Pharmacology and therapeutics of bronchodilators

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, β(2)-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily β(2)-AR agonists or ultra-long-acting β(2)-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.     

Bronchodilator combination therapy for the treatment of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and its prevalence is rising worldwide. Bronchodilators remain the cornerstone of COPD treatment, especially inhaled β2-adrenergic receptor agonists and inhaled anticholinergics. Long-acting bronchodilators are considered more effective and convenient than short-acting bronchodilators for the maintenance treatment in patients with moderate to very severe COPD. There are currently 3 long-acting inhaled bronchodilators available in the United States: the β2-adrenergic receptor agonists formoterol and salmeterol, and the anticholinergic, tiotropium. All 3 long-acting bronchodilators have been shown to be effective and well tolerated for the management of patients with stable COPD in clinical studies. The combination of β2-adrenergic receptor agonists and anticholinergics has been shown to provide superior bronchodilatory effect than either agent alone, possibly because of different mechanisms of action of these agents. The current treatment guidelines recommend the use of one or more long-acting bronchodilators for patients with moderate to severe stable COPD who remain symptomatic with single-agent bronchodilator therapy. The objective of this article is to review clinical data on combined bronchodilator therapy with β2-adrenergic receptor agonists and anticholinergics in patients with COPD.     

An update on bronchodilators in Phase I and II clinical trials

Introduction: Inhaled bronchodilators are the mainstay of the current management of COPD at all stages of the disease, and are critical in the symptomatic management of asthma. Therefore, there is still considerable interest in finding novel classes of broncholytic drugs or, at least, in improving the existing classes of bronchodilator.

Areas covered: This review paper mainly focuses on bronchodilators that are in Phase I and II clinical trials.

Expert opinion: To date, finding new classes of bronchodilators has proved difficult. Consequently, many research groups have sought to improve the existing classes of bronchodytic drugs. The majority of programs in development for novel bronchodilators are focused on developing new ligands that interact with β₂-adrenoceptors and/or muscarinic acetylcholine receptors in a manner that enhances their bronchodilator effectiveness and duration of action, which allows only one administration per day, although the twice-daily dosing of bronchodilators is still considered a useful approach to the symptomatic treatment of COPD, and improving their safety profiles. Moreover, the current opinion is that it is advantageous to develop inhalers containing combinations of long-acting bronchodilator drugs in an attempt to simplify treatment regimes as much as possible. Another goal is to develop novel combinations of one or two classes of long-acting bronchodilators along with inhaled corticosteroids.     

慢性阻塞性肺病诊治进展

慢性阻塞性肺疾病(COPD)是一种持续性、进展性的高发病率、高病死率的疾病。单独采用肺功能评估不能很好地反映疾病的状况,应对症状、肺功能、急性加重风险和合并症等进行综合评估。目前没有一种药物能够阻止疾病进展并有效地抑制气道炎症,支气管舒张药、抗炎药物(主要是吸入糖皮质激素)是目前主要的治疗药物,应该根据患者综合评估的结果合理选择药物治疗方案。许多新型的支气管舒张药和更有效的抗炎药物正在研发过程中。     

Anticholinergic bronchodilators in combination

Chronic obstructive pulmonary disease (COPD), which affects approximately 14 million Americans, is the fourth leading cause of death in the United States and is responsible for an estimated US$6.5 billion in direct and indirect costs per year [1,2]. Its usual course is a slow deterioration of lung function and progressive breathlessness with activities. The age-adjusted death rate for COPD rose 71% from 1967 to 1987, and the 10 year mortality rate is about 50%. Bronchodilators form one of the mainstays of therapy in COPD patients. The judicious use of these agents increases airflow and reduces dyspnea in patients with COPD. Patients often experience a reduction in symptoms and improvement in their quality of life. There are several classes of bronchodilators available for the treatment of COPD, each with specific clinical benefits: anticholinergics, short-acting beta 2 agonists, combination anticholinergic and short-acting beta 2 agonist, long-acting beta 2 agonists and methylxanthines. This chapter reviews the use of an anticholinergic (ipratropium bromide) concomitantly with other bronchodilators, focusing on patients with COPD.     

