Clinical indication for use

The general indication for mucoactive therapy is to reduce the accumulation of airway secretions, with concomitant improvement in pulmonary function and gas exchange and the prevention of repeated infection and airway damage. Diseases in which mucoactive therapy is indicated are those with hypersecretion or poor clearance of airway secretions, including cystic fibrosis (CF), acute bronchitis and chronic bronchitis (CB), pneumonia, diffuse panbronchiolitis (DPB), primary ciliary dyskinesia, asthma, and bronchiectasis. Not all patients with mucus retention benefit from mucoactive drug therapy; patients with adequately preserved expiratory airflow and cough usually have a better response. The use of mucoactive therapy to promote secretion clearance should be considered after therapy to decrease infection and inflammation and after minimizing or removing irritants to the airway, including tobacco smoke.³

Identification of agents

Table 9-1 presents general information about mucoactive agents that are approved, available, or commonly administered as inhaled aerosols in the United States. Table 9-2 presents similar information for other countries.⁴ Greater detail is given on indications, dosage and administration, hazards and side effects, and assessment of drug therapy in discussions of individual agents.

Mucoactive agents differ in their mechanism of action. Secretion properties that impair airway clearance also differ between different diseases and at different times in the course of a disease. The source and properties of airway secretions and the mechanisms of action for the mucoactive agents are the basis for clinical use of this class of drugs.

Terminology

There has been confusion regarding the nomenclature used to classify mucoactive medications. Although some authors have used “mucolytic” as a generic term for these agents, most of these medications are thought to mobilize secretions by mechanisms other than by the direct “thinning” of mucus. For example, although the mucociliary transportability of sputum may be improved by reducing sputum viscosity while preserving elasticity, the ability to clear secretions via cough seems to be greater with increased sputum viscosity and decreased adhesivity. Knowledge of mucus properties has given us tools to understand better the mechanisms of airway disease and mucoactive therapy. The currently accepted terminology is defined in the Key Terms and Definitions list at the start of this chapter. For more details on current terminology and its evolution, see Reid and Clamp,⁶ Basbaum,⁷ and King and Rubin.⁸

Surface epithelial cells

The surface of the trachea and bronchi includes primarily ciliated cells and goblet cells, at a ratio of approximately 5:1. There are more than 6000 goblet cells per square millimeter of normal airway mucosa. Goblet cells do not seem to be directly innervated in human lung, although they respond to irritants by increasing the production of mucus. Figures 9-2 and 9-3 show scanning electron micrographs of the mucus lining (Figure 9-2) and of the bronchiolar surface with the mucus stripped away (Figure 9-3). In addition to ciliated and goblet cells, microvilli, which may have a reabsorptive function, can be seen in Figure 9-3.

Submucosal mucous glands

Submucosal glands below the epithelial surface are thought to provide much of the airway surface mucin. The submucosal gland is under parasympathetic (vagal) control and responds to cholinergic stimulation by increasing the amount of mucus secreted. Evidence also suggests that submucosal glands in the respiratory tract are innervated by sympathetic axons and the peptidergic nerve system.

Two types of cells, mucous and serous, are found in the glands. Figure 9-4 shows a section of the ferret airway stained for mucin, with the surface mucous (goblet) cells and the submucosal gland serous and mucous cells identified. Secretions from the serous and mucous cells mix in the submucosal gland and are transported through a ciliated duct onto the airway lumen.

Ciliary system

Droplets of mucus from the secretory cells form plaques in the distal, nonciliated airway, and these coalesce into a continuous layer in the more proximal ciliated airway. Mucociliary transport results from the movement of the mucus gel by the beating cilia. There are approximately 200 cilia on each cell. Cilia are about 7 μm in length in larger airways and shorten to 5 μm or slightly less in smaller bronchioles. Luk and Dulfano⁹ examined the ciliary beat frequency on biopsy samples from various tracheobronchial regions and found rates of 8 to 18 Hz (Hz = 1 cycle/sec) at 37° C. A ciliary beat is composed of an effective (power) stroke and a recovery stroke with about a 1:2 ratio. In the effective stroke, the cilium moves in an upright position through a full forward arc, to contact the underside of the mucus layer and propel it forward. In the recovery stroke, the cilium swings back around to the starting point near the cell surface, to avoid pulling secretions back. Cilia beat in a coordinated or metachronal wave of motion to propel airway secretions. A functional surfactant layer lies at the tips of the cilia and separates the periciliary fluid from the mucus gel. This layer allows the cilia to transmit kinetic energy effectively to the mucus without becoming entangled. This layer also facilitates mucus spreading as a continuous layer and prevents water loss from the periciliary fluid. The properties of cilia are described in detail in an earlier review.¹⁰

