Rubin Mucoactive CIPP 8

Rubin. Mucoactive medications. Page # 1 The pharmacologic approach to airway clearance: Mucoactive agents Bruce K. Rubin, MEngr, MD, MBA, FRCPC Professor and Vice-Chair of Pediatrics Professor of Biomedical Engineering, Physiology and Pharmacology Wake Forest University School of Medicine Medical Center Blvd. Winston-Salem, NC 27157-1081 Rubin. Mucoactive medications. Page # 2 Outline 1. Introduction 2. Expectorants 3. Medications that change the biophysical properties of secretions 3.1 Mucolytic agents 3.1.1 Classic mucolytics 3.1.2 Peptide Mucolytics 3.1.3 Nondestructive mucolytics 4. Mucokinetic agents 5. Cough clearance promotors 6. Mucoregulatory medications 7. Summary 1. Introduction The airway mucosa responds to infection and inflammation in a variety of ways. This response often includes surface mucous (goblet) cell and submucosal gland hyperplasia and hypertrophy with mucus hypersecretion. Products of inflammation including neutrophil derived DNA and filamentous actin (F-actin), effete cells, bacteria, and cell debris all contribute to mucus purulence and, when this is expectorated it is called sputum. Mucoactive medications are intended to serve one of two purposes; either to increase the ability to expectorate sputum or to decrease mucus hypersecretion. Mucoactive medications have been classified according to their proposed method of action (1). Sputum is expectorated mucus mixed with inflammatory cells, cellular debris, polymers of DNA and F-actin, as well as bacteria. Mucus is usually cleared by airflow and ciliary movement, and sputum is cleared by cough (2). In this review, I will discuss each of these classes of medication, their proposed mechanism of action, and their potential use in treating patients with chronic airways diseases associated with poor mucus clearance and with mucus hypersecretion. Rubin. Mucoactive medications. Page # 3 2. Expectorants Expectorants are defined as medications that are taken to improve the ability to expectorate purulent secretions. This term is now taken to mean medications that increase airway water or the volume of airway secretions. The most commonly used of these are simple hydration including both bland aerosol administration and oral hydration, iodide containing compounds such as SSKI or iodinated glycerol, glyceryl guaiacolate or guaifenesin, and the more recently developed ion channel modifiers such as the P2Y2 purinergic agonists. Most of these medications or maneuvers are ineffective at adding water to the airway and those that are effective are also mucus secretagogues increasing the volume of both mucus and water in the airways. Despite widespread use, iodinated compounds, guaifenesin, and simple hydration are ineffective as expectorants (3). In fact, over-hydration has been shown to decrease airway mucus clearance in some patients with chronic airway disease, particularly with acute asthma (4). For many years, sputum induction using hyperosmolar saline inhalation has been used to obtain specimens for the diagnosis of pneumonia. As summarized in the Cochrane Database, the long term use of inhaled hyperosmolar saline improves pulmonary function in patients with cystic fibrosis (CF) (5) and inhaled hyperosmolar saline or mannitol is beneficial in non-CF bronchiectasis (6). Although this therapy is readily available and inexpensive, it has been reported that hypertonic saline aerosol is not as effective as dornase alfa in the therapy of CF lung disease (7). Agents that increase transport across ion channels such as the CFTR chloride channel, calcium dependent chloride channel, or agents that increase water transport across the airway aquaporin water channels may increase the hydration of the periciliary fluid and so may aid expectoration. These medications (including gene transfer vectors) are actively being investigated. Early results using UTP to stimulate chloride secretion or amiloride to block epithelial sodium channels were disappointing in that these did not produce a sustained Rubin. Mucoactive medications. Page # 4 improvement in pulmonary function in persons with CF (8) but newer P2Y2 chloride channel activators appear to be more effective (9, 10). In general, expectorant medications have not been consistently demonstrated to be effective for the treatment of airway disease associated with mucus stasis or hypersecretion. 