Long-acting Inhaled β2-Agonists in Asthma Therapy Robert H. Moore, MD, Ayesha Khan, MD, Burton F. Dickey, MD  CHEST  Volume 113, Issue 4, Pages 1095-1108 (April 1998) DOI: 10.1378/chest.113.4.1095 Copyright © 1998 The American College of Chest Physicians Terms and Conditions

FIGURE 1 Milestones in the development of β2-agonist therapy of asthma. Beginning with the first documented use of a β2-agonist to treat respiratory illness (an ephedrine-containing herb in China 5,000 years ago), agonists of greater receptor selectivity and longer duration of action have been introduced successively. This progress has been coupled with the efficient delivery of β2-agonists by inhalation to increase safety, convenience, and efficacy. MDI = metered-dose inhaler. CHEST 1998 113, 1095-1108DOI: (10.1378/chest.113.4.1095) Copyright © 1998 The American College of Chest Physicians Terms and Conditions

FIGURE 2 Structures of representative β2-agonists. The generic catecholamine structure is illustrated at the top, and the structures of epinephrine and selected phenylethanolamine analogs are compared below. Increases in the bulk of N-substituents, as in isoproterenol, increase β-adrenoceptor activity, decrease α-adrenoceptor activity, and promote resistance to metabolism by monoamine oxidase (MAO); further increases in N-substituent bulk increase β2 selectivity. Rearrangement of the phenyl hydroxyls, as in metaproterenol (a resorcinol), or their substitution, as in albuterol (a saligenin), increases resistance to metabolism by catechol-O-methyltransferase (COMT) and by sulfation. Drugs with these modifications have extended durations of action and are orally active. Formoterol (a formanilide) and salmeterol (a saligenin) have highly extended N-substituents that make them β2-selective, hydrophobic, and along with the COMT-resistanee of the head groups, resistant to metabolism. CHEST 1998 113, 1095-1108DOI: (10.1378/chest.113.4.1095) Copyright © 1998 The American College of Chest Physicians Terms and Conditions

FIGURE 3 Pulmonary function vs time after treatment. Mean FEV1 in three treatment groups as a percentage of their predicted values. For the second treatment dose, placebo was given to the salmeterol and placebo groups, and albuterol was given to the albuterol group (reprinted with permission of Pearlman et al42). CHEST 1998 113, 1095-1108DOI: (10.1378/chest.113.4.1095) Copyright © 1998 The American College of Chest Physicians Terms and Conditions