**11.2.3 Anti-inflammatory medications**

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 newer phosphodiesterases have shown promise.

i. Corticosteroids:

140 Chronic Obstructive Pulmonary Disease – Current Concepts and Practice

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

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

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.

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

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

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

Ipratropium produces bronchodilation in 10 to 15 minutes and lasts for 4 to 6 hours.

SD,2010)

ii. Anti-cholinergics:

as cited in Shapiro SD,2010).

function (Tashkin et al.,2008).

anti-cholinergic agents.

iii. Theophylline:

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

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 remodelling.

Current Overview of COPD with Special Reference to Emphysema 143

There are no supportive data advocating a beneficial role for cromolyn, nedocromil, or cysteinyl leukotriene antagonists in treating COPD(DeJong et al,1994 as cited in Shapiro

The treatment strategies for A1PI deficiency involve reducing the neutrophil elastase burden, primarily by smoking cessation, and augmenting the levels of A1PI. Available augmentation strategies include pharmacologic attempts to increase endogenous production of A1PI by the liver (ie, danazol, tamoxifen) or administration of purified A1PI by periodic intravenous infusion or by inhalation. Tamoxifen can increase endogenous production of A1PI to a limited extent, so this may be beneficial in persons with the PISZ phenotype.

Intravenous augmentation therapy is the only available approach that can increase serum levels to greater than 11 mmol/L, the protective threshold. Studies show that the infusions can maintain levels of more than 11 mmol/L, and replacement is administered weekly (60 mg/kg), biweekly (120 mg/kg), or monthly (250 mg/kg) (Buist et al,1989;Sandhaus,2009 as cited in Shapiro SD,2010). Uncontrolled observations of patients suggest that the FEV1 may fall at a slower rate in patients who receive A1PI replacement. It seems reasonable to weigh carefully the advantages and disadvantages of augmentation therapy and to reach a decision jointly with elderly persons or with those with severe lung function impairment

Mucolytic agents like acetylcysteine, dornase(DNAse), guaifenesin reduce sputum viscosity and improve secretion clearance. however, studies have failed to justify a role for these medications in management of COPD(Decramer et al,2005 as cited in Shapiro SD,2010). The role of oral expectorants like guaifenesin in promoting mucous clearance in COPD patients

Chronic infection or colonization of the lower airways with *S pneumoniae, H influenzae,* and/or *Moraxella catarrhalis* is common and in later stage disease, with Gram-negative organisms such as *Pseudomonas*. Macrolides like erythromycin, may have additional antiinflammatory effects. Patients whose COPD is associated with, bronchiectasis may benefit from chronic antibiotic therapy. However, at present, chronic antibiotics are not

The use of antibiotics for the treatment of acute COPD exacerbations and pneumonias is well supported (Adams et al.,2008). The patients who benefited most from antibiotic therapy were those with exacerbations that were characterized by at least 2 of the following: increases in dyspnea, sputum production, and sputum purulence (The Winnipeg criteria).

Infection is a common cause of COPD exacerbation and vaccination is the most effective way of prophylaxis. Pneumococcal polysaccharide vaccine should be offered to patients

iii. Cromolyn Sodium Nedocromil and Leukotriene Antagonists :

(FEV1 values < 0.8 L)(Buist et al,1989 as cited in Shapiro SD,2010).

**11.2.4 Adjuvant pharmacologic agents** 

ii. Mucoactive and expectorant agents:

recommended for stable COPD management.

remains controversial. iii. Antibiotic therapy:

iv. Vaccine prophylaxis:

i. Augmentation therapy for A1PI deficiency:

SD,2010).

Inhaled corticosteroids are only minimally absorbed and therefore systemic adverse effects are limited. Local effects include oral candidiasis and dysphonia(Pauwels et al,1999 as cited in Shapiro SD,2010). Systemic effects include increased bruising and reduced bone density, and possible susceptibility for pneumonia(Calverley et al.,2007 as cited in Shapiro SD,2010). Appropriate caution and monitoring is recommended although the clinical importance of these effects remains uncertain.

Systemic steroids have been widely used in the treatment of acute exacerbation of COPD. A meta-analysis concluded that systemic corticosteroids significantly reduced treatment failure and need for additional medical treatment and increased the rate of improvement in lung function and dyspnea over the first 72 hours(Rice et al,2000 as cited in Shapiro SD,2010). The use of oral steroids in persons with chronic stable COPD is not recommended given the adverse effect profile, which includes hypertension, glucose intolerance, osteoporosis, fractures, and cataracts, among others(Burge et al,2003 as cited in Shapiro SD,2010).

Inhaled glucocorticoids are typically used in combination with a long-acting bronchodilator for patients in GOLD stage III-IV, who have significant symptoms or repeated exacerbations, despite an optimal bronchodilator regimen. Steroids may be introduced earlier if there are signs of inflammation or an asthmatic component to the COPD(Ferguson et al.,2008 as cited in Shapiro SD,2010). In the TORCH (Toward a Revolution in COPD Health) trial involving patients with moderate to severe COPD, salmeterol plus fluticasone significantly improved the lung function, health status, and the rate of exacerbations compared to placebo, salmeterol alone, or fluticasone alone(Calverley et al.,2007). It also minimally decreased mortality compared to placebo (10.3 versus 12.6 percent, hazard ratio 0.81, 95% CI, 0.67-0.98). The Investigating New Standards for Prophylaxis in Reduction of Exacerbations (INSPIRE) trial included 1323 patients with stable, mostly severe COPD and results failed to show significant benefits of combining inhaled steroids with LABAs(Wedzicha et al.,2008).

"Triple inhaler therapy" - with a long-acting beta agonist plus an inhaled glucocorticoid plus a long-acting anticholinergic is often used in refractory COPD patients. This approach is supported by some studies(Tashkin et al.,2008). These data are insufficient to warrant a change in the current guidelines in which the first step is initiation of a long-acting bronchodilator alone and then if response is inadequate or disease advances, to introduce a combination of long-acting beta agonist plus an inhaled glucocorticoid.

ii. Phosphodiesterase inhibitors :

Phosphodiesterase-4 (PDE-4) inhibition decreases inflammation and promotes airway smooth muscle relaxation. Cilomilast and roflumilast are highly specific, oral, secondgeneration PDE-4 inhibitors being considered for use in patients with asthma and COPD(Gamble et al.,2003;Profita et al.,2003 as cited in Shapiro SD,2010). Recent trials have supported their inclusion in COPD combination treatment plans(Calverly et al.,2009;Chong et al.,2011as cited in Shapiro SD,2010). Several randomized, double-blind, placebocontrolled multicenter trials revealed increased FEV1 (*P* < .0001) and the rate of COPD exacerbations was reduced by 17% (*P* <.0003) in patients who received roflumilast compared with placebo. Additional studies are necessary before PDE-4 inhibitors can be recommended for routine use in patients with stable COPD.

iii. Cromolyn Sodium Nedocromil and Leukotriene Antagonists :

There are no supportive data advocating a beneficial role for cromolyn, nedocromil, or cysteinyl leukotriene antagonists in treating COPD(DeJong et al,1994 as cited in Shapiro SD,2010).
