Diana Silva1,2, Tiago Jacinto3,4 [email protected] 1Serviço de Imunoalergologia, Centro Hospitalar São João, EPE, Porto, Portugal. 2Laboratory of Immunology, Basic and Clinical Immunology Unit, Faculty of Medicine, University of Porto, Porto, Portugal. 3Allergology, CUF Porto Hospital and Instituto, Porto, Portugal. 4CINTESIS – Center for Research in Health Technologies and Information Systems, Faculty of Medicine, University of Porto, Porto, Portugal. Inhaled β2-agonists in asthma management: an evolving story Cite as: Silva D, Jacinto T. Inhaled β2-agonists in asthma Landmark papers in respiratory medicine management: an evolving story. Breathe 2016; 12: 379–381. From the beginning… was inadequate for control of nocturnal symptoms and limited their use for maintenance treatment [1]. Sympathomimetic agents have been known in For these reasons, long-acting β2-agonists (LABA) Chinese medicine for at least 5000 years as a drug were developed in the 1980s. to treat disorders of respiratory tract; however, they With duration of action that reached 12 h, were introduced to western medicine mainly in the formoterol and salmeterol were considered for beginning of the 20th century [1]. long-term treatment, particularly among patients Adrenaline and isoproterenol were the first who did not achieve control under regular inhaled to be introduced, although, being unselective corticosteroids. The mechanisms for their long β-agonists, they were prone to significant side- duration have been debated, and it seems that effects. Through the years, new formulations and different physicochemical properties in contact routes of administration of these drugs, namely with the cell membrane and with the β2-receptor the inhaled route, were associated with more might explain their characteristics. According to bronchodilation effect and fewer side-effects than Anderson et al. [4], the lipophilicity of formoterol the oral or subcutaneous ones [2].The discovery by and salmeterol allows them to enter and be stored Lands et al. [3] that β-receptors can be subdivided in the cell membranes, promoting a depot release of in β1, located in the heart and intestinal smooth the drug: the “plasmalemma diffusion microkinetic muscle, and β2, located in bronchial, vascular and model”. Regarding formoterol, as it is moderately uterine smooth muscle, directed the research to lipophilic, some molecules are kept in the aqueous new selective β2-agonists drugs. phase outside the cells and interact immediately In the 1960s, fenoterol, salbutamol and with the β2-receptor, which explains its faster onset terbutaline were developed [1, 2]. These β2- of action [1]. The use of SABA in comparison with selective agonists were more tolerable and LABA for maintenance treatment started to be efficient. Therefore, they were easily accepted, and compared both for efficacy and safety. salbutamol became the most widely used short- The Serevent Nationwide Surveillance (SNS) acting β2-agonist (SABA) for the relief of asthma study [5] compared the use of salmeterol (50 µg, symptoms [1, 2]. However, one major limitation of twice daily) with that of salbutamol (200 µg, four these drugs was their short duration of action, which times per day) in a large randomised double-blind @ ERSpublications The history and the future of inhaled β2-agonists in asthma management http://ow.ly/s1s4305l4k4 http://doi.org/10.1183/20734735.017116 Breathe | December 2016 | Volume 12 | No 4 379 Inhaled β2-agonists in asthma management clinical trial in parallel groups over 16 weeks, which and induced tolerance to their bronchoprotective recruited asthma patients from general practices effect, and dysrhythmias, might be the most likely throughout UK (3516 general practitioners). associated mechanism, particularly if drugs were This study reported results from more than used at high doses. Recently, there has been an 25 000 patients with asthma and showed that association of β2-adrenoreceptor polymorphisms the overall asthma control, assessed by use of with a poor response to β2-agonists, which might oral corticosteroids and need for a relief inhaler, increase the need for higher doses to reach efficacy was better with salmeterol than with salbutamol. [1, 2] and therefore be associated with serious Similarly, general practitioners’ classification adverse effects. of severity significantly decreased more in the Apprehension over LABA use in maintenance salmeterol than in the salbutamol group. Overall, treatment for asthma started soon after their almost 70% of the individuals were already on launch, considering the previous history with SABA inhaled corticosteroid maintenance treatment. and the possibility that long-term bronchodilators Regarding formoterol, the FACET could mask deteriorating asthma and be associated (Formoterol and Corticosteroids Establishing with severe exacerbations. The SNS study reported Therapy) study [6] was also a multicentre an increase of asthma-related deaths in patients randomised double-blind clinical trial in parallel treated with salmeterol compared with salbutamol groups and compared the association of formoterol [5]. During the study, 12 deaths occurred due to to budesonide, at 100- or 400-µg dosages, versus respiratory and asthma-related causes, 7.1 per budesonide alone, at 100- or 400-µg dosages. 