General Therapeutic Principles

• Pharmacotherapy is highly valuable for the following:
  • Prevention & control of symptoms
  • Reduction of the frequency & severity of exacerbations
  • Improvement of health status
  • Improvement of exercise tolerance

• Drug therapy for COPD is determined by individualized assessment of symptoms & exacerbation risk
• Based on studies the existing pharmacotherapy for COPD do not modify the long-term decline in lung function; however, limited evidence suggests that regular treatment with long-acting beta₂-agonists, inhaled corticosteroid & its combination can decrease the rate of decline in lung function
• The following table summarizes treatment recommendations by patient category of COPD:



Patient Category	Recommended treatment
A	Short-acting anticholinergic or short-acting beta2-agonist as required (1st choice) Long-acting anticholinergic or long-acting beta2-agonist or short-acting beta2-agonist & short-acting anticholinergic (2nd choice) Theophylline (alternative choice*)
B	Long-acting anticholinergic or long-acting beta2-agonist (1st choice) Long-acting anticholinergic & long-acting beta2-agonist (2nd choice) Short-acting beta2-agonist &/or short-acting anticholinergic or Theophylline (alternative choice*)
C	Inhaled corticosteroid + long-acting beta2-agonist or long-acting anticholinergic (1st choice) Long-acting anticholinergic & long-acting beta2-agonist or Long-acting anticholinergic & phosphodiesterase-4 inhibitor or Long-acting beta2-agonist & phosphodiesterase-4 inhibitor (2nd choice) Short-acting beta2-agonist &/or short-acting anticholinergic or Theophylline (alternative choice*)
D	Inhaled corticosteroid + long-acting beta2-agonist &/or long-acting anticholinergic (1st choice) Inhaled corticosteroid + long-acting beta2-agonist & long-acting anticholinergic or Inhaled corticosteroid + long-acting beta2-agonist & phosphodiesterase-4 inhibitor or Long-acting anticholinergic & long-acting beta2-agonist or Long-acting anticholinergic & phosphodiesterase-4 inhibitor (2nd choice) Carbocysteine or short-acting beta2-agonist &/or short-acting anticholinergic or Theophylline or N-acetylcysteine (alternative choice*)

Adapted from Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2017 report.
* May be used alone or in combination with the 1st or 2nd choice medication options

Bronchodilators

• Classes (listed alphabetically): Anticholinergics, beta₂-agonists, methylxanthines
• All bronchodilators increase exercise capacity
• Inhaled bronchodilators are recommended for all symptomatic patients with stable COPD with FEV₁ of <60%
  • May also be used for symptomatic stable COPD patients with predicted FEV₁ of 60-80%
  • Inhaled therapy is preferred to oral, because of decreased likelihood of adverse effects

• Given on a “when required” basis for immediate relief of symptoms or on a regular basis to prevent or reduce symptoms
• Regular treatment with long-acting bronchodilators is more effective & convenient but can be more expensive
  • When possible, therapy should be via the inhaled route but if cost is a barrier, then oral bronchodilators (beta₂-agonists, Theophylline) can be considered
  • Inhaled bronchodilators are preferred to Theophylline because of the latter’s potential toxicity

• Combination therapy with inhaled long acting anticholinergics, long-acting beta₂-agonists, or corticosteroids are recommended for symptomatic patients with stable COPD & FEV₁ of <60% predicted
  • Combining drugs with different mechanisms of action may increase bronchodilatation with less side effects compared to simply increasing the dose of a bronchodilator

• Choice of drugs will depend on the patient’s response & preference, together with drug’s side effects & cost

Anticholinergics

• Eg (long-acting) Aclidinium, Glycopyrronium, Tiotropium, Umeclidinium, (short-acting) Ipratropium, Oxitropium
• Block the effects of acetylcholine on M2 & M3 (short-acting), & M1 & M3 (long-acting) receptors
• Long-acting inhaled anticholinergics are recommended for symptomatic patients with FEV₁ of <60% predicted
• Short-acting anticholinergics generally have a longer duration of bronchodilatation than short-acting beta₂-agonists
• Based on a large, long-term, randomized, controlled study in patients with moderate to very severe COPD, Tiotropium with concurrent respiratory medication other than another inhaled anticholinergic agent, resulted in the following benefits:
  • Positive effects on quality of life
  • Reduced risk of exacerbations & exacerbation-related hospitalizations
  • Reduced respiratory morbidity including respiratory failure & cardiac morbidity

• Have been shown to be very safe at a wide range of doses
• Based on short-term, clinical studies in patients with moderate to severe COPD, combination of short-acting anticholinergic & short-acting beta₂-agonist may provide superior bronchodilatation than either medication alone
• Aclidinium & Glycopyrronium have effects on lung function & breathlessness comparable to that of Tiotropium but further studies are needed

