Treatment

  Treatment Guidelines / Chronic Obstructive Pulmonary Disease Overview / Treatment

Treatment

MANAGEMENT OF COPD

Non-Pharmacological Therapy

Smoking Cessation
  • Smoking cessation is the single most effective & cost effective method to reduce the risk of developing COPD & to stop its progression
    • Counseling may be employed to aid patient
    • Pharmacotherapies to aid smoking cessation eg Nicotine preparations, Bupropion & Nortriptyline may be considered (See Smoking Cessation Disease Management Chart)
Patient Education It plays an important role in the following:
  • Increasing patient’s knowledge & understanding of the disease
  • Improving skills in symptom recognition, breathing & physical exercise, medication use including proper technique & environmental modification
    • Important to note that adherence to inhaled medications has been associated w/ reduced risk of death & hospital admission due to COPD exacerbations
    • Measures must be taken to reduce total personal exposure to tobacco smoke, occupational dusts & chemicals & air pollutants
  • Improving attitude toward nutrition & exercise, smoking cessation, quality of life factors & coping skills (eg relaxation techniques, stress management)
  • Improving patient responses to exacerbations
  • Initiating discussions about end-of-life issues including advance directives
Pulmonary Rehabilitation
  • Multidisciplinary program for patients w/ chronic resp impairment that is individually designed to maximize a patient’s physical & social performance & autonomy
    • In regions w/ limited resources, simplified pulmonary rehabilitation programs are useful & are recommended
  • Includes exercise training, nutrition counseling, education & psychological support
  • Recommended for symptomatic patients w/ FEV1 of <50% predicted
    • May also be considered in symptomatic patients w/ FEV1 of >50% predicted w/ exercise limitations, patients w/ mMRC >1, & following acute exacerbations
  • Program should last ≥2 mth to be effective; the longer it continues, the better the results

Pharmacological Therapy

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 w/ 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. Updated 2015.
* May be used alone or in combination w/ 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 w/ stable COPD w/ FEV1 of <60%
    • May also be used for symptomatic stable COPD patients w/ 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 w/ 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 w/ inhaled long acting anticholinergics, long-acting beta2-agonists, or corticosteroids are recommended for symptomatic patients w/ stable COPD & FEV1 of <60% predicted
    • Combining drugs w/ different mechanisms of action may increase bronchodilatation w/ less side effects compared to simply increasing the dose of a bronchodilator
  • Choice of drugs will depend on the patient’s response & preference, together w/ drug’s side effects & cost
1. 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 w/ 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 w/ moderate to very severe COPD, Tiotropium w/ concurrent resp 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 resp morbidity including resp failure & cardiac morbidity
  • Have been shown to be very safe at a wide range of doses
  • Based on short-term, clinical studies in patients w/ 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

1.1 Long-Acting Anticholinergics (Inhaled)1

  • Adverse Reactions:
    • Resp effects (URTI, bronchitis, sinusitis, pharyngitis); CV effects (chest pain, palpitation); CNS effects (headache, dizziness); GI effects (dry mouth, bad taste, dyspepsia, nausea, constipation, diarrhea); Hypersensitivity reactions (urticaria, angioedema, rash, bronchospasm)
  • Special Instructions:
    • Use w/ caution in patients w/ prostatic hyperplasia, unstable ischemic heart disease, severe renal impairment, patients predisposed to narrow-angle glaucoma, bladder neck obstruction, urinary retention
    • Avoid contact w/ eyes w/ inhalation soln
    • Check patient’s inhaler technique for optimum delivery of drug
    • Glycopyrronium: not for initial treatment of bronchospasm
  • Dosage Guidelines:

    a. Glycopyrronium bromide

    • 50 mcg/inhalation breezhaler DPI
      • 50 mcg inhaled PO 24 hrly
      • Max dose: 1 dose/day

    b. Tiotropium

    • 18 mcg/dose HandiHaler DPI
      • 1 dose inhaled PO 24 hrly
    • 2.5 mcg/dose soln for inhalation Respimat inhaler
      • 2 puffs PO 24 hrly, puff at the same time each day

