Outpatient Management of COPD: Pharmacotherapy (A2)

  1. Patient with COPD Requiring Pharmacotherapy

    This algorithm outlines the criteria for the medication treatment of COPD. The aim of therapy is to use those medications needed to maintain control and improve function and quality of life with the least risk for adverse effects. The medication plan for COPD is summarized in Table I.

    Table II. Step Care In COPD

    Step

    Symptoms and FEV1

    Therapy

    1

    Asymptomatic AND
    FEV1 > 50 percent of predicted (1)

    Smoking cessation, vaccination, employ education. No medication indicated.

    2a

    Symptoms less than daily AND
    FEV1 > 50 percent of predicted (2)

    Smoking cessation, vaccination, employ education. Inhaled short-acting beta2-agonist (2 puffs PRN up to 12 puffs/day)

    2b

    Asymptomatic AND
    FEV1 < 50 percent of predicted

    Smoking cessation, vaccination, employ education. Inhaled anticholinergic (2 puffs qid)

    Consider use of inhaler containing a short acting beta2-agonist and an anticholinergic.

    2c

    Symptoms less than daily AND
    FEV1 < 50 percent of predicted

    OR

    Daily symptoms

    Smoking cessation, vaccination, employ education. Inhaled anticholinergic (2 puffs qid)
    Short-acting beta2 agonist (2 puffs PRN up to 12 puffs/day)

    Consider use of inhaler containing a short acting beta2-agonist and an anticholinergic.

    3

    Symptoms not controlled (2)

    Increase dose of both:

    Inhaled anticholinergic (2 to 6 puffs qid) and
     inhaled short-acting beta2 agonist (2 -4 puffs PRN up to 12 puffs/day)

    4

    Symptoms not controlled (2)

    Consider adding long-acting inhaled beta2-agonist. (3)

    5

    Symptoms not controlled (2)

    Consider adding theophylline trial (slow release theophylline adjusted to level of 5 to 12 µg/ml) (4)

    6

    Symptoms not controlled (2)

    Consider adding corticosteroid trial (prednisone 40 to 60 mg po qd or high dose inhaled steroids (5).

    Consider specialist consultation.

    7

    Symptoms not controlled (2)

    Refer to specialist promptly.



    1. Spirometry is essential to confirm the presence of airflow obstruction (low FEV1 and FEV1/VC ratio). Base therapy on symptoms, but consider alternate diagnoses (heart disease, pulmonary emboli, etc.) if out of proportion to spirometry.

    2. Use the lowest level of therapy that satisfactorily relieves symptoms and maximizes activity level. Assure compliance and proper use of medications before escalating therapy.

    3. Inhaled long acting beta2-agonists should not be used as rescue therapy. Short-acting inhaled beta2-agonist (less than 12 puffs/day) may continue to be used PRN. Nighttime symptoms are frequently better controlled with long-acting inhaled beta2-agonist. Oral beta2-agonists are associated with a higher rate of side effects, and should be reserved for patients who cannot take inhaled beta2-agonist medications.

    4. Theophylline should be used with caution because of potential for severe side effects. Nighttime respiratory symptoms are frequently controlled but theophylline may lead to insomnia. Theophylline should be discontinued if a symptomatic or objective benefit is not evident within several weeks.

    5. A corticosteroid trial of prednisone (40 to 60mg/day) 10 to 14 days, or high dose inhaled steroids (equivalent to 880 µg or more of fluticasone or 800 µg or more of budesonide) of 14 to 21 days can help identify patients who may benefit from long term steroid use. Responders to oral steroids should transition to the lowest effective dose of inhaled steroids, or to the lowest effective dose of a combination of inhaled and oral steroids, if possible, to avoid the long term complications of systemic corticosteroids. If oral steroids are used other than for an acute exacerbation, obtain spirometry prior to and after trial to confirm an objective response.


  2. Are Symptoms Occurring Less frequently than Daily AND FEV1 is > 50% of predicted?

    OBJECTIVE

    To identify patients with COPD who may benefit from therapy.

