Lipworth B J
Department of Clinical Pharmacology, Ninewells Hospital & Medical School, Dundee, Scotland.
Drug Saf. 1997 May;16(5):295-308. doi: 10.2165/00002018-199716050-00002.
Regular treatment with both long- and short-acting beta 2-agonists results in tolerance to their bronchoprotective effects, although the relevance of this phenomenon in terms of long term asthma control remains unclear. However, there appears to be no appreciable difference between the 2 long-active beta 2-agonists, salmeterol and formoterol, in their propensity to induce beta 2-adrenoceptor down-regulation and subsensitivity. The degree of subsensitivity appears to be somewhat greater with indirect stimuli such as exercise and allergen challenge, compared with direct stimuli such as histamine and methacholine. This loss of functional antagonism with long-acting beta 2-agonist therapy is partial and is not prevented by concomitant inhaled corticosteroid therapy. However, the protective effects of inhaled corticosteroids on their own appear to be additive to those of long-acting beta 2-agonists when both drugs are concomitantly administered in the long term. The subsensitivity to bronchoprotection may be of clinical relevance in terms of patients who are inadvertently exposed to indirect bronchoconstrictor stimuli such as allergens or exercise, suggesting that long-acting beta 2-agonists should not be taken on a regular basis for this particular indication. There is a greater tendency for bronchodilator subsensitivity to develop with longer-acting, than with shorter-acting beta 2-agonists, and this may reflect the longer duration of beta 2-adrenoceptor occupancy and consequent downregulation. As with the bronchoprotective effects of long-acting beta 2-agonists, the development of bronchodilator subsensitivity is only partial and occurs regardless of whether patients are taking concomitant inhaled corticosteroid therapy. The long-term bronchodilator action of the long-acting beta 2-agonist itself is maintained within the twice daily administration interval. However, subsensitivity occurs in relation to a blunted response to repeated doses of short-acting beta 2-agonists, as in the setting of an acute asthma attack. There is considerable inter-individual variability in the propensity for downregulation and subsensitivity, which is determined by genetic polymorphism of the beta 2-adrenoceptor. Current international asthma management guidelines suggest that long-acting beta 2-agonists should be used on a regular basis in patients who ware inadequately controlled on inhaled corticosteroid therapy, so the addition of long-acting beta 2-agonist therapy is an alternative to using higher doses of inhaled corticosteroids. There are, however, concerns that regular long-acting beta 2-agonists might result in masking of inadequately treated inflammation in patients receiving suboptimal inhaled corticosteroid therapy. Physicians should be aware of the airway subsensitivity that develops with long-acting beta 2-agonist therapy, and patients should be warned that they may have to use higher than conventional dosages of short-acting beta 2-agonists to relieve acute bronchoconstriction in order to overcome this effect. In patients receiving an optimised maintenance dose of inhaled corticosteroid, if long-acting beta 2-agonists are to be used on an as required basis, it would seem rational to use formoterol for this purpose, due to its faster onset of action than salmeterol.
长期和短期使用β2受体激动剂进行常规治疗会导致对其支气管保护作用产生耐受性，不过这一现象在长期哮喘控制方面的相关性仍不明确。然而，两种长效β2受体激动剂沙美特罗和福莫特罗在诱导β2肾上腺素能受体下调和敏感性降低的倾向方面似乎没有明显差异。与组胺和乙酰甲胆碱等直接刺激相比，运动和过敏原激发等间接刺激导致的敏感性降低程度似乎更大。长效β2受体激动剂治疗导致的功能性拮抗作用丧失是部分性的，吸入糖皮质激素联合治疗并不能预防这种情况。然而，长期同时使用这两种药物时，吸入糖皮质激素自身的保护作用似乎与长效β2受体激动剂的保护作用具有相加性。对于意外接触过敏原或运动等间接支气管收缩刺激的患者，支气管保护作用的敏感性降低可能具有临床相关性，这表明针对这一特定适应证，长效β2受体激动剂不应常规使用。长效β2受体激动剂比短效β2受体激动剂更容易出现支气管扩张剂敏感性降低，这可能反映了β2肾上腺素能受体占据时间更长以及随之而来的下调。与长效β2受体激动剂的支气管保护作用一样，支气管扩张剂敏感性降低的发生也是部分性的，且无论患者是否同时接受吸入糖皮质激素治疗都会出现。长效β2受体激动剂本身的长期支气管扩张作用在每日两次给药间隔内得以维持。然而，在急性哮喘发作等情况下，对重复剂量短效β2受体激动剂的反应减弱会出现敏感性降低。β2肾上腺素能受体基因多态性决定了下调和敏感性降低的倾向存在相当大的个体差异。当前国际哮喘管理指南建议，对于吸入糖皮质激素治疗控制不佳的患者应常规使用长效β2受体激动剂，因此添加长效β2受体激动剂治疗是使用更高剂量吸入糖皮质激素的一种替代方法。然而，有人担心常规使用长效β2受体激动剂可能会掩盖接受次优吸入糖皮质激素治疗患者未得到充分治疗的炎症。医生应意识到长效β2受体激动剂治疗会导致气道敏感性降低，并且应告知患者，为了克服这种影响，他们可能需要使用高于常规剂量的短效β2受体激动剂来缓解急性支气管收缩。在接受优化维持剂量吸入糖皮质激素的患者中，如果要根据需要使用长效β2受体激动剂，由于福莫特罗的起效速度比沙美特罗快，因此似乎有理由为此目的使用福莫特罗。
