The lungs need to be deflated: effects of glycopyrronium on lung hyperinflation in COPD patients
© Sanguinetti; licensee BioMed Central Ltd. 2014
Received: 12 March 2014
Accepted: 25 March 2014
Published: 1 April 2014
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation caused by bronchial alterations, small airways disease and parenchymal destruction. In patients with COPD the structural and functional lung alterations can progress more or less rapidly from the initial small airways disease to an overt COPD where a severe expiratory flow limitation takes place. In these conditions, lung hyperinflation develops characterized by increase in functional residual capacity (FRC) and decrease in inspiratory capacity (IC). Thus, IC is an easy and reliable index to monitor lung hyperinflation and to assess the efficacy of bronchodilator drugs. When FRC increases, tidal volume (VT) is located in a more flatted upper part of the P –V curve of the respiratory system and respiratory muscles must sustain a greater elastic workload. Furthermore, due to inadequate time for expiration, there is a positive alveolar pressure at the end of expiration (PEEPi). This represents a further elastic workload for the inspiratory muscles. This impairment of ventilatory mechanics generates dyspnea that in most severely compromised patients occurs also for small efforts causing activity limitation and worst health-related quality of life (HRQoL). Due to these respiratory alterations, bronchodilators are the cornerstone of the long-term treatment of COPD in order to decrease airways resistances, lung hyperinflation and exacerbation rate, and improve patient’s symptoms, exercise tolerance and health status. Long-acting antimuscarinic bronchodilators (LAMAs) have proven to be very useful in terms of lung deflation and exercise tolerance. Recently, new LAMAs with several positive characteristics have been introduced into clinical use among which glycopyrronium bromide has shown to be particularly effective. Glycopyrronium has a longer-lasting effect compared to other anticholinergic drugs, therefore it allows a single daily administration and facilitates the therapy of a disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways determined by repeated bronchoconstriction and increasing patient’s adherence to treatment plan with better clinical results. Several studies demonstrated that glycopyrronium is able to positively and significantly decrease lung hyperinflation, symptoms, and improve psycho-physical status of COPD patients, with a low rate of adverse events, similar to that of placebo.
Chronic obstructive pulmonary disease (COPD) is a pathological respiratory condition characterized by persistent airflow limitation caused in various measures by bronchial alterations (chronic bronchitis), small airways disease and parenchymal destruction (pulmonary emphysema). The disease is determined by a chronic abnormal response to noxious inhaled substances, mainly tobacco smoke, presents with persistent cough, sputum production, dyspnea and decreased exercise tolerance, and is associated with various complications and comorbidities, especially cardiovascular and metabolic [1–3]. COPD charges a relevant social and economic burden, affecting almost 4.5% of population in Italy . The main symptom of COPD is dyspnea and the patients reduce their daily activities in an attempt to relieve this symptom; but by avoiding the physical activity patient enters a vicious circle which leads to deconditioning and having more dyspnea.
This article addresses the respiratory alterations occurring in COPD that lead to lung hyperinflation and dyspnea, their pathophysiologic and clinical consequences and the role of bronchodilators with a particular focus on glycopyrronium at improving health status and health related quality of life of COPD patients by decreasing the hyperinflation.
Pathophysiology and consequences of lung hyperinflation in COPD
In the volumetric partition of VC  particular value is now attributed to inspiratory capacity (IC, sum of VT and IRV) because, when reduced, it may testify a condition of lung hyperinflation (LH), caused by the increase in RV, FRC, and TLC , as frequently observed in COPD patients . In these patients, IC showed a more significant correlation with the exercise tolerance than the forced expiratory volume in one second (FEV1) . In addition, several studies demonstrated that IC, also when standardized for TLC (IC/TLC), as marker of lung hyperinflation both in resting conditions (static LH) and during exercise (dynamic LH),is an independent predictive factor of mortality in COPD patients [9, 10], and also indicative of a longer hospital stay following thoracic surgery . Therefore, an ideal bronchodilator should demonstrate to be able to decrease the hyperinflation of the patient, increase inspiratory capacity and, consequently, increase exercise tolerance. Based on many functional and clinical observations, IC, besides FEV1, is increasingly used as an index to assess the efficacy of bronchodilator drugs in COPD patients.
