Tiotropium trospium and tiotropium

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ABSTRACT

BACKGROUND: Anticholinergics and Β2-agonists have generally been considered equivalent choices for bronchodilation in chronic obstructive pulmonary disease (COPD).

OBJECTIVE: To assess the safety and efficacy of anticholinergics and Β2-agonists in COPD.

DESIGN: We comprehensively searched electronic databases from 1966 to December 2005, clinical trial websites, and references from selected reviews. We included randomized controlled trials of at least 3 months duration that evaluated anticholinergic or Β2-agonist use compared with placebo or each other in patients with COPD.

MEASUREMENTS: We evaluated the relative risk (RR) of exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and deaths attributed to a lower respiratory event.

RESULTS: Pooled results from 22 trials with 15,276 participants found that anticholinergic use significantly reduced severe exacerbations (RR 0.67, confidence interval [CI] 0.53 to 0.86) and respiratory deaths (RR 0.27, CI 0.09 to 0.81) compared with placebo. Β2-Agonist use did not affect severe exacerbations (RR 1.08, CI 0.61 to 1.95) but resulted in a significantly increased rate of respiratory deaths (RR 2.47, CI 1.12 to 5.45) compared with placebo. There was a 2-fold increased risk for severe exacerbations associated with Β2-agonists compared with anticholinergics (RR 1.95, CI 1.39 to 2.93). The addition of Β2-agonist to anticholinergic use did not improve any clinical outcomes.

CONCLUSION: Inhaled anticholinergics significantly reduced severe exacerbations and respiratory deaths in patients with COPD, while Β2-agonists were associated with an increased risk for respiratory deaths. This suggests that anticholinergics should be the bronchodilator of choice in patients with COPD, and Β2-agonists may be associated with worsening of disease control.

Long-Acting Bronchodilators With or Without Inhaled Steroids in COPD

Risk for moderate COPD exacerbations, but not severe exacerbations, was lower with combined therapy.

Most experts advocate early detection of COPD and active intervention to stop smoking. Smoking cessation has been shown to halt the accelerated loss of lung function associated with COPD. It also stops the loss of lung function in younger patients with relatively mild disease.[4] However, any COPD patient can benefit from smoking cessation, no matter how advanced the disease.

(LT 3)

Bronchodilators help open narrowed airways. There are three main categories: sympathomimetics (isoproterenol, metaproterenol, terbutaline, albuterol) which can be inhaled, injected, or taken by mouth; parasympathomimetics (atropine, ipratropium bromide); and methylxanthines (theophylline and its derivatives) which can be given intravenously, orally, or rectally.

Treatment is designed to relieve symptoms and prevent complications. Because most patients with COPD receive outpatient treatment, they need comprehensive teaching to help them comply with therapy and understand the nature of this chronic, progressive disease. If programs in pulmonary rehabilitation are available, encourage patients to enroll.

The main goal of treatment is to relieve symptoms and prevent complications. Bronchodilators can help alleviate bronchospasm and enhance mucociliary clearance of secretions. Effective coughing, postural drainage, and chest physiotherapy can help mobilize secretions

The patient is usually treated with beta-agonist bronchodilators (albuterol or salmeterol), anticholinergic bronchodilators (ipratropium), and corticosteroids (beclomethasone or triamcinolone). These are usually given by metered-dose inhaler, requiring that the patient be taught the correct administration technique.

( LT 1)

Bronchodilators

Bronchodilators are a class of medications that relax the muscles around the bronchi to allow easier breathing. They are typically indicated for the relief of bronchospasm, which are contractions of the smooth muscle in the walls of the bronchi and bronchioles that cause the airways to constrict or narrow.[8] Anticholinergic bronchodilators fall into this class of COPD medications, as do short-acting beta2-agonists, long-acting beta2- agonists, methylxanthines (e.g., theophylline), and a combination of an anticholinergic bronchodilator and a short-acting beta2-agonist.

All major guidelines for COPD management recommend beginning treatment with aerosol bronchodilators, which are inhaled directly into the lungs and have few side effects.[18,19,21,22]

Anticholinergic bronchodilators

In response to irritants such as cigarette smoke, the body produces a chemical "messenger" called acetylcholine that induces the airways to constrict. Anticholinergics are the only medications that act by blocking acetylcholine, thereby relaxing the muscle tissue and keeping the airways open.[24] Anticholinergic medications work via part of the parasympathetic nervous system, which controls airway size.

In addition to helping COPD patients take fuller breaths,[24] maintenance use of anticholinergic medication may also help lower the incidence of acute exacerbations in COPD patients.[25]

The American Thoracic Society, a leading medical authority on respiratory illnesses, recommends anticholinergics as the first line of maintenance therapy for patients with daily COPD symptoms.[9] The Global Initiative for Chronic Obstructive Lung Disease also recognizes anticholinergics as an important treatment for COPD.[19]

Anticholinergics are most often administered through metered-dose inhalers, or "puffers," as they are commonly called. The effects of the medication generally last from four to six hours, so physicians typically prescribe use four times a day.[9] Inhaled anticholinergics are minimally absorbed, resulting in relatively few side effects. Some common side effects of ipratropium bromide, an inhaled anticholinergic therapy, include cough and nervousness.[24]

Anticholinergic bronchodilators, as a class, are the number one prescribed bronchodilator used in the treatment of COPD.[26] Currently, the leading anticholinergic medication prescribed by physicians is ipratropium bromide. It is sold alone under the brand name ATROVENT, Inhalation Aerosol or in combination with albuterol sulfate under the brand name COMBIVENT, Inhalation Aerosol.

