Owing to its major burden on secondary health care, chronic obstructive pulmonary disease (COPD) is widely established as a health challenge, with predictions that it will be the third leading cause of global mortality and reduced health status within the next 10 years (World Health Organization (WHO), 2020). Fluctuations in stable states of COPD is the second largest cause of emergency hospitalisation (National Institute for Health and Care Excellence (NICE), 2011) and, given the expanding COPD population in Northern Ireland (Department of Health, Social Services and Public Safety, 2015) where the author is based, the assessment and management of such individuals is common within the practice of respiratory nurse specialists (RNSs). The RNS can have a direct role in advising and prescribing treatment for this patient population, and it is therefore necessary that the RNS makes prescribing decisions based on the best available evidence.
Pathophysiology of COPD
COPD is described as a preventable and treatable group of lung conditions characterised by airflow obstruction that is not fully reversible (Global Initiative for Chronic Obstructive Lung Disease (GOLD), 2019). It is represented by two pathologies associated with an abnormal inflammatory response of the respiratory airways (Barnes et al, 2009), with chronic bronchitis and emphysema both responsible for developing airflow resistance within the large and small air passages of the lung (Porth, 2015). Such heightened inflammatory responses occur mostly as a result of exposure to inhaled noxious particles (MacNee, 2011), with tobacco smoking the leading aetiology of COPD development (GOLD, 2019, NICE, 2019).
The respiratory system is divided into the upper and lower respiratory tracts, with structures including the nose, pharynx, larynx and trachea within the upper tract, and the bronchial tree and lungs within the lower (McLafferty et al, 2013). Its primary function is concerned with gaseous exchange of oxygen and carbon dioxide between the blood and the atmosphere (Hinkle and Cheever, 2014), achieved through the process of ventilation (Bearsley et al, 2012), whereby the movement of gas through the conducting and respiratory airways is dependent on pressure changes from respiratory muscle innervation (West, 2012). Gaseous exchange occurs on an alveolar level (Porth, 2015), with normal regulation of diffusion gradients between the alveoli and blood in the capillaries essential for stable internal homeostasis (McLafferty et al, 2013).
The effectiveness of this mechanism is inhibited in the pathological development of COPD, with resistance to airflow in narrowed airways due to recurrent inflammatory processes representative of chronic bronchitis (Lynes, 2007). Porth (2015) identified increased airflow limitation in chronic bronchitis as a result of smooth muscle hypertrophy, hyperplasia of mucous-secreting glands with associated hypersecretion, reduced ciliary function and fibrosis of bronchiolar walls (Tam, 2012). Emphysema destroys the walls of gas exchange airways, resulting in loss of elasticity and over-distention of alveoli (Hinkle and Cheever, 2014), leading to eventual lack of ventilation, altered diffusion gradients and impairment of gas transfer (Porth, 2015). Such pathophysiological remodelling of the large and small airways will therefore manifest in persistent respiratory symptoms such as cough, sputum production and breathlessness (Shapiro et al, 2010), the latter of which have minimal variability and are progressive by nature (GOLD, 2019).
Exacerbations of COPD
COPD is associated with periods of instability, referred to as exacerbations (Decramer et al, 2012). Wedzicha and Seemungal (2007) defined an exacerbation as an acute deterioration of usual respiratory symptoms requiring additional therapy, with severe classifications usually resulting in hospitalisation (GOLD, 2019). The causative factors for exacerbations have been thoroughly explored, with studies identifying viral and bacterial infections as the most common trigger in hospitalised unstable COPD (Wilkinson et al, 2006).
Increased airway and systemic inflammation is the main sign of COPD exacerbation (Hurst et al, 2006), with bronchitic abnormalities of oedema, increased mucous production and bronchoconstriction manifesting symptoms of cough, dyspnoea and wheeze (Wedzicha and Seemungal, 2007). The combination of these factors elicit an abrupt increase in airflow resistance, with the consequence of dynamic hyperinflation through worsening expiratory flow limitation and compromised time available for lung emptying (O'Donnell and Parker, 2006). The physiological response is a rapid and shallow breathing pattern, recognised as the main cause of acute dyspnoea and the most common symptom of the COPD exacerbation (Wedzicha and Seemungal, 2007). MacNee (2006) highlighted how respiratory muscle fatigue is an eventuality in this process, with the consequence of insufficient ventilation and life-threatening respiratory failure if poorly treated.
