Cough is one of the most frequently encountered symptoms physicians need to diagnose. A number of cough mixtures are available for prescription, but it is vital to understand the aetiology of cough, the nature of the mixture ingredients and possible side effects.
The lungs are remarkably resistant to environmental injury, despite continuous exposure to pathogens, particles, and toxic chemicals in inhaled air, but this resistance depends on a highly effective defense provided by airway mucous (Fahy and Dickey 2010). Effective mucous clearance is essential for lung health, and airway disease is a typical consequence of poor clearance (Zanasi et al 2017). Physiologically, mucous is a gel with low viscosity and elasticity that is easily transported by ciliary action, whereas pathologic mucous has higher viscosity and elasticity and is less easily cleared (Zanasi et al 2017).
The conversion from healthy to pathologic mucous occurs by multiple mechanisms that change its hydration and biochemical constituents; these include (Fahy and Dickey 2010):
- abnormal secretion of salt and water;
- increased production of mucins;
- infiltration of mucous with inflammatory cells; and
- heightened bronchovascular permeability.
Mucous is the collective term for mucins, ions, water and other substances normally present on mucosal surfaces which, by virtue of highly glycosylated secreted mucins, lipids, and soluble proteins, bind and entrap a broad array of inhaled particles (Livraghi and Randall 2007). Since increased airway secretions characterise obstructive lung diseases, including asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), treatment modalities have paid particular attention to the regulation of mucous secretory cell number, mucin gene expression and glycoprotein production, and the secretory pathways that mediate mucin release (Livraghi and Randall 2007).
Airway inflammation, mucous hypersecretion and impaired mucociliary clearance are the major characteristics of a variety of pulmonary diseases (Zanasi et al 2017). Altered mucous clearance likely contributes to the initiation, progression, and chronicity of airway diseases characterised by inflammation and mucous secretory cell hyper/metaplasia that afflict millions worldwide, including COPD (Livraghi and Randall 2007).
A five-part reflex is responsible for cough production (Truter 2007):
1. Receptors located mainly in the pharynx, larynx, trachea and bifurcations of the large bronchi are stimulated via mechanical, irritant or thermal mechanisms.
2. Neural impulses are then carried along afferent pathways of the vagal and superior laryngeal nerves, which terminate at the cough centre in the medulla.
3. Efferent fibres of the vagus and spinal nerves carry neural activity to the muscles of the diaphragm, chest wall and abdomen.
4. The diaphragm muscles contract.
5. This causes the sudden opening of the glottis.
Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists (De Blasio et al 2011). As a clinical symptom, cough is primarily linked to upper respiratory tract infection (Kerkar 2019).
Cough is an important defensive reflex that enhances the clearance of secretions and particles from the airways and protects the lower airways from the aspiration of foreign materials (De Blasio et al 2011). As cough is a vital protective reflex for the airways, this predicates that the goal of cough treatment must be the restoration of a normal cough reflex (Morice et al 2004).
In addition to being an airway defence mechanism, coughing is a very common symptom observed in many diseases other than those affecting the respiratory system, so recognising its cause is not always an easy task (De Blasio et al 2011). Besides the commonly known classification of cough into either wet (with phlegm) or dry (without phlegm), it is possible for cough to be characterised according to duration of cough, as either (Chang et al 2006):
- Acute cough: cough duration of < 2 weeks;
- Protracted acute cough: cough duration between 2 and 4 weeks; and
- Chronic cough: cough duration of > 4 weeks
Many patients will say that they are not producing sputum, although they go on to say that they “can feel it on their chest” (Truter 2007). In these cases the cough is probably productive/wet in nature and should be treated as such (Truter 2007). While a cough can be a common symptom of both a cold and flu, many patients have trouble differentiating between these two types of coughs, and may end up using the incorrect treatments, leading to a cough remaining untreated for longer than necessary (Kerkar 2019).
Referrals for cough
Although cough is usually diagnosed and treated at a primary care level, trigger points indicative of referral for cough are (Truter 2007):
- Cough accompanied by chest pain.
- Recurrent and nocturnal cough.
- Cough lasting three weeks or longer without improvement.
- Patient has general malaise, persisting sweats or fever.
- Haemoptysis or sputum is discoloured, with pain on inspiration.
