Long-acting b 2 -agonists in maintenance treatment of asthma

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1 e 1 Long-acting b 2 -agonists in maintenance treatment of asthma The Lung Pharmacology Group, Göteborg University, Sweden Key words: β 2 -agonists, formoterol, salmeterol, asthma Summary. Many patients with asthma have symptoms despite treatment with inhaled corticosteroids. In these patients, the therapeutic alternatives are two; either increasing the dose of inhaled corticosteroids or adding a long-acting β 2 -agonist as regular treatment on top of the lower dose of inhaled corticosteroid. Greater improvements in lung function are achieved with the addition of a long-acting β 2 -agonist to ICS therapy, rather than doubling the dose of ICS. Two long-acting β 2 -agonists are available for asthma patients; Formoterol and salmeterol. These drugs have similar long duration of effect. However, as a result of their different chemical structures, there are some differences in their time to onset. Thus formoterol is causes more rapid bronchodilation as compared to salmeterol. Long-acting β 2 -agonists are also safe to use as regular treatment, and in fact reduce the frequency of exacerbation of asthma, and should therefore be considered as additions to ICS therapy for the management of moderate to severe asthma. Introduction β 2 -adrenergic receptor agonists are effective bronchodilators in asthma, and are important in the management of this disease. Short-acting β 2 - agonists are generally used for symptom relieve, and for the reversal of acute bronchoconstriction. Long-acting β 2 -agonists have been proved to be beneficial in the addition to inhaled corticosteroids for the long-term management of asthma. However, long-acting β 2 -agonists should be used only together with inhaled corticosteroids (ICS), which is the first-line management of asthma. If a paitnets asthma is not adequately controlled with ICS therapy alone, the addition of a long-acting β 2 - agonist can be considererd [4; 6; 15]. In fact, addition of a long-acting β 2 -agonist to ICS therapy leads to greater improvements in lung function than can be achieved through doubling the dose of ICS [7; 20; 29], and will also reduce the frequency of asthma exacerbations, making this an important treatment alternative. The long-acting β 2 -agonists, formoterol and salmeterol, are commonly used in the treatment of asthma. These agents have been shown to improve lung function [2; 3; 13; 27] for at least 12 hours. This article will discuss the pharmacology and the clinical profile of long-acting β 2 -agonists, and will also suggest some ways to use these drugs for Clinical effects of long-acting b 2 -agonists Inhlaed formoterol and salmeterol represent important advances in the management of asthma, in view of their effective bronchodilating effects and long-term improvement in lung function. Formoterol has been shown to provide a rapid bronchodilating effect, occurring within minutes after inhalation of the measured doses of 6-24µg ( µg delivered) [18], which is more rapid than the effect observed with salmeterol (50 µg measured). Despite the more rapid onset of action with formoterol, there apparent to be no difference in the duration of effect between these two agents up to 12 hours. Long-term large multi centre studies have confirmed the beneficial effects of both salmeterol and formoterol given as regular treatment (Figure 1 and 2) [7; 20]. Clearly, lung function was improved to a greater degree with the addition of either of the long-acting β 2 -agonsts compared with doubling the dose of of the inhaled glucocorticoid [7; 20]. In the later study, it was also shown that the addition of formoterol reduced exacerbations of asthma on top of a low dose of inhaled glucocorticoid. Furthermore, the same study showed that quadrupling the dose of the inhaled glucocorticoid also reduced exacerbation frequency. Therefore, overall, it seems that adding a long-acting β 2 - successful management of asthma. agonist to a lower dose of an inhaled glucocorticoid, Correspondence to be sent to: Dr J Lötvall, Göteborg University, Sahlgrenska University Hospital, Department of Respiratory Medicine and Allergology, Bruna Stråket 11, S Göteborg, Sweden. lotvallj@mailer.mednet.gu.se

2 e 2 D PEF (L/min) P< BDP 200µg + Salmeterol 50µg b.d. (n=220) BDP 500µg b.d. (n=206) Weeks of treatment Figure 1. Effect on lung function (PEF) of 6 months treatment with either a high dose of Beclomethasone Diproprionate (BDP 1000 micrograms daily) compared with a lower dose of BDP (400 micrograms daily) plus salmeterol (100 micrograms daily). Redrawn from Greening et al (1993). Adding the long-acting beta-2-agonist salmeterol to a low dose of inhaled glucocorticoid causes greater improvement in lung function than increasing the the dose of inhaled glucocorticoid only. FEV 1 (% pred) 90 Bud Fo * Bud Fo Bud 800 Bud BL may be a preferred approach. When the regular treatment with formoterol or salmeterol is directly compared, similar improvement in lung function is observed over a long observation period. Therefore, for such a therapeutic approach, there seems to be no difference in the clinical effects of these drugs Months of treatment Figure 2. Effects on lung function (FEV1 as % predicted) of two doses of budesonide (BUD; 200 or 800 micrograms daily) with or without the addition of the long acting beta-2-agonist formoterol (9 micrograms measured dose, given twice daily). Redrawn from Pauwels et al., 1997). Adding the longacting beta-2-agonist formoteorl to an inhaled glucocorticoid causes improvement in lung function. In this study, adding formoterol also reduced the frequency of asthma exacerbations. 12 Pharmacology of formoterol and salmeterol As mentioned, there are some differences in the onset-of-action between formoterol and salmeterol. The difference in the effects of these drugs may in part be explained by their different diffusion in the airway microenvironment. After inhalation of a drug, it is deposited on the surface of the airway epithelial lining fluid, where it is dissolved. Subsequently, these drugs diffuse through the

