Continuing Education Column Inhaled Corticosteroids in Asthma Jong Myung Lee, MD Department of Internal Medicine, Kyungpook University School of Medicine E mail : jomlee@knu.ac.kr J Korean Med Assoc 2007; 50(10): 894-902 Asthma is characterized by airway inflammation, hyperresponsiveness, and remodeling, which are responsible for the variable airway obstruction and respiratory symptoms. Although a number of anti asthma drugs have been developed, none has succeeded in managing symptoms and underlying airway inflammation as effectively as corticosteroids. However, systemic effects of the drugs were a major obstacle to use them in asthma therapy. A significant breakthrough in asthma therapy occurred when corticosteroids became available as inhaled preparations, reducing the potential for systemic effects while achieving excellent therapeutic efficacy. The first inhaled corticosteroid (ICS) having such characteristics was beclomethasone 17, 21 dipropionate, which was introduced in the early 1970s. With growing information on their efficacy and the recognition of chronic inflammation as a fundamental component of asthma, ICSs have become the cornerstone of asthma therapy since the early 1990s. The potent anti inflammatory effect of ICSs seems to be resulted mainly from the reduction of the number and activation of inflammatory cells in the bronchial mucosa and through their inhibitory effects on the synthesis of various mediators and cytokines. In addition, the airway selectivity is thought to come from a high hepatic first pass inactivation rate of the drugs. A number of ICSs are currently on the market, and some drugs are available as the combination of an ICS and a long acting beta2 agonist in a single inhaler. The present paper comprises a short background behind the development of ICSs, their pharmacologic and clinical profiles, and the current positions in asthma treatment. Keywords : Inhaled corticosteroid; Asthma Abstract 894
Inhaled Corticosteroids in Asthma Figure 1. The mechanism by which inhaled drug particles deposit in the airway lumen 895
Lee JM Table 1. Lipophilicity (log P), receptor binding affinity (RBA), and oral bioavailability (F%) of inhaled corticosteroids Drug Iog P RBA F% Beclomethasone dipropionate 4.40 0.3 25 (?) Triamcinolone acetonide 2.53 0.5 23 Flunisolide 2.28 0.2 21 Budesonide 3.24 1.0 6 13 Fluticasone propionate 4.20 2.3 <1 Momethasone furoate 2.8 <1 Figure 2. Schematic overview of pharmacokinetics of inhaled steroid. Each steroid has a different rate of the hepatic first pass deactivation. 896
Inhaled Corticosteroids in Asthma Figure 3. Action mechanism of corticosteroid (Modified from Am J Respir Crit Care Med 1998; 157: 51-53): Glucocorticoids enter the cell and bind to a glucocorticoid receptor (GR), which is complexed with two molecules of the 90 kda heat shock protein (hsp90) and with p59 protein. Upon ligand binding, GR dissociates from hsp90 and translocates to the nucleus, where it binds as a dimer to a glucocorticoid response element (GRE) located within the promoter of target genes. GR can also interact as a monomer, via direct protein protein interaction, with transcription factors such as NFkB and AP 1, activated by cytokines and other pro inflammatory stimuli. The resulting mutual repression prevents both GR and the other transcription factors from binding to theirrespective DNA response elements (RE). 897
Lee JM Table 2. Estimated equipotent daily doses ( g) of inhaled steroids for adults Drug Low dose Medium dose High dose Beclomethasone dipropionate 200 500 >500 1,000 >1,000 2,000 Budesonide 200 400 >400 800 >800 1,600 Ciclesonide 80 160 >160 320 >320 1,280 Flunisolide 500 1,000 >1,000 2,000 >2000 Fluticasone 100 250 >250 500 >500 1,000 Mometasone furoate 200 400 >400 800 >800 1,200 Triamcinolone acetonide 400 1,000 >1,000 2,000 >2,000 898
Inhaled Corticosteroids in Asthma Figure 4. Biological effects of corticosteroids on inflammatory cells and structural cells in the airways. 899
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Lee JM Peer Reviewer Commentary 902