Page 361 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 347

classified in a more severe category if their history indicates they thought to attract and activate eosinophils, stimulate IgE produc-
are prone to frequent or severe exacerbations (“exacerbation- tion by B lymphocytes, and stimulate mucus production by bron-
prone” versus “exacerbation-resistant”). chial epithelial cells. It is not clear whether lymphocytes or mast
Until recently, the entire range of asthma severity was regarded cells in the airway mucosa are the primary source of the mediators
as eminently treatable, because treatments for quick relief of responsible for the late inflammatory response, but the benefits
symptoms of acute bronchoconstriction (“short-term reliev- of corticosteroid therapy are attributed to their inhibition of the
ers”) and treatments for reduction in symptoms and prevention production of proinflammatory cytokines in the airways and of the
of attacks, especially using inhaled corticosteroids (“long-term response of airway epithelial cells to them.
controllers”), had been shown to be effective in many large, A major limitation to this classic conception of asthma as an
well-designed randomized clinical trials, pragmatic clinical trials, allergic disease is that it applies only to a subgroup of patients with
observational studies, and evidence-based reviews. The persistence asthma, those with evidence of allergy. Allergic asthma accounts
of high medical costs for asthma, driven largely by the costs of for a great proportion of asthma that develops in childhood, but
emergency department and hospital treatment of asthma exac- a smaller proportion of adult-onset asthma. This is implied by the
erbations, was thus believed to reflect underutilization of the use of modifying terms to describe asthma in different patients, such
treatments available. Reconsideration of this view was driven by as “extrinsic” versus “intrinsic,” “aspirin-sensitive,” “adult-onset,”
recognition that the term “asthma” is applied to a variety of differ- “postviral,” and “obesity-related.” The allergen challenge model
ent disorders sharing common clinical features but fundamentally fails to account for all the features of the condition even in allergic
different pathophysiologic mechanisms. Attention has thus turned asthmatics. Many pathways and mechanisms other than produc-
to the possibility that there are different asthma phenotypes, some tion of IgE and activation of mast cell degranulation are involved in
of which are less responsive to the current mainstays of asthma asthma’s pathogenesis (Figure 20–2), and most asthma attacks are
controller therapy. The current view of asthma treatment may not triggered by inhalation of allergens, but instead by viral respira-
be summarized as follows: that the treatments commonly used tory infections. Asthmatic bronchospasm can also be provoked by
at present are indeed effective for the most common form of the nonallergenic stimuli such as distilled water aerosol, exercise, cold
disease, as it presents in children and young adults with allergic air, cigarette smoke, and sulfur dioxide. This tendency to develop
asthma, but that there are other phenotypes of asthma for which bronchospasm on encountering nonallergenic stimuli—assessed by
these therapies are less effective, and that represent an unmet med- measuring the fall in maximal expiratory flow provoked by inhal-
ical need. Accordingly, this chapter first reviews the pathophysiol- ing serially increasing concentrations of the aerosolized cholinergic
ogy of the most common form of asthma (classic allergic asthma) agonist methacholine—is described as “bronchial hyperreactivity.”
and the basic pharmacology of the agents used in its treatment. It is considered fundamental to asthma’s pathogenesis because it is
This is followed by a discussion of different forms or phenotypes nearly ubiquitous in patients with asthma, and its degree roughly
of asthma and the efforts to develop effective therapies for them. correlates with the clinical severity of the disease.
The mechanisms underlying bronchial hyperreactivity are
incompletely understood but appear to be related to inflammation
PATHOGENESIS OF ASTHMA of the airway mucosa. The anti-inflammatory activity of inhaled
corticosteroid (ICS) treatment is credited with preventing the
Classic allergic asthma is regarded as mediated by immune globulin increase in bronchial reactivity associated with the late asthmatic
(IgE), produced in response to exposure to foreign proteins, like response (Figure 20–1).
those from house dust mite, cockroach, animal danders, molds, and Whatever the mechanisms responsible for bronchial hyperreac-
pollens. These qualify as allergens on the basis of their induction tivity, bronchoconstriction itself results not simply from the direct
of IgE antibody production in people exposed to them. The ten- effect of the released mediators but also from their activation of
dency to produce IgE is at least in part genetically determined, and neural pathways. This is suggested by the effectiveness of musca-
asthma clusters with other allergic diseases (allergic rhinitis, eczema, rinic receptor antagonists, which have no direct effect on smooth
food allergy) in family groups. Once produced, IgE binds to high- muscle contractility, in inhibiting the bronchoconstriction caused
affinity receptors (FCεR-1) on mast cells in the airway mucosa by inhalation of allergens and airway irritants.
(Figure 20–1), so that re-exposure to the allergen triggers the release The hypothesis suggested by this conceptual model—that
of mediators stored in the mast cells’ granules and the synthesis and asthmatic bronchospasm results from a combination of release of
release of other mediators. The histamine, tryptase, leukotrienes C mediators and an exaggeration of responsiveness to their effects—
4
and D , and prostaglandin D released cause the smooth muscle predicts that drugs with different modes of action may effectively
4
2
contraction and vascular leakage responsible for the acute bron- treat asthma. The bronchospasm provoked by exposure to allergens
choconstriction of the “early asthmatic response.” This response is might be reversed or prevented, for example, by drugs that reduce
often followed in 3–6 hours by a second, more sustained phase of the amount of IgE bound to mast cells (anti-IgE antibody), reduce
bronchoconstriction, the “late asthmatic response,” associated with the number and activity of eosinophils in the airway mucosa (anti-
an influx of inflammatory cells into the bronchial mucosa and with IL-5 antibody), block the receptor for IL-4 and IL-13 (anti-IL-4α
an increase in bronchial reactivity. This late response is thought receptor antibody), prevent mast cell degranulation (cromolyn or
to be due to cytokines characteristically produced by T2 lympho- nedocromil, sympathomimetic agents, calcium channel blockers),
cytes, especially interleukins (IL) 5, 9, and 13. These cytokines are block the action of the products released (antihistamines and