Pharmacotherapeutics of salbutamol
Bronchodilators in COPD
Bronchodilator agents are core pharmacological treatments in COPD (Wedzicha et al, 2012), with short-acting preparations arguably most effective in reducing airflow obstruction and relieving respiratory symptoms in acute exacerbations (Rodriguez-Roisin, 2006). Recent guidelines provide support, recommending short-acting bronchodilator agents such as salbutamol as best practice in the initial treatment of unstable COPD (GOLD, 2019).
Bazargani et al (2014) described salbutamol as a short-acting selective beta-2 adrenergic receptor agonist, classified in the family of bronchodilators in the British National Formulary, (Joint Formulary Committee, 2020). Its primary function is relaxation of inflamed and contracted airway smooth muscle (McFadden, 2014) commonly triggered by bacterial illness (Burt and Corbridge, 2013), with symptoms of severe bronchoconstriction causing acute respiratory distress in unstable COPD (Jones et al, 2011).
Airway smooth muscle tone is controlled by the autonomic nervous system (McFadden, 2014) whereby parasympathetic nerve stimulation initiates constriction and sympathetic nerves dilate. Porth (2015) described how sympathetic innervation releases adrenaline, a circulatory hormone that binds to beta-2 adrenergic receptors of airway smooth muscle cells (Lilley et al, 2017). Binding to such receptors initiates bronchial smooth muscle relaxation throughout the respiratory airways (Porth, 2015). Salbutamol is therefore classified as a sympathomimetic agent, whereby it binds to beta-2 adrenergic receptors due to its similar structure to adrenaline (Boarder et al, 2010).
Binding of salbutamol to beta-2 adrenergic receptors in the airways stimulates the enzyme adenylate cyclase (Lilley et al, 2017), of which is responsible for converting energy-carrying molecules of adenosine triphosphate into cyclic adenosine monophosphate (Woo, 2016). Elevated intracellular levels of this cyclic compound increases protein kinase A activation, modifying regulatory proteins involved in smooth muscle tone control and inhibiting release of ionic calcium concentrations from intracellular stores (Malhatra and Shafique, 2011). This signalling cascade causes rapid relaxation of airway smooth muscle (Billington and Hall, 2011), with the effects of bronchodilation being therapeutic in alleviating acute symptoms of wheeze and dyspnoea in COPD exacerbations (Rodriquez-Roisin, 2006).
Waller et al (2014) highlighted how salbutamol can also promote bronchodilation by inhibiting release of bronchoconstricting agents associated with airway inflammation in the COPD exacerbation. This supported Malhatra and Shafique (2011), who argued that beta-2 adrenoceptor activation supresses inflammatory mediator release from mast cells in the airways, subsequently reducing airflow limitation and enhancing mucociliary clearance (Gladson, 2011).
Inhaled administration of salbutamol has been long recognised as a core standard treatment in obstructive lung disease (GOLD, 2019). Delivery via a pressurised metered-dose inhaler (pMDI) is the most widely used method due to its low cost, effectiveness and simplicity of use (Lavorini and Fontana, 2009). Despite this, it is important to recognise that the pMDI is frequently used incorrectly (Crompton, 1982; Vincken et al, 2018). Sanchis et al (2016) argued that more than two-thirds of people take their inhaled therapy erroneously, and that even with optimal technique pMDIs can deliver at best only 20% of the inhaled drug. This was supported by Newman et al (1982) and Vincken et al (2018). The addition of a spacer device or valved holding chamber (VHC) to a pMDI device has been found to improve medication delivery to the airways (McIvor et al, 2018), and it is now recommended in national and international guidelines that a VHC device is used with pMDIs for both regular and emergency use of medications (NICE, 2019; GOLD, 2019).
Various studies have shown that emergency use of salbutamol in the context of an exacerbation of airways disease via the use of a pMDi with VHC is at least as effective as nebulised therapy (Cates et al, 2013; Van Geffen et al, 2016). National guidelines support the use of either pMDi or nebulised methods of salbutamol in acute exacerbations of COPD; however, the choice of delivery system should reflect the dose of drug required and the ability of the individual to use the device effectively (NICE, 2019). GOLD (2019) therefore recommends that the nebulised route may be the easier delivery method for more acutely unwell patients in the COPD exacerbation.
Aerosolised formulations of salbutamol are considered effective in acute COPD exacerbations. Nakpheng et al (2017) identified that therapeutic efficiency of salbutamol was optimised through delivery directly into the airways. Several authors have argued this is best achieved through nebulisation (Turner et al, 1997; Boe et al, 2001), whereby rapid conversion of salbutamol solution into small droplets for inhalation radically improves acute bronchoconstriction (Laube et al, 2011).
