).
Having said that, the dosage of long acting beta2 agonists must be tightly controlled and managed to prevent desensitisation of beta adrenoreceptors, which leads to exacerbations, and the initial prescription must be strictly limited to patients already on glucocorticosteroids. Despite some theories concerning LABA's anti-inflammatory properties, nothing concrete has been proven, and so they must be accompanied by a potent steroid, which would act as a prophylactic.
Patient adherence is crucial if their condition is to be well controlled. In my view, based on the literature and clinical experience, the rise in adverse events is more related to lack of patient adherence than to any pharmacological shortcoming of LABA. To ensure patient adherence, a mixed inhaler containing suitable doses of both glucocorticosteroid and indeed a long acting beta2 agonist has been advocated, combining maintenance and reliever therapies together and notably decreasing the risk and rate of asthma exacerbations (McKeage K and Keam SJ, 2009).
A possible therapeutic breakthrough is worthy of mention: treatment with beta2 antagonists is currently being experimented for its possible long term bronchoprotective properties. Just as in heart failure, short term beta antagonists would be detrimental, but considering the beta adrenoreceptor desensitisation that their agonist counterparts eventually cause, small doses of beta antagonist are in fact more beneficial in the long run (Lipworth BJ and Williamson PA, 209). For the moment, however, I think that whilst such a hypothesis is being investigated and clinically proven by a number of different sources, the mixed corticosteroid and LABA inhaler provides an ideal method for hand in hand bronchoprotection and alleviation of sudden asthma attacks, whilst minimising the risk of possible adverse events.
Until further progress is made in that field, I believe that beta agonists are safe and effective to use, within the reasonable guidelines in place, and without their use, the consequences of asthma and their mismanagement might be far-reaching amongst the population concerned, as well as the healthcare services.