Sleep Disorders, Asthma, General | April 7, 2015 | Author: The Super Pharmacist
The survival of all mammals, birds, and reptiles depends on the essential and complex tasks of the lung organs. Not only do they absorb oxygen and expel carbon dioxide, they have crucial defense mechanisms which protect against disease. The major components of the respiratory system are the bronchi, the larger conducting airways that begin at the end of the trachea and go into the lung; the bronchioles, the more narrow airways that branch from the bronchi; and alveoli, the tiny air sacs located at the end of the bronchioles.
In the traditional view, mechanical clearance of mucus is considered the primary innate airway defense mechanism. In general, the hydration of mucosal surfaces determines the efficiency of mechanical transport, for example, during blinking and swallowing. It was widely assumed that ciliary activity and mucin secretion were the major determinants of airway mucus clearance. While both are important, the balance of evidence suggests that hydration is the dominant variable governing mucus clearance.
The inner airway is lined by small beating hairs called ‘cilia.' The airway is also coated with a liquid bilayer composed of a watery layer surrounding the cilia and a mucus layer that rests on the watery layer. A thin layer of surfactant (a compound that lowers the surface tension between two liquids) is believed to separate the watery and mucus layers. The mucus layer is a complex mixture of water, proteins and glycoproteins, lipids and salts; some of which possess protective functions such as anti-microbial, anti-protease, and anti-oxidant activity. Glycoprotein compounds called ‘mucins’ are mainly responsible for the viscoelastic property of mucus, which is crucial for the effective clearance of inhaled particles. Mucins may also contribute important antimicrobial and anti-inflammatory properties. The small beating hairs of cilia move the mucus, and collect dirt, bacteria, viruses, pollen and other potential contaminants thereby preventing them from entering the lungs, nose and throat. Mucus is transported from the lower respiratory tract into the pharynx by the mechanism termed ‘mucociliary clearance.’
Mucociliary clearance describes the self-clearing mechanism of respiratory secretions from the bronchi up to the oropharynx (mouth).
Foreign particles and microorganisms can become lodged in the mucus layer. Within the watery layer of the respiratory secretions, the cilia act out movements coordinated in the direction of the pharynx. Thereby, the viscous film of mucus along with any contaminants are transported toward the mouth, where they are either swallowed or expelled via coughing. The amount of mucus produced at a given level in the bronchial tree depends on the number of mucus-producing cells at that level, which is related to the total airway surface, so more mucus is produced in the peripheral (small) airways than in the central airways. In normal situation, the total amount of mucus that reaches the trachea is about 10–20 mL/day. The decrease of the total airway surface from the peripheral to the central airways is proportionally related to a decrease in the number of ciliated cells. That is, the number of ciliated cells per unit of airway surface decreases from the peripheral to the proximal central airways, so the central airways have less mucociliary transport capacity than the peripheral airways.
In the central airways, airflow is the primary mechanism of mucus transport. In patients with airways disease, mucociliary transport may be impaired and airflow transport may become the most important mucus transport mechanism. Thus, the two main mechanisms for clearing mucus from the lower respiratory tract into the pharynx are by mucociliary clearance and expiratory airflow.
Disruption of normal secretion or mucociliary clearance impairs pulmonary function and lung defense and increases the risk of infection.
The general term for medications that are meant to affect mucus properties and promote secretion clearance is “mucoactive.” Mucoactive drugs can be classified as expectorants, mucolytics, mucokinetics, or mucoregulators based on their presumed mechanism of action. Mucoactive medications are intended either to increase the ability to expectorate sputum or to decrease mucus hyper secretion.
An expectorant can be defined as an agent that induces discharge or expulsion of mucus from the respiratory tract. This typically requires a coughing or sneezing action to loosen and bring up the mucus from the lungs or upper respiratory tract. These events can be seen as beneficial if mucus plugs that obstruct large, medium or small airways are dislodged. This may in turn reduce the mechanical effort of breathing and dyspnoea. Some frequently used expectorants include aerosol (hypertonic saline), iodide-containing compounds, guaifenesin and ion channel modifiers, such as the P2Y2 purinergic agonists.
The structural integrity of a cell depends upon its cytoskeleton. This cytoskeleton is much like a scaffold composed of three polymers: F-actin, microtubules and intermediate filaments. Living cells have the ability to move and change shape in response to environmental stimuli as a consequence of the dynamic nature of the cytoskeleton and its actin network. Certain biochemical conditions promote single actin units (monomers) to join (polymerise) and form filaments (F-actin). These polymers together with various cross-linking and associated proteins influence the degree of viscoelasticity of gel-like substances such as mucus. Mucociliary clearance depends in part, on the optimal viscoelasticity of airway secretions. Mucolytics can be defined as drugs that decrease mucus viscosity. There are two categories of mucolytics: classic mucolytics and peptide mucolytics.