Following deposition onto airway epithelial cells, salbutamol is rapidly absorbed from the bronchi (Kee et al, 2015). The Electronic Medicines Compendium (EMC) (2020) states that less than 20% of inhaled salbutamol reaches the lungs, with the remainder staying in the oral cavity or ingested into the stomach. De Alwis and Weiner (2012) also suggested that only a fifth of the drug reaches the airways due to smaller tidal volumes as a consequence of acute bronchoconstriction.
Upon bronchial absorption, salbutamol experiences transcellular transport due to the compact interconnection of bronchial epithelial cells (Schneeberger and Lynch, 2004), reaching airway smooth muscle cells through glycoprotein and organic cation conveyance (Ehrhardt et al, 2005). Salbutamol molecules bind to protein-based beta-adrenergic receptors on airway smooth muscle membranes (McFadden, 2014), which are ideal targets due to their predominant lung distribution and high bronchial smooth muscle density in comparison to other cell types (Waller et al, 2014).
Salbutamol has a rapid onset of action, exerting its pharmacotherapeutic properties within 5 minutes with symptomatic bronchodilation in less than 15 minutes (Kee et al, 2015). Peak plasma levels occur within 90 minutes, with overall duration of action lasting up to 6 hours (Vallerand et al, 2015). Hodgson and Kizior (2014) identifed the terminal half-life of salbutamol as 3.8 hours.
The distribution of inhaled preparations is not fully understood (Skidmore-Roth, 2015), with variable protein binding capacity estimated as 10% (Kee et al, 2015). Waller et al (2014) stated that salbutamol has low systemic levels, affecting mainly the cardiovascular and skeletal muscle organ systems on distribution. Salbutamol does not cross the blood-brain barrier to any significant extent (Ebadi, 2008); however, it does cross the placenta and is present in breast milk (Skidmore-Roth, 2015).
Metabolism of salbutamol occurs extensively and almost exclusively in the liver (Vallerand et al, 2015). Gardenhire (2016) argued that, because both bronchial and gastrointestinal absorption occurs following aerosolised administration, there is considerable first-pass metabolism in the liver and also the gastrointestinal wall. Malhatra and Shafique (2011) stated that metabolism of salbutamol does not occur in the lung and it has no active metabolites.
Salbutamol excretion occurs primarily in the kidneys (Hodgson and Kizior, 2014), with up to two-thirds remaining unchanged (Ashley and Dunleavy, 2014) and over 80% eliminated in the urine within 24 hours of administration (Kee et al, 2015). Malhatra and Shafique (2011) suggested that excretion occurs rapidly given salbutamol's short plasma half-life. Woo (2016) added to this by identifying that less than 10% of salbutamol is excreted in the faeces.
Woo (2016) argued that ideal bronchodilator agents would only target beta-2 receptors in airway smooth muscle and have no other systemic effects. Waller et al (2014) acknowledged this ideal; however; they stressed that all preparations of salbutamol have unintended interactions with other adrenergic receptors in skeletal muscle and the cardiovascular system. It is possible to minimise side effects by gaining selectivity of action through selective beta-adrenoceptor agonist preparations, with beta-1 selective agonists more active on the heart and beta-2 more active in the airways (McFadden, 2014). Salbutamol demonstrates the greatest selectivity between beta-1 and beta-2 receptors than any other formulation available, and is therefore the most commonly used (Sears and Lötvall, 2005).
Using inhaled preparations is beneficial because the required smaller doses directly target the respiratory tract and are therefore less likely to cause adverse effects in comparison to oral and parental administration (Boushey, 2012). Symptoms of tachycardia and palpitation through stimulation of beta-1 receptors in the heart are common (McFadden, 2014), with associated tremor due to beta-2 receptor activation in skeletal muscle (Skidmore-Roth, 2015). Malhatra and Shafique (2011) stated that tremor is the most common side effect, observed in up to a fifth of individuals receiving inhaled salbutamol in unstable COPD. Waller et al (2014) cautioned that, in rare cases, salbutamol can inadvertently cause life-threatening bronchospasm.
Skidmore-Roth (2015) argued that while pharmacokinetic interactions of salbutamol are not unusual, pharmacodynamic relationships are of concern whereby accessory use with other beta-2 agonists increases hypokalaemia risk and associated arrhythmia. Vallerand et al (2015) added to this, highlighting increased adrenergic side effects of tachycardia and tremor when used with other sympathomimetic agents. Caution in use with beta-blocking agents is advised (Malhatra and Shafique, 2011), whereby non-selective preparations block beta-2 receptors and inadvertently precipitate bronchospasm in COPD (Kee et al, 2015).
