Albuterol and terbutaline are also available in oral form. One tablet two or three times daily is the usual regimen; the principal adverse effects are skeletal muscle tremor, nervousness, and occasional weakness. This route of administration presents no advantage over inhaled treatment and produces more pronounced adverse effects and is thus rarely prescribed.
Of these agents, only terbutaline is available for subcutaneous injection (0.25 mg). The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective—but it should be remembered that terbutaline’s longer duration of action means that cumulative effects may be seen after repeated injections. Large doses of parenteral terbutaline are sometimes used to inhibit the uterine contractions associated with premature labor.
Long-acting β2-selective agonists (LABA), with 12-hour durations of action, such as salmeterol and formoterol, were developed to facilitate asthma management. These drugs generally achieve their long duration of bronchodilating action as a result of high lipid solubility. This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to “mooring” molecules in the vicinity of the adrenoceptor. These drugs appear to interact with inhaled corticosteroids to improve asthma control. Because they have no anti-inflammatory action, they should not be used as monotherapy for asthma. Ultra-long-acting β agonists, such as indacaterol, olodaterol, vilanterol, and bambuterol, need to be taken only once a day, but because their prolonged bronchodilation masks symptoms of bronchial inflammation, they should be used only in combination with an ICS for asthma. However, they may be used as mono-therapy for treatment of COPD.
Concerns over the potential toxicities of acute treatment of asthma with inhaled sympathomimetic agents—worsened hypoxemia and cardiac arrhythmia—have been largely put to rest. Although the vasodilating action of β2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2), this effect is small, is easily overcome by the routine administration of supplemental oxygen, and is made irrelevant after a short period of time by the increase in oxygen tension that follows β-agonist-induced bronchodilation. The other concern, precipitation of cardiac arrhythmias, appears unsubstantiated. In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange effected by bronchodilator treatment and oxygen administration.
Another concern about the administration of β-agonists is their induction of tachyphylaxis. A reduction in the bronchodilator response to low-dose β-agonist treatment can be shown after several days of regular β-agonist use, but maximal bronchodilation is still achieved well within the range of doses usually given. Tachyphylaxis is more clearly reflected by a loss of the protection afforded by acute treatment with a β agonist against a later challenge by exercise or inhalation of allergen or an airway irritant. It remains to be demonstrated in a clinical trial, however, whether this loss of bronchoprotective efficacy is associated with adverse outcomes.