The benefits of LABAs to keep asthma under control generally outweigh the risks — if they're used as recommended.
If you have any questions about your asthma medications, talk to your doctor. James T C Li, M. There is a problem with information submitted for this request. Sign up for free, and stay up-to-date on research advancements, health tips and current health topics, like COVID, plus expert advice on managing your health. Error Email field is required. Error Include a valid email address. To provide you with the most relevant and helpful information and to understand which information is beneficial, we may combine your e-mail and website usage information with other information we have about you.
If we combine this information with your PHI, we will treat all of that information as PHI, and will only use or disclose that information as set forth in our notice of privacy practices. You may opt-out of e-mail communications at any time by clicking on the Unsubscribe link in the e-mail.
Our Housecall e-newsletter will keep you up-to-date on the latest health information. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. Any use of this site constitutes your agreement to the Terms and Conditions and Privacy Policy linked below. Mayo Clinic is a nonprofit organization and proceeds from Web advertising help support our mission.
Mayo Clinic does not endorse any of the third party products and services advertised. A single copy of these materials may be reprinted for noncommercial personal use only.
This content does not have an English version. This content does not have an Arabic version. See more conditions. Request Appointment. Products and services. I've heard that long-acting beta agonists LABAs can cause severe asthma attacks. Should I stop taking them? Thank you for Subscribing Our Housecall e-newsletter will keep you up-to-date on the latest health information. Please try again. Something went wrong on our side, please try again.
Show references Lemanske RF. Beta agonists in asthma: Controversy regarding chronic use. Accessed Dec. Fanta CH. However, here has been some concern with regard to cardiovascular safety and use of B 2 agonists. Salpeter et al 41 suggested increased cardiovascular risk with LABAs compared with placebo, a fact hotly debated but disproven in subsequent meta-analyses in COPD. Para-sympathetic activity mediates both bronchial smooth muscle contraction and the release of mucus into the airway lumen through stimulation of muscarinic receptors, of which there are five distinct types M1—M5.
M1 receptors are expressed in peribronchial ganglia, whilst M3 receptors are present on bronchial smooth muscle cells; their relationship to one another is shown in Figure 2. Both mediate bronchomotor tone and reflex bronchoconstriction. M2 receptors are located in the post ganglionic para-sympathetic nerve and act as auto receptors. Agonistic stimulation of these receptors provides feedback and inhibition of further acetylcholine release; thus, optimal inhibition of the parasympathetic pathway would be achieved by selectively blocking M1 and M3 receptors.
Notes: M1 receptors are expressed in peribronchial ganglia, whilst M3 are present on bronchial smooth muscle cells; both mediate bronchomotor tone and reflex bronchoconstriction. The figure shows their relationship to one another. Adapted from Lipson DA Ipratropium bromide is the most widely used following the discontinuation of Oxitropium bromide in Ipratropium blocks all muscarinic receptors without sub-type selectivity.
Its onset of action is within minutes, with peak activity occurring between 1 and 2 hours and duration of action approximately 4 hours in the majority of patients. Until recently there was only one LAMA on the market tiotropium , but two other products have recently been licensed glycopyrronium and aclidinium. The Cochrane review of LABAs versus LAMAs 17 was only able to consider trials using tiotropium due to their search dates and concluded that its effects were superior to LABAs in terms of preventing exacerbations and disease related hospitalization.
Nevertheless, drug choice for the individual patient may still suggest LABA as a good choice for some, ie, in patients with severe glaucoma; thus current guidance places the 2 classes of drug equal in therapy algorithms. Aclidinium has been studied alongside tiotropium, but this trial was a small study of crossover design, 46 and therefore larger, more definitive studies are still needed.
A summary of clinical effects, as demonstrated by the various LAMA trials, is shown in Table 3 ; since most effects with the exception of speed of onset appear to be roughly equivalent between the 3 drugs they have been tabulated together.
Notes: The table shows results against placebo unless otherwise stated. Tiotropium was the first available LAMA and is administered once daily. It binds to M1—M3 receptors and is 10 times more potent than ipratropium bromide. It dissociates slowly from M1 and M3 receptors, giving it its long acting effect, but dissociates relatively rapidly from the M2 receptor, giving it a unique kinetic selectivity.
The drug is not extensively metabolized but the portion that is undergoes hydrolysis into two major metabolites, a carboxylic acid derivative and an alcohol derivative, neither of which have any affinity for any of the muscarinic receptor subtype. A larger proportion of the drug is eliminated via renal secretion which means there is some accumulation in renal impairment.
