Bronchodilators in the therapy of COPD

Until recently, physicians may have felt they had little to offer patients with chronic obstructive pulmonary disease (COPD). When the condition worsened patients were simply expected to suffer frequent exacerbations, decreasing lung function and a decline in their quality of life. However, treatment options are now undergoing a transformation and in the second of a series focusing on COPD, we will be discussing the importance of bronchodilators in the therapy of COPD.

Today, bronchodilators form the cornerstone of therapy to improve symptoms and treat any reversible component of airflow obstruction.

Although reversibility testing is an essential part of the diagnostic process, a small or minimal change in lung function after a bronchodilator is not always a good predictor of improvement. It is, therefore, most important to prescribe a trial course of bronchodilators, either beta-agonists or anti-cholinergic inhalers for three to four weeks. Such trials must be conducted when the patient is stable.

 

How do bronchodilators work?

 

Bronchodilators reverse the increased bronchomotor tone found in the airways of COPD patients by relaxing the smooth muscle and reducing airway resistance
(Fig 1).

Hyperinflation is reduced, and it is easier and more comfortable for the patient to breathe. Breathlessness and the effort of breathing are reduced so that the patient can walk further. Three types of bronchodilator are in common clinical use:

1. b2-Adrenoceptor agonists
2. Anticholinergic drugs
3. Methylxanthines

 

Bronchodilator administration

As in asthma, the preferred way to use a bronchodilator is by inhalation. Although oral bronchodilators may be just as effective in providing symptom relief, they have the disadvantages of more side-effects, potential interactions with other drugs and a slower onset of action.

Metered dose inhalers (MDIs) are inexpensive and effective and work rapidly to provide symptom relief. However, the need for correct timing and co-ordination makes them difficult to use and less than 50 percent of patients can inhale from them effectively. With the addition of a spacer, a large number of patients can use MDIs effectively.

Dry powder devices are simpler to use and equally effective.

 

Types of bronchodilator

1. Short-acting b2-agonist
e.g. salbutamol

These drugs have a rapid onset of action (usually within five minutes) and their action lasts for three to four hours. These are recommended for regular treatment as well as for emergency relief of symptoms.

Patients who do not have a significant spirometric response may still show benefit in terms of alternative outcomes like walking distances. Studies comparing short-acting b2 -agonist with placebos have shown significant increases in FEV1, PEF and symptom score (Table 1)

2. Long-acting b2-agonist
e.g. salmeterol & formoterol

The physiological effects of long acting b2 -agonists match those of short-acting agents. However, the duration of action at 12 hours is considerably longer. Salmeterol has a slower onset of action than formoterol.

Some patients with COPD undoubtedly get symptomatic benefit. Studies have shown that they produce improvements in FEV1, health status and breathlessness score (Table 2).

(Oral: The use of oral long-acting beta-agonist in COPD also needs further study. However, they may be justified in a patient with severe COPD who finds it difficult to use any form of inhaled therapy).

 

3. Anticholinergics
e.g. ipratropium

Cholinergic nerve are the main neural bronchoconstrictor pathway in the airways and the resting tone is increased in COPD patients. Guidelines recommend the use of anticholinergic as the first line bronchodilator as a maintenance therapy for COPD. The onset of action of ipratropium is slower than that of short-acting beta agonists, but they produce more sustained bronchodilation (up to eight hours) and are at least as effective. Unlike b2 -agonists anticholinergic bronchodilators have a beneficial effect on sleep quality. Anticholinergics should be used in all patients who remain symptomatic despite using short-acting b2 -agonists.

4. Methylxanthines

Theophyllines produce only small amounts of bronchodilation in COPD and tend to be most effective in the higher parts of the narrow therapeutic range (i.e. blood levels of 10-20 mg/litre). If theophylline are used, it is preferable to give them in a slow-release form, and to monitor serum theophylline levels regularly.

5. Combination therapy

The use of short-acting beta-agonist with an anticholinergic may have an additive effect in some patients. Combined therapy may produce greater improvements in exercise tolerance and a greater degree of bronchodilation.

If symptoms improve with a combination of salbutamol and ipratropium, there is a clinical advantage in a combined inhaler. Patients may find this more convenient and compliance is likely to improve.

Conclusion

No conventional drug therapy reduces the relentless progression of COPD, also the current available bronchodilators do not have significant effect on improvement of exercise tolerance and reduction in exacerbation rate. Table 5 compares the therapeutic outcomes of currently available agents.

There is a pressing need for more effective drug treatment for COPD. Among the desirable attributes of any pharmacologic treatment for COPD is face validity, i.e. there should be a rationale for using a drug in a particular condition combined with appropriate pharmacologic properties. COPD patients often have comorbidities and are taking other treatment, so drug interactions must be avoided. Hence a drug for COPD should have low bioavailability and should be targeted to where it is needed, in the airway. It is almost self-evident that a drug with a long duration of action has considerable advantages in both prevention of symptoms developing and also in simplifying the treatment regimen. Tiotropium is a very long-acting drug with an extremely simple treatment regimen and low bioavailability.

References

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2. COPD 2001; Drug therapy in stable COPD: 60-80

3. Primary Care Resp Journal 2002; 11 S1 S7- S11

4. Respiration 2001; 68: 441-448

5. New drugs for asthma, allergy and COPD 2001; 31: 24-29

6. Chest 2000; 117 (Suppl 2): 67S-69S

7. Resp Medicine 1999; 93:227-229