Classic mucolytics: Classic mucolytics decrease the viscosity of respiratory secretions by degrading the mucins found in the mucus layer of airway secretions. The mucin polymer network is essential for normal mucus clearance. The best known of these agents is N-acetyl L-cysteine (NAC). There are no data that support the clinical use of aerosol NAC for the therapy of lung disease. A large, prospective, randomised trial in subjects with chronic bronchitis showed no benefit of high dose oral NAC over placebo. Orally administered NAC does not penetrate into the airway or bronchial lavage fluid11and inhaled NAC can cause bronchospasm and airway inflammation.12 No evidence convincingly demonstrates that any classic mucolytic, including NAC, improves the ability to expectorate mucus. It is also theoretically possible that NAC aerosol can increase the risk of airway infection and inflammation by disrupting the protective mucin layer.6 Because there are no data that show aerosol NAC to be effective for lung disease, and because of its potentially adverse effects, its use is not recommended.
Peptide mucolytics: With airway inflammation and inflammatory cell necrosis, a secondary polymer network of DNA and F-actin develops in purulent secretions. In contrast to the mucin network, this pathologic polymer gel serves no obvious purpose in airway protection or mucus clearance. Peptide mucolytics degrade these abnormal polymers. Dornase alfa (Pulmozyme) is widely used for the treatment of cystic fibrosis (CF) airway disease and this peptide mucolytic has been shown to improve pulmonary function and decrease the frequency of pulmonary exacerbations when used daily as an aerosol. However dornase has not been shown to be effective in treating any pulmonary disease other than CF. Thymosin β4 has also shown promise in vitro as a peptide mucolytic and potentially an anti-inflammatory agent for the treatment of CF.
These agents act on cilia and increase ciliary beat frequency, these agents have little effect on mucociliary clearance in patients with pulmonary disease. Mucokinetic medications include bronchodilators, tricyclic nucleotides and ambroxol. Surfactants also promote cough clearance of mucous by decreasing the surface adhesion between mucous and airway epithelium.
Bronchodilators: There is evidence in favour of the use of β2-adrenergic agonists (e.g. salbutamol) to enhance mucociliary clearance. However, other reports have observed little effect on mucociliary clearance. Interestingly, recent reports have shown that salmeterol could restore secretory functions in CF airway submucosal gland serous cells, and that β2-adrenergic agonists can enhance mucociliary clearance in patients with airway reversibility.
Ambroxol: This agent is thought to stimulate surfactant and mucous secretion, yet promote normalisation of mucous viscosity. The results of clinical studies of ambroxol are conflicting in that some found clinical benefit, whereas others did not. However, a recent systematic review provides evidence of a generalised benefit using ambroxol for a range of parameters, including secretolytic activity (promoting mucus clearance), anti-inflammatory and antioxidant activity and local anaesthetic effect.
Mucoregulatory agents inhibit mucus production or mucus secretion. Anticholinergic medications are the most well studied agents in this class. Anticholinergics can reduce the volume of stimulated secretions without increasing viscosity. The topical anticholinergic bronchodilator, oxitropium bromide, has been shown to decrease the volume of secretions in patients with chronic bronchitis without changing mucus viscoelasticity. In one study with COPD patients without exacerbations, tiotropium bromide treatment did not improve tracheobronchial clearance when compared with placebo. Inflammation leads to mucous gland hyperplasia and many inflammatory mediators are potent secretagogues. Indomethacin has been administered by aerosol for the treatment of mucus hypersecretion in persons with diffuse panbronchiolitis, chronic bronchitis, or bronchiectasis. Macrolide antibiotics can reduce airway mucin secretion by virtue of their immunomodulatory activity. Erythromycin and clarithromycin have been successfully used to treat mucus hypersecretion in patients with bronchorrhea, asthma, and sinusitis. Low dose and long term azithromycin therapy is now routinely used for the therapy of CF.
Acute upper respiratory infections include pharyngitis, sinusitis, and the common cold. Acute cough due to upper respiratory tract infection is a common symptom. Non-prescription over-the-counter (OTC) medicines are frequently recommended as a first-line treatment. The updated 2012 Cochrane review of the use of over-the-counter (OTC) medications for acute cough in ambulatory settings included 26 randomised controlled trials involving 4037 participants. Specifically, with regard to the efficacy of expectorants, two trials with a total of 304 participants compared the expectorant, guaifenesin, with placebo. In the larger study which included 239 adults,3775% of participants taking guaifenesin stated that the medicine was helpful in terms of reducing cough frequency and intensity compared to 31% in the control group at 72 hours.