Like tiotropium it has a sustained 24 hour bronchodilator effect, 45 and higher selectivity for the M3 receptor than the M2 receptor. Elimination is predominately via the kidneys. Owing to its short plasma half-life and rapid metabolism, very little is excreted in the urine, such that no adjustments are required in renal disease. The adverse effects encountered with LAMAs are largely those attributed to its anti-cholinergic activity, with dry mouth being one of the most commonly reported side effects.
A study prior to the publication of UPLIFT suggested that use of tiotropium increased cardiovascular morbidity and mortality; 62 data from UPLIFT refuted this demonstrating a non-significant reduction in all cause cardiovascular mortality. Later analyses of trial data using the Respimat device not licensed in the USA, but available in at least 55 countries worldwide still suggested an adverse cardiovascular mortality effect with tiotropium.
Ipratropium and tiotropium are actively transported through the bronchial epithelium using the OCTN2 transporter, which is also present in the human heart. In the meantime there has been a call in the UK for withdrawal of the Respimat device as a result of safety concerns.
It is clear that ICS reduce airway inflammation, airflow limitation, and symptoms in asthma and are therefore the mainstay of treatment. The inflammation in COPD is dominated by neutrophilic infiltration, with an increased numbers of macrophages and CD8 T lymphocytes; neutrophilic infiltration is not as responsive to steroids as the eosinophilic inflammation seen in asthma.
Their use in COPD has recently been reviewed by the Cochrane collaboration, which concluded that although use of ICS is associated with a reduction in exacerbation rates and possibly a reduced rate of decline in FEV 1 , these benefits need to be weighed against increased pneumonia risks and local side effects. The primary actions of glucocorticoids arise by activation of specific glucocorticoid receptors GCR which are found in the cytoplasm of most mammalian cell types.
The mechanism of action via the GCR is shown in Figure 3. Nf-kB is upregulated in many cell types during inflammation and favors the expression of pro inflammatory genes.
This dimerization is necessary for the binding of the GCR to the glucocorticoid response element GRE which is an area of DNA responsible for up or down regulating gene expression. Whilst the potency—and therein pharmacological response—of ICS is related to its affinity at the GCR, other factors such as particle size and pulmonary deposition will determine its therapeutic effect.
Table 5 outlines the pharmacokinetic and pharmacodynamic features of both drugs. Budesonide is several times less lipophilic than fluticasone and, as a result, dissolves more readily in airway mucus and is more rapidly absorbed into the airway tissue and systemic circulation. Fluticasone, being more lipophilic and thus less water soluble, is more likely to be retained in the lumen of the airways; it therefore has a greater chance of being removed from the airways by mucociliary clearance and cough.
The adverse effects of ICS are related to its local and systemic absorption. The amount of inhaled steroid reaching the systemic circulation is the sum of the pulmonary and orally bioavailable fractions. Given that most ICS have relatively low oral bioavailability, it is largely the absorption from the pulmonary vasculature which determines the systemically available steroid.
Although adrenal suppression is a theoretical risk, it has not been reported in COPD, though it has been seen in bronchiectasis. Both are a combination of a LABA with an ICS; thus, for the purposes of this article, the term combination therapy is synonymous with these drugs. The pharmacokinetics and pharmacodynamics of the component drugs have been discussed in the preceding sections. Current national and international guidelines advocate the use of combination inhalers in severe and very severe disease.
Abbreviations: P, placebo; F, formoterol; S, salmeterol; B, budesonide. Exposure to exogenous LABA or SABA leads to uncoupling by phosphorylation of the receptor via various pathways, which theoretically can lead to drug tolerance. Exposure to corticosteroids restores receptors to their previously sensitized state. A number of secondary analyses of TORCH data have also been published, detailing determinants of change in health status, 85 beneficial effects on FEV 1 decline, 86 and stratifying analysis for disease stage.
Similar to the use of ICS, the most significant adverse event is the risk of pneumonia with combination inhalers. A recent systematic review and indirect comparison of trials looking at Symbicort and Seretide suggests that the risk of pneumonia is greater with Seretide, perhaps due to overall elevation in steroid load. Roflumilast is a selective phosphodiesterase 4 PDE4 inhibitor; PDE4 is an enzyme which is expressed in many pro-inflammatory cells.
The therapeutic effects of roflumilast are thought to be mediated via increased levels of cellular cAMP and include inhibition of microvascular leakage, inhibition of trafficking, release of cytokines, and chemokines from inflammatory cells, and mild bronchodilation.
Peak plasma concentrations occur within one hour, mean elimination half-life is 17 hours, and a steady state is achieved after 4 days. The major metabolic pathway for roflumilast elimination after oral administration is pyridine N-oxidation, with the formation of roflumilast N-oxide; this metabolite is an active compound with pharmacokinetics distinct from its parent compound.