GOLD (2019) has recommended the use of long-acting bronchodilators in the long-term management of COPD. Dong et al (2015) argued that inhaled long-acting bronchodilators are more convenient and more effective than short-acting bronchodilators. While short-acting preparations such as salbutamol are recognised as important rescue remedies for acute respiratory symptoms, regular or over use can result in undesired side effects. Therefore, maintenance use of long-acting agents can provide a lesser side-effect profile while providing significant therapeutic benefit, with evidence showing reduced symptoms of dyspnoea, improved health status and reduced risk of COPD exacerbations with daily use of inhaled long-acting beta-2 agonists (Cazzola et al, 2013; Koch et al, 2014), or inhaled long-acting antimuscarinic antagonists (Karner et al, 2014; Melani, 2015). Further to this, combinations of both forms of long-acting bronchodilators can provide additional benefit to the COPD population, with evidence showing greater efficacy in combined therapy opposed to monotherapy in preventing exacerbations (Wedzicha et al, 2013) and improving health status in COPD patients (Mahler et al, 2015; GOLD, 2019).
Pharmacotherapeutics of amoxicillin
Antibiotics in COPD
Antibiotic therapy use in COPD exacerbations has been debated (Vollenweider et al, 2012) It has been argued that not only are bacterial triggers for airway inflammation difficult to accurately assess (Wedzicha and Seemungal, 2007), but are also difficult to differentiate from viral precipitants (Woodhead et al, 2005). Wilkinson et al (2006) suggested that bacterial infection is common in this disease group, with evidence identifying its presence in sputum cultures in more than two-thirds of COPD exacerbations. De Alwis and Weiner (2012) supported this view, with evidence identifying bacterial triggers in over 50% of hospitalised unstable COPD individuals.
Antibiotic treatment in COPD exacerbations is therefore indicated only when there are clinical signs of bacterial infection, with increases in dyspnoea and sputum volume and purulence recognised as cardinal symptoms (Miravittles et al, 2012). Quon et al (2008) have supported this, with evidence identifying reductions in mortality, treatment failure and respiratory symptoms with antibiotic therapy in infective COPD exacerbations. GOLD (2019) therefore recommends that antibiotics are used in COPD exacerbations when such surrogate markers are present, with aminopenicillins such as amoxicillin identified as suitable agents (Llor et al, 2012), for use for up to 5 to 7 days (Masterton and Burley, 2001; GOLD, 2019).
Amoxicillin belongs to a family of medications called beta-lactams, recognised as such due to a functional group known as a beta-lactam ring within its simple molecular structure (McFadden, 2014). Its function is bactericidal, whereby it employs its pharmacological activity by inhibiting bacterial cell wall synthesis (Gardenhire, 2016).
Bacteria cell walls contain peptidoglycan, a structural molecule synthesised by the bacterial enzyme transpeptidase (McFadden 2014). Amoxicillin binds to these penicillin-binding proteins in bacteria (Waller et al, 2014), preventing their coupling to the structural molecules, which is crucial in bacterial cell wall development (Gardenhire, 2016). Drawz and Bonomo (2010) stated that inactivation of transpeptidase enzymes occurs by opening of the beta-lactam internal lactam ring, preventing the final stage of bacterial cell wall completion. Inhibition of this process activates an internal mechanism of self-digestion known as autolysis (Kaur et al, 2011), resulting in unstable bacterial cell walls and eventual cell death (McFadden, 2014). Drawz and Bonomo (2010) added to this, highlighting how transpeptidase is unique to bacterial cells and is therefore an ideal target for amoxicillin as normal human cells will not be affected.
Absorption of amoxicillin occurs readily and almost completely from the gastrointestinal tract with up to 90% oral bioavailability (Waller et al, 2014), and is not influenced by food (Lilley et al, 2017). Amoxicillin has a quick onset of action (Skidmore-Roth, 2015), with peak plasma levels within 2 hours, lasting up to 8 hours (Vallerand et al, 2015), and terminal half-life approximated as 60 to 90 minutes (Kee et al, 2015). With oral absorption of amoxicillin producing high peak concentration levels, less frequent dosing intervals are required (Bush, 2010).