Several previous studies [12, 13] demonstrated undeniably that the damage caused by the inhalation of toxic compounds, like cigarette smoke and environmental pollutants, primarily involves the “small airways”. This definition refers to bronchioles with an internal diameter equal to or lower than two millimeters, that is the terminal and respiratory bronchioles, thus a very peripheral site in the lung and very close to gas exchanging zone of pulmonary alveoli . Patency of small airways is normally maintained, especially in expiration, by the integrity of bronchial walls that, while lacking in cartilagineous framework, collapse only when the lung empting is almost complete, and by the alveolar-airways attachments acting as elastic bands to maintain the bronchial calibre. In smokers, the structural and functional lung alterations progress more or less rapidly from the initial small airways disease to an overt COPD [15, 16]. At the beginning of the disease, small airways closure may occasionally occur during tidal expiration, while with the progression of the disease this alteration is constant and associated with a severe expiratory flow limitation (EFL) [17, 18]. EFL is caused by the increase in airways resistance consequence of a reduction of bronchial-bronchiolar caliber due to structural remodeling and augmented vagal tone, together with the destruction of elastic pulmonary tissue. The flows normally utilized are thus maximal,that is the maximum expiratory flow is within the tidal volume , and any further increase in pleural pressure does not increase the expiratory flow which is only dependent on the elastic recoil of the lung . Since the elastic recoil pressure raises in parallel with the increase in lung volume,when EFL occurs patients must breath at a higher pulmonary volume to exploit the only mechanism able to increase their expiratory flow. In these conditions, residual volume increases due to the closure of the airways at higher pulmonary volume and consequently FRC increases because the volume at which the balance between the elastic pressures of the lung and chest wall occurs is increased, leading, starting from dynamic hyperinflation, eventually to a static lung hyperinflation (sLH). This has important implications in that the work of inspiratory muscles increases to counteract the augmented elasticity of lung tissue. In addition, the increased pulmonary volume determines a shortening of the inspiratory muscles which consequently generate a lower pressure for a certain stimulus. In the natural history of the anatomic and functional damage of COPD a progressive alteration of pulmonary volumes occurs characterized by a progressive increase in FRC and parallel decrease in IC until the patient inevitably develops dyspnea even during quiet breathing and it is impossible to increase the extent of ventilation beyond a certain limit  (Figure 1B). Thus, lung hyperinflation and the consequent alterations of respiratory mechanics determine an increased respiratory work that in turn leads to fatigue of respiratory muscles that must sustain a greater load, with inefficiency of respiration and onset of respiratory failure, initially characterized only by hypoxemia and then also by hypercapnia. Dyspnea usually arises when gas exchange is inefficient as in ventilation/perfusion mismatching, exercise-induced hypoxemia, and impaired respiratory mechanics, where an uncoupling occurs between the increased ventilatory stimulus and the decreased mechanical performance. In the most severely compromised COPD patients, dyspnea occurs also for small efforts and consequently an activity limitation develops that leads to deconditioning and worsening of health-related quality of life (HRQoL) .
When these dynamic conditions develop, a rapid increase in FRC takes place caused by air trapping at the end of expiration and dynamic hyperinflation of the lungs, together with a parallel decrease in IC, because patients increase the breathing frequency and further shorten the expiratory time. In fact, while in the normal subject at the onset of an exercise there is a fall of EELV, such as the respiratory system remains on the steeper part of the pressure-volume relationship, and VT increases also utilizing part of the inspiratory reserve (IRV), in a subject with EFL and LH tidal volume cannot be increased beyond a certain level because any further elevation of pressure cannot generate any volume increase [18, 27]. However, the breathing frequency is augmented as a compensation attempt, resulting in further rise of EELV. In addition, the new positioning of VT along the pressure-volume curve of the respiratory system is such that VT lies closer to TLC, and the IRV is decreased. This is a further limiting factor because the “dyspnea limit”, that is the volume level at which dyspnea becomes unbearable, has been shown to be when IRV is lower than half a litre . Bronchodilators, the cardinal of COPD therapy, break this vicious circle by reducing the airway obstruction, which leads to decreasing of the residual volume allowing patients longer exercise time which has many beneficial aspects for the patients daily life and disease progress. A significant correlation also appeared between the IC decrease and the dyspnea presence and degree both during exercise testing and during normal daily activities in COPD patients .
Effects of glycopyrronium on lung hyperinflation and its consequences
Due to persistent airflow limitation in COPD, bronchodilators, especially the long-acting ones, are the cornerstone of the long-term treatment of this disease, with the aim of decreasing to the minimum the airways resistances and improving the parameters closely correlated with the patient’s health status and prognosis, like symptoms, acute exacerbations, exercise tolerance and physical and psychic general conditions.
