**11.2.1 Bronchodilators**

Bronchodilators are the mainstay of any COPD treatment plan. The mechanism of action is primarily by dilating airways and thereby decreasing airflow resistance increasing airflow and decreasing dynamic hyperinflation which is the origin of early stage symptoms. Many patients with COPD will have reduced dyspnea and improved exercise tolerance with bronchodilator therapy, even if improvement in resting spirometry is very modest(O'Donnell,2000 as cited in Shapiro SD,2010). Unlike asthma, COPD patients mostly need bronchodilators both on a chronic basis as well as for "rescue". All symptomatic patients with COPD should be prescribed a short-acting bronchodilator for as-needed basis and a regularly scheduled long-acting bronchodilator should be added if symptoms are inadequately controlled. Bronchodilators include beta agonists, anticholinergics, and theophylline, which is used less often.

The initial choice of agent remains debated. Historically, β2 agonists were considered first line and anticholinergics added as adjuncts. Studies have shown combination therapy results in greater bronchodilator response and provides greater relief. The degree of bronchodilation achieved by short-acting beta agonists and anticholinergics is additive. The adverse effect profile may help guide therapy.

#### i. Beta2(β2)-agonists:

138 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

health care providers should participate in setting the target date and should follow up with respect to maintenance. Successful cessation programs should include patient education, target date to quit, follow-up support, relapse prevention, advice for healthy lifestyle

According to the US Preventive Services Task Force(USPSTF) guidelines, recommends "5- A" approach to counseling that includes i)Ask about tobacco use, ii)Advise to quit through personalized messages, iii)Assess willingness to quit, iv)Assist with quitting, v)Arrange follow-up care and support. Behavioral counseling and pharmacotherapy are most effective

Supervised use of pharmacologic agents is an important adjunct as withdrawal from nicotine may cause unpleasant adverse effects during the first weeks after quitting smoking. Nicotine replacement therapies are available in the form of chewing gum and transdermal patches to counter the withdrawal symptoms(U.S. Public Health Service Clinical Practice Guideline,2008). Long-term success rates have been 22-42%, compared with 2-25% with placebos. The use of an antidepressant medication, bupropion (Zyban,150 mg bid) has been shown to be effective for smoking cessation and may be used in combination with nicotine replacement therapy. Varenicline (Chantix), is a partial agonist selective for α4, β2 nicotinic acetylcholine receptors and action is thought to result from partial agonist activity at a nicotinic receptor subtype while simultaneously preventing nicotine binding. Nortriptyline and clonidine have also been proposed to help in cessation of smoking (U.S. Public Health

The U.S. Food and Drug Adminstration (FDA) recommends five treatment end points be considered for COPD: improvement in airflow obstruction, providing symptom relief, modifying or preventing exacerbations, altering disease progression (including mortality), and modifying lung structure. Effective treatment of the COPD patient requires effective integration of pharmacologic treatment and nonpharmacologic therapy, most importantly

Bronchodilators are the mainstay of any COPD treatment plan. The mechanism of action is primarily by dilating airways and thereby decreasing airflow resistance increasing airflow and decreasing dynamic hyperinflation which is the origin of early stage symptoms. Many patients with COPD will have reduced dyspnea and improved exercise tolerance with bronchodilator therapy, even if improvement in resting spirometry is very modest(O'Donnell,2000 as cited in Shapiro SD,2010). Unlike asthma, COPD patients mostly need bronchodilators both on a chronic basis as well as for "rescue". All symptomatic patients with COPD should be prescribed a short-acting bronchodilator for as-needed basis and a regularly scheduled long-acting bronchodilator should be added if symptoms are inadequately controlled. Bronchodilators include beta agonists, anticholinergics, and

The initial choice of agent remains debated. Historically, β2 agonists were considered first line and anticholinergics added as adjuncts. Studies have shown combination therapy

changes, social support systems, pharmacological agents.

when used together.(USPSTF,2009)

Service Clinical Practice Guideline,2008).

**11.2 Pharmacologic treatment** 

pulmonary rehabilitation.

**11.2.1 Bronchodilators** 

theophylline, which is used less often.

This group of medications bind to the β-adrenergic receptor present on airway smooth muscle, resulting in bronchodilation and improvement in airflow. They may also help by increasing ciliary beating frequency and improving mucus transport and may improve endurance of fatigued respiratory muscles(Nava et al,1992;Santa Cruz et al,1974 as cited in Shapiro SD,2010).

Beta agonists are available in short-acting and long-acting inhaled formulations. The shortacting-β agonists(SABA) like albuterol, its racemer levalbuterol, pirbuterol and terbutaline, have a relatively rapid onset of action after inhalation, in about 5 to 15 minutes, and the bronchodilation lasts for 2 to 4 hours. Long-acting β-agonists (LABAs) like salmeterol, formoterol, arformoterol and indacaterol have a longer onset and bronchodilation lasting for up to 12 hours or more. Salmeterol has also shown anti-inflammatory effects, to reduce edema, and to reduce airway epithelial cell injury in model systems.

