Airway subsensitivity with long acting beta(2) agonists - Is there cause for concern?
Airway subsensitivity with long acting beta(2) agonists - Is there cause for concern?
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DOI：
10.2165/00002018-199716050-00002
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发表时间：
1997-05-01
期刊：
影响因子：
4.2
通讯作者：
Lipworth, BJ
中科院分区：
文献类型：
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作者：
Lipworth, BJ
定期使用长效和短效 β(2) 激动剂进行治疗会导致对其支气管保护作用的耐受，尽管这种现象与长期哮喘控制的相关性仍不清楚。然而，两种长效 β(2) 激动剂（沙美特罗和福莫特罗）在诱导 β(2) 肾上腺素受体下调和敏感性降低的倾向方面似乎没有明显差异。与组胺和醋甲胆碱等直接刺激相比，运动和过敏原激发等间接刺激的敏感性降低程度似乎稍高。长效β(2)-激动剂治疗的功能拮抗作用的丧失是部分的，并且不能通过同时吸入皮质类固醇治疗来预防。然而，当两种药物长期同时服用时，吸入皮质类固醇本身的保护作用似乎与长效 β(2) 激动剂相加。对于无意中暴露于间接支气管收缩刺激（如过敏原或运动）的患者，对支气管保护的不敏感性可能具有临床相关性，表明不应服用长效 β(2) 激动剂与短效 β(2) 激动剂相比，长效 β(2) 激动剂更容易出现支气管扩张剂不敏感性，这可能反映了 β(2) 肾上腺素受体占用时间较长以及随之而来的下调。与长效 β(2) 激动剂的支气管保护作用一样，支气管扩张剂不敏感的发生只是部分的，并且无论患者是否同时服用吸入性皮质类固醇治疗，都会发生。长效β(2)激动剂本身的长期支气管扩张作用在每天两次的给药间隔内得以维持。然而，亚敏感性的发生与对重复剂量的短效β(2)-激动剂的迟钝反应有关，例如在急性哮喘发作的情况下。下调和不敏感的倾向存在相当大的个体间差异，这是由β(2)-肾上腺素受体的遗传多态性决定的。当前的国际哮喘管理指南建议，长效β(2)-激动剂只能定期用于吸入皮质类固醇治疗控制不佳的患者，因此添加长效β(2)-激动剂治疗是使用更高剂量β(2)-激动剂的替代方案。吸入皮质类固醇。然而，有人担心，在接受次优吸入性皮质类固醇治疗的患者中，常规长效 β(2) 激动剂可能会掩盖治疗不当的炎症。医生应意识到单效 β(2) 激动剂治疗引起的气道敏感性降低。应警告患者，他们可能必须使用高于常规剂量的短效 β(2) 激动剂来缓解急性支气管收缩，以克服这种影响。在接受最佳维持剂量吸入皮质类固醇的患者中，如果要根据需要使用长效 β(2) 激动剂，则使用福莫特罗似乎是合理的，因为它比沙美特罗起效更快。
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-acting beta(2)-agonists, salmeterol and formoterol, in their propensity to induce beta(2)-adrenoceptor downregulation 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 only be used on a regular basis in patients who are 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 lone-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.