The efficacy of long-acting bronchodilators in COPD has been extensively documented in studies performed both with beta2-agonists (LABAs) [30, 31] and with muscarinic antagonists (LAMAs) [32, 33], as the cholinergic tone is recognized as the major reversible component of the airflow obstruction in this disease . In almost all studies the primary outcome measure to assess the drug efficacy was the FEV1, whose changes however are poorly correlated with the variations of symptoms and exercise tolerance, which instead are related to changes of lung hyperinflation [35, 36]. Therefore, in order to assess the efficacy of a bronchodilator in COPD, the physiologically more reliable parameter is the inspiratory capacity, which correlates inversely with FRC and can thus be considered a marker of changes of LH.
In fact, it has been demonstrated that LH is, at least in part, reversible with administration of bronchodilators, and lung deflation causes an increase in IC and symptoms improvement in COPD patients. In these patients, the increase in FEV1 after bronchodilation is generally small, if any, while the most important effect is the increase in IC, which sustains the symptoms improvement, even if the indices expressing the rate of bronchial caliber, like the FEV1/FVC ratio, may sometimes be scarcely improved [37, 38]. Noteworthy is the observation that FRC increases exponentially with the progressive reduction of FEV1 and the most significant change after bronchodilation is the decrease in FRC and RV, that is in LH, independently from the basal FEV1 value . During dynamic conditions it has been also observed that the prolongation of “endurance time” (ET), i.e. the span of time in which the exercise is tolerated, is more related to the effect of bronchodilators than other parameters assessed during cycloergometer exercise or 6 minutes walking test (6MWT) . This means that bronchodilators decrease directly the hyperinflation and increase the exercise capacity.
Beneficial effects on IC increase have been obtained also with beta2-agonists characterized by a particularly long duration (lasting 24 hours) of action (“ultra-LABA”) that allows a single daily administration. In a trial  comparing formoterol and indacaterol the latter at 300 mcg OD provided a greater effect on bronchial obstruction and LH than the former at usual dose of 12 mcg BID in patients with COPD. A short-term trial by Rossi et al.  eventually confirmed that indacaterol 150 mcg OD is capable of increasing IC significantly more than placebo. In the same study the effect was also numerically higher than tiotropium bromide (TB) without reaching significance. Interestingly, taking into account the maximum increase of IC, more patients with indacaterol exceeded 20% and 30% improvement compared to TB indicating that indacaterol is capable of producing great improvements in some patients.
On the other hand, also antimuscarinic bronchodilators have proven to be very useful in terms of lung deflation and exercise tolerance. Recently, new long-acting LAMAs with several positive characteristics have been introduced into clinical use among which glycopyrronium has shown to be particularly effective.
Glycopyrronium bromide (GB) has a quaternary ammonium structure and low oral bioavailability, that reduces the drug’s systemic effects . Glycopyrronium is delivered by a dry-powder inhaler (DPI), the Breezhaler®, that has a low resistance and requests a lower inspiratory flow, thus easy to be utilized by COPD patients of different age and severity, and already widely used to inhale indacaterol dry-powder [43, 44].
The longer-lasting effect of GB compared to other anticholinergic drugs allows a single daily administration, which can facilitate the therapy of a disease that needs a chronic bronchodilation by decreasing the mechanic stress of the airways avoiding repeated bronchoconstriction, and by increasing patient’s adherence to treatment plan and thus obtaining better clinical results [45–47].
Quite recently, the results of this study have been confirmed by a new evaluation of efficacy and safety of glycopyrronium versus blinded tiotropium  in a 12-week study with 657 patients with moderate-to-severe COPD. The choice of blinding TB has been taken to minimize possible sources of bias that could arise in open-label studies. In fact, patients who know they are given an active drug or have had previous experience of it may be more prone to report favorable results, or may be influenced on their decision about remaining on treatment . This was the first trial where GB has been compared with blinded TB. Briefly, following the first dose on the 1st day of treatment GB produced greater FEV1 values than TB with least squares mean (LSM) differences of 51 mL and 63 mL compared to TB at 5 min and 15 min post-dose respectively (both p < 0.001), and FEV1 was greater with GB than with TB at all time points from 0 to 4 hours post-dose (p < 0.001). Glycopyrronium also determined a significantly higher increase in inspiratory capacity than tiotropium at 30 min (p < 0.001) and 2 hours (p < 0.001) after the dose administration indicating to a higher reduction of hyperinflation. At week 12 FEV1 and other spirometric variables were comparable between GB and TB, as well as TDI focal score, SGR total score, incidence of moderate or severe COPD exacerbations, whereas the mean daily total symptom score was significantly (p = 0.035) lower with GB than with TB. The safety of glycopyrronium was confirmed also in this recent investigation, because the overall incidence of AEs, SAEs and AEs leading to discontinuation was low and similar between the two treatment groups. This study designed to minimize the possible bias once more demonstrates that in patients with moderate-to-severe COPD glycopyronium has similar efficacy and safety to tiotropium, but provides a faster onset of action compared with tiotropium on the first day of therapy.