3. Medications that change the biophysical properties of secretions The principal polymer component of normal airway mucus is mucin glycoprotein. The mucin protein is heavily decorated with oligosaccharide side chains and the elongated glycoproteins linearly polymerize and form a “tangled network” secondary structure. This accounts for the gel structure of normal airway mucus. With chronic inflammation there is thought to be hypersecretion of mucin although this has not been proven. In fact it has been shown that there is mucus hyposecretion in the CF airway (11) and this may predispose the airway to chronic infection with biofilm producing organisms. In sputum, a secondary polymer network comprised of neutrophil derived DNA and F-actin also forms within the airway. This DNA forms rigid polymer chains that copolymerize with cell wall associated actin (12). This secondary polymer network is responsible for many of the abnormal properties of purulent secretions. 3.1 Mucolytics Mucolytic medications depolymerize either the mucin network (classic mucolytics) or the DNA-actin polymer network (peptide mucolytics) and in so doing reduce the viscosity and elasticity of airway secretions. Mucus has viscoelastic properties of both liquids (viscosity) and solids (elasticity). Thus it is a gel and both the viscous (energy loss) and elastic (energy storage) properties are essential for mucus spreading and clearance (13). Mucociliary clearance appears to be dependent upon there being an optimal ratio of viscosity to elasticity (14). Mucolytic agents have the potential to improve mucus rheology thus improving mucociliary or cough clearance, Rubin. Mucoactive medications. Page # 5 but these medications are also potentially able to over liquify secretions and this would decrease clearance (15). 3.1.1 Classic Mucolytics Classic mucolytics depolymerize the mucin glycoprotein oligomers by hydrolyzing the disulfide bonds linking the mucin monomers. This is usually accomplished by free thiol (sulfhydryl) groups hydrolyzing disulfide bonds attached to cysteine residues of the protein core. The best known of these agents is N-acetyl L-cysteine (NAC) which is widely used for the treatment of chronic bronchitis in Europe and Asia. There are few data available from placebo controlled clinical trials of NAC or its derivatives, and these data do not demonstrate that NAC improves mucus clearance or pulmonary function (16). The aerosol is available in the United States but is often poorly tolerated by patients because of its sulfurous odor and because the pH of 2.2 is associated with bronchospasm. NAC is an antioxidant and has been used to treat acetaminophen overdose. The orally available compound is also available in Europe but despite being a potent anti oxidant there are no data demonstrating that this medication is effective in the treatment of chronic airway disease (17). There are a number of similar compounds containing sulfhydryl groups that can effectively depolymerize mucin polymers in vitro. Although many of these are better tolerated than NAC, none have been clearly demonstrated to be effective in improving mucus clearance. 3.1.2 Peptide mucolytics The mucin polymer network is essential for normal mucus clearance. It may be that the classic mucolytics are generally ineffective because they are depolymerizing essential components of the mucous gel. With airway inflammation and inflammatory cell necrosis, a secondary polymer network develops in purulent secretions. In contrast to the mucin network, this pathologic polymer gel serves no obvious purpose in airway protection or mucus clearance. Rubin. Mucoactive medications. Page # 6 The peptide mucolytics are designed specifically depolymerize the DNA polymer (dornase alfa) or the F-actin network (e.g. gelsolin, thymosin beta 4). Dornase alfa has seen wide acceptance as a peptide mucolytic for the treatment of cystic fibrosis airway disease (18). When used as prescribed, its use is associated with improved pulmonary function, decreased antibiotic use, and decreased hospitalization rate for many patients with CF (19). For reasons that are not clear, this medication is not uniformly effective for the treatment of CF airway disease and efficacy does not seem to be related to sputum DNA content. There are limited and anecdotal data suggesting that dornase alfa may be effective in treating some persons with non CF bronchiectasis including some patients with primary ciliary dyskinesia (20). Although dornase alfa was not effective for the therapy of severe chronic bronchitis, there are no published studies evaluating its potential efficacy in patients with milder disease. Both gelsolin and thymosin ß4 have been demonstrated to depolymerize the pathologic DNA/F-actin network in CF sputum. These agents have never been studied in controlled clinical trials. 3.1.3 Nondestructive mucolytics Mucin is a polyionic tangled network and the charged nature of the oligosaccharide side chains help to hold this network together as a gel. Several agents have been proposed that can “loosen” this network by charge shielding. Such agents include low molecular weight dextran, heparin, and other sugars or glycoproteins (21). 4. Mucokinetic

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