- Wheezing, difficulty breathing and/or shortness of breath.
- Pertussis (whooping) cough is suspected.
- An adverse drug reaction is suspected.
- Cough with unexplained weight loss.
- GORD is the suspected cause of the cough.
- Smoker’s cough that has changed in nature.
- Any persistent cough in patients exposed to occupational lung diseases, such as miners and chemical factory workers.
General cough treatment
Where possible, the clinician should avoid treatment based on symptoms which often only serve the purpose to reassure the patient or the parents (in the case of a paediatric patient), although this is sometimes justified as a therapeutic technique (De Blasio et al 2011). Dry cough is normally treated with antitussives while wet cough is commonly treated with an expectorant (Kerkar 2019). Antituttives help in suppressing a cough, while expectorants are responsible for softening and expelling a cough (Kerkar 2019). Health professionals often recommend the use of self-prescribe OTC preparations for the initial treatment of cough, although there is little evidence for their effectiveness (De Blasio et al 2011).
In South Africa, cough mixtures may be a combination of many different active ingredients, and there are more than 40 different cough mixtures listed for use in the Monthly Index of Medical Specialities (MIMS) (Hanson 2018). Treatment with cough mixtures should be individualised for each patient and is indicated for short-term, symptomatic treatment of acute cough (Hanson 2018). This sort of targeted treatment for pathologic airway mucous not only improves symptoms of cough and dyspnea but also decreases the frequency of disease-related exacerbations and slows disease progression (Fahy and Dickey 2010).
Drug therapy with cough mixtures is tailored to the component of the cough reflex that is being treated, and the recommended treatments are (Hanson 2018):
- For a non-productive cough: Antitussive-dextromethorphan and Pholcodine is preferred to codeine
- For bronchoconstriction associated with cough: Bronchodilators combined with expectorants/mucolytics.
- For cough originating from the pharyngeal region: Demulcent syrups combined with a cough suppressant, as well as a cough suppressant/decongestant combination.
Wet cough treatment
When it comes to treating a wet cough, one of the most common treatments is the use of an expectorant, which have been proven to to facilitate the expulsion of bronchial secretions (Truter 2007). Expectorant combinations include decongestants, bronchodilators and cough suppressants, although combinations of expectorant and cough suppressant are not advisable, as they have opposing actions on the mucus, the one suppressing the cough and the other assisting with coughing out of mucus (Hanson 2018). Combinations of decongestants, expectorants and bronchodilators could be of benefit for patients with blocked noses, wheeze and cough with mucous hypersecretion (Hanson 2018).
Expectorants and Mucolytics
Cough mixtures for wet coughs either contain a single ingredient or a combination of ingredients to promote coughing and make it easier to cough up mucous or phlegm (Truter 2007). Guaifenesin is the most common expectorant and the dose required to be effective is 100–200 mg per dose for adults (Hanson 2018). It has no mucolytic action but may reduce bronchial sputum surface tension (Hanson 2018).
Because a wet cough should not be suppressed, as the phlegm or mucous may cause breathing problems or infection, mucolytics such as bromhexine are useful, since they help to decrease mucous viscosity, making it easier for the patient to cough up mucus (Van Schoor 2012). Bromhexine directly loosens and thins bronchial secretions by reducing the surface tension and viscosity of mucous (Hanson 2018).
Bromhexine is a widely prescribed mucoactive over-the-counter drug used to treat a range of respiratory conditions, mainly conditions associated with mucous secretion disturbances (Zanasi et al 2017). These conditions are predominantly associated with augmented inflammation and vulnerability to the development of infections (Zanasi et al 2017). Various clinical studies have demonstrated that bromhexine influences cough, demonstrating that bromhexine treatment leads to a normalisation in expectoration, and reduces the severity and frequency of coughing (Zanasi et al 2017).
Treatment with bromhexine is associated with favorable improvements in mucous clearance and is indicated in various respiratory disorders with abnormal mucous secretion and impaired mucus transport (Zanasi et al 2017). Furthermore, bromhexine is well tolerated and studies showed low incidence of mild side effects (Zanasi et al 2017).