Amoxicillin binds to plasma proteins (Kaur et al, 2011), primarily albumin (Amin et al, 1994), with a protein-binding capacity of 20% (Hodgson and Kizior, 2014). The distribution of oral preparations is relatively extensive (Waller et al, 2014), with an apparent volume of distribution estimated as 0.3 litres per kilogram (Ashley and Dunleavy, 2014), diffusing into most organ systems and tissues including the liver, lungs, muscle, and ascitic, pleural and synovial fluid (Kaur et al, 2011), including exchange across the placenta (Vallerand et al, 2015). Jeske (2014) argued that amoxicillin has poor infiltration of the blood-brain barrier except when significant inflammation of the meninges is present, with associated pathologies including meningitis commonly described (Nau et al, 2010).
Metabolism of amoxicillin is relatively limited (Yagiela et al, 2011), with 30% metabolised by the liver (Vallerand et al, 2015) and up to a quarter metabolised into penicillotic acid following hydrolytic opening of the lactam ring (Bush, 2010). Excretion occurs predominately through the renal system, eliminated by both glomerular and tubular secretion (Geddes and Gould, 2010), with 80% of the drug recoverable in the urine (Bush, 2010). Vallerand et al (2015) identified that 70% of excreted amoxicillin remains unchanged, predisposing to high urinary concentrations. Furthermore, low concentrations of amoxicillin are present in breast milk (Hodgson and Kizior, 2014).
Amoxicillin is generally well tolerated, with minor side-effects common to most penicillins (Bush, 2010). Waller et al (2014) highlighted its suitability given its high therapeutic index and low toxic threshold. Symptoms of nausea, vomiting and diarrhoea are the most commonly reported side effects (Jeske, 2014). However, as absorption occurs readily, gastrointestinal disturbances are infrequent (Bush, 2010). Adverse reactions of severe allergy, hypersensitivity and anaphylaxis have been reported, but are relatively rare (Lilley et al, 2017), with urticaria the most common allergic reaction (Skidmore-Roth, 2015).
Many medications interact with amoxicillin, with positive relationships observed with clavulanic acid enhancing bactericidal effect (Lilley et al, 2017), and negative interactions of decreased renal elimination of methotrexate and enhanced anticoagulation effect of warfarin (Ashley and Dunleavy, 2014). Non-steroidal anti-inflammatory agents compete for protein binding, inadvertently resulting in more free circulating amoxicillin, which may be of therapeutic benefit (Lilley et al, 2017).
Comparison of salbutamol and amoxicillin
Although salbutamol and amoxicillin are not known to interact pharmacokinetically, their pharmacodynamic properties clearly complement each other. It is important to recognise that acute bronchoconstriction is a symptom manifested from the COPD exacerbation, and while salbutamol is essential for rapid bronchodilation to alleviate acute respiratory symptoms, amoxicillin is required to treat the bacterial infection that precipitated the event. They therefore work collaboratively, targeting different receptors with their specific modes of action to achieve the same therapeutic outcome in treating COPD exacerbations.
Implications for practice
Although high-quality evidence is lacking for the efficacy of short-acting bronchodilators in COPD exacerbations, their mechanism in relieving acute symptoms of dyspnoea and wheeze is considered clinically worthwhile. There may be ethical limitations for further evaluation because this is already accepted standard treatment, and large-scale research would be required to determine their short- and long-term outcomes in unstable COPD. In the absence of this best practice guidance, GOLD continues to recommend short-acting beta-2 agonists such as salbutamol as the initial bronchodilator of choice for acute treatment of COPD exacerbations (GOLD, 2019).
The risk of inappropriate and excessive antibiotic therapy in unstable COPD has been debated (Rodriquez-Roisin, 2006). This supports early evidence identifying growing antibiotic resistance among common respiratory pathogens (Wilson, 2001), likely related to unnecessary antibiotic prescriptions in non-infective COPD exacerbations (Goossens et al, 2005). Further research could help to accurately determine the presence of bacterial infection, providing advancements in antibiotic management for COPD (Wilson, 2008). Antibiotics should be considered when there are clinical signs of bacterial infection, with oral aminopenicillins recognised as usual empirical treatment to achieve clinical improvements in dyspnoea and sputum purulence in the acute infective exacerbation of COPD (GOLD, 2019).
Conclusion
The author recognises that, although there is a requirement for further developments in the treatment of unstable COPD, reduction of the negative impact of acute exacerbations and associated mortality remains central to the role of the RNS. RNS practice is therefore informed by the current evidence base, with the use of salbutamol in relieving acute symptoms of dyspnoea and wheeze, and the addition of amoxicillin where appropriate to treat bacterial infective exacerbations of COPD.