Anticholinergic bronchodilators in combination

Chronic obstructive pulmonary disease (COPD), which affects approximately 14 million Americans, is the fourth leading cause of death in the United States and is responsible for an estimated US$6.5 billion in direct and indirect costs per year [1,2]. Its usual course is a slow deterioration of lung function and progressive breathlessness with activities. The age-adjusted death rate for COPD rose 71% from 1967 to 1987, and the 10 year mortality rate is about 50%. Bronchodilators form one of the mainstays of therapy in COPD patients. The judicious use of these agents increases airflow and reduces dyspnea in patients with COPD. Patients often experience a reduction in symptoms and improvement in their quality of life. There are several classes of bronchodilators available for the treatment of COPD, each with specific clinical benefits: anticholinergics, short-acting ₂ agonists, combination anticholinergic and short-acting ₂ agonist, long-acting ₂ agonists and methylxanthines. This chapter reviews the use of an anticholinergic (ipratropium bromide) concomitantly with other bronchodilators, focusing on patients with COPD.     

Is combination therapy with inhaled anticholinergics and beta2-adrenoceptor agonists justified for chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterised by progressive, irreversible airflow limitation. The economic and social burden of the disease is enormous. The treatment of COPD is guided by the stage of the disease and is aimed primarily at control of symptoms. Bronchodilators are the cornerstone of pharmacological management of COPD. Short-acting bronchodilators (beta(2)-adrenoceptor agonists and anticholinergics) have been available for many years and have been extensively studied as individual agents and in combination. When administered in combination, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. However, the improvement in bronchodilation does not translate into an improvement in quality-of-life (QOL) indices. More recently, long-acting beta(2)-adrenoceptor agonists (LABAs) and anticholinergics have been introduced, and current guidelines recommend regular use of these agents in COPD of Global initiative for chronic Obstructive Lung Disease (GOLD) stage II or more. Combining short-acting anticholinergics with LABAs for daily use has been evaluated, but this combination does not confer any advantage in terms of subjective improvement or prevention of exacerbations. Combining the long-acting anticholinergic tiotropium bromide with formoterol given once or twice daily improves airway obstruction and hyperinflation. However, the effects of combinations of long-acting bronchodilators on patients' symptom scores, QOL and exacerbations remain to be studied. Ultra-LABAs, which are in development, may enable use of a combination of long-acting bronchodilators in a single inhaler for once-daily use, thus simplifying the regimen. This article discusses the results of various clinical trials comparing the efficacy of bronchodilators given alone or in combination to patients with COPD, with emphasis on the effects of these agents on bronchodilation, symptomatic and objective improvements in QOL and prevention of exacerbations.     

Novel bronchodilators in the treatment of asthma and COPD

This review analyses the patents published during the period January 1998 to August 2001 concerning bronchodilators, with special emphasis on their applications for the most important pulmonary diseases, which include asthma and COPD. Bronchodilators are the mainstay for the COPD and asthma therapies, according to the recommendations of different guidelines about their treatment. Bronchodilator drugs include β₂-agonists, anticholinergics and theophyllines. In addition, the leukotriene antagonists and phosphodiesterase 4 inhibitors have also been included in this review, due to their incidence and relevance in the treatment of these pulmonary diseases.     

支气管扩张剂对老年阻塞性气道疾病的治疗现状

 阻塞性气道疾病（如COPD、哮喘）是老年人的常见病,随增龄出现的解剖、心理和生理上的一些变化会对这类疾病的治疗产生影响,而同时伴有的其他系统的慢性疾病也会对这类疾病的药物治疗产生影响。支气管扩张剂是治疗这类疾病的基本药物,但即便是吸入剂型也会出现局部甚至全身的不良反应。由于增龄而出现的药物吸收、代谢、分布、排泄方面的改变会导致老年阻塞性气道疾病患者出现与年轻患者不同的药物反应。文中从老年人药动学特点、常见支气管扩张剂包括β2受体激动剂、抗胆碱药、磷酸二酯酶抑制剂的作用机制、体内外活性、安全性等方面综述支气管扩张剂对老年阻塞性气道疾病的治疗进展。     

Therapeutic options for chronic obstructive pulmonary disease: present and future