10 000 patients in salmeterol group versus 2.4 per Addition of formoterol to inhaled corticosteroid 10 000 patients in the salbutamol group. As the treatment lead to an improvement of asthma- number of events was very small, this difference symptom scores and lung function, and reduced did not reach statistical significance. These reports the need for asthma medication, and reduced increased the discussion in the US Food and Drug severe and mild exacerbations; the individuals under Administration (FDA) regarding safety of LABA. the combination of a β2-agonist and a high dose of In 2003, a black box warning was added to inhaled corticosteroids had the greatest reduction. the drug labels based also in the data from the The use of combination treatment has now become Salmeterol Multi-Center Asthma Research Trial one of the cornerstones of asthma management. (SMART) [8]. SMART was a multicentre, randomised, Nevertheless, some apprehension regarding safety double-blind, parallel-group, placebo-controlled appeared due to the increase in asthma-related trial of 28 weeks duration involving 26 355 mortality during the evolution of β2 agonists. asthma patients in which it was compared the usual maintenance treatment for asthma to the association of salmeterol (50 µg twice daily) to their usual therapy. Baseline use of inhaled corticosteroids Safety of inhaled β2-agonists: controversies regarding a in the population was 47%. This study showed an increase in the respiratory-related and asthma- black box related deaths in the salmeterol group, particularly in the African-American individuals. In order to assess Asthma-related deaths showed two peaks, in the the risk and benefits of LABA, and to provide the 1950s and 1970s. The mortality increase in the scientific community with a clarification, the FDA 1950s occurred shortly after the introduction of began considering results from additional studies. a high dose of inhaled isoproterenol. This peak A large, comprehensive meta-analysis of asthma subsided after publicity against overuse of this drug clinical trials was conducted in 2010 by the FDA and and the appearance of selective β2-agonists [1]. included 110 trials with more than 60 000 patients. However, a second peak of asthma-related deaths Despite SMART having an important weight in these began in the late 1970s, reported by a matched results due to its larger sample, the pooled data case–control study from New Zealand with 117 showed an increase risk of asthma-related events patients [7]. In this study, the relative risk of asthma with LABA in comparison with SABA, particularly if deaths was 1.55 (95% CI 1.04–2.33) among those the use of inhaled corticosteroids in combination using fenoterol in a metered-dose inhaler. was not mandatory. New safety requirements were Concerns increased about the regular use created based on these results [9]: of SABA for asthma treatment, and several studies started to show an association of chronic ●● contraindication of single use of LABA use of fenoterol with asthma exacerbations, ●● step-down treatment with LABA after control a significant decline in lung function and an is achieved increase in airway hyperresponsiveness [1]. The ●● in those under control with low and medium multiple mechanisms that might have explained doses of inhaled corticosteroids, LABA should these results were nicely summarised by Anne not be added Tattersfield [2]. However, tachyphylaxis resulting ●● prefer fixed-dose combinations of LABA and in reduced bronchodilator sensitivity to β-agonists inhaled corticosteroid to increase compliance 380 Breathe | December 2016 | Volume 12 | No 4 Inhaled β2-agonists in asthma management Furthermore, the FDA requested new large of asthma [12]. The once-a-day posology might prospective trials to evaluate the safety of increase adherence in long-term treatment of combining LABA with inhaled corticosteroids. These asthma. However, superiority to twice-a-day LABA studies have recently been released for salmeterol still cannot be concluded with the currently available (AUSTRI) [10] and formoterol [11], though results evidence [12]. In addition, no serious adverse effects seem reassuring, with no significantly higher risk have been observed,