Expectorant combinations include decongestants, bronchodilators and cough suppressants (Hanson 2018). Combinations of expectorant and cough suppressant are not advisable, as they have opposing actions on the mucous, the one suppressing the cough and the other assisting with coughing out of mucous (Hanson 2018).
Bronchodilators are drugs often used to widen the air passages by relaxing the bronchial muscle (Gadomski and Scribani 2014). Bronchodilators like salbutamol work by reversing bronchoconstriction of the airways due to bronchospasm induced by asthma triggers, viruses, exposure to toxic inhalants, etc (Gadomski and Scribani 2014). International guidelines suggest that long-acting bronchodilator therapy should always be considered in both the treatments of COPD and asthma (Cazzola and Matera 2008).
Salbutamol is a β2-selective adrenergic bronchodilator which acts by stimulating β2-adrenergic receptors in the lungs to relax bronchial smooth muscle (Wong et al 1990). It is used to rapidly treat asthma, bronchospasm and reversible airways obstruction by widening the airways of the lungs (Austin et al 2018). It appears that salbutamol can improve mucociliary clearance in some patients with COAD (Pacifici and Allegaert 2015). In a study, clearance rates (percentage activity cleared per hour) from the lungs in the hour after salbutamol inhalation averaged 33.1% +/- 13.5 (SD) per hour, for patients (control 12.2% +/- 5.6 (SD) per hour, p less than 0.001) and 16.1% +/- 4.3 (SD) per hour for normals (control 7.8% (Lafortuna and Fazio 1984).
At present, three major classes of bronchodilators, β2-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination (Hanson 2018). Theophylline (xanthine), and orciprenaline (β2-adrenoceptor (AR) agonists) as bronchodilators are frequently combined with mucolytics such as bromhexine (Hanson 2018).
The current opinion is that it will be advantageous to develop medications containing combinations of several classes of long-acting bronchodilator drugs in an attempt to simplify treatment regimens as much as possible (Cazzola and Matera 2008).
Demulcents include simple linctus and products containing ingredients such as honey and lemon, syrup or glycerol (Truter 2007). They are thought to coat the pharyngeal mucosa, soothing inflammation and reducing irritation, and can be used to treat both productive and non-productive coughs, but there is as yet no evidence for their efficacy (Truter 2007).
Demulcents can be safely taken by most patients, including pregnant women and children, although their high sugar content should be noted (Truter 2007). Demulcents may help reduce coughing associated with a dry irritated throat, although some demulcents contain up to 40% alcohol and should never be used (Hanson 2018).
Possibility of cardiac side-effects
The use of bronchodilators, while effective for cough treatment, could lead to cardiac side-effects (Bennett and Tattersfield 1997). Bronchodilators used in the treatment of airway disease have been shown to have a variety of cardiac effects that may contribute to the occurrence of life-threatening events such as cardiac arrhythmias and cardiac arrest (Suissa et al 1996).
In a double-blind, crossover, placebo-controlled study, the airway response and cardiovascular and hypokalaemic effects of fenoterol, salbutamol, and terbutaline given in multiples of standard doses from metered-dose inhalers were studied in ten patients with mild asthma (Wong et al 1990). All three drugs produced similar bronchodilatation, however, the rises in heart rate, QTc interval, and tremor and the fall in plasma potassium were greater after fenoterol than after terbutaline or salbutamol (Wong et al 1990).
In a study of a population-based cohort of 12 301 subjects aged 5 to 54, spanning the period 1978 to 1987, results suggested that the use of theophylline and beta-agonists administered orally or by nebulisation should be avoided in subjects with significant cardiac disease or at high risk for such disease, especially acute coronary insufficiency and congestive cardiomyopathy (Suissa et al 1996). On the other hand, the use of beta-agonists administered by metered-dose inhalers (MDIs) was not associated with an increased risk of cardiovascular death (Suissa et al 1996).
Targeted treatment of pathologic airway mucus not only improves symptoms of cough and dyspnea but also decreases the frequency of disease-related exacerbations and slows disease progression (Fahy and Dickey 2010). Elucidation of how mucin production is controlled is still needed, since that might allow the development of additional therapies to prevent overproduction (Fahy and Dickey 2010). That said, patients often consider cough preparations beneficial and often report improvements in symptoms following their use (Hanson 2018).