By 2020, chronic obstructive pulmonary disease (COPD) will become the third leading cause of mortality and fifth leading cause of disability worldwide. Although traditionally therapeutic nihilism has dominated the approach to the management of COPD patients, it is becoming increasingly clear that COPD is a highly preventable and treatable condition. Smoking cessation is the most important therapy because it is the only intervention that has been shown to modify the accelerated decline in lung function that is characteristic of COPD. Domiciliary oxygen therapy for those who are hypoxemic at rest results in improved survival. Vaccinations and immunizations against influenza and pneumococcus should be encouraged. Bronchodilators are used for symptomatic relief. Recent introduction of long-acting bronchodilators facilitates good control of dyspnea with once or twice daily dosing. In conjunction with inhaled corticosteroids, they appear to produce added clinical benefits. Pulmonary rehabilitation and lung transplantation are other therapeutic options for select groups of patients. Many promising compounds are in various stages of development as future therapies in COPD. Drugs such as phosphodiesterase 4 inhibitors, tyrosine kinase blockers and peroxisome proliferator-activated gamma receptor agonists show great promise as disease-modifying agents in COPD.     

Emerging drugs for chronic obstructive pulmonary disease

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a major public health problem with increasing morbidity and mortality. It is characterized by airflow obstruction that is usually progressive, not fully reversible and does not change markedly over several months. It is associated with an enhanced inflammatory response in the airways and the lung to noxious particles or gases. Therefore, bronchial relaxation and inflammatory response suppression represent a mechanistic approach to the treatment of COPD. AREAS COVERED: This review article is focused on emerging treatment for COPD that is mainly based on new bronchodilators and anti-inflammatory drugs. We also mention new pharmacologic agents whose mechanisms of action target protease activity at the enzymatic level and the potential regenerative therapy for COPD. EXPERT OPINION: New drugs for the treatment of COPD are greatly needed, but development of novel drugs for COPD has proved to be very difficult. Nevertheless, in these last years, several new potential targets have been identified and novel agents for these new targets, as well for known targets, have been developed. Rational therapy depends on elucidating the cellular and molecular mechanisms that are involved in bronchodilation and inflammation in COPD patients, and the structural changes and aberrant repair mechanisms that characterize the pathophysiology of COPD.     

Novel therapy for COPD

The incidence of chronic obstructive pulmonary disease (COPD) is increasing throughout the world. Much less is known about the pathogenesis of COPD than that of asthma and there is little response to current therapy. Most patients with COPD have acquired their lung disease through smoking cigarettes, and the major step in management is to minimise further damage by stopping this habit. A number of therapies are being developed for the treatment of COPD; including new bronchodilators such as tiotropium bromide, agents to block inflammation induced by neutrophils and macrophages, as well as strategies to combat proteases and oxidants. The long-term goal is to provide therapy that retards the accelerated loss of lung function occurring in COPD. Development of novel therapies for COPD requires reliable Phase II decision making before entering large scale Phase III studies. The patient with COPD is often overlooked compared to their asthmatic counterpart, who benefit from an urgent need to identify novel targets and better therapy.     

Emerging drugs for the treatment of chronic obstructive pulmonary disease

By 2020 chronic obstructive pulmonary disease (COPD) will be the third leading cause of mortality and fifth leading cause of morbidity. Research over the past two decades has shed important insights on the pathobiology of COPD, leading to the development of novel drugs. In the past, symptomatic treatment with bronchodilators was the predominant focus of COPD management. With increased awareness of the importance of airway inflammation in COPD progression, there has been a shift in emphasis to drugs that attack various targets in the inflammatory cascade. These drugs include phosphodiesterase 4 inhibitors, leukotriene modifiers and TNF antagonists, which are poised to enter the COPD market in the very near future. Tyrosine kinase antagonists, inhibitors of NF-kappaB, neutrophil elastase inhibitors, chemokine antagonists, mucolytics and novel antibiotics are being evaluated for possible effectiveness in COPD. Many of these drugs may enter the COPD market within the next decade. This paper reviews the molecular rationale for these emerging drugs and their potential efficacy in COPD.     