Based on the results of the above mentioned studies, glycopyrronium has proven to be capable of inducing favourable effects on lung hyperinflation and its functional and clinical consequences. Bronchodilation afforded by glycopyrronium is more rapid than that of tiotropium since the first dose, and maintains this effect all over 24 hours with a single daily dose. This certainly represents an advantage in terms of adherence to therapy, because it is well known that the efficacy of a therapy also depends on the patient’s adherence to treatment, that must be agreed by the patient once the therapeutical plan has been justified and explained in all details.
Among the crucial factors for adherence, particularly important are the easiness and reliabity of the device and the dosing regimen , especially for COPD patients who mostly are old and can present cognitive defects. In fact, incorrect use of inhalation devices is not rare in COPD and it may be determined not only by patient-related factors, but also by the inhaler characteristics and patient’s education [57–59]. The dose of drug delivered from a DPI depends on a correct handling of the device, the internal resistance of the inhaler, and its ability to generate fine particles that can spread till peripheral airways . In this context the Breezhaler® appears a very reliable and user-friendly device: besides having a low intrinsic resistance facilitating high inspiratory flow rates (in excess of 60 L/min) , the fine particle fraction (FPF) generated by Breezhaler® is 26.8% of the delivered dose versus 9.8% of HandiHaler® (the DPI to deliver tiotropium)  such as the former provides greater mean intrathoracic drug deposition (31% vs. 22%) and lower extrathoracic drug deposition (57% vs. 71%) than the latter. In an open-label, multicenter, two-period, 7-day crossover study  including 82 patients with moderate-to-severe COPD were assessed the patient’s corrected inhaler use and the patient’s inhaler preference for Breezhaler® and Handihaler® relatively to the various steps in use. The percentage of patients correctly using the inhaler increased from 1st to 7th day and there was no significant difference between the two devices. On the contrary, patients expressed the preference for Breezhaler® in a significantly higher percentage compared to Handihaler® (61% vs. 31% p < 0.01) because of its greater overall comfort, simplicity and confidence in use (confidence that inhalation of drug has been correctly performed).
Semplification of therapeutical regimen by reducing the number of doses to take led to a greater adherence to treatment in patients affected with chronic diseases and mainly with COPD [61, 62]. In addition, a lower adherence to treatment has been found to cause a marked worsening of health status , whereas the adherence to inhalant therapy in COPD is associated with a lower risk of death and hospitalization for acute exacerbations . Even the rapidity of action of a drug and the perception of the effect it produces when correctly taken according to physician’s instructions are important factors to strengthen the adherence to therapy. In fact, it has been demonstrated that patients more adherent to therapy are those who take it correctly, report a substantial improvement due to therapy, and think their doctor is an effective support . Thus, in relation to these issues glycopyrronium appears particularly reliable due to rapidity of its action, the easiness of inhaler, and the clinically important long-lasting bronchodilation and symptoms control it provides.
As to concerns the characteristic of particularly long bronchodilation afforded by GB, Beeh  points out that, differently from short-acting or twice daily bronchodilators, after GB administration there is a marked increase in AUC 0-24 of FEV1 and an increased value of trough FEV1 in the morning, that is the worst time of day for COPD symptoms  particularly in patients with severe disease , suggesting that the drug behaves like an endobronchial pharmacological stent that guarantees a continuous patency of the airways. This can positively affect lung hyperinflation and inspiratory capacity because it is conceivable that the greater and persistent bronchodilation, especially at the level of peripheral airways, determines a more complete pulmonary empting during tidal breathing and improves the respiratory mechanics, with consequent decrease in dyspnea and increase in exercise capacity. Such effect has been assimilated to that induced by surgical reduction of lung volume that is successfully performed in patients with upper lobes emphysema (pharmacological lung volume reduction).
Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Italy. We thank Dr. Evren Karayel and Dr. Francesco Sergio from Novartis Pharmaceuticals Italy for their medical editorial assistance with this manuscript.
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