Beta₂-agonists

• Eg Arformoterol, Fenoterol, Formoterol, Indacaterol, Levalbuterol, Olodaterol, Salbutamol (Albuterol), Salmeterol, Terbutaline, Tulobuterol
• Long-acting inhaled beta₂-agonists are recommended for symptomatic patients with FEV₁ of <60% predicted
• Relax airway smooth muscle by stimulating beta₂-adrenergic receptors
• Salmeterol & Formoterol significantly improves FEV₁, lung function, dyspnea, quality of life & exacerbation rate
• Based on several clinical trials, combination of long-acting beta₂-agonists (eg Salmeterol) & inhaled corticosteroids (eg Fluticasone) may reduce COPD exacerbation & may improve lung function & quality of life better than when each drug is used alone
• Inhaled beta₂-agonists have a faster onset of action & less side effects than oral preparations

Methylxanthines

• Eg Aminophylline, Theophylline
• May act as non-selective inhibitor of phosphodiesterase, but have also been observed to exert a range of non-bronchodilator actions
• Though effective in COPD, inhaled bronchodilators are preferred to Theophylline, owing to the latter’s potential toxicity
• Combination of a beta₂-agonist, an anticholinergic &/or Theophylline may produce additional improvements in health status & lung function
• All studies that have shown efficacy of Theophylline in COPD made use of slow-release preparations

Corticosteroids

• Eg (inhaled) Beclomethasone, Budesonide, Fluticasone, (systemic) Prednisolone, Methylprednisolone
• Regular treatment with inhaled corticosteroids alone does not change the long-term decline of FEV₁
• Regular treatment with inhaled corticosteroids is appropriate in patients with FEV₁ <50% predicted or ≥2 exacerbations/year & repeated exacerbations (eg 3 exacerbations in the last 3 years)
  • May reduce airway hyper-reactivity in these patients & decrease symptoms of COPD including exacerbations

• In patients with more advanced COPD & repeated exacerbation, treatment with inhaled corticosteroids can be beneficial
• Dose-response relationships & long-term safety of inhaled corticosteroids in COPD are not known
• On a 3-year period treatment in COPD patients with high prevalence of osteoporosis, therapy with high-dose Fluticasone alone or in combination with Salmeterol was not associated with decreased bone mineral density (BMD) compared with placebo
  • Previous long-term trials investigating BMD in COPD patients produced conflicting results

• The use of combination therapy with inhaled corticosteroids & long-acting beta₂-agonist is more effective in reducing exacerbations & improving pulmonary function than either medication alone; however, the combination produces a small increased risk of non-fatal pneumonia
  • In patients with FEV₁ <60%, treatment with long-acting beta₂-agonist, inhaled corticosteroids & its combination have been shown to reduce the rate of decline of pulmonary function; addition of the combination to an anticholinergic (eg Tiotropium) appears to provide additional benefits

• Long-term use of oral corticosteroids is not recommended
• Short-course trials of oral corticosteroids may not reliably predict which patients will respond to inhaled corticosteroids

Inhalation Devices

• Effective drug delivery & training in inhaler technique should be emphasized & re-checked as necessary
• Choice of device depends on price, availability, the prescribing doctor, & the skills & ability of the patient
• Metered dose inhaler (MDI)
  • COPD patients may have poorer coordination & experience more difficulty with MDI use
  • Use of spacers with the MDI may be advised for patients who find it hard to master MDI inhaler technique

• Dry powder inhaler (DPI)
  • Breath-activated & may therefore require less hand-&-mouth coordination
  • May be more convenient & may provide improved deposition of the drug

• Nebulizer
  • Not recommended for routine use because of greater cost of treatment
• Assessment of inhaler technique should be done prior to modifying current therapy

Phosphodiesterase-4 Inhibitor

• Eg Roflumilast
• Reduce inflammation through inhibition of the breakdown of intracellular cyclic AMP
• Has no direct bronchodilator effects but has been shown to improve FEV₁ in patients treated with Tiotropium or Salmeterol
• Roflumilast has been shown to reduce exacerbations in patients with severe to very severe COPD (FEV₁ <50% predicted) with chronic bronchitis treated with oral corticosteroids
  • Same effect on exacerbation reduction has been noted when added to long-acting bronchodilators

• Roflumilast can not be administered with Theophylline
• Has more side effects compared to inhaled medications

Other Pharmacologic Agents

Alpha-1 Antitrypsin Augmentation Therapy

• May help halt the development & progression of pulmonary disease in patients with AATD
• Studies demonstrated a reduction in spirometric progression with alpha-1 antitrypsin augmentation therapy in patients with FEV₁ 35-49% predicted 
• Especially recommended for nonsmoking patients or those who stopped smoking with FEV₁ 35-60% predicted
• Further studies are needed to prove the efficacy versus cost of this treatment

Antibiotics

• Not recommended except for treatment of infectious bacterial exacerbations
• Treatment with macrolides may be considered for previous smokers