Factors affecting mucociliary transport

Mucociliary transport velocity varies in the normal lung and has been estimated at about 1.5 mm/min in peripheral airways and 20 mm/min in the trachea. Transport rates are slower in the presence of the following conditions or substances, many of which are associated with airway damage:

Table 9-3 summarizes the effects of drug groups commonly used in respiratory care on ciliary beat, mucus output, and overall transport.

Food intake and mucus production

A common belief is that drinking dairy milk increases the production of mucus and congestion in the respiratory tract. Respiratory care personnel may be asked for advice on withholding milk from children with colds, respiratory infections, or chronic respiratory conditions such as CF. Pinnock et al.¹¹ inoculated 60 healthy subjects with rhinovirus-2 in a study designed to answer the following question: Does milk make mucus? Milk intake ranged from 0 to 11 glasses a day. The investigators reported no association between milk and dairy product intake and upper or lower respiratory tract symptoms of congestion or nasal secretion weight. There was a trend for cough to be “loose” with increasing intake of milk, although this was not significant. None of the subjects were allergic to cow’s milk. The investigators concluded that the data do not support the withholding of milk or the belief that milk increases respiratory tract congestion.

Structure and composition of mucus

The structure and major constituents of the mucus secreted by submucosal glands and surface goblet cells are pictured in Figure 9-5 and have been reviewed elsewhere.^5,7,12–14a Airway mucus forms a protective barrier between the respiratory tract epithelium and the environment. Mucus is composed mainly of water and ions, with approximately 5% of the content from proteins secreted by airway cells and lipids.^15–17 In health, the mucin glycoproteins are the major macromolecular component of the mucus gel. Mucins are responsible for the protective and clearance properties of mucus.^18–20

There are two major classes of mucins: the secreted and the membrane-tethered mucins.^21,22 Several secreted mucins (MUC2, MUC5AC, MUC5B, and MUC6) have genes that are clustered on chromosome 11p15 and contain domains with significant homology to the von Willebrand factor D domains that are sites for oligomerization.²³ In sputum, MUC5AC and MUC5B are the major oligomeric mucins.²⁴ MUC5AC apparently is produced primarily by the goblet cells in the tracheobronchial surface epithelium, whereas MUC5B is secreted primarily by the submucosal glands.²⁵ The membrane-tethered mucins, MUC1, MUC3, MUC4, MUC12, and MUC13, contain a transmembrane domain and a short cytoplasmic domain.²³ At least 12 mucin genes (MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7, MUC8, MUC11, MUC13, MUC15, MUC19, and MUC20) have been observed at the mRNA level in tissues of the lower respiratory tract from healthy individuals.^{21,23,26–32}

Mucus is a complex, high-molecular-weight macromolecule consisting of a mucin protein backbone to which carbohydrate (oligosaccharide) side chains are attached. At the time of this writing,²² distinct mucin proteins have been identified, but airway mucus is almost entirely composed of the MUC5AC and MUC5B secreted gel-forming mucins.²⁷ The carbohydrate content is 80% or more of the total weight of the macromolecule. This structure is similar to a bottlebrush in appearance. This general structure of protein and attached oligosaccharide side chains is termed a glycoprotein. Mucin forms a flexible, threadlike strand 200 nm to 6 μm in length³³ that is linearly cross-linked with disulfide bonds from adjacent cysteine residues. Strands may also be linked with each other by hydrogen bonding and van der Waals forces. The result is a gel that consists of a high water content (90% to 95%) organized around the structural elements and that is intensely hydrophilic and spongelike.^34,35

