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The goals of treatment for mucus hypersecretion in asthma should
be to reduce mucus volume, normalize mucus composition, and improve mucus
clearance. The effects of currently available antiasthma medications on mucus
volume, mucus composition, or mucus clearance are largely unknown, however,
because these outcomes are difficult to quantitate in clinical practice or in
clinical research studies. Recently developed immunoassays for mucins based on
specific monoclonal antibodies
(119)
(120)
(121)
should facilitate future clinical studies of the effects of pharmacologic
agents on mucin hypersecretion. Presently the pharmacologic
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Box 39-3. Pharmacotherapy of Mucus Hypersecretion in Asthma Bronchodilators
Antiinflammatory agents
Mucolytic agents
Expectorants
Newer agents
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beta-Adrenergic agonists and methylxanthines have beneficial effects on mucociliary clearance independent of their bronchodilator activity. For example, beta-agonists and methylxanthines increase intracellular cyclic adenosine monophosphate levels, which in turn increase ciliary beat frequency and mucus secretion. (122) Subcutaneously administered terbutaline, oral metaproterenol, and inhaled albuterol all have been shown to augment radioaerosol clearance in normal volunteers and in asthmatic subjects. (123) (124) Aminophylline acutely increases tracheal mucus velocity in dogs. (125) beta-Agonists may also have additional beneficial effects on mucus volume and composition by decreasing the plasma protein content of airway mucus by decreasing bronchovascular permeability. (126)
The role of anticholinergic drugs such as ipratropium bromide, oxitropium bromide, or atropine in the treatment of mucus hypersecretion is uncertain because these drugs have multiple effects on the mucociliary apparatus and some of these effects are beneficial, whereas others are not. (127) For example, because cholinergic stimuli are potent secretagogues for mucin and other products of goblet cells and submucosal gland cells, (38) (128) anticholinergic drugs may decrease airway mucus levels. This effect might be beneficial in treating airway mucus hypersecretion so long as the reduction in secretion of mucus components does not render the residual mucus more difficult to clear because of unfavorable changes in its viscoelastic properties. Atropine decreases tracheal mucus secretion in dogs and changes some of the physical properties of residual mucus. (128) Ipratropium bromide, however, does not change the physical properties of sputum in patients with chronic bronchitis, (129) and oxitropium bromide does not change the physical properties of sputum from patients with chronic bronchitis or asthma. (130) In addition, because cholinergic stimuli increase ciliary beat frequency, anticholinergic drugs may decrease ciliary beat frequency and possibly decrease mucociliary clearance. This effect seems most pronounced for atropine, (131) however, and does not occur with ipratropium bromide (132) or oxitropium bromide. (130) Finally,
Inhaled corticosteroids can be expected to decrease mucus hypersecretion and improve mucociliary clearance by their antiinflammatory actions. (133) These include reduction in leukocyte numbers in the airway mucosa, reduction in levels of leukocyte and mast cell mucin secretagogues, restoration of airway epithelial integrity, and reduction in bronchovascular permeability. (134) In addition, corticosteroids have some specific effects on mucus-secreting cells. For example, dexamethasone directly inhibits both basal glycoconjugate secretion and stimulated secretion in feline airway submucosal glands, (135) and both dexamethasone and methylprednisolone produce dose-related suppression of the spontaneous release of radiolabelled mucous glycoproteins from cultured human airways. (136) Recently, it has been demonstrated that dexamethasone decreases steady-state mRNA levels of mucin genes (MUC-2 and MUC-5) in airway mucus-producing cancer cells. (137)
Corticosteroids represent critically important pharmacotherapy for the treatment of acute severe asthma attacks. (138) The mechanism of action of the beneficial effects of corticosteroids in the management of acute asthma is unknown but may involve steroid-induced reductions in mucus secretion, reductions in adhesiveness and viscosity of mucus plugs, and steroid-induced improvements in mucociliary clearance. Direct proof of these effects of corticosteroids in asthmatic subjects is lacking because of the difficulty of measuring these outcomes during acute severe asthma attacks. In stable asthmatics inhaled budesonide has been shown to decrease goblet cell numbers in the airway epithelium. (139)
N-acetylcysteine and S-carboxymethyl cysteine have been advocated for the treatment of mucus hypersecretion for many decades. These agents break the disulfide bonds that form the bridges between mucin chains, and in vitro studies convincingly show that they have favorable effects on the viscoelastic properties of asthmatic sputum. (140) In addition to these ""mucolytic"" effects, N-acetylcysteine and S-carboxymethylcysteine have antioxidant effects, which may have relevance for an effect on mucus hypersecretion. For example, N-acetylcysteine or S-carboxymethylcysteine administered concurrently during 2 weeks of cigarette smoke exposure significantly inhibits the development of mucus hypersecretion in the rat. (141) The mechanism for this effect is probably a direct or indirect antioxidant effect. The direct antioxidant effect may be to increase intracellular stores of reduced glutathione or to block oxidant-induced depletion of glutathione. The indirect effect (relevant only for N-acetylcysteine) may be a direct oxygen-scavenging effect. Despite these favorable in vitro and animal experiments with cysteine derivatives, the clinical experience with N-acetylcysteine in asthma has not been very favorable mainly because it causes bronchoconstriction when administered by aerosol. (142) Thus the use of aerosolized or oral preparations of N-acetylcysteine or S-carboxymethylcysteine cannot be recommended.