The second study of 65 adults evaluated the antitussive effect of guaifenesin rather than its efficacy as an expectorant. Nevertheless, 96% of participants taking guaifenesin reported a significant reduction in sputum thickness compared to 54% in the placebo group.
One trial involving 99 participants compared the mucolytic, bromhexine, 5mg three times daily for an average of four days with placebo. Frequent cough (every two to five minutes) was more prevalent in the placebo group (15.2%) compared to the treatment group leading to a risk ratio reduction of about 50% for frequent cough. The review concluded that there was no reliable evidence either for or against the efficacy of these medications in acute respiratory infections. The results should be interpreted with caution because of the small number of trials in each group of drugs, the poor overall quality of the studies, and their conflicting results.
Acute bronchitis has been the term used for an acute respiratory infection that is manifested predominantly by cough with or without phlegm production that lasts for up to 3 weeks. The absence of an infiltrate on the chest radiograph rules out pneumonia as a cause of acute cough and sputum production. Acute bronchitis is a lower respiratory tract infection that causes reversible bronchial inflammation. In up to 95 percent of cases, the cause is viral. One reason that acute bronchitis is such a common diagnosis in primary care practice is that physicians often lump various conditions together under the diagnosis of bronchitis. Cough from upper respiratory tract infections, sinusitis or allergic syndromes (e.g. mild asthma or viral pneumonia) may be diagnosed as acute bronchitis. True acute purulent bronchitis is characterised by infection of the bronchial tree with resultant bronchial oedema and mucus formation. Because of these changes, patients develop a productive cough and signs of bronchial obstruction, such as wheezing or dyspnoea on exertion. The inflammation in acute bronchitis is transient and usually resolves soon after the infection clears. In some patients, however, the inflammation can last several months. There have been no consistent favourable effects shown with expectorant and mucolytic agents on the cough associated with acute bronchitis in several therapeutic trials. The trials have shown conflicting results, and the number of trials in each group of drugs is small. These preparations appear to be safe, based on the reported side effects. However, there is no consistent evidence demonstrating their efficacy in acute bronchitis.
Airway mucus hypersecretion is a prominent feature of these severe respiratory diseases. There appears to be growing evidence to support the very selective use of mucoactive drugs in these conditions.
According to the latest 2015 update of the GOLD (Global Initiativefor Chronic Obstructive Lung Disease), the widespread use of mucolytic, mucokinetic, mucoregulatory and antioxidant agents cannot be recommended. The GOLD statement confirms the possible antioxidant effects of drugs like N-acetylcysteine and that, on this basis, it may play a role in the treatment of patients with recurrent COPD exacerbations. It also indicates that in patients treated with or without inhaled corticosteroids, high doses of N-acetylcysteine significantly reduce exacerbation rates, but these findings only apply to patients with GOLD stage II (ie, moderate disease) patients. Finally, in patients not receiving inhaled corticosteroids, treatment with mucolytics such as carbocysteine and N-acetylcysteine may reduce exacerbations of COPD.
According to the latest 2011 guidelines for the management of adult lower respiratory tract infections issued jointly by the European Respiratory Society (ERS) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID), the prescription of oral mucolytics through the winter months should be considered for those patients who have frequent or prolonged exacerbations, or those who are repeatedly admitted to hospital with exacerbations of COPD and for whom inhaled corticosteroids are not prescribed.
The 2011 ERS/ESCMID guidelines also state that although oral mucolytics have been shown to prevent acute exacerbations in patients with chronic bronchitis, it has not been shown that these agents prevent infection in the general population.
The updated 2010 guidelines for COPD issued by the National Institute for Health and Care Excellence (NICE) recommend the use of mucolytics in patients with a chronic productive cough and, if symptoms do improve, mucolytic medications should be continued. The routine use of mucolytics to prevent exacerbations of COPD is not recommended. The U.S. Food and Drug Aministation (FDA) approved dornase alfa (rhDNase) in 1993. It was the first drug developed specifically for cystic fibrosis. The Pulmonary Therapies Committee of Cystic Fibrosis Foundation recommends long-term use of hypertonic saline for patients with cystic fibrosis aged 6 years or older to improve lung function and to reduce the number of exacerbations.
In a 2012 update, NICE recommended mannitol dry powder for inhalation as a treatment option for cystic fibrosis in adults who could not use dornase alfa due to intolerance or inadequate response and in whom lung function was rapidly declining in a setting where other agents were not considered appropriate.