    ANNOTATION

    1. Typical daily symptoms of COPD include exertional dyspnea, wheezing, or cough. Chest tightness is common, but should be further evaluated to exclude co-existing heart disease. These symptoms may occur daily or less than daily, thus resulting in different medication recommendations.

    2. Routine use of ipratropium does not slow the rate of decline in pulmonary function in patients with mild COPD. Patients with symptoms less often than daily may be medicated as needed.

    3. A trial of inhaled anticholinergic therapy is recommended in apparently asymptomatic patients with an FEV1 of less than 50 percent of predicted, since this degree of obstruction is usually associated with dyspnea. A lack of symptoms may result from the patient avoiding activities and adapting to his/her disability, or from the assumption that dyspnea is part of the natural aging process.

    4. Asymptomatic patients with an FEV1 less than 50 percent predicted may benefit from regular inhaled anticholinergic therapy without a short acting inhaled beta2-agonist (SAIBA). Symptomatic patients in this category should be prescribed both a chronic anticholinergic inhaler or SAIBA as well as a beta2-agonist for prn use, especially prior to exertion.


  3. Short Acting Inhaled Beta2-Agonists

    OBJECTIVE

    To initiate or adjust appropriate prn therapy with SAIBA.

    ANNOTATION

    1. Short acting beta2-agonists are available in MDI, dry powder inhalers, nebulizer and oral forms. They can improve function and quality of life.

    2. Short-acting selective inhaled beta2-agonists such as albuterol are preferred for prn use because of demonstrated efficacy, rapid action, and selective action on airways. The short-acting adrenergic agents have similar efficacy, though inhaled beta2 selective agents should be favored for lower side effect profiles.

    3. SAIBA should be prescribed for prn use in most symptomatic patients with COPD. The usual maximum dose in stable patients is 12 puffs per day for short-acting agents such as albuterol, metaproterenol or terbutaline. Patients who have not responded to greater than maximum doses such as 12 to 20 puffs over three to four hours during an acute exacerbation of COPD should seek medical attention.

    4. Symptoms may improve without substantial improvement in FEV1, indicating that continuation of therapy does not depend on routine assessment with spirometry. For example, SAIBA and ipratropium can improve exercise performance without necessarily improving FEV1.

    5. SAIBA, but not ipratropium, may increase the alveolar-arterial oxygen difference, and this may be a reason to decrease the dose of beta2-agonist while titrating a patient’s medication.


  4. Inhaled Anticholinergics

    OBJECTIVE

    To initiate or adjust appropriate therapy with inhaled anticholinergics.

    ANNOTATION

    1. Ipratropium bromide, the prototype anticholinergic bronchodilator, is available as a metered dose inhaler (MDI) or as a nebulizer solution.

    2. Ipratropium bromide has similar, or according to some studies, greater efficacy than SAIBA. It has a slower onset of action, a longer duration of action, and minimal systemic absorption. It may cause fewer systemic side effects than beta2-agonists. For these reasons, it is preferred as a regularly scheduled inhaled bronchodilator.

    3. In patients with COPD, ipratropium bromide at peak effect typically increases the FEV1 by 0.15 to 0.35 L. At high doses, ipratropium bromide can improve exercise tolerance.

    4. The starting dose of ipratropium should be at least two puffs tid. Use of typical recommended doses of ipratropium (two puffs qid) produces less than maximal bronchodilation. Improvement in pulmonary function is maximal at 6 to 14 puffs as a single dose of ipratropium. If symptoms do not resolve with two to four puffs qid, up to six and possibly eight puffs qid may be needed. Improvement in level of function and in activities in daily living can be used to guide therapy. The risk of toxicity at higher doses appears to be relatively low compared to inhaled beta2-agonists.

    5. The sequence of administration of ipratropium and SAIBA does not generally make any difference in the bronchodilator benefit.


  5. Combination Therapy with Inhaled Anticholinergics and Short Acting Beta2-Agonists

    OBJECTIVE

    To initiate or adjust appropriate therapy with a combination of inhaled SAIBA.