Inhaled route is preferable owing to more favorable ratio of therapeutic effect to undesirable side effects(Shim & Williams,1983 as cited in Shapiro SD,2010). A metered dose inhaler (MDI), dry powder inhaler (DPI) is the preferred mode to deliver a bronchodilator medication by inhalation as it simplifies therapy, improves compliance, and may reduce extra medication usage and patient cost. Nebulizers may be more effective in patients too weak to use an inhaler device, in those with altered mental status, or in those whose inspiratory capacity is too limited to permit effective inhalation (Tenholder et al,1992 as cited in Shapiro SD,2010).

Benefits of treatment include improvement in airflow obstruction and symptom relief. Although the magnitude of improvement is less and incomplete as compared to asthma patients, 25-30% patients achieve "positive bronchodilator response" as defined by the ATS. Improvement in FEV1( about 200- to 300-mL) and symptoms assessed by SGRQ have been elicited in multiple randomized placebo-controlled trials(Appleton et al,2006;Calverley et al,2003;Rodrigo et al,2008 as cited in Shapiro SD,2010). Modest benefit is noted in prevention of exacerbations with LABAs to the tune of 20-30% reduction in frequency of exacerbations(Appleton et al,2006;Sin et al,2003 as cited in Shapiro SD,2010). However, they have no effect on disease progression and alteration of lung structure(Calverley et al.,2007 as cited in Shapiro SD,2010).

Side-effects commonly include tremor, palpitations, anxiety, and insomnia. Ventricular arrhythmias and hypokalemia may also occur. These effects are dependent on systemic absorption and hence, spacer devices, DPIs,MDIs are preferable. R-enantiomer of albuterol, levalbuterol was promoted widely based on the possibility to have lesser side effects such as tachycardia and tremors as well as lacking the inflammatory effect of the S-enantiomer. The small difference noted in studies has raised doubts of its clinical relevance(Donahue et al,2008 as cited in Shapiro SD,2010).

A significant proportion of COPD patients have concurrent cardiac co-morbidities and although recent studies have failed to show any clinically significant adverse outcome of β2

Current Overview of COPD with Special Reference to Emphysema 141

arrhythmias.Hence, use of theophylline is usually limited to an add-on therapy when symptoms continue in patients with more severe disease despite the use of other treatments.

Historically, β2 agonists were considered first line and anticholinergics added as adjuncts. Most patients in GOLD stage I disease will have acceptable relief of symptoms with one short acting bronchodilator used on as needed basis. Combination therapy with short and long acting β2-agonists and anticholinergics is supported by trials indicating greater bronchodilator response and achieving better symptom relief(Cazzola et al,2004;CIAS Group,1994;VanNoord et al.,2000 as cited in Shapiro SD,2010). In patients with GOLD stage II and above, whose symptoms are not well-controlled with a single long-acting bronchodilator, the combination of both an anticholinergic and a β2-agonist long-acting bronchodilator may provide better symptom relief and improve quality of life

SABA, LABA, anticholinergics have been tried in various combinations and data suggests improved FEV1 and symptom control with combinations than either agent alone. The choice and order of agents can be guided by response, side-effects and co-morbidity profile (ATS/ERS Task Force, 2004; GOLD, 2006). Although clinical responses among individual patients may vary, poor compliance and ineffective use of the device must be considered

COPD is characterized by both airway and systemic inflammation as discussed in the pathogenesis and the primary reason of disease progression. Bronchodilators achieve temporary symptom control but have failed to show any effect on the underlying inflammation. Corticosteroids are by far the leaders of this class of medication, and some

Inhaled glucocorticoids decrease frequency of exacerbations and modestly slow the progression of respiratory symptoms, but appear to have little impact on lung function and mortality. Because of their lack of effect on bronchodilation, inhaled glucocorticoids can be

Benefits from therapy include reduction in the frequency and severity of exacerbations of COPD by 25-30%, comparable to LABAs(Calverley et al.,2003,2007;Szafranski et al,2003 as cited in Shapiro SD,2010). Effect on improvement of airflow obstruction and symptom relief is minimal, although some additive benefit is reported for combination therapy with LABAs(Burge et al,2000;Pauwels et al,1999 as cited in Shapiro SD,2010). Though the antiinflammatory effect promises possible alteration of disease progression and slowing of decline in FEV1, studies have failed to show any such benefit(Highland et al,2003;Soriano et al,2007;Sutherland et al.,2003 as cited in Shapiro SD,2010). Some studies have reported equivocal reduction in hospital admission and mortality rates(Sin & Tu,2001;Soriano et al,2002 as cited in Shapiro SD,2010). No study has proven any effect on lung structure

used only as part of a combined regimen, but are not as sole therapy.