Scott H. Randell and Richard C. Boucher. Effective mucus clearance is essential for respiratory health. American Journal of Respiratory Cell and Molecular Biology. 2006; 35(1): 20-28.
Knowles MR, Boucher RC. Mucus clearance as a primary innate defense mechanism for mammalian airways. J Clin Invest. 2002 Mar;109(5):571-7.
Toremalm NG. The daily amoung of tracheo-bronchial secretions in man. A method for continuous tracheal aspiration in laryngectomized and tracheotomized patients. ActaOtolaryngolSuppl 1960; 158: 43-53.
Van der Schans, Cees P. Bronchial mucus transport. Respir Care 2007;52(9):1150 –1156.
Rubin BK, van der Schans CP, editors. Therapy for mucus clearancedisorders. Biology of the Lung Series, Claude Lenfant (NIH) Executive editor. New York: Marcel Dekker; 2004.
Rubin BK. Mucolytics, expectorants, and mucokinetic medication. Resp Care.July 2007; 52 (7): 859-865.
Balsamo R, Lanata L, Egan CG. Mucoactive drugs. EurRespir Rev. June 1, 2010;19(116): 127-133.
Alberts B., Bray D., Johnson A., et al. Essential cell biology. An introduction to the molecular biology of the cell. New York: Garland Publishing, 1998.
Rogers DF, Rubin BK.Mucolytics for COPD. In Chronic Obstructive Pulmonary Disease. Edited by Stockley RA, Steven R, Klaus R, Bartolome C. Oxford: Blackwell Publishing; 2006.
Decramer M, Rutten-van Mölken M, Dekhuijzen PN, et al. Effects of N-acetylcysteine on outcomes in chronic obstructive pulmonary disease (Bronchitis Randomized on NAC Cost-Utility Study, BRONCUS): a randomised placebo-controlled trial.Lancet2005; 365:1552-1560.
Cotgreave IA, Eklund A, Larsson K, Moldeus PW.No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid. Eur J Respir Dis 1987; 70:73-77.
Dano G:Bronchospasm caused by acetylcysteine in children with bronchial asthma. ActaAllergol 1971, 26:181-190.
Fuchs HJ, Borowitz DS, Christiansen DH, et al. Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. The Pulmozyme Study Group.N Engl J Med 1994, 331:637-642.
Laube BL, Auci RM, Shields DE, Christiansen DH, et al. Effect of rhDNase on airflow obstruction and mucociliary clearance in cystic fibrosis. Am J RespirCrit Care Med 1996; 153:752-760.
Rubin BK: Who will benefit from DNase?PediatrPulmonol 1999; 27:3-4.
Rubin BK, Kater AP, Goldstein AL. Thymosin β4 sequesters actin in cystic fibrosis sputum and decreases sputum cohesivity in vitro. Chest 2006; 130:1433-1440.
Isawa T, Teshima T, Hirano T, et al. Effect of oral salbutamol on mucociliary clearance mechanisms in the lungs. Tohoku J Exp Med 1986; 150: 51–61.
Anzueto A, Jubran A, Ohar JA, et al. Effects of aerosolized surfactantin patients with stable chronic bronchitis: a prospective randomized controlled trial. JAMA 1997;278:1426–1431.
Daviskas E, Anderson SD, Eberl S, et al. Effects of terbutaline incombination with mannitol on mucociliary clearance. EurRespirJ 2002;20:1423–1429.
Frohock JI, Wijkstrom-Frei C, Salathe M. Effects of albuterolenantiomers on ciliary beat frequency in ovine tracheal epithelial cells. J ApplPhysiol 2002;92:2396–2402.
Mortensen J, Hansen A, Falk M, et al. Reduced effect of inhaledb2-adrenergic agonists on lung mucociliary clearance in patients with cystic fibrosis. Chest 1993;103:805–811.
Delavoie F, Molinari M, Milliot M, et al. Salmeterol restores secretory functions in cystic fibrosis airway submucosal gland serous cells. Am J Respir Cell MolBiol2009;40:388–397.
Sears MR. Safety of long-acting b-agonists: are new data really required? Chest 2009;136:604–607.
Germouty J, Jirou-Najou JL. Clinical efficacy of ambroxol in the treatment of bronchial stasis: clinical trial in 120 patients at two different doses. Respiration 1987; 51: 37–41.
Guyatt GH, Townsend M, Kazim F, et al. A controlled trial of ambroxol in chronic bronchitis. Chest 1987; 92: 618–620.