    c. Umeclidinium2

    • 62.5 mcg/inhalation
      • 1 inhalation PO 24 hrly

1.2 Short-Acting Anticholinergics (Inhaled)1

    a. Ipratropium bromide
    • 20 mcg/puff MDI
      • 1-2 puffs PO 6-8 hrly
      • Max dose: 12 puffs/day
    • 40 mcg/cap DPI
      • 1 cap inhaled PO 6-8 hrly
      • Max dose: 320 mcg/day
    • 250 mcg/2 mL, 500 mcg/2 mL inhalation soln unit dose
    • 0.025% inhalation soln
      • 1 unit dose (500 mcg) via nebulizer 6-8 hrly as required
      • 2 mL via nebulizer 6-8 hrly as required

    1Inhaled bronchodilator combinations are available. Please see the latest MIMS for specific formulations.

    2Available in combination w/ Vilanterol. Please see the latest MIMS for specific formulations?.

    2. Beta2-agonists

    • Eg Arformoterol, Fenoterol, Formoterol, Indacaterol, Levalbuterol, Olodaterol, Salbutamol (Albuterol), Salmeterol, Terbutaline, Tulobuterol
    • Long-acting inhaled beta2-agonists are recommended for symptomatic patients w/ 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
    SELECTIVE BETA2-AGONISTS BRONCHODILATORS
    Long-Acting Short-Acting
    Arformoterol Clenbuterol
    Bambuterol1 Fenoterol
    Formoterol Hexoprenaline
    Indacaterol Levalbuterol
    Olodaterol Orciprenaline2
    Salmeterol Procaterol
    Tulobuterol Salbutamol (Albuterol)3
      Terbutaline3
      Trimetoquinol

    1Prodrug of Terbutaline.

    2Less selective than Salbutamol.

    3Long-acting extended-release oral preparations are available.

    2.1. Long-Acting Beta2-agonists Bronchodilators (Inhaled)1

    • Adverse Reactions
      • CV effects (angina, palpitation, chest pain, tachycardia); CNS effects (headache, irritability, seizure); Dermatologic effects (urticaria, rash); Endocrine effects (hyperglycemia, hypokalemia); Resp effects (dyspnea, bronchospasm, cough, viral infection); Other effects (anaphylaxis, allergy, pain, diarrhea)
    • Special Instructions
      • Use w/ caution in patients w/ hyperthyroidism, DM, MI, HF, arrhythmia, hypertension, glaucoma, hypokalemia, seizure disorder
      • Monitor K levels
      • Check patient’s inhaler technique for optimum delivery of drug
    • Dosage Guidelines:

    a. Arformoterol

    • 15 mcg/2 mL soln for inhalation
      • 15 mcg inhaled via nebulization 12 hrly
      • Max dose: 30 mcg/day

    b. Formoterol

    • 4.5 mcg/dose, 6 mcg/dose, 9 mcg/dose turbuhaler DPI
      • 1-2 doses inhaled PO 12-24 hrly
      • Max dose: 8 doses/day
    • 12 mcg/cap DPI
      • 1-2 cap inhaled PO 12 hrly

    c. Indacaterol

    • 150 & 300 mcg/cap DPI
      • 1 cap inhaled 24 hrly
      • Max dose: 300 mcg 24 hrly

    d. Olodaterol

    • 2.5 mcg/puff soln for inhalation Respimat inhaler
      • 2 puffs PO 24 hrly, puff at the same time each day

    e. Salmeterol

    • 25 mcg/puff MDI
      • 2-4 puffs PO 12 hrly
    • 50 mcg/dose accuhaler DPI, diskhaler DPI
      • 1-2 doses inhaled PO 12 hrly as required

    1Inhaled bronchodilator combinations are available. Please see the latest MIMS for specific formulations.

