Page 369 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 355

They do not relax airway smooth muscle directly but reduce A special problem caused by inhaled topical corticosteroids
bronchial hyperreactivity and reduce the frequency of asthma is the occurrence of oropharyngeal candidiasis. This is easily
exacerbations if taken regularly. Their effect on airway obstruc- treated with topical clotrimazole, and the risk of this com-
tion is due in part to their contraction of engorged vessels in plication can be reduced by having patients gargle water and
the bronchial mucosa and their potentiation of the effects of expectorate after each inhaled treatment. Ciclesonide, a prodrug
β-receptor agonists, but their most important action is inhibi- activated by bronchial esterases, is comparably effective to other
tion of the infiltration of asthmatic airways by lymphocytes, inhaled corticosteroids and is associated with less frequent can-
eosinophils, and mast cells. The remarkable benefits of systemic didiasis. Hoarseness can also result from a direct local effect of
glucocorticoid treatment for patients with severe asthma have ICS on the vocal cords. Although a majority of the inhaled dose
been noted since the 1950s. So too have been its numerous is deposited in the oropharynx and swallowed, inhaled cortico-
and severe toxicities, especially when given repeatedly, as is steroids are subject to first-pass metabolism in the liver and thus
necessary for a chronic disease like asthma. The development of are remarkably free of other short-term complications in adults.
beclomethasone in the 1970s as a topically active glucocorticoid Nonetheless, chronic use may increase the risks of osteoporosis
preparation that could be taken by inhalation enabled delivery and cataracts. In children, ICS therapy has been shown to slow
of high doses of a glucocorticoid to the target tissue—the bron- the rate of growth by about 1 cm over the first year of treatment,
chial mucosa—with little absorption into the systemic circula- but not the rate of growth thereafter, so that the effect on adult
tion. The development of ICS has transformed the treatment height is minimal.
of all but mild, intermittent asthma, which can be treated with Because of the efficacy and safety of inhaled corticosteroids,
“as-needed” use of albuterol alone. national and international guidelines for asthma management
recommend their prescription for patients with persistent asthma
Clinical Uses who require more than occasional inhalations of a β agonist for
relief of symptoms. This therapy is continued for 10–12 weeks
Clinical studies of corticosteroids consistently show them to be and then withdrawn to determine whether more prolonged
effective in improving all indices of asthma control: severity of therapy is needed; inhaled corticosteroids are not curative. In most
symptoms, tests of airway caliber and bronchial reactivity, fre- patients, the manifestations of asthma return within a few weeks
quency of exacerbations, and quality of life. Because of severe after stopping therapy even if they have been taken in high doses
adverse effects when given chronically, oral and parenteral corti- for 2 or more years. A prospective, placebo-controlled study of
costeroids are reserved for patients who require urgent treatment, the early, sustained use of inhaled corticosteroids in young chil-
ie, those who have not improved adequately with bronchodilators dren with asthma showed significantly greater improvement in
or who experience worsening symptoms despite high-dose main- asthma symptoms, pulmonary function, and frequency of asthma
tenance therapy. exacerbations over the 2 years of treatment, but no difference in
For severe asthma exacerbations, urgent treatment is often overall asthma control 3 months after the end of the trial. inhaled
begun with an oral dose of 30–60 mg prednisone per day or corticosteroids are thus properly labeled as “controllers.” They are
an intravenous dose of 0.5–1 mg/kg methylprednisolone every effective only so long as they are taken.
6–12 hours; the dose is decreased after airway obstruction has Another approach to reducing the risk of long-term, twice-
improved. In most patients, systemic corticosteroid therapy can daily use of ICS is to administer them only intermittently,
be discontinued in 5–10 days, but symptoms may worsen in other when symptoms of asthma flare. Taking a single inhalation
patients as the dose is decreased to lower levels. of an ICS with each inhalation of a short-acting β-agonist
Inhalational treatment is the most effective way to avoid the reliever (eg, an inhalation of beclomethasone for each inhala-
systemic adverse effects of corticosteroid therapy. The introduc- tion of albuterol) or taking a 5- to 10-day course of twice-
tion of ICS such as beclomethasone, budesonide, ciclesonide, daily high-dose budesonide or beclomethasone when asthma
flunisolide, fluticasone, mometasone, and triamcinolone has symptoms worsen has been found to be nearly as effective
made it possible to deliver corticosteroids to the airways with as regular daily therapy in adults and children with mild to
minimal systemic absorption. An average daily dose of 800 mcg moderate asthma, although these approaches to treatment are
of inhaled beclomethasone is equivalent to about 10–15 mg/d neither endorsed by guidelines for asthma management nor
of oral prednisone for the control of asthma, with far fewer sys- approved by the FDA.
temic effects. Indeed, one of the cautions in switching patients
from chronic oral to ICS therapy is to taper oral therapy slowly
to avoid precipitation of adrenal insufficiency. In patients requir- CROMOLYN & NEDOCROMIL
ing continued prednisone treatment despite standard doses of an
ICS, higher inhaled doses are often effective and enable tapering Cromolyn sodium (disodium cromoglycate) and nedocromil
and discontinuing prednisone treatment. Although these high sodium were once widely used for asthma management, especially
doses of inhaled steroids may cause mild adrenal suppression, in children, but have now been supplanted so completely by
the risks of systemic toxicity from their chronic use are negli- other therapies that they are mostly of historic interest as asthma
gible compared with those of the oral corticosteroid therapy treatments. These drugs are thought to act by inhibiting mast cell
they replace. degranulation and, as such, have no direct bronchodilator action,