    ANNOTATION

    1. Patients with COPD whose symptoms are inadequately controlled with the recommended doses of either an inhaled short acting inhaled beta2-agonist or ipratropium should be treated with a combination of both inhaled agents. The combination at recommended doses provides added symptomatic benefit without incurring the risk of toxicity from using very high doses of single agents.

    2. SAIBA may be added to ipratropium as regularly scheduled medications, typically two to four puffs qid, as well as additional prn dosing, to a usual recommended maximum of 12 puffs per day. Demonstration of an acute improvement in FEV1 is not necessary in order to obtain clinical benefit. The lack of an immediate bronchodilator response should not preclude a clinical trial of these medications.

    3. As the dose of ipratropium or inhaled SAIBA increases, the added benefit becomes less from the other agent, but some patients will have an added benefit even with high doses of each. There is no way to predict, other than in a trial of therapy, which patients will have this combined effect.

    4. A product that dispenses 90 µg albuterol and 18 µg ipratropium per puff from one metered dose inhaler is available commercially (Combivent ™). This should not generally be used as a first line agent, but may provide enhanced compliance and resultant benefit in patients who require combination therapy. Patients taking a regularly scheduled combination inhaler should continue to use a SAIBA for breakthrough symptoms.


  6. Consider Adding Long-Acting Inhaled Beta2-Agonist

    OBJECTIVE

    To initiate or adjust appropriate therapy with long acting inhaled beta2-agonists.

    ANNOTATION

    1. The long acting inhaled beta2-agonist, salmeterol (2 puffs or 50 µg bid), is an effective bronchodilator in COPD patients, and has been approved for use in COPD.

    2. Salmeterol produces a similar peak bronchodilator response to SAIBA, but the onset is delayed. The bronchodilator effect is prolonged compared to short-acting agents. This has the potential to produce more consistent control of symptoms than SAIBA in some patients.

    3. Chronic use is not associated with significant tachyphylaxis, and may decrease the need for rescue use of SAIBA.

    4. Strong evidence for symptomatic benefit of salmeterol over other regularly inhaled short acting bronchodilators in patients with COPD is not currently available. Thus, its place in the scheme of therapy is not well defined at this time. It may be considered for patients whose need for SAIBA exceeds 8 to 12 puffs daily.

    5. The principle advantage of salmeterol is its long duration of action, which may be of benefit in treating nocturnal dyspnea. Additionally, enhanced compliance with a twice daily rather than qid regimen may provide smoother symptomatic control.

    6. Because the onset and duration of action are both prolonged compared to SAIBA, salmeterol should not be used for prn, rescue use. Patients should be educated to continue to use SAIBA prn.

    7. Oral forms of beta2-agonists may be useful in patients who cannot use any inhaled form, although such cases are rare. The risk of systemic adverse reactions is increased significantly with oral beta2-adrenergic bronchodilators.

    8. Inhaled salmeterol should be continued only in those patients who experience symptomatic benefit from its addition to their regimen.


  7. Consider Theophylline Trial

    OBJECTIVE

    To initiate or adjust appropriate therapy with oral theophylline.

    ANNOTATION

    1. Theophylline can be added to improve pulmonary function, symptoms, or activities in patients with COPD who do not achieve adequate symptom control with inhaled bronchodilators.

    2. Many theophylline preparations are available, but sustained release formulations may provide longer control and better benefit for nocturnal dyspnea.

    3. Theophylline has a narrow therapeutic index, with the potential for dose related adverse reactions that include insomnia, anxiety, nausea, vomiting, tremor, arrhythmias, delirium, seizures, and death.

    4. Typical starting doses are 400 to 600 mg daily, but blood levels should be measured carefully at the start of therapy. The therapeutic target for most patients should be a blood level of 10 µg/ml (range 5-12 µg/ml). In some cases, if benefit has been demonstrated and with careful monitoring, a blood level of 15 µg/ml of theophylline can be a therapeutic target. However, with an increase in concentrations over 12 µg/ml, the risk to benefit ratio increases, especially in older patients. After initial stability, repeat levels should be obtained when symptoms change, acute illness develops, potentially interacting drugs are added, non-compliance is suspected, dose adjustments are made, or symptoms suggestive of toxicity develop.