Beta2-agonists

Beta2-agonists work via part of the nervous system that controls muscle tissue around the airways. They work by stimulating receptors in the sympathetic nervous system, leading to dilation of air passages.[8] Two types of beta2-agonists are available: short-acting beta- agonists and long-acting beta-agonists.

Short-acting beta2-agonists

These medications are recommended by the American Thoracic Society for patients with COPD who experience intermittent symptoms.[9] They are also used as a "rescue" medication to fend off an impending attack of shortness of breath. Short-acting beta2- agonists are typically prescribed along with anticholinergics to open up the airways of COPD patients with continuing symptoms.[9] The short-acting beta2-agonist most commonly prescribed by physicians is albuterol.[26] In clinical studies, the most common side effects of albuterol included tremor, nausea, tachycardia, palpitations and nervousness.[27]

Long-acting beta-agonists

These bronchodilators are taken twice a day and, like short-acting beta-agonists, work via part of the nervous system that controls muscle tissue around the airways. They are recognized as a treatment for COPD by the Global Initiative for Chronic Obstructive Lung Disease.[19]

Long-acting beta-agonists are often prescribed for nighttime breathing problems because they provide up to 12 hours of relief.[19] Patients using long-acting beta-agonists need to be reminded to continue using their short-acting beta-agonist for "rescue" therapy, because long-acting beta-agonists do not work as quickly and are indicated for use only twice a day.[28] The most common side effects seen with use of long-acting beta-agonists by patients with COPD include headache, upper respiratory tract infection, nasopharyngitis and cough.[27]

Combination bronchodilators

The combination of an anticholinergic and short-acting beta2-agonist works via the part of the nervous system that controls airway size, as well as the part that controls muscle tissue around the airways. Increased efficacy is seen with this combination agent over the individual components, without an increase in side effects.[29] The most common side effects include bronchitis, upper respiratory tract infection and headache. [30

(meta analysis)

Treatment with inhaled corticosteroids has been shown to reduce local inflammatory cells and systemic markers such as C-reactive protein, improve respiratory symptoms, reduce COPD exacerbations, and slow the progression of lung function decline.5-9 Anticholinergic bronchodilators inhibit bronchoconstriction as well as mucus secretion, and have been shown to improve symptoms and reduce exacerbations without producing tolerance to their effects over time.10-16 Inhaled anticholinergics are poorly absorbed from the gastrointestinal tract and lung, so that systemic adverse effects are rare.10,17 Β2-Agonists are bronchodilators that relax bronchial smooth muscle and are effective in the short-term relief of COPD symptoms.18 However, long-term use may be associated with tolerance to their effects.11,14

The 2 types of bronchodilators, anticholinergics and Β2-agonists, have generally been considered to be equivalent choices for use in patients with COPD.1,33,34 Despite the fact that anticholinergics have been shown to have equal or superior efficacy compared with Β2-agonists,15,35-39 surveys have shown that prescriptions for Β2-agonists in COPD are 10 times more common than anticholinergics in the United States and 2 times more common in the United Kingdom and Europe.40-42 The objective of this meta-analysis is to compare the effects of Β2-agonists and anticholinergics on exacerbations requiring withdrawal from the trial, severe exacerbations requiring hospitalization, and respiratory deaths in patients with COPD.

In summary, both anticholinergics and Β2-agonists may be effective bronchodilators and improve symptoms in patients with COPD. Anticholinergics reduced severe exacerbations and respiratory deaths in patients with COPD. However, Β2-agonists had no effect on severe exacerbations and resulted in an increased rate of respiratory deaths, possibly owing to a reduction in disease control. Concomitant corticosteroids were used in over one-half of patients treated with Β2-agonists, but it is not clear if this provided some protection against the adverse effects. The results of this meta-analysis suggest that anticholinergics should be the bronchodilator of choice in patients with COPD. The long-term safety of Β2-agonists in patients with COPD should be addressed.

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Management of stable COPD

[edit] Bronchodilators

Bronchodilators are medicines that relax smooth muscle around the airways, increasing the calibre of the airways and improving air flow. They can reduce the symptoms of shortness of breath, wheeze and exercise limitation, resulting in an improved quality of life for people with COPD.[36] They do not slow down the rate of progression of the underlying disease.[2] Bronchodilators are usually administered with an inhaler or via a nebulizer.

There are two major types of bronchodilator, Β2 agonists and anticholinergics. Anticholinergics appear to be superior to Β2 agonists in COPD. Anticholinergeics reduce respiratory deaths while Β2 agonists have no effect on respiratory deaths.[37] Each type may be either long-acting (with an effect lasting 12 hours or more) or short-acting (with a rapid onset of effect that does not last as long).

[edit] Β2 agonists

Β2 agonists stimulate Β2 receptors on airway smooth muscles, causing them to relax. There are several Β2 agonists available. Salbutamol or albuterol (common brand name: Ventolin) and terbutaline are widely used short acting Β2 agonists and provide rapid relief of COPD symptoms. Long acting Β2 agonists (LABAs) such as salmeterol and formoterol are used as maintenance therapy and lead to improved airflow, exercise capacity, and quality of life.[38]

[edit] Anticholinergics

Anticholinergic drugs cause airway smooth muscles to relax by blocking stimulation from cholinergic nerves. Ipratropium is the most widely prescribed short acting anticholinergic drug. Like short-acting Β2 agonists, short-acting anticholinergics provide rapid relief of COPD symptoms and a combination of the two is commonly used for a greater bronchodilator effect. Tiotropium is the most commonly prescribed long-acting anticholinergic drug in COPD. It is has more specificity for M3 muscarinic receptors so may have fewer side-effects than other anticholinergic drugs. Regular use is associated with improvements in airflow, exercise capacity, quality of life and possibly a longer life.[39][40]

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