Under normal circumstances, bonding within mucus produces low viscosity but moderate elasticity. Although mucus incorporates water during its formation, a gel acts like both a liquid and a solid. An analogy is gelatin, which is mostly water but organizes into a semisolid by its chemical structure as the liquid gels. It is important clinically that sufficient water must be available to form mucus with normal physical properties, but once formed, mucus does not readily incorporate topically applied water.³⁶

Phospholipids are also present in the serous cell granules of the submucosal glands. When released onto the airway surface, phospholipids may serve as lubricants affecting the surface-active and adhesive properties of mucus, both of which can affect mucociliary transport function.³

In addition to the mucus gel secreted in the airway, bronchial secretions contain serum and secreted proteins, lipids, and electrolytes. Antibacterial defense in the airway is provided by mucin, secretory IgA, IgG, lysozyme, lactoferrin, defensins, and peroxidase and serine proteases. Bronchial secretions control the potentially destructive action of protease enzymes with two major antiproteases: α₁-protease inhibitor and secretory leukoprotease inhibitor (sLPI), a cationic protein found in serous secretory glandular cells.³ In healthy airways, antiproteases are present in higher quantities than protease enzymes and provide a protease screen.³⁷

Epithelial ion transport

The composition and volume of the periciliary fluid layer is regulated in part by ion transport across the epithelial cells lining the airway lumen. If the periciliary layer is not approximately the height of an extended cilium, effective mucus movement cannot occur.³⁸ Defective ion transport contributes to the cycle of retained secretions and infection seen in CF.^39,40 Normal airway epithelial ion transport is illustrated in Figure 9-6.

In the basal, unstimulated state, sodium (Na⁺) absorption into the epithelial cell is the dominant ion exchange that absorbs liquid from the airway periciliary layer. Sodium absorption occurs as an active transport process through sodium channels (epithelial sodium channel [ENaC]) on the apical (airway) side of the cell. Sodium in the epithelial cell is pumped from the cell, driven by a sodium/potassium-ATPase pump on the basolateral membrane of the epithelial cell shown in Figure 9-6. When sodium is absorbed from the airway surface liquid, there is an accompanying absorption of chloride ions and water.⁴¹ Chloride secretion can occur through at least two different types of chloride channel in the cell apex. One channel is dependent on cyclic adenosine 3′,5′-monophosphate (cAMP), the cystic fibrosis transmembrane ion conductance regulator (CFTR) channel; the other channel is calcium activated.

To summarize, under normal conditions, healthy airway epithelia can absorb salt and water driven by an active sodium transport. Normal epithelia can also secrete liquid into the periciliary fluid driven by active chloride transport through ion channels and passively through aquaporins or water channels.

Mucus in disease states

The normal clearance of airway mucus can be altered by changes in the volume, hydration, or composition of the secretion. Mucus is produced and secreted by surface goblet cells and submucosal gland cells. Water content is a function of transepithelial chloride secretion, active sodium absorption, and water transport. The composition of respiratory mucus is undergoing investigation based on structural analysis techniques.^42,43

Knowledge of these features of respiratory mucus may lead to a better understanding of diseases characterized by an abnormal production of mucus, such as CB and asthma, in which there is mucus hypersecretion, and CF, in which there is decreased intact mucin. Although it had been hypothesized that patients with CF hypersecrete viscous mucus leading to airway obstruction, it has now been shown that tenacious (but not viscous) secretions that characterize CF airway disease are composed almost entirely of DNA-rich pus.⁴⁴ Airway damage may predispose to bacterial infections in CB because of impaired clearance of mucus.

Sputum, or expectorated phlegm, is composed of mucus mixed with inflammatory cells, cellular debris, polymers of DNA and filamentous (F)-actin, and bacteria. Mucus is usually cleared by airflow and ciliary movement, and sputum is cleared by cough.⁴⁵ Purulent, green phlegm is caused by the neutrophil-derived enzyme myeloperoxidase, indicating neutrophil activation; this sputum contains very little mucin and can be considered pus.⁴⁶ Bronchial obstruction by secretions, either mucus or pus, can increase airflow resistance and lead to complete airway obstruction and atelectasis.¹² Regardless of whether the airway is full of mucus or phlegm, effective airway clearance is vital to airway hygiene.