Bromhexine is another oral agent classified as a mucolytic (though it does not break disulfide bonds) and is one of the few mucolytic drugs the therapeutic efficacy of which has been examined in a placebo-controlled trial in patients with acute severe asthma. Unfortunately it proved no better than placebo in affecting outcomes that included rate of recovery, measures of oxygenation and ventilation, and measurements of peak flow. (143)
The term expectorant is ultimately derived from the Latin words ex pectore, which means `from the chest. Thus drugs that allow patients to cough up sputum more easily are considered expectorants. Concerning expectorants in this chapter for the third edition of this textbook in 1983, Hirsch wrote: ""Of the areas in modern treatment, none remain more firmly attached to tradition than the use of bitter, sour, salty, and/or sweet medicaments in various preparations and at various temperatures as cough medicines. Each prescription of potassium iodide, ammonium chloride, terpin hydrate, guaiphenesin, honey and lemon, or ethyl alcohol associated with antihistamines and cough depressants carries with it the fervent hope of the physician that the prescription will dislodge the phlegm and the cough will subside. It is my conviction that, although these drugs may have some therapeutic action in patients with acute bronchitis, the zeal with which the physician prescribes the drug is as therapeutic as the ingredients."" (144) Over 20 years later, the zeal with which expectorants are prescribed does not seem to have subsided, despite the lack of any new body of research supporting their use.
Expectorants such as ammonium chloride and members of the terpin hydrate group may have some ciliostimulatory effects, but there are no published reports of their efficacy in clinical trials. Some expectorants such as guaifenesin (glycerol guaiacolate) are emetics and are given in subemetic doses for the theoretic possibility that gastric irritation promotes an increase in mucus secretion by a cholinergic reflex mechanism. (145) The clinical data to support the efficacy of guaifenesin is conflicting and, on balance, unimpressive. (122) (146) (147) The mechanism of action of the iodide salts (iodinated glycerol and potassium iodide) on the mucociliary system in unknown. They are believed to improve mucus expectoration by improving mucus hydration, perhaps through increased epithelial water secretion or serous cell secretion. In placebo-controlled trials the administration of iodide salts results in improved symptoms in patients with airway disease whose lung function has not improved significantly. For example, iodinated glycerol treatment for 6 months in children with asthma resulted in improved asthma symptom scores, but objective measures of pulmonary function did not change significantly, and the treatment was associated with the development of palpable goiter in 15% of patients. (148) In addition, the administration of iodinated glycerol for 8 weeks in patients with COPD resulted in significant improvements in airway symptom scores, but objective measures of pulmonary function, sputum volume, or mucus flow characteristics were not measured. (149)
Sodium thiophene carboxylate decreases the viscosity and elasticity of pig mucin collected from a tracheal pouch but has no effect on pulmonary function or airway mucus rheologic characteristics in patients with COPD and asthma. (150) Inhaled indomethacin has a significantly greater effect than inhaled placebo in reducing sputum volume in patients with bronchorrhea secondary to chronic bronchitis. (63) Two case reports have reported that erthyromycin reduces sputum volume significantly in asthmatic patients with bronchorrhea. (151) (152) This effect of erythromycin may be mediated by a direct effect of erythromycin on mucus secretion rather than an indirect antibacterial effect because in vitro studies have demonstrated that erythromycin suppresses baseline mucus secretion and stimulated secretion. (153)
Recently advances have been made in the treatment of mucus hypersecretion in cystic fibrosis, and some of these advances may later prove relevant in asthma. For example, aerosolized recombinant human DNAase improves pulmonary function and reduces CF-related pulmonary exacerbations in patients with cystic fibrosis (87) (88) presumably by liquefying DNA-rich CF sputum and enhancing mucus clearance. In addition, aerosolized amiloride slows the loss of forced vital capacity and improves sputum viscosity and elasticity in patients with cystic fibrosis presumably by blocking sodium channels in airway epithelial cells and increasing mucus hydration. (154) Finally, aerosolized uridine 5`-triphosphate (in combination with aerosolized amiloride) improves mucociliary clearance from the periphery of the lungs in patients with cystic fibrosis (155) presumably by stimulating airway ciliary beat frequency.
Chest physical therapy is probably most helpful in asthmatic patients with allergic bronchopulmonary aspergillosis because these patients
Figure 39-8 Airway casts recovered from
bronchoalveolar lavage from an asthmatic subject in acute exacerbation.
(From Lang DM, Simon RA, Gathison DA, et al:
Annals of Allergy 67:324-330, 1990.)
Bronchoscopy and bronchoalveolar lavage (BAL) with saline or saline and N-acetylcysteine has been advocated as a treatment for acute severe asthma for over 30 years. (156) No controlled trials of this therapy have been performed, however. The most recent uncontrolled series was in 19 asthmatic subjects refractory to at least 48 to 72 hours of aggressive inpatient medical management. (157) A total of 51 bronchoscopies (one to six per patient) were performed transnasally with local anesthesia. Mucus visualized in the large airways was removed by suction and mucus in smaller more peripheral airways was removed by lavage with a total of 50 to 300 ml of saline. Airway casts were recovered in the BAL in some instances (Figure 39-8) . Complications included three episodes of transient mild hypoxemia and four episodes of bronchospasm responsive to bronchodilator therapy. Mean FEV1 values before bronchoscopy were 41% of predicted and increased to 60% of predicted within 96 hours of bronchoscopy. Despite these encouraging uncontrolled data, the expense and potential dangers of bronchoscopy in acutely ill asthmatics require that a properly controlled randomized study be completed before BAL is recommended as a treatment for acute severe asthma refractory to usual therapeutic measures.
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