Peak plasma concentrations occur after 4 hours and its elimination half is approximately 27 hours. Although the major elimination route for both the drug and its metabolite is the kidney, studies have shown that dose adjustment is not required in renal impairment. Theophylline is a non-selective phosphodiesterase inhibitor. Through the enzymatic inhibition of phosphodiesterase, levels of cAMP and cGMP are increased giving it its weak bronchodilator effect.
Recent evidence has shown that theophylline has some anti-inflammatory action and maybe able to modulate inflammatory gene expression by its interaction with the histone deacetylase. Peak plasma concentration occurs between 1 and 2 hours, and it has an elimination half-life of 8 hours.
Roflumilast appears to work best in the subset of COPD patients who have chronic bronchitis. Treatment-related adverse events were higher in the roflumilast treatment arms of the clinical trials in Table 7. Gastrointestinal side effects, namely weight loss and nausea, were the most common, followed by neuropsychiatric effects. Although dropout rates overall were similar between roflumilast and placebo, more patients in the roflumilast arm dropped out within the first few weeks.
Theophylline has been used for a number of years in airway disease and still has a role in the management of COPD. Unfortunately it has a narrow therapeutic index and drug monitoring should be undertaken at regular intervals. The propensity for theophylline to interact with other drugs is another drawback to its use.
Mucus hypersecretion and resultant chronic cough can often be a feature of COPD. Mucolytics have been used to reduce sputum viscosity and to aid expectoration; those most widely used are carbocysteine and N-acetylcysteine NAC.
Others include erdosteine and ambroxol. NAC and to a lesser extent carbocysteine have antioxidant properties. The awareness that oxidative stress and the formation of reactive oxygen species play a role in COPD, especially during exacerbations, has suggested that treatment with mucolytics may be able to influence exacerbation rates.
Carbocysteine is a blocked thiol derivative of the amino acid L-cysteine. While the mechanism of action is not completely understood, it has the ability to split glycoprotein bonds in mucus. In vitro studies also suggest a mucoregulatory mechanism. Carbocysteine is well absorbed and peak serum concentration as achieved at between 1 and 1.
The fraction of the drug not excreted in this manner undergoes metabolism via varying pathways with great inter-individual variability.
NAC is recognized as a mucolytic agent with direct and indirect antioxidant properties. It differs from carbocysteine in that it has a free thiol group capable of interacting with reactive oxygen species, leading to NAC disulfide as an end product. It is rapidly absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours and has a plasma half-life of 6. NAC undergoes mainly hepatic metabolism. The most recent systematic review of clinical effectiveness of mucolytics included 30 studies and demonstrated a small but significant reduction in exacerbations in treated patients with COPD.
One of the largest trials with the power to demonstrate this was undertaken by Decramer et al. Overt or relative hypoxia is one of the hallmarks of COPD, especially in the latter stages of the disease.
Oxygen therapy to ameliorate this has been proven to be effective for patients who have severe resting hypoxia, and it is considered a prescription intervention in many countries. Whilst it is beyond the scope of this article to review all evidence pertaining to oxygen in detail, some key points and major studies can be included.
SBOT criteria are poorly defined, and in general no benefits are seen; it should therefore be used only in a palliative setting. Tobacco smoke is arguably the most important etiological factor for the development of COPD in the developed world. The impact of continued smoking and its cessation on lung function FEV 1 is well known and illustrated via the Fletcher-Peto Curve.
Over the last few years the neurochemical basis of nicotine addiction has been better understood; it is thought that the addictive properties of nicotine are a result of dopamine release mediated via stimulation of the alpha4beta2 nicotinic receptors.
Varenicline is a selective nicotinic receptor partial agonist. It mimics the effects of nicotine on dopamine release in the nucleus accumbens when given alone but attenuates this response to a subsequent nicotine challenge and reduces nicotine self-administration.
Therefore, in limiting reuptake the symptoms of withdrawal are attenuated. All three modalities — have proven to be effective compared to placebo in smoking cessation, with available evidence favoring the superiority of Varenicline over Bupropion. Despite optimal management of COPD with the above pharmacotherapies, dyspnoea can be problematic, especially in the advanced stages of the disease process.
In addition, the sedative effect of opiates may reduce anxiety. The use of opiates to manage dyspnoea was the subject of a systematic review in This benefit was also seen when the subgroup analysis for patients solely with COPD was undertaken. One of the major concerns and possibly barriers to opiate usage is respiratory depression, especially in opioid naive patients. However, when appropriately administered and monitored at lower doses, they do not appear to cause significant respiratory depression.