Malerba M, Ragnoli B. Ambroxol in the 21st century: pharmacological and clinical update. Expert Opin Drug MetabToxicol 2008; 4: 1119–1129.
Bateman ED, Rennard S, Barnes PJ, Dicpinigaitis PV, Gosens R, Gross NJ, Nadel JA, Pfeifer M, Racké K, Rabe KF, Rubin BK, Welte T, Wessler I: Alternative mechanisms for tiotropium. Pulm Pharm Therapeutics 2009, 22:533-542.
Tamaoki J, Chiyotani A, Tagaya E, Sakai N, Konno K: Effect of long term treatment with oxitropium bromide on airway secretion in chronic bronchitis and diffuse panbronchiolitis. Thorax 1994, 49:545-548.
Hasani A, Toms N, Agnew JE, Sarno M, Harrison AJ, Dilworth P: The effect of inhaled tiotropium bromide on lung mucociliary clearance in patients with COPD. Chest 2004, 125:1726-1734.
Tamaoki J, Chiyotani A, Kobayashi K, Sakai N, Kanemura T, Takizawa T: Effect of indomethacin on bronchorrhea in patients with chronic bronchitis, diffuse panbronchiolitis, or bronchiectasis.Am Rev Respir Dis 1992, 145:548-552.
López-Boado YS, Rubin BK: Macrolides as immunomodulatory medications for the therapy of chronic lung diseases. Curr Opinion Pharmacol 2008, 8:286-289.
Rubin BK, Tamaoki J: Macrolide antibiotics as biological response modifiers. CurrOpinInvestig Drugs 2000, 1:169-172.
Rubin BK: Immunomodulatory properties of macrolides: overview and historical perspective.Am J Med 2004, 117:2S-4S.
Rubin BK, Henke MO: Immunomodulatory activity and effectiveness of macrolides in chronic airway disease.Chest 2004, 125(2 Suppl):70S-78S.
Southern KW, Barker PM, Solis A: Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2004, 2:CD002203.
Smith SM, SchroederK, Fahey T.Over-the-counter (OTC) medications for acute cough in children and adults in ambulatory settings. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD001831.
Robinson RE, Cummings WB, Deffenbaugh ER. Effectiveness of guaifenesin as an expectorant: a cooperative double-blind study. Current Therapeutic Research 1977;22 (2):284–96.
Kuhn JJ, Hendley JO, Adams KF, Clark JW, GwaltneyJMJr. Antitussive effect of guaifenesin in young adults with natural colds. Chest 1982;82(6):713–8.
Nesswetha W. Criteria of drug testing in industrial practice, demonstrated by a cough remedy [Kriterien der Arzneimittelpruefung in der werksaerztlichen Praxis, dargestellt am BeispieleinesHustenloesers]. Arzneimittelforschung1967;17(10):1324–6.
Gonzales R, Sande M. Uncomplicated acute bronchitis. Ann Intern Med 2000; 133:981–991.
Perlman PE, Ginn DR. Respiratory infections in ambulatory adults. Choosing the best treatment. Postgrad Med. 1990;87(1):175–84.
Hueston WJ, MAainous AG 3rd. Acute bronchitis. Am Fam Physician. 1998 Mar 15;57(6):1270-6, 1281-2.
Williamson HA Jr. A randomized, controlled trial of doxycycline in the treatment of acute bronchitis. J FamPract. 1984;19(4):481–6.
Schroeder K, Fahey T. Over-the-counter medications for acute cough in children and adults in ambulatory settings. Cochrane Database Syst Rev (database online). Issue 4, 2004.
Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2015. Available from: http://www.goldcopd.org/ Accessed 1 Apr 2015.
Woodhead, M., Blasi, F., Ewig, S., Garau, J., Huchon, G., Ieven, M., Ortqvist, A., Schaberg, T., Torres, A., van der Heijden, G., Read, R., Verheij, T. J. M. and Joint Taskforce of the European Respiratory Society and European Society for Clinical Microbiology and Infectious Diseases (2011), Guidelines for the management of adult lower respiratory tract infections - Full version. Clinical Microbiology and Infection, 17: E1–E59.
Chronic obstructive pulmonary disease. NICE guidelines [CG101] June 2010.Available at: http://www.nice.org.uk/Guidance/CG101/Resources. Accessed 1 April 2015.
[Best Evidence] Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J RespirCrit Care Med. Nov 15 2007;176(10):957-69.
Mannitol Dry Powder for Inhalation for Treating Cystic Fibrosis. NICE Technology Appraisal Guidance No. 266. Available at: http://guidance.nice.org.uk/TA266. Accessed 1 April 2015.