    2.2. Long-Acting Beta2-agonists Bronchodilators (Oral)2

    • Adverse Reactions
      • CV effects (angina, palpitation, chest pain, tachycardia); CNS effects (headache, irritability, seizure); Dermatologic effects (urticaria, rash); Endocrine effects (hyperglycemia, hypokalemia); Resp effects (bronchospasm, cough, viral infection); Other effects (anaphylaxis, allergy)
    • Special Instructions
      • Use w/ caution in patients w/ hyperthyroidism, DM, myocardial insufficiency, arrhythmia, hypertension, HF, glaucoma, hypokalemia, seizure disorder
      • Monitor K levels
    • Dosage Guidelines:

    a. Bambuterol

    • 10 mg PO 24 hrly
    • May be increased to 20 mg PO 24 hrly after 1-2 wk

    b. Formoterol

    • 80 mcg PO 12 hrly

    c. Salbutamol (Albuterol)

    • Extended-release: 8 mg PO 12 hrly
    • Max dose: 32 mg/day in divided doses

    d. Terbutaline

    • Extended-release: 5-7.5 mg PO 12 hrly

    e. Tulobuterol

    • Initial dose: 1-2 mg PO 12 hrly
    • May increase dose up to 2 mg 8 hrly

    2.4 Short-Acting Beta2-agonists Bronchodilators (Oral)1

    • Adverse Reactions
      • CV effects (angina, palpitation, chest pain, tachycardia); CNS effects (headache, irritability, seizure); Dermatologic effects (urticaria, rash); Endocrine effects (hyperglycemia, hypokalemia); Resp effects (bronchospasm, cough, viral infection); Other effects (anaphylaxis, allergy)
    • Special Instructions
      • Use w/ caution in patients w/ hyperthyroidism, DM, myocardial insufficiency, arrhythmia, hypertension, HF, glaucoma, hypokalemia, seizure disorder
      • Monitor K levels
    • Dosage Guidelines:

    a. Clenbuterol

    • 20-40 mcg PO 12 hrly
    • Max dose: 80 mcg/day

    b. Fenoterol

    • 2.5-5 mg PO 8 hrly

    c. Hexoprenaline

    • 0.5-1 mg PO 8-24 hrly

    d. Orciprenaline

    • 20 mg PO 6-8 hrly

    e. Procaterol

    • 50 mcg PO 12-24 hrly
    • Minitab: 25-50 mcg PO 12 hrly

    f. Salbutamol (Albuterol)

    • 2-4 mg PO 6-8 hrly
    • Max dose: 32 mg/day in divided doses

    g. Terbutaline

    • 2.5-5 mg PO 8-12 hrly
    • May increase to 5 mg PO 8 hrly after 1-2 wk
    • Max dose: 15 mg/day

    h. Trimetoquinol 

    • 3-12 mg/day PO divided 8-12 hrly

    2.5 Long-Acting Beta2-agonists Bronchodilators (Topical)

    • Adverse Reactions
      • Musculoskeletal effects (fine tremors, muscle cramps); CV effects (tachycardia, nervous tension, palpitations, peripheral vasoconstriction); Other effects (hypersensitivity reactions)
    • Special Instructions
      • Use w/ caution in patients w/ hyperthyroidism, myocardial insufficiency, arrhythmias, susceptibility to QT-interval prolongation, hypertension, DM
    • Dosage Guidelines

    a. Tulobuterol

    • 2 mg via transdermal patch 24 hrly

    See Acute Exacerbation of COPD section for the Dosage Guidelines of short-acting inhaled beta2-agonists.

    1Inhaled bronchodilator combinations are available. Please see the latest MIMS for specific formulations.

    2Oral bronchodilator combinations are available. Please see the latest MIMS for specific formulations.

    3. 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

    3.1 Methylxanthines (Oral)

      • Adverse Reactions:
        • GI effects (irritation, N/V, abdominal pain, diarrhea, gastroesophageal reflux); CNS effects (CNS stimulation, headache, anxiety, restlessness, dizziness, tremor); CV effects (palpitations, tachycardia)
        • Serum conc >15-20 mcg/mL (85-110 micromol/L) are associated w/ increased risk of adverse effects including lethal adverse reactions
      • Special Instructions:
        • Use w/ caution in elderly patients, w/ peptic ulcer, hyperthyroidism, hypertension, cardiac arrhythmias or other CV disease, epilepsy, HF, hepatic dysfunction or chronic alcoholism, acute febrile illness
        • Many drug interactions occur w/ Theophylline including smoking (which increases Theophylline clearance)
        • Serum conc monitoring is necessary to ensure conc are w/in therapeutic range
        • Serum conc needs to be measured if a patient is changed from one extended-release product to another
        • Optimal therapeutic conc: 5-15 mcg/mL (28-85 micromol/L)
      • Dosage Guidelines:

      a. Acefylline

      • 500 mg-2 g/day PO in divided doses

      b. Aminophylline

      • Extended-release: 100-450 mg PO 12 hrly

      c. Choline theophyllinate

      • Initial dose: 0.2-0.4 mg PO 24 hrly
      • Maintenance dose: 0.8-1.2 g PO divided 6-8 hrly

      d. Diprophylline

      • 15 mg/kg/dose PO 6 hrly

      e. Doxofylline

      • 400 mg PO 8-12 hrly up to 1200 mg/day

      f. Heptaminol acefyllinate

      • 500 mg-1 g PO 8 hrly

      g. Theophylline1

      • 125-150 mg PO 6-8 hrly
      • Extended-release:
        • Initial dose: 5-8 mg/kg/day PO divided 12 hrly
        • Usual dose: 7-12 mg/kg/day divided 12 hrly
        • Max dose: 1000 mg/day

      1Many different formulations for Theophylline are available. Please see the latest MIMS for specific formulations.

      Corticosteroids

      • Eg (inhaled) Beclomethasone, Budesonide, Fluticasone, (systemic) Prednisolone, Methylprednisolone
      • Regular treatment w/ inhaled corticosteroids alone does not change the long-term decline of FEV1
      • Regular treatment w/ inhaled corticosteroids is appropriate in patients w/ FEV1 <50% predicted or ≥2 exacerbations/yr & repeated exacerbations (eg 3 exacerbations in the last 3 yr)
        • May reduce airway hyper-reactivity in these patients & decrease symptoms of COPD including exacerbations
      • In patients w/ more advanced COPD & repeated exacerbation, treatment w/ inhaled corticosteroids can be beneficial
      • Dose-response relationships & long-term safety of inhaled corticosteroids in COPD are not known
      • On a 3-yr period treatment in COPD patients w/ high prevalence of osteoporosis, therapy w/ high-dose Fluticasone alone or in combination w/ Salmeterol was not associated w/ decreased bone mineral density (BMD) compared w/ placebo
        • Previous long-term trials investigating BMD in COPD patients produced conflicting results
      • The use of combination therapy w/ 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 w/ FEV1 <60%, treatment w/ 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
      APPROXIMATE EQUIPOTENT DAILY DOSES OF CORTICOSTEROIDS (INHALED)
      Drug Adults
      Low Dose (mcg) Medium Dose (mcg) High Dose (mcg)
      Beclomethasone dipropionate 200-500 >500-1000 >1000-2000
      Budesonide 200-400 >400-800 >800-1600
      Ciclesonide 80-160 >160-320 >320-1280
      Flunisolide 500-1000 >1000-2000 >2000
      Fluticasone 100-250 >250-500 >500-1000
      Mometasone furoate 200-400 >400-800 >800-1200
      Triamcinolone acetonide 400-1000 >1000-2000 >2000

      1. Corticosteroids (Inhaled)1

      • Adverse Reactions:
        • Local effects (oropharyngeal candidiasis, cough from upper airway irritation, dysphonia); Paradoxical bronchospasm
        • Risk of systemic effects will depend on dose, potency of the corticosteroid, absorption from the gut, delivery system, use of spacers & drug’s pharmacokinetics
        • Long-term use of high-dose steroids may result in cataracts, glaucoma, skin thinning, easy bruising & adrenal suppression
      • Special Instructions:
        • Local effects may be minimized by using a spacer, gargling & spitting out w/ water, or gargling w/ 1:50 dilution of Amphotericin B
        • Not for relief of acute bronchospasm
        • Contraindicated in patients w/ recent nasal septal ulcers, surgery or trauma
        • Use w/ caution in patients w/ heart failure, acute MI, DM, GI diseases, hepatic/renal impairment, myasthenia gravis, osteoporosis, seizure disorder, thyroid disease
      • ?Dosage Guidelines:

      a. Beclomethasone dipropionate

      • Available Strength:
        • 50, 100, 200, 250 mcg/puff MDI; 100, 250 mcg/puff easi-breathe
        • 200 mcg/dose easyhaler DPI

      b. Budesonide

      • Available Strength:
        • 100, 200 mcg/puff MDI
        • 100, 200, 400 mcg/dose turbuhaler DPI; 100, 200, 400, 800 mcg/cap DPI
        • 250 mcg/mL, 500 mcg/2 mL, 1 mg/2 mL soln for inhalation unit dose

      c. Fluticasone

      • Available Strength:
        • 50, 125, 250 mcg/puff MDI
        • 50, 100, 250 mcg/dose accuhaler DPI; 50, 250 mcg/dose diskhaler DPI
        • 0.5 mg/2 mL, 2 mg/2 mL soln for inhalation unit dose

      1Corticosteroids combined w/ bronchodilators are available. Please see the latest MIMS for specific formulations.

      2. Corticosteroids (Systemic)

      • Adverse Reactions:
        • GI effects (gastritis, abdominal pain, diarrhea, dyspepsia, nausea); Endocrine effects (adrenocortical insufficiency, impaired glucose tolerance); Musculoskeletal effects (osteoporosis, muscle wasting, pain or weakness); Other effects (increased susceptibility to infection, impaired wound healing, electrolyte imbalances, wt gain, skin thinning leading to striae & easy bruising, cataracts, glaucoma)
      • Special Instructions:
        • Patients on long-term corticosteroids should receive preventive treatment for osteoporosis
        • Contraindicated in patients w/ fungal infections & those receiving live/attenuated vaccines
        • Use w/ caution in patients w/ heart failure, acute MI, DM, GI diseases, hepatic/renal impairment, myasthenia gravis, osteoporosis, seizure disorder, thyroid disease, Cushing’s syndrome, infection
        • Long-term treatment is not recommended due to its side-effects
      • Dosage Guidelines:

      2.1. Prednisone/Prednisolone/Methylprednisolone

      • 30-40 mg/day PO of Prednisone or its equivalent x 7-14 days or
      • 0.5 mg/kg IV 6 hrly x 3 days or 125 mg IV 6 hrly x 3 days during exacerbations

      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 w/ MDI use
        • Use of spacers w/ 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

      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 w/ Tiotropium or Salmeterol
      • Roflumilast has been shown to reduce exacerbations in patients w/ severe to very severe COPD (FEV1 <50% predicted) treated w/ oral corticosteroids
        • Same effect on exacerbation reduction has been noted when added to long-acting bronchodilators
      • Roflumilast can not be administered w/ Theophylline
      • Has more side effects compared to inhaled medications
      • Adverse Reactions
        • GI effects (diarrhea, nausea, abdominal pain); Other effects (decrease wt & appetite, insomnia, headache)
      • Special Instructions
        • Can be taken w/ or w/o food
        • Contraindicated in patients w/ moderate to severe liver impairment
        • Body wt should be monitored
        • Use w/ caution in patients w/ severe immunological diseases, severe acute infectious diseases, cancers (except basal cell carcinoma), CHF & in immunosuppressants
      • Dosage Guidelines:
        • 500 mcg 12 hrly

      Other Pharmacologic Agents
      1. Antibiotics

      • Not recommended except for treatment of infectious bacterial exacerbations

      2. 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 w/ viscous mucous, but overall benefits seem to be very small
      • May be considered in patients w/ 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 w/o inhaled corticosteroid treatment

      a. Acetylcysteine (N-acetylcysteine)