**11.2.2 Choice of bronchodilator and combination therapy** 

index(ATS/ERS Task Force,2004;GOLD,2006).

before changing medications.

i. Corticosteroids:

remodelling.

**11.2.3 Anti-inflammatory medications** 

newer phosphodiesterases have shown promise.

agonists, caution is warranted.(Cazzola et al,1998;Anthonisen et al,2002 as cited in Shapiro SD,2010)

ii. Anti-cholinergics:

Anticholinergic agents block M2 and M3 cholinergic receptors and result in bronchodilation (Rennard,2000 as cited in Shapiro SD,2010). In airway smooth muscle cells, acetylcholine stimulates the production of neutrophil chemotactic activity and anticholinergics could, theoretically, have anti-inflammatory action (Koyama et al,1992;Wessler & Kirkpatrick,2001 as cited in Shapiro SD,2010).

Short-acting anticholinergic agents like ipratropium and oxitropium improve lung function and symptoms. In double-blinded studies, ipratropium improved lung function, increased exercise capacity, decreased dyspnea, and decreased cough when compared to placebo. Ipratropium produces bronchodilation in 10 to 15 minutes and lasts for 4 to 6 hours.

Tiotropium is a longer-acting anticholinergic because it dissociates from the receptor extremely slowly achieving peak bronchodilator activity after 1 to 2 hours, but duration of action lasts long enough for once daily dosing. When administered chronically, the bronchodilator effect of tiotropium increases with daily dosing and is maximal after 1 week (Hansel & Barnes,2002;Littner et al,2000 as cited in Shapiro SD,2010). It is relatively selective for M3 receptor, and this may have better clinical efficacy as it doesn't alter the M2 mediated feedback inhibition of acetylcholine (On et al,2001 as cited in Shapiro SD,2010). The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial studied the effects of use over a 4-year period and showed improvements in lung function, quality of life, and exacerbations but did not show a decrease in the rate of decline of lung function (Tashkin et al.,2008).

Benefits of treatment are similar to beta-agonist agents including improvement in airflow obstruction and symptom relief. Tiotropium improves airflow and lung volumes, reduces dyspnea, and improves health status and exercise performance(Tashkin et al,2008). In combination with albuterol tiotropium has been reported to reduce risk of COPD exacerbation to the magnitude of the risk reduction by 20% to 25%( Niewoehner et al,2005;Sin et al,2003 as cited in Shapiro SD,2010). However, as with other bronchodilators, anticholinergics have no effect on disease progression and alteration of lung structure. Reported adverse effects include dry mouth, metallic taste, and prostatic symptoms. Equivocal data exist regarding possible increased adverse cardiac events with chronic use of anti-cholinergic agents.

#### iii. Theophylline:

Theophylline is the only methylxanthine currently used to treat COPD patients. It has modest bronchodilator activity, but it also has additional potentially beneficial effects including anti-inflammatory, modest inotropic and diuretic effects, and may also augment skeletal muscle strength(Barnes,2003;Culpitt et al,2002 as cited in Shapiro SD,2010). Doserelated adverse effects of theophylline include nausea and vomiting, seizures, and arrhythmias. Its use is also complicated by many drug interactions and concurrent morbidity that affecting liver and cardiac function can alter theophylline levels. The therapeutic index of theophylline is narrow and desired serum levels are 8 to 12 µg/mL. Dose-related adverse effects of theophylline include nausea and vomiting, seizures, and arrhythmias.Hence, use of theophylline is usually limited to an add-on therapy when symptoms continue in patients with more severe disease despite the use of other treatments.

### **11.2.2 Choice of bronchodilator and combination therapy**

Historically, β2 agonists were considered first line and anticholinergics added as adjuncts. Most patients in GOLD stage I disease will have acceptable relief of symptoms with one short acting bronchodilator used on as needed basis. Combination therapy with short and long acting β2-agonists and anticholinergics is supported by trials indicating greater bronchodilator response and achieving better symptom relief(Cazzola et al,2004;CIAS Group,1994;VanNoord et al.,2000 as cited in Shapiro SD,2010). In patients with GOLD stage II and above, whose symptoms are not well-controlled with a single long-acting bronchodilator, the combination of both an anticholinergic and a β2-agonist long-acting bronchodilator may provide better symptom relief and improve quality of life index(ATS/ERS Task Force,2004;GOLD,2006).

SABA, LABA, anticholinergics have been tried in various combinations and data suggests improved FEV1 and symptom control with combinations than either agent alone. The choice and order of agents can be guided by response, side-effects and co-morbidity profile (ATS/ERS Task Force, 2004; GOLD, 2006). Although clinical responses among individual patients may vary, poor compliance and ineffective use of the device must be considered before changing medications.