    5. Drug interactions with theophylline are common, and may either increase or decrease theophylline metabolism. All changes in medical regimens should be evaluated for potential impact on theophylline levels.

    6. Theophylline should be continued only in patients who demonstrate a symptomatic benefit, such as improved dyspnea or exercise tolerance. The improvement in function from theophylline may not be evident in pulmonary function testing. However, therapy should be discontinued in patients who demonstrate no subjective or objective improvement after several weeks of theophylline therapy.


  8. Consider Corticosteroid Trial

    OBJECTIVE

    To initiate or adjust appropriate therapy with corticosteroids in patients with COPD.

    ANNOTATION

    1. Unlike the high response rate seen in asthma, in patients with COPD a response to chronic oral corticosteroid use is beneficial in less than about 20 to 25 percent. The benefit from inhaled steroids is not precisely defined.

    2. Patients on maximal bronchodilator therapy who have not had a satisfactory response may be considered candidates for a corticosteroid trial. An objective measure of improvement should be sought in all patients undergoing a steroid trial. A response may be defined as an improvement in symptoms and an increase in FEV1 of > 20 percent from baseline. An objective measurement of the steroid effects can only be obtained in patients who are otherwise stable.

    3. A typical trial of oral prednisone is 40 to 60 mg/day for 10 to 14 days. There is less published experience with high-dose inhaled steroids, but in some patients this may be a reasonable alternative. The appropriate dose of inhaled steroids has not been determined, but a trial for 14 to 21 days of the equivalent of beclomethasone 1500 µg/day (30 puffs) or fluticasone 880 µg /day has been suggested.

    4. Patients who show no objective response to a steroid trial should have their steroids promptly discontinued. Patients who have a response should be tapered to the lowest possible dose. Supplementation or substitution with a high-dose inhaled steroid may allow further reduction or discontinuation of the oral steroid.

    5. Adverse effects of oral corticosteroids are numerous and include: hypertension, hyperglycemia, weight gain, immunosupression, skin thinning, personality, purpura, mental status changes, depression, glaucoma, cataracts, and adrenal suppression. Patients requiring long-term steroids should be evaluated for risk of osteoporosis and preventive measures instituted, such as calcium and vitamin D supplements, weight-bearing exercise and hormone replacement therapy if appropriate. The risks of long-term treatment should be discussed with the patient.

    6. The role of chronic inhaled corticosteroids in COPD remains under investigation. Preliminary work suggests that chronic inhaled steroid use may slow the rapid decline in FEV1 typically seen in patients with COPD. Response to an oral steroid trial, as well as a brisk bronchodilator response may help identify patients who will respond better to inhaled steroids.

    7. The use of MDI spacers and rinsing of the mouth after drug use is recommended to help improve drug delivery to the lung and avoid local complications, such as hoarseness or oral candidiasis.


  9. Review Precautions and Recommendations for Medications?

    OBJECTIVE

    To apply precautions and educate patients about the use of medications.

    ANNOTATION

    Method of administering aerosols

    1. Metered-Dose Inhalers (MDI).

      1. Inhaled bronchodilators are preferred to oral medications to reduce the risk of systemic adverse effects.

      2. Ensure proper education and technique in the use of MDIs (see DISCUSSION).

      3. Use spacers as required to enhance drug delivery.

      4. Emphasize the maximum doses of bronchodilators to avoid overuse.

      5. Educate the patient to use bronchodilators before exercise.

      6. Compliance declines when inhaler regimens become complicated.

      7. Consider other drug delivery systems (such as dry powder inhalers) if patient cannot use MDI with spacer.


    2. Small Volume Nebulizer.

      1. There is little evidence that nebulizer delivery offers improvement in control over adequate MDI delivery for management of the stable COPD patient.

      2. Situations where a nebulizer is preferable include difficulty in managing a MDI (with spacer) due to impaired hand strength or dexterity, visual impairment, cognitive problems, or severe dyspnea.