      • Adverse Reactions:
        • GI disturbances; N/V; Hypersensitivity reactions (bronchospasm, rashes); Other effect (hypotension)
      • Special Instruction:
        • Use w/ caution in patients w/ gastric or duodenal ulcer
      • Dosage Guidelines:
        • 200 mg PO 8 hrly

      b. Ambroxol

      • Adverse Reactions:
        • GI disturbances; N/V; Hypersensitivity reactions (bronchospasm, rashes); Other effect (hypotension)
      • Special Instruction:
        • Use w/ caution in patients w/ gastric or duodenal ulcer
      • Dosage Guidelines:
        • 60-120 mg PO divided 8-12 hrly
        • Extended-release: 75 mg PO 24 hrly

      c. Bromhexine

      • Adverse Reactions:
        • GI disturbances; N/V; Hypersensitivity reactions (bronchospasm, rashes); Other effect (hypotension)
      • Special Instruction:
        • Use w/ caution in patients w/ gastric or duodenal ulcer
      • Dosage Guidelines:
        • 8-16 mg PO 6-8 hrly

      d. Carbocisteine (Carbocysteine)

      • Adverse Reactions:
        • GI disturbances; N/V; Hypersensitivity reactions (bronchospasm, rashes); Other effect (hypotension)
      • Special Instruction:
        • Use w/ caution in patients w/ gastric or duodenal ulcer
      • Dosage Guidelines:
        • Initial dose: 750 mg PO 6-8 hrly, then 1.5 g/day PO in divided doses

      e. Cyclidrol (Sobrerol)

      • Adverse Reactions:
        • GI effect (stomach pain); Hypersensitivity reaction (rashes)
      • Special Instruction:
        • Use w/ caution in patients w/ renal failure
      • Dosage Guidelines:
        • 200 mg PO 12 hrly or up to 800 mg daily in divided doses

      f. Erdosteine

      • Adverse Reactions:
        • GI disturbances (GI discomfort, rarely taste alterations); Other effects (rarely, headache, dyspnea, urticaria, erythema, dermatitis)
      • Special Instruction:
        • Contraindicated in patients w/ hepatic cirrhosis, hepatic impairment, cystathionine-synthetase enzyme deficiency & severe renal failure
      • Dosage Guidelines:
        • 300 mg PO 8-12 hrly

      g. Guaifenesin

      • Adverse Reactions
        • GI disturbances (GI discomfort, N/V)
      • Special Instruction
        • Use w/ caution in patients w/ persistent or chronic cough, asthma, chronic bronchitis or emphysema
        • Discontinue use if cough persists for >7 days w/ fever, rash or persistent headache
      • Dosage Guidelines:
        • 600 mg PO 12 hrly or 200 mg 4 hrly
        • Max dose: 1200 mg in 24 hr

      Vaccines
      Influenza Vaccine

      • May decrease morbidity & mortality rates due to Influenza
      • Should be given yrly, 1-2 mth prior to anticipated peak influenza season, because of new antigens & waning immunity from the previous yr
      • Associated w/ reduced risk of all-cause mortality

      Pneumococcal Polysaccharide Vaccine

      • Recommended in COPD patients ≥65 yr & in younger patients w/ significant comorbidities (eg cardiac disease)
      • Reduces occurrence of community-acquired pneumonia in patients <65 yr w/ FEV1 <40% predicted
      • Generally given only once, but revaccination may be considered in 5-10 yr

      O2Therapy

      • Long-term administration of O2 (>15 hr/day) increases survival in patients w/ chronic resp failure
        • O2 therapy may also benefit hemodynamics, hematologic characteristics, exercise capacity, lung mechanics & mental state
      • Given to patients w/ stage IV (very severe) COPD w/ the following:
        • PaO2 ≤55 mmHg (7.3 kPa) or SaO2 ≤88% w/ or w/o hypercapnia confirmed 2x over a 3-wk period or
        • PaO2 between 55-60 mmHg (7.3-8 kPa) or SaO2 88%, if there is evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythemia
      • Aim is to increase baseline PaO2 to ≥60 mmHg (8 kPa) &/or produce SaO2 ≥90%, thus preserving vital organ function
      • Inappropriate use of O2 therapy may result in resp depression
      • Patients must be given adequate instructions about the source of O2 to be used, method of delivery, duration of use, & flow rates to be used for different levels of physical activity (eg at rest, during exercise, during sleep)
      • Patients should be warned to discontinue smoking when prescribed O2