The multicomponent nature of COPD has meant that therapeutic strategies have been trialed in an attempt to gain additional benefit to the interventions outlined above.
Ameliorating sequelae such as pulmonary hypertension PH , improving nutrition, and trying to reduce systemic inflammation all have theoretical merits.
Vasoactive compounds used in primary PH sildenafil, bosentan, and nitric oxide have been investigated in COPD and are shown in Table 8. Since some trials have shown worse HRQoL in treated patients, these drugs are not used routinely, although trial periods to see if benefit is seen are sometimes employed in selected patients by specialist centers.
Over the last few years a number of studies have shown a relationship between vitamin D deficiency and severe COPD, whereby its deficiency seems to correlate with the degree of airflow obstruction.
However, no benefit in lung function or exacerbations was seen in the treatment arm, except in the severely deficient in whom supplementation would be indicated for other reasons. Some studies have used other forms of nutritional supplementation in the context of pulmonary rehabilitation, albeit with limited benefits.
Consequently, nutritional supplementation is not routinely used therapeutically in COPD. The updated GOLD guidance 1 has made some changes to the way that the therapies detailed above are recommended.
Other national guidance eg, British NICE guidance 5 differs markedly in the order of which drugs are used. Table 9 compares the main differences between guidelines, some of which are described below. Whilst it is recognised that spirometry or exacerbations and mMRC or CAT may result in different groups for some patients, GOLD recommends that treatment should be according to whichever method chosen results in the higher risk.
Notes: First choice treatment shown in italics. The use of bronchodilators is central to the management of COPD and, although not extensively discussed, the use of short acting agents are best used for rescue of symptoms. The choice of which agent depends on patient preference, tolerability, and cost.
Based on current evidence, tiotropium and indacaterol are essentially equivalent, with indacaterol being slightly more favorable at influencing HRQoL. The place of aclidinium and glycopyrronium is likely to be as an alternative to tiotropium or LABA. Thus, when it comes to prescribing maintenance therapy for patients with COPD, a trial of either indacaterol or tiotropium should be used in the first instance as they provide significantly better bronchodilation and reduce the risk of severe exacerbations.
What has been proven to be relatively consistent is their ability to reduce exacerbations. The tradeoff for this benefit is an increased risk of local side effects and pneumonia. It is in these patients who suffer recurrent exacerbations that the risk benefit ratio is greatest. Whilst this section of the review focuses on the use of ICS in COPD, a growing body of evidence suggests that an overlap syndrome of COPD and asthma exists, — although the syndrome is not clearly defined.
In this subset of patients ICS therapy may have greater benefit and should be employed earlier. In most of the clinical trials patients were selected on the basis of chronic bronchitis, recurrent exacerbations requiring oral corticosteroids, or the need for hospital admission.
Its use provided modest but significantly improved FEV 1 compared with placebo and a reduction in exacerbation rates when used with a long acting bronchodilator.
UK guidance advocates its use in GOLD3 patients with a history of recurrent bronchitis or exacerbations. The place of theophylline is seemingly more variable. International guidelines advocate its use as an alternative to inhaled bronchodilators in mild disease, but also as an adjunct from moderate to very severe disease.
UK guidelines only suggest its use after a trial of short or long acting bronchodilators or in those who cannot tolerate inhaled therapy. The pharmacological management of COPD is driven by symptoms. As a progressive disease it is clear that over time increasing intervention will be required to manage symptoms appropriately.
This review has outlined the key pharmacological treatments used. Unfortunately however, no treatment has been shown conclusively to reduce mortality and very few slow the rate of decline in lung function in COPD. ICS have not proven to be as effective as in asthma and what benefits are derived need to be balanced against the increased risk of pneumonia. Since bronchodilators are the mainstay of current management the search to improve existing bronchodilators will continue; so also will the search for novel anti-inflammatory agents and therapeutic strategies to reverse the corticosteroid resistance seen in COPD.
Author Contributions. Wrote the first draft of the manuscript: SE. Contributed to the writing of the manuscript: AMT. Made critical revisions and approved final version: AMT. All authors reviewed and approved of the final manuscript.
Disclosures and Ethics. As a requirement of publication the authors have provided signed confirmation of their compliance with ethical and legal obligations including but not limited to compliance with ICMJE authorship and competing interests guidelines, that the article is neither under consideration for publication nor published elsewhere, of their compliance with legal and ethical guidelines concerning human and animal research participants if applicable , and that permission has been obtained for reproduction of any copyrighted material.