    3. Precautions when using beta2-agonists.

      1. Inhaled beta2-agonists may cause tremor, increased heart rate, insomnia, restlessness, hypokalemia, or a paradoxical reduction in arterial oxygenation.

      2. Avoid overuse. Check number of metered dose inhalers (MDIs) used per month against number of puffs per MDI (200 to 300+, depending on brand).

      3. Instruct patients on maximum number of puffs per day (usually 8 to 12) and on number allowed during an exacerbation (e.g., 12 to 24 over 3 to 4 hours) before additional intervention is required.

      4. If a long-acting agent is used for maintenance therapy, educate the patient that only SAIBA should be used for breakthrough symptoms.

      5. Home nebulizers with inhalant solutions providing large dosages are rarely needed.


    4. Precautions when using ipratropium

      1. Inhaled ipratropium may cause dry mouth or increased heart rate, or exacerbate glaucoma, benign prostatic hypertrophy or other conditions potentially worsened by the drug’s anti-cholinergic activity.

      2. Patients should generally use a spacer and should avoid spraying into eyes.

      3. Caution patients that onset of effect is relatively slow compared to SAIBA, and that additional doses should not be taken for acute symptom relief.

      4. In general, dose related systemic side effects of inhaled anticholinergics are less severe when using ipratropium than those produced by inhaled beta2-agonists.


    5. Precautions when using theophylline.

      1. Theophylline has dose related side effects that include insomnia, anxiety, nausea, vomiting, tremor, arrhythymias, delirium, seizures, and death.

      2. Drug interactions with theophylline are common, and all changes in a patient’s medical regimen should be reviewed for their potential impact on serum theophylline levels.

      3. Initiate treatment with a low dose (e.g., 400 mg/day) and adjust after a few days.

      4. Aim for a serum level of 5 to 12 µg/ml; adjust dosage and follow serum level when indicated.

      5. Check the serum level of theophylline when symptoms change, acute illness develops, new drugs are added, or symptoms suggestive of toxicity develop.

      6. Reduce dosage if drug clearance is likely to be impaired because of illness, liver malfunction, or concomitant drugs.

      7. Instruct patients not to take additional theophylline preparations.

      8. Theophylline should be taken at the same time each day with respect to meals.

      9. Attempts to withdraw theophylline, even at lower plasma levels, should be done cautiously, since deterioration in pulmonary function and exercise performance may occur.


    6. Precautions when using oral corticosteroids.

      1. Adverse effects of oral corticosteroids include hypertension, hyperglycemia, weight gain, personality changes, depression, immunosuppression, glaucoma, cataracts, skin thinning, purpura, osteoporosis, osteonecrosis, and adrenal supression. In general, side effects are more common with prolonged therapy.

      2. Reduce dosage to lowest effective daily dose or to alternate-day dosing as quickly as symptoms allow.

      3. Administer stress dose steroid therapy to patients with severe illness or injury who have received prolonged oral corticosteroid treatment. Adrenal insufficiency may extend for up to a year following the discontinuation of steroids.

      4. Prevent or treat osteoporosis with calcium, vitamin D, hormone replacement therapy or other therapies as appropriate for patients on prolonged oral corticosteroid therapy.


    7. Precautions when using inhaled corticosteroids.

      1. Adverse effects of inhaled corticosteroids include oral candidiasis, hoarseness, and possible adrenal suppression at high doses.

      2. Instruct patients to use a spacer and rinse the mouth after use to decrease the likelihood of local complications.

      3. Be aware that systemic effects of corticosteroids may occur in skin, bone, eyes, and other organs, especially with the use of high dose inhaled corticosteroids.

      4. Stress dose oral or intravenous corticosteroids may be necessary in some patients with severe illness or injury who have been treated with high dose inhaled corticosteroids.

      5. Seek objective evidence of the value of this therapy, because its use may decrease compliance with other aerosol usage.

      6. When introducing aerosol steroids in a patient taking an oral steroid, wean slowly off the oral drug.