      Surgery

      • Surgery may be considered in patients who have large bullae, or have severe COPD w/ marked functional impairment in spite of maximal medical treatment
      • Surgical procedures for COPD include the following:
        • Bronchoscopic lung volume reduction (BLVR)
        • Bullectomy
        • Lung volume reduction surgery (LVRS)
        • Lung transplantation

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      MANAGEMENT OF ACUTE EXACERBATION OF COPD

      O2Therapy

      • Cornerstone of hospital treatment for COPD exacerbations & in patients w/ chronic resp failure
      • Goal of O2 therapy is to maintain SaO2 >90% w/o precipitating resp acidosis or worsening hypercapnia
      • SaO2 >93% is not advisable as patient may become drowsy from CO2 retention
      • Once O2 is started, ABG must be checked after 30-60 min to ensure adequate oxygenation w/o CO2 retention or acidosis
        • Blood gases must be monitored regularly depending on response to treatment

      Hydration & Nutrition

      • Fluid balance & nutritional status must be monitored & maintained at an optimal level

      Pharmacological Therapy

      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 w/ caution because of the increased likelihood of drug interactions & toxic effects
        • Close monitoring of serum Theophylline levels is recommended

      1. Short-Acting Inhaled Beta2-Agonists

      • Adverse Reactions
        • CV effects (angina, palpitation, chest pain, tachycardia); CNS effects (headache, irritability, seizure); Dermatologic effects (urticaria, rash); Endocrine effects (hyperglycemia, hypokalemia); Resp effects (bronchospasm, cough, viral infection); Others (anaphylaxis, allergy)
        • Orciprenaline is less selective for beta2 receptors & therefore side effects may be more common
      • Special Instructions
        • Use w/ caution in patients w/ hyperthyroidism, DM, myocardial insufficiency, arrhythmia, hypertension, HF, glaucoma, hypokalemia, seizure disorder
        • Monitor K levels
        • Check patient’s inhaler technique for optimum delivery of drug
      • Dosage Guidelines

      a. Fenoterol

      • 100 mcg/puff, 200 mcg/puff MDI
        • 1-2 puffs PO 6-8 hrly as required
        • Max dose: 8 puffs/day
      • 1.25 mg/2 mL soln for inhalation
        • 1 unit dose (1.25 mg) via nebulizer up to 6 hrly as required

      b. Levalbuterol

      • 45 mcg/puff MDI
        • >4 yr: 2 puffs PO 4-6 hrly
      • 1.25 mg/0.5 mL soln for inhalation
        • Childn 6-11 yr: 0.31 mg via nebulizer 8 hrly
        • Max dose: 0.63 mg via nebulizer 6-8 hrly/day
        • >6 yr: 0.63 mg via nebulizer 6-8 hrly
        • >12 yr:1.25 mg via nebulizer 8 hrly

      c. Orciprenaline (Metaproterenol)

      • 750 mcg/puff MDI
        • 1-2 puffs PO repeat as required
        • Max dose: 12 puffs/day

      d. Procaterol

      • 10 mcg/puff MDI/Swinghaler/CFC-free
        • 2 puffs PO up to 6 hrly as required
        • Max dose: 8 puffs/day
      • 100 mcg/mL inhalation soln
        • 30-50 mcg via nebulizer

      e. Salbutamol (Albuterol)

      • 100 & 200 mcg/dose easy-breathe, 100 mcg/puff MDI, 200 mcg/dose DPI, 200 mcg/dose accuhaler DPI, 200 & 400 mcg/cap DPI, 200 mcg/dose diskhaler DPI
        • Inhale 100-400 mcg PO 6-8 hrly as required
      • 1 mg/mL, 2.5 mg/2.5 mL, inhalation soln unit dose
        • 2.5-5 mg via nebulizer 6-8 hrly as required
      • 5 mg/mL (0.5% soln) inhalation soln
        • 0.5 via nebulizer 6-8 hrly

      f. Terbutaline

      • 250 mcg/puff MDI
        • 250-500 mcg PO 6-8 hrly as required
        • Max dose: 8 puffs/day
      • 100, 200 mcg/dose, 500 mcg/dose DPI, turbuhaler DPI
        • 200-800 mcg inhaled PO 6-12 hrly as required
        • For severe exacerbations: 3 doses
        • Max dose: 12 doses/day
      • 2.5 mg/mL, 5 mg/2 mL, 10 mg/mL inhalation soln
        • 2.5-5 mg via nebulizer 6-12 hrly as required

