Page 373 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 20 Drugs Used in Asthma 359

of asthma. Other possible markers of heightened risk are unstable after 4–6 weeks, the dose of treatment should be stepped down
pulmonary function (large variations in FEV from visit to visit, to no more than is necessary to control symptoms and maintain
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large change with bronchodilator treatment), extreme bronchial pulmonary function.
reactivity, high numbers of eosinophils in blood or sputum, and An issue for ICS treatment is patient adherence. Analysis of
high levels of nitric oxide in exhaled air. Assessment of these prescription renewals shows that only a minority of patients take
features may identify patients who need increases in therapy for corticosteroids regularly. This may be a function of a general “ste-
protection against future exacerbations. roid phobia” fostered by emphasis in the lay press on the hazards
of long-term oral corticosteroid therapy and by ignorance of the
difference between glucocorticoids and anabolic steroids, taken to
BRONCHODILATORS enhance muscle strength by now-infamous athletes. This fear of
corticosteroid toxicity makes it hard to persuade patients whose
Bronchodilators, such as inhaled albuterol, are rapidly effective, symptoms have improved after starting treatment that they should
safe, and inexpensive. Patients with only occasional symptoms of continue it for protection against attacks. This context accounts
asthma require no more than an inhaled bronchodilator taken on for the interest in reports that instructing patients with mild but
an as-needed basis. If symptoms require this “rescue” therapy more persistent asthma to take ICS therapy only when their symptoms
than twice a week, if nocturnal symptoms occur more than twice worsen is nearly as effective in maintaining pulmonary function
a month, or if the FEV is less than 80% of predicted, additional and preventing attacks as is taking the ICS twice each day.
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treatment is needed. The treatment first recommended is a low Two options for asthma inadequately controlled by a standard
dose of an ICS, although a leukotriene receptor antagonist may dose of an ICS are to (1) double the dose of ICS or (2) combine it
be used as an alternative. with another drug. The addition of theophylline or a leukotriene
An important caveat for patients with mild asthma is that receptor antagonist modestly increases asthma control, but the most
although the risk of a severe, life-threatening attack is low, it is not impressive benefits are afforded by addition of a long-acting inhaled
zero. All patients with asthma should be instructed in a simple β -receptor agonist (LABA, eg, salmeterol or formoterol). Many
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action plan for severe, frightening attacks: to take up to four puffs of studies have shown this combination to be more effective than dou-
albuterol every 20 minutes over 1 hour. If no improvement is noted bling the dose of the ICS. Combinations of an ICS and an LABA
after the first four puffs, additional treatments should be taken while in a single inhaler are now available in fixed-dose preparations (eg,
on the way to an emergency department or other higher level of care. fluticasone and salmeterol [Advair]; budesonide and formoterol
[Symbicort]; mometasone and formoterol [Dulera]; fluticasone and
vilanterol [Breo]). The rapid onset of action of formoterol enables
MUSCARINIC ANTAGONISTS novel use of its combination with a low dose of budesonide. The
combination of 80 mcg of budesonide plus 12.5 mcg of formoterol
Inhaled muscarinic antagonists have so far earned a limited place taken twice daily and additionally for relief of symptoms (ie, taken
in the treatment of asthma. The effects of short-acting agents (eg, as both a “controller” and a “reliever”) is as effective an inhalation of
ipratropium bromide) on baseline airway resistance are nearly as a four-times-higher dose of budesonide with albuterol alone taken
great as, but no greater than, those of the sympathomimetic drugs, for relief of symptoms. Use of this flexible dosing strategy is wide-
so they are used largely as alternative therapies for patients intoler- spread in Europe but is not approved in the USA.
ant of β-adrenoceptor agonists. The airway effects of antimuscarinic Until recently, a shadow hung over the use of combination
and sympathomimetic drugs given in full doses have been shown to ICS-LABA therapy for moderate and severe asthma, generated by
be additive only in reducing hospitalization rates in patients with evidence of a statistically significant increase in the very low risk of
severe airflow obstruction who present for emergency care. fatal or near-fatal asthma attacks from use of an LABA even when
The long-acting antimuscarinic agents tiotropium and acli- taken in combination with an ICS. This evidence prompted the
dinium have not yet earned a place in the treatment for asthma, FDA to require the addition of a “black box” warning to the pack-
although the addition of tiotropium to an ICS has been shown age insert issued with each ICS-LABA inhaler. The major message
to be as effective as the addition of an LABA. As a treatment for of the warning is that a possible increase in risk of a severe rare
COPD, these agents improve functional capacity, presumably event, including asthma fatality, from the use of an LABA should
through their action as bronchodilators, and reduce the frequency be discussed with the patient in presenting options for treatment.
of exacerbations through currently unknown mechanisms. The concerns underlying the “black box” warning have been
assuaged by two large, placebo-controlled, double-blind FDA-
CORTICOSTEROIDS mandated trials showing no significant increase in severe asthma
exacerbations or asthma fatalities from the addition of an LABA
to ICS treatment in patients with moderate to severe asthma.
If asthmatic symptoms occur frequently, or if significant airflow
obstruction persists despite bronchodilator therapy, inhaled corti- Despite these reassuring findings, patients prescribed combination
costeroids should be started. For patients with severe symptoms or treatment should also be provided with explicit instructions to
severe airflow obstruction (eg, FEV < 50% of predicted), initial continue use of a rapid-acting inhaled β agonist, such as albuterol,
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treatment with a high dose of an ICS in combination with an for relief of acute symptoms and, as for all patients with asthma,
LABA is appropriate. Once clinical improvement is noted, usually to follow an explicit action plan for severe attacks.