Cough & Cold Preparations

• Eg Ambroxol, Carbocysteine, Erdosteine, N-acetylcysteine
• Antitussives are not recommended because cough has a protective effect in COPD
• Expectorants & mucolytics were seen to have benefits in few patients with viscous mucous, but overall benefits seem to be very small
  • May be considered in patients with chronic cough productive of sputum
  • Therapy may be continued if there is a decrease in the frequency of cough & sputum production

• N-acetylcysteine may help reduce exacerbations in COPD patients without inhaled corticosteroid treatment

Vaccines

Influenza Vaccine

• May decrease morbidity & mortality rates due to influenza
• Should be given yearly, 1-2 months prior to anticipated peak influenza season, because of new antigens & waning immunity from the previous years
• Associated with reduced risk of all-cause mortality

Pneumococcal Polysaccharide Vaccine [Pneumococcal conjugate vaccine (PCV13) & 23-valent pneumococcal polysaccharide vaccine (PPSV23)] 

• Recommended in COPD patients ≥65 years & in younger patients with significant comorbidities (eg cardiac disease, chronic pulmonary disease)
• PPSV23 reduces occurrence of community-acquired pneumonia (CAP) in patients <65 years with FEV₁ <40% predicted or comorbidities
• Studies showed that PSV13 exhibited significant efficacy for both CAP & vaccine-type invasive pneumococcal disease in adults ≥65 years with efficacy lasting for at least 4 years
  • Possesses comparable or even greater efficacy when compared to the immunogenicity of PPSV23
• Generally given only once, but revaccination may be considered in 5-10 years

Bronchodilators

Hospital Management

• Short-acting inhaled beta₂-agonists are typically preferred for treating acute COPD exacerbations
• An anticholinergic may be added if the patient does not respond immediately to short-acting inhaled beta₂-agonists
• Oral or IV Theophylline & other methylxanthines should only be used as adjunctive treatment, when the response to inhaled bronchodilators is insufficient
  • May be considered in more severe exacerbations
  • Should be used with caution because of the increased likelihood of drug interactions & toxic effects
  • Close monitoring of serum Theophylline levels is recommended

Home Management

• The dose &/or frequency of ongoing bronchodilator treatment should be increased
• An anticholinergic, if not yet in use, may be added until improvement is noted
• High-dose nebulized therapy may be given when required for several days
  • Long-term use of nebulizer therapy after an exacerbation is not recommended

Corticosteroids

Hospital Management

• Oral or IV corticosteroids are recommended as an addition to bronchodilator therapy, in the absence of significant contraindications
• Shorten recovery time & help hasten restoration of lung function
• As much as possible, a course of oral corticosteroid must not exceed 14 days as there is no advantage to prolonged therapy & the risk of side effects is increased

Home Management

• Addition of oral corticosteroid to existing bronchodilator therapy may be considered if patient’s baseline FEV₁ is <50% predicted
• Nebulized Budesonide alone or in combination with Formoterol may be used as an alternative to oral corticosteroids; may cause significant reduction of complications (eg hyperglycemia)

Antibiotics

• Given in patients who presents with increased purulence of sputum together with increase in dyspnea & sputum volume or in patients who need mechanical ventilation
• Local antibiotic sensitivity patterns for Streptococcus pneumoniae, Haemophilus influenzae & Moraxella catarrhalis must be taken into account when choosing an antibiotic agent

Heparin (SC/Low Molecular Weight)

• Consider administration of SC/LMW Heparin to reduce the risk of pulmonary embolism in patients with polycythemia or dehydration, with or without a history of thromboembolic disease

Pulmonary Rehabilitation

• Multidisciplinary program for patients with chronic respiratory impairment that is individually designed to maximize a patient’s physical & social performance & autonomy
  • In regions with limited resources, simplified pulmonary rehabilitation programs are useful & are recommended

• Includes exercise training, nutrition counseling, education & psychological support
• Recommended for symptomatic patients with FEV₁ of <50% predicted
  • May also be considered in symptomatic patients with FEV₁ of >50% predicted with exercise limitations, patients with mMRC >1, & following acute exacerbations

• Program should last ≥2 months to be effective; the longer it continues, the better the results

Site of Care

Please refer to the Symptom and Risk Evaluation for COPD table for characteristics per patient category

• Patients belonging to category A or B may be managed on an outpatient basis during exacerbations
• Patients belonging to category C or D may require hospitalization & more aggressive management during exacerbations

Indications for Hospital Treatment for Chronic Obstructive Pulmonary Disease Exacerbations:

• Significant increase in symptoms (eg sudden development of resting dyspnea)
• Severe underlying COPD
• Onset of new symptoms (eg cyanosis, peripheral edema)
• Absence of response to initial medical treatment
• Significant comorbidities (eg heart failure or newly occurring arrhythmias)
• Frequent exacerbations
• Older age
• Lack of home support