      2. Anticholinergics

      See Management of COPD section for Dosage Guidelines of Anticholinergics

      3. Methylxanthines

      ?3.1 Methylxanthines (Parenteral)

      • Adverse Reactions:
        • GI effects (irritation, N/V, abdominal pain, diarrhea, gastroesophageal reflux); CNS effects (CNS stimulation, headache, anxiety, restlessness, dizziness, tremor); CV effects (palpitations, tachycardia)
        • Serum conc >15-20 mcg/mL (85-110 micromol/L) are associated w/ increased risk of adverse effects including lethal adverse reactions
      • Special Instructions:
        • Administer IV inj very slowly to prevent dangerous CNS & CV side effects
        • Use w/ caution in elderly patients, w/ peptic ulcer, hyperthyroidism, hypertension, cardiac arrhythmias or other CV disease, epilepsy, HF, hepatic dysfunction or chronic alcoholism, acute febrile illness
        • Many drug interactions occur w/ Theophylline including smoking (which increases Theophylline clearance)
        • Serum conc monitoring is necessary to ensure conc are w/in therapeutic range
        • Optimal therapeutic conc: 5-15 mcg/mL (28-85 micromol/L)
      • Dosage Guidelines:

        a. Acefylline

        • 1.5-2 g/day IM or 0.5-1 g/day IV

        b. Aminophylline

        • Loading dose for patients not taking methylxanthine: 5-6 mg/kg IV over 20-30 min
        • Max rate: 25 mg/min
        • Maintenance dose: 0.5 mg/kg/hr

      See Management of COPD section for Dosage Guidelines of Oral Methylxanthines

      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 w/ Formoterol may be used as an alternative to oral corticosteroids; may cause significant reduction of complications (eg hyperglycemia)

      Antibiotics

      • Given in patients who presents w/ increased purulence of sputum together w/ 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 w/ polycythemia or dehydration, w/ or w/o a history of thromboembolic disease

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      Mechanical Ventilation

      Non-invasive Mechanical Ventilation (NIV)

      • First-line treatment of acute hypercapnic respiratory failure in COPD exacerbation in patients w/o contraindications
      • Usually employed in patients w/ any of the ff: severe dyspnea w/ signs of respiratory muscle fatigue, &/or increased work of breathing (eg use of accessory muscles, intercostal space retraction), acidosis (pH <7.35 &/or PaCO2 >6.0 kPa, 45 mmHg)
      • Has been shown to increase pH, reduce PaCO2, reduce severity of breathlessness in the 1st 4 hr of treatment & decrease length of hospital stay, mortality & intubation rate

      Invasive Mechanical Ventilation

      • Utilized in patients w/ the ff:
        • Severe dyspnea
        • Impending resp or cardiac failure,
        • Apnea w/ loss of consciousness
        • Gasping for air
        • Altered mental status in spite of aggressive pharmacotherapy
        • Life-threatening hypoxemia unresponsive to NIV
        • Severe hemodynamic compromise unresponsive to hydration & medications   
        • Massive aspiration
        • Unable to suction resp secretions
        • <50 bpm PR w/ loss of consciousness
        • Severe ventricular arrhythmias
        • W/ contraindications to non-invasive mechanical ventilation or failed non-invasive mechanical ventilation
        • Psychomotor agitation unresponsive to sedatives
        • There is a major risk of ventilator-associated pneumonia, barotrauma & failure to wean

      All dosage recommendations are for non-elderly adults w/ normal renal & hepatic function unless otherwise stated.

      Not all products are available or approved for above use in all countries.

      Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information. 

      Click the link below for specific prescribing information of products available in respective countries.

      Brands available in: Hong Kong   Indonesia   Malaysia   Philippines   Singapore   Thailand   Vietnam 

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