Handley D
Sepracor, Inc., Marlborough, MA 01752, USA.
J Allergy Clin Immunol. 1999 Aug;104(2 Pt 2):S69-76. doi: 10.1016/s0091-6749(99)70276-9.
Beta(2 ) agonists were designed to emulate the bronchodilation and mast cell suppression effects of human adrenaline, an endogenous neuromediator. Endogenous adrenaline is produced exclusively as the single enantiomer or isomer, (R)-adrenaline, although all selective beta(2 ) agonists are marketed as racemic drugs, composed of a precise 50:50 mixture of R and S isomers. Isomers are compounds that are nonsuperimposable mirror images. The R isomers of beta agonists, essentially all congeners of (R)-adrenaline, exhibit the observed bronchodilation and clinical benefit of the racemate. The S isomers of the racemic beta agonists are devoid of clinical benefit, are assumed to be benign, and have not been studied until recently. In contradistinction to their assumed benign status, extensive studies with (S)-albuterol have shown that it opposes the bronchodilation effects of (R)-albuterol (levalbuterol), may be proinflammatory, and exhibits the potential to exacerbate airway reactivity to a variety of spasmogens by enhancing contractile responses. Clinically, (S)-albuterol can increase airway reactivity and, because of its slow metabolism, exists in higher and prolonged plasma concentrations than levalbuterol. The sustained presence of (S)-albuterol may help to explain why racemic beta agonists have not demonstrated a significant clinical anti-inflammatory potential. Furthermore, the adverse effects (S)-albuterol may contribute to paradoxic bronchospasm and the occurrence of severe reagenic-like reactions seen with racemic albuterol. These adverse effects of (S)-albuterol are completely avoided with single isomer version of (R)-albuterol (levalbuterol). The removal of (S)-albuterol increased the clinical potency of levalbuterol, such that bronchodilator efficacy is achieved at one-fourth the dose of racemic albuterol, but with marked reduction in side effects. Levalbuterol, a third generation beta agonist, retains the clinical benefit of racemic albuterol without the proinflammatory and potentially detrimental effects of (S)-albuterol.
β₂激动剂旨在模拟内源性神经介质人肾上腺素的支气管扩张和肥大细胞抑制作用。内源性肾上腺素仅作为单一对映体或异构体（R）-肾上腺素产生，尽管所有选择性β₂激动剂都作为外消旋药物上市，由R和S异构体精确的50:50混合物组成。异构体是不可重叠的镜像化合物。β激动剂的R异构体，基本上都是（R）-肾上腺素的同系物，表现出观察到的外消旋体的支气管扩张作用和临床益处。外消旋β激动剂的S异构体没有临床益处，被认为是良性的，直到最近才进行研究。与其假定的良性状态相反，对（S）-沙丁胺醇的广泛研究表明，它会对抗（R）-沙丁胺醇（左沙丁胺醇）的支气管扩张作用，可能具有促炎作用，并表现出通过增强收缩反应而加剧气道对多种致痉剂反应性的潜力。临床上，（S）-沙丁胺醇可增加气道反应性，并且由于其代谢缓慢，其血浆浓度比左沙丁胺醇更高且持续时间更长。（S）-沙丁胺醇的持续存在可能有助于解释为什么外消旋β激动剂没有显示出显著的临床抗炎潜力。此外，（S）-沙丁胺醇的不良反应可能导致反常性支气管痉挛以及外消旋沙丁胺醇所见的严重类过敏反应的发生。使用单一异构体形式的（R）-沙丁胺醇（左沙丁胺醇）可完全避免（S）-沙丁胺醇的这些不良反应。去除（S）-沙丁胺醇提高了左沙丁胺醇的临床效力，使得在四分之一剂量的外消旋沙丁胺醇时即可达到支气管扩张疗效，但副作用明显减少。左沙丁胺醇作为第三代β激动剂，保留了外消旋沙丁胺醇的临床益处，而没有（S）-沙丁胺醇的促炎和潜在有害作用。
