Drugs Used in Asthma
Asthma is characterized clinically by recurrent bouts of shortness of breath, chest tightness, and wheezing, often associated with coughing; physiologically by widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial respon-siveness to inhaled stimuli; and pathologically by lymphocytic, eosinophilic inflammation of the bronchial mucosa. It is also char-acterized pathologically by “remodeling” of the bronchial mucosa, with thickening of the lamina reticularis beneath the airway epi-thelium and hyperplasia of the cells of all structural elements of the airway wall—vessels, smooth muscle, and secretory glands and goblet cells.
In mild asthma, symptoms occur only occasionally, as on expo-sure to allergens or certain pollutants, on exercise, or after viral upper respiratory infection. More severe forms of asthma are asso-ciated with frequent attacks of wheezing dyspnea, especially at night, or with chronic airway narrowing, causing chronic respira-tory impairment. These consequences of asthma are regarded as largely preventable, because effective treatments for relief of acute bronchoconstriction (“short-term relievers”) and for reduction in symptoms and prevention of attacks (“long-term controllers”) are available. The persistence of high medical costs for asthma care, driven largely by the costs of emergency department or hospital treatment of asthma exacerbations, are believed to reflect under-utilization of the treatments available.
The causes of airway narrowing in acute asthmatic attacks, or “asthma exacerbations,” include contraction of airway smooth muscle, inspissation of viscid mucus plugs in the airway lumen,girl uses an inhaler (albuterol) but “only when really needed” because her parents are afraid that she will become too dependent on medication. She administered two puffs from her inhaler just before coming to the hospital, but “the inhaler doesn’t seem to have helped.” What emergency mea-sures are indicated? How should her long-term management be altered? and thickening of the bronchial mucosa from edema, cellular infiltration, and hyperplasia of secretory, vascular, and smooth muscle cells. Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy; reversal of the edema and cellular infiltration requires sustained treatment with anti-inflammatory agents.
Short-term relief is thus most effectively achieved by agents that relax airway smooth muscle, of which β-adrenoceptor stimu-lants are the most effective and most widely used. Theophylline, a methylxanthine drug, and antimuscarinic agents are sometimes also used for reversal of airway constriction.
Long-term control is most effectively achieved with an anti-inflammatory agent such as an inhaled corticosteroid. It can also be achieved, though less effectively, with a leukotriene pathway antagonist or an inhibitor of mast cell degranulation, such as cro-molyn or nedocromil. Finally, clinical trials have established the efficacy of treatment for severe asthma with a humanized monoclo-nal antibody, omalizumab, which is specifically targeted against IgE, the antibody responsible for allergic sensitization.
The distinction between “short-term relievers” and “long-term controllers” is blurred. Inhaled corticosteroids, regarded as long-term controllers, produce modest immediate bronchodilation. Theophylline, regarded as a bronchodilator, inhibits some lympho-cyte functions and modestly reduces airway mucosal inflammation. Theophylline may also enhance the anti-inflammatory action of inhaled corticosteroids. This is also true of long-acting β-adrenoceptor stimulants, like salmeterol and formoterol, which are effective in improving asthma control when added to inhaled corticosteroid treatment, though neither is anti-inflammatory when taken as a single agent.
A 10-year-old girl with a history of poorly controlled asthma presents to the emergency department with severe shortness of breath and audible inspiratory and expiratory wheezing. She is pale, refuses to lie down, and appears extremely fright-ened. Her pulse is 120 bpm and respirations 32/min. Her mother states that the girl has just recovered from a mild case of flu and had seemed comfortable until this afternoon. The girl uses an inhaler (albuterol) but “only when really needed” because her parents are afraid that she will become too dependent on medication. She administered two puffs from her inhaler just before coming to the hospital, but “the inhaler doesn’t seem to have helped.” What emergency mea-sures are indicated? How should her long-term management be altered?
CASE STUDY ANSWER
This patient demonstrates the destabilizing effects of a respi-ratory infection on asthma, and the parents demonstrate the common (and dangerous) phobia about “overuse” of bron-chodilator or steroid inhalers. The patient has signs of immi-nent respiratory failure, including her refusal to lie down, her fear, and her tachycardia—which cannot be attributed to her minimal treatment with albuterol. Critically important immediate steps are to administer high-flow oxygen and to start albuterol by nebulization. Adding ipratropium (Atrovent) to the nebulized solution is recommended. A corticosteroid (0.5–1.0 mg/kg of methylprednisolone) should be adminis-tered intravenously. It is also advisable to alert the intensive care unit, because a patient with severe bronchospasm who tires can slip into respiratory failure quickly, and intubation can be difficult.
Fortunately, most patients treated in hospital emergency departments do well. Asthma mortality is rare (fewer than 5000 deaths per year among a population of 20 million asthmatics in the USA), but when it occurs, it is often out of hospital. Presuming this patient recovers, she needs adjust-ments to her therapy before discharge. The strongest predic-tor of severe attacks of asthma is their occurrence in the past. Thus, this patient needs to be started on a long-term control-ler, especially an inhaled corticosteroid, and needs instruc-tion in an action plan for managing severe symptoms. This can be as simple as advising her and her parents that if she has a severe attack that frightens her, she can take up to four puffs of albuterol every 15 minutes, but if the first treatment does not bring significant relief, she should take the next four puffs while on her way to an emergency department or urgent care clinic. She should also be given a prescription for prednisone, with instructions to take 40–60 mg orally for severe attacks, but not to wait for it to take effect if she remains severely short of breath even after albuterol inhala-tions. Asthma is a chronic disease, and good care requires close follow-up and creation of a provider-patient partner-ship for optimal management.