This article was subject to blind, independent, expert peer review. The reviewers reported no competing interests. Provenance: the authors were invited to submit this paper. Neither author received funds specific to the writing of this review. Competing Interests. National Center for Biotechnology Information , U. Published online Apr Stan Ejiofor 1 and Alice M Turner 2, 3.
Find articles by Stan Ejiofor. Find articles by Alice M Turner. Author information Copyright and License information Disclaimer. Corresponding author email: ku.
This article has been cited by other articles in PMC. Abstract This review article summarizes the main treatments for chronic obstructive pulmonary disease, their mechanisms, and the key evidence from trials supporting their use.
Keywords: chronic obstructive pulmonary disease, pharmacotherapies, disease management. Introduction Chronic obstructive pulmonary disease COPD is a multi-component disease which is both preventable and treatable.
Bronchodilators Dyspnoea is one of the hallmark symptoms of COPD and one of the most common reasons for health resource utilization and increasing anxiety in affected patients.
Beta 2 adrenoceptor agonists B2-agonists Mechanism of action B 2 adrenergic receptors B 2 AR are present in high density in airway smooth muscle cells. Open in a separate window. Figure 1. Mechanism of action of Beta agonists. Salmeterol and formoterol Salmeterol and formoterol are LABAs with extended duration of action maintained 12 hours after inhalation of a single dose, 19 which has led to their twice daily dosing. Table 2 Major RCTs for indacaterol.
Muscarinic antagonists Mechanism of action Para-sympathetic activity mediates both bronchial smooth muscle contraction and the release of mucus into the airway lumen through stimulation of muscarinic receptors, of which there are five distinct types M1—M5.
Figure 2. Location of anti-muscarinic receptors. Safety The adverse effects encountered with LAMAs are largely those attributed to its anti-cholinergic activity, with dry mouth being one of the most commonly reported side effects.
Inhaled Corticosteroids It is clear that ICS reduce airway inflammation, airflow limitation, and symptoms in asthma and are therefore the mainstay of treatment. Figure 3. Mechanism of action of ICS. Table 5 Relative therapeutic effects of ICS. Safety The adverse effects of ICS are related to its local and systemic absorption. Phosphodiesterase Inhibitors Mechanism of action Roflumilast is a selective phosphodiesterase 4 PDE4 inhibitor; PDE4 is an enzyme which is expressed in many pro-inflammatory cells.
Safety Treatment-related adverse events were higher in the roflumilast treatment arms of the clinical trials in Table 7. Table 7 Major RCTs of phophodiesterase inhibitors. Oxygen Overt or relative hypoxia is one of the hallmarks of COPD, especially in the latter stages of the disease. Smoking Cessation Tobacco smoke is arguably the most important etiological factor for the development of COPD in the developed world.
Opiates Despite optimal management of COPD with the above pharmacotherapies, dyspnoea can be problematic, especially in the advanced stages of the disease process. Other Potential Pharmacotherapies The multicomponent nature of COPD has meant that therapeutic strategies have been trialed in an attempt to gain additional benefit to the interventions outlined above.
Figure 4. Classifying disease severity by GOLD. First line treatment The use of bronchodilators is central to the management of COPD and, although not extensively discussed, the use of short acting agents are best used for rescue of symptoms. Disclosures and Ethics As a requirement of publication the authors have provided signed confirmation of their compliance with ethical and legal obligations including but not limited to compliance with ICMJE authorship and competing interests guidelines, that the article is neither under consideration for publication nor published elsewhere, of their compliance with legal and ethical guidelines concerning human and animal research participants if applicable , and that permission has been obtained for reproduction of any copyrighted material.
Funding Neither author received funds specific to the writing of this review. References 1. Global Initiative for Obstructive Lung Disease. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. Effect of exacerbation on quality of life in patients with chronic obstructive pulmonary disease.
Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. National Institute for Health and Clinical Excellence. Chronic Obstructive Pulmonary Disease. Jun, Systemic manifestations and comorbidities of COPD. J Assoc Physicians India. Prevalence and outcomes of diabetes, hypertension and cardiovascular disease in COPD. Eur Respir J.
Effect of indacaterol on dynamic lung hyperinflation and breathlessness in hyperinflated patients with COPD. Cooper CB. Airflow obstruction and exercise. Resp Med. Beta-agonist intrinsic efficacy: measurement and clinical significance. Fazio F, Lafortuna C. Effect of inhaled salbutamol on mucociliary clearance in patients with chronic bronchitis. Salmeterol, a beta2-receptor agonist, attenuates lipopolysaccharide-induced lung inflammation in mice.
0コメント