New treatments for chronic obstructive pulmonary disease and viable formulation/device options for inhalation therapy

Chronic obstructive pulmonary disease (COPD) is an increasingly important cause of morbidity and mortality, pathological features of which are pulmonary inflammation and irreversible airflow obstruction. Current therapies for COPD are aimed at improvement of clinical symptoms and reduction of inflammation in the respiratory systems. There is a pressing need for the development of new COPD medication, particularly as no existing treatment has been shown to reduce disease progression. In spite of a better understanding of the underlying disease process, there have been limited advances in the drug therapy of COPD, in contrast to the enormous advances in asthma management. Several new therapeutic targets and strategies have been proposed, and new drug candidates, including bronchodilators, protease inhibitors anti-inflammatory drugs and mediator antagonists, are now in clinical development for COPD treatment. New dry powder inhaler (DPI) systems for inhaled COPD therapy have also been developed to maximize drug concentrations in the airway systems, while minimizing systemic exposure and associated toxicity. This article aims to review recent developments in COPD drugs and the delivery systems for inhalation therapy, with particular emphasis on device options and formulations of DPI systems.     

Advances in the management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible airflow limitation with extreme economic and social burden. It is estimated that over the next two decades, it will become the 5(th) most prevalent disease and the 3(rd) most common cause of death in the world. A better understanding of the pathogenesis of airway inflammation and alveolar destruction allows for the development of new therapeutic targets. Tobacco smoking is the most important risk factor in the development of COPD, thus making smoking cessation of the outermost importance. This article provides a critical review of present therapy for COPD. In addition to conventional treatment (bronchodilators, corticosteroids and antibiotics) and smoking cessation therapies, novel approaches with potential benefit are discussed.     

Advances in the management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible airflow limitation with extreme economic and social burden. It is estimated that over the next two decades, it will become the 5^th most prevalent disease and the 3^rd most common cause of death in the world. A better understanding of the pathogenesis of airway inflammation and alveolar destruction allows for the development of new therapeutic targets. Tobacco smoking is the most important risk factor in the development of COPD, thus making smoking cessation of the outermost importance. This article provides a critical review of present therapy for COPD. In addition to conventional treatment (bronchodilators, corticosteroids and antibiotics) and smoking cessation therapies, novel approaches with potential benefit are discussed.     

Prospects for COPD treatment

The management of chronic obstructive pulmonary disease (COPD) is fundamentally still heavily dependent on the use of bronchodilators and corticosteroids. Therefore, there is a need for alternative, more effective and safer therapeutic approaches. In particular, since inflammation in COPD lungs is often poorly responsive to corticosteroid treatment, novel pharmacological anti-inflammatory approaches are needed to optimally treat COPD patients. There have been multiple attempts to develop drugs that inhibit recruitment and activation of inflammatory cells, such as macrophages, neutrophils and T-lymphocytes, in the lungs of patients with COPD or target inflammatory mediators that are important in the recruitment or activation of these inflammatory cells or released by such cells. This review article focuses on novel classes of anti-inflammatory drugs that have already been tested in humans as possible treatments for patients with COPD.     

Advances in the management of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death, seems to be increasing in worldwide prevalence, and carries with it a significant health and economic burden. Smoking cessation is the only available intervention proven to halt disease progression. The authors discuss the role of the newly approved agent, varenicline, in promotion of smoking cessation. The remainder of presently available therapies treat the symptoms of COPD, but do not impact progression of disease. As the understanding of the pathogenesis of COPD improves, new targets for therapies are emerging. Given the large number of potential targets and the results of recent studies, it seems unlikely that a single new agent will result in a cure. Rather, management of COPD should involve a multi-pronged approach including smoking cessation, bronchodilators, treatment of infection, and eventual targeting of inflammatory pathways and genetic predispositions. In this article, the authors discuss presently available therapies as well as agents under development.     

Targeting the issues in chronic obstructive lung disease

Chronic obstructive pulmonary disease (COPD) is a disease of unclear aetiology and variable pathology among patients. Little is known about the cellular mechanisms which cause this condition and, although the incidence of COPD has been rising worldwide for some time, research efforts have only very recently increased. Medication thus far has focused on symptom treatment rather than targeting identifiable disease mechanisms. Such treatment has consisted primarily of bronchodilators, both beta-agonists and anticholinergic in action. Treatment with steroids has been disappointing, except in the case of acute exacerbation, and this has shifted the research focus to characterising the inflammatory process in COPD as distinct from that in asthma. New targets for pharmacotherapy are coming to light as information is gained about specific inflammatory mediators active in COPD and the role of oxidative stress in this disease. In addition, new approaches include describing the role of exogenous antiproteases in restoring the balance between protease-antiprotease mechanisms that may be defective in this disease. Ultimately, exploration of the molecular genetics of COPD will provide new targets for future pharmacological agents.