FIGURE 20–2 Inflammatory mechanism of asthma. Airway epithelial cells exposed to activation stimuli, including allergens, viruses, and irritants, release cytokines that promote dendritic cell (DC) mobilization to draining lymph nodes, where they present antigens and thereby activate naive CD4 T cells. These T cells then induce B-cell class switching and maturation into plasma cells, which produce IgE. TH2 cells also migrate into the airway subepithelial mucosa, where they release inflammatory cytokines such as IL-5 and IL-13, which induce goblet cell metaplasia and mucus production, and act as a chemokine for eosinophils, mast cells, and basophils. Unbound IgE secreted by plasma cells binds the FcεRI receptor on submucosal mast cells and basophils and, when crosslinked by an antigen, induces the release of preformed mediators such as histamine and leukotrienes, as well as the release of inflammatory cytokines. (Modified and reproduced, with permission, from Fahy JV: Type 2 inflammation in asthma: Present in most, absent in many. Nat Rev Immunol 2015;15:57.) elsewhere (see Chapters 9 and 39). In this chapter, we review their pharmacology relevant to asthma.
Adrenoceptor agonists are mainstays in the treatment of asthma. Their binding to β-adrenergic receptors—abundant on airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP (Figure 20–3), thereby relaxing airway smooth muscle and inhibiting release of bronchoconstricting mediators from mast cells. They may also inhibit microvascular leakage and increase mucociliary transport. Adverse effects, especially of adrenoceptor agonists that activate β1 as well as β2 receptors, include tachycardia, skeletal muscle tremor, and decreases in serum potassium levels.
Sympathomimetic agents now widely used in the treatment of asthma include albuterol and other β2-selective agents (Figure 20–4). The place of epinephrine and isoproterenol has markedly diminished because of their effects on the rate and force of cardiac contraction (mediated mainly by β1 receptors).
In general, β-adrenoceptor agonists are best delivered by inhalation. This results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on the particle size, the pattern of breathing, and the geometry of the airways. Even with particles in the optimal size range of 2–5 μm, 80–90% of the total dose of aerosol is deposited in the mouth or pharynx. Particles under 1–2 μm remain suspended and may be exhaled. Bronchial deposition of an aerosol is increased by
FIGURE 20–3 Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by β-adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC), or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.
slow inhalation of a nearly full breath and by 5 or more seconds of breath-holding at the end of inspiration.