3 Long-acting β 2 -agonists in maintenance treatment of asthma e 3 20 FEV 1 (%) Fo18 Fo9 Fo * Sm50 0 Plac Time (min) Time (h) Figu Figure 3. Onset-of-action of formoterol ( micrograms delivered dose) on lung function (FEV1) up to 60 minutes, and the duration of effect up to 12h. Redrawn from Palmqvist et al., Formoterol has a rapid onset of action, in addition to the long duration of effect, which has suggested that this drug may be used as a reliever medication (Tattersfield et al, 2001). epithelium and the submucosa to reach the bronchial smooth muscle. Salmeterol and formoterol are quite lipophilic, and salmeterol is more lipophilic than formoterol. Therefore, these drugs, and especially salmeterol, with enter any cell membranes in the microenvironement. The portion of drug that is present in cell membranes with have a greater difficulty to rapidly pass through the tissues, and will therefore reach the smooth muscle at sufficient concentrations at a later time. This simple difference in chemistry may explain why formoterol has a more rapid onset of action than salmeterol. Formoterol is thus less lipophilic than salmeterol, and a portion of this drug will therefore stay outside cell membranes, and will thus diffuse to the smooth muscle rapidly [1]. The lipophilicity of both formoterol and salmeterol may explain their long duration of effect. Because high concentrations of these drugs remain in cell membranes around the smooth muscle for a prolonged time, these drugs are available for the β 2 - receptor and receptor activation for at least 12 h [1; 18]. It has also been argued that salmeterol may have an anchored binding within the β 2 -receptor, explaining its long duration of action [23]. Pharmacological studies using smooth muscle cell preparation from animals and humans have shown that formoterol has a greater maximal effect as compared with salmeterol (high pharmacological efficacy/ high intrinsic activity) [11]. Thus, strongly contracted smooth muscle will relax to a lesser extent with salmeterol compared with formoterol, showing that salmeterol is a partial agonist at the β 2 -receptor site in relation to formoterol [11]. Similarly, in asthma patients in vivo, high doses of formoterol protects more against methacholineinduced bronchoconstriction than salmeterol does [19]. Thus, increasing the pre-treatment dose of formoterol up to 120µg measured dose, caused almost a 5-doubling dose protection agaist methacholine, whereas the maximal effect of salmeterol was approximately 2.7 doubling doses. This argues that formoterol can be given to patients to reverse severe bronchoconstriction, and that additional effects can be observed by increasing the dose of formoterol. However, more systemic side effects will be observed in such a case. Salmeterol, on the other hand, had no clear dose-dependent effect, and should therefore be used only as a stable regular treatment, without titrating the dose up and down to any great extent. Theoretically, a partial agonist, such as salmeterol, can inhibit the effect of a full agonist [9]. However, clinical studies argues against any important inhibitory effect of salmeterol on the effect of salbutamol. Therefore, both salmeterol and formoterol seem to be safe in this regard. Formoterol - an alternative to relieve asthma symptoms? The rapid onset of effect of formoterol have suggested that this agent could be used as a reliever

4 e 4 medication in patients with asthma. This possibility is also supported by the high pharmacological efficacy of formoterol [19]. Formoterol has been approved in the European Union for as-needed treatment of asthma in addition to its use in maintenance therapy, based primarily on one study that has shown similar or superior effectiveness compared with the short-acting β 2 -agonists terbutaline [25]. Furthermroe, formoterol has a very rapid onset of action, similar to salbutamol [24]. Systemic effects of long-acting b 2 -agonists Although both short- and long-acting β 2 -agonists are very safe, systemic effects such as increase in heart rate and skeletal muscle tremor will develop when higher doses are given. Tolerance to b 2 -agonists The use of short-acting β 2 -agonists as regular treatment has been associated with the induction of tolerance in asthmatic patients. This is not very obvious when evaluating the bronchodilating effects of for example salbutamol before and after a period of regular treatment, whereas the side effects of this treatment shows pronounced tolerance (thus less side effects during regular treatment). Regular treatment with the long acting β 2 -agonists will also result in some reduced effects. The tolerance is not clear on bronchodilation, but more obvious regarding the protective effect on bronchial challenges [5; 14; 16; 21]. There is more evidence that regular long acting β 2 -agonist treatment causes a decrease in the protective effect of these drugs on provoked bronchoconstriction, induced by methacholine, exercise, or allergen. Importantly, however, regular formoterol will reduce the number of exacerbations of asthma in a large multi center study [20]. Combining inhaled glucocorticoids and longacting b 2 -agonists Both formoterol and salmeterol should be used in combination with ICS and studies have demonstrated a clear clinical benefit in terms of lung function for the combination compared with ICS alone. Therefore, two products combining longacting β 2 -agonists and inhaled glucocorticoids have become available (the combination of Fluticasone and Salmeterol; Seretide, and the combination of Budesonide and Formoterol; Symbicort). These products have been shown to be highly effective and have become very popular in the clinical use. It has been argued that these products will increase the compliance to asthma treatment, because they contain a symptom reliever (the β 2 -agonists) and a disease controller (the inhaled glucocorticoid). However, there is no scientific strong evidence for an increased compliance, but future studies will be able to prove or disprove such an hypothesis. Conclusions Long duration of effect and high tolerability allow formoterol and salmeterol to be considered as beneficial additions to inhaled glucocorticoids for the management of patients with asthma that are not fully controlled on a low or a moderate dose of an inhaled glucocorticoid. Formoterol has a rapid onset of action and a high pharmacological efficacy, and may therefore be used as a reliever medication. Increasing the dose of salmeterol over 50µg twice daily causes little additional benefit, and the dose of this drug should therefore be maintained constant. Furthermore, the introduction of single inhaler therapy which combines these two long-acting β 2 - agonists with highly effective inhaled glucocorticoids will give us new opportunities to treat asthma, that may improve compliance to treatment.

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