Chapter 24 Pulmonary System
Beta 2 (β2) Agonists (Bronchodilators)
MOA (Mechanism of Action)
Stimulation of β2 receptors in bronchial smooth muscle results in relaxation of bronchial smooth muscle. This results in a larger diameter airway, resulting in lower resistance to airflow in and out of the lungs (Figure 24-1).
Pharmacokinetics
These drugs are all typically administered via inhalation: via metered dose inhaler (MDI), dry powder inhaler, or nebulizer (atomizes liquid drug into a mist). Inhalation delivers the drug to the lungs, where the highest concentrations are desired, thereby reducing the probability of side effects.
Contraindications
Severe bronchospasm is life-threatening. Therefore the indication for a β2 agonist would outweigh most reasons not to give it.
Side Effects
Important Notes
SABAs as required may be used as sole therapy in mild episodic asthma. Neither SABAs nor LABAs should be used as sole therapy in persistent asthma but should be combined with antiinflammatory therapy.
The combination of LABAs and ICSs has become standard therapy in the management of asthma. There are two reasons why this combination is believed to be so effective. First, the use of a bronchodilator is believed to open up the airways to improve distribution of the steroid. Second, it appears that chronic ICS use up-regulates β2 receptors in the lungs. This is important because chronic use of β2 agonists is believed to lead to a down-regulation of β2 receptors in the lungs. Some available drugs are combinations of a bronchodilator and steroid together in one inhaler (Table 24-1).
TABLE 24-1 Fixed-Dose Combinations of Inhalers
| Salmeterol + fluticasone | Advair |
| Formoterol + budesonide | Symbicort |
| Salbutamol + ipratropium | Combivent |
Evidence
Long-Acting β Agonists with or without Inhaled Corticosteroids in Adults or Children with Asthma
A 2007 Cochrane review (67 studies, 42,333 participants) examined the use of LABAs (salmeterol, 50 studies; formoterol, 17 studies) versus placebo. In these studies, patients were followed for 4 to 52 weeks. Patients were allowed to combine inhaled corticosteroids (ICSs) with LABAs in 40 studies, 24 studies did not permit ICSs, and three studies were unclear about ICS use. Use of LABAs, with or without ICSs, was associated with improvements in pulmonary function, symptoms, rescue medication use, and quality-of-life scores.Formoterol Plus Inhaled Corticosteroids in Asthma
A 2009 Cochrane review (3 studies, N = 5905 patients) compared combinations of formoterol and ICSs with SABAs alone for relief of asthma symptoms. No clinically important advantages were found for the combination in patients with mild asthma. However, in more severe asthma, one study found that patients not well controlled on high-dose ICSs and who had had an exacerbation in the prior year had a reduced risk of exacerbations requiring oral steroids when using the combination versus terbutaline or formoterol monotherapy for relief. A study in children also found less serious adverse events with the combination of budesonide and formoterol for maintenance and relief.Regular Formoterol versus Placebo or Short-Acting β Agonists in Chronic Asthma
A 2008 Cochrane review (22 studies, 8032 patients) compared serious adverse event rates for regular formoterol use with placebo or SABAs in chronic asthma. Nonfatal serious adverse events were increased versus placebo (odds ratio [OR] 1.57), but no increase was detected versus salbutamol or terbutaline. The increased risk over placebo was also seen in patients taking ICSs.
Parasympathetic stimulation of muscarinic receptors of the bronchioles results in bronchoconstriction and also increased bronchial secretions. These actions are largely mediated through M3 receptors, and to a lesser extent, M1 (Figure 24-2).
Ipratropium and tiotropium are inhaled. They are quaternary compounds (therefore polarized and not apt to cross hydrophobic cell membranes). They do not readily cross the pulmonary membranes into the blood. Therefore, systemic absorption is low.
Side effects are minimal because of minimal systemic absorption. Side effects would include the predictable effects of muscarinic antagonism in various organs.
Ipratropium is slightly slower to act and possibly less effective than β2 agonists for treatment of bronchial asthma.
Cardiovascular Safety
A 2008 meta-analysis (17 trials, N = 14,783 patients) found an increased risk of the composite of cardiovascular death, myocardial infarction (MI), and stroke in patients on inhaled anticholinergics (1.8%) versus control therapy (1.2%). Specifically, risk of MI and cardiovascular death was increased, whereas risk of stroke was not.Ipratropium versus Short-Acting β2 Agonists in Chronic Obstructive Pulmonary Disease
A 2006 Cochrane review (11 studies, N = 3912 patients) found small benefits of ipratropium over SABAs on measures of lung function, quality of life, and the requirement for oral steroids. The combination of ipratropium and SABAs was better than a β2 agonist alone with respect to postbronchodilator lung function and a reduction in the need for oral steroids.
Leukotriene Receptor Antagonists
Leukotrienes are biologically active fatty acids derived from the oxidative metabolism of arachidonic acid, via the enzyme 5-lipoxygenase.
Leukotriene receptor antagonists competitively and selectively block the LTD4 receptor (Figure 24-3).
These drugs are not indicated for acute exacerbations of the disease. They are recommended for prophylaxis and chronic treatment of asthma.
LRTAs versus Inhaled Corticosteroids (ICSs) for Chronic Asthma
A 2000 Cochrane review (27 trials) compared the safety and efficacy of antileukotrienes to ICS in mild to moderate asthma. Patients treated with antileukotrienes were more likely to have an exacerbation requiring systemic steroids (NNH = 26). ICS also improved pulmonary functions (FEV1), symptoms, nocturnal awakenings, rescue medication use, and quality of life to a greater extent than did antileukotrienes. More patients treated with antileukotrienes withdrew due to poor asthma control. The risk of side effects was no different between groups.
LTRAs Plus ICSs versus Long-Acting β2 Agonists (LABAs) Plus ICSs for Chronic Asthma
A 2006 Cochrane review (16 studies) evaluated the effect of adding LTRAs vs. LABAs to ICS in patients with chronic asthma. The findings showed a lower rate of requiring systemic steroids (RR = 0.83) with LABAs. Other endpoints including lung function tests, symptoms, and use of rescue β2 agonists were also superior with LABAs. Withdrawals from treatment and side effects were similar in both groups.
Zileuton is a 5-lipoxygenase inhibitor approved for use in the United States but not in some other jurisdictions, due to safety concerns.
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