Tolerance to ß2-Agonists in Patients with Chronic Obstructive Pulmonary Disease

doi:10.1378/chest.97.2.280

Chest

Volume 97, Issue 2, February 1990, Pages 280-284

https://doi.org/10.1378/chest.97.2.280 Get rights and content

Eleven patients with severe COPD were examined to determine whether tolerance to ß₂-agonists developed after long-term inhalation therapy with these agents. Before the study all patients were on regular treatment with inhaled salbutamol for six months. At the beginning of the study, response of FEV₁ to inhaled salbutamol was measured. Dose-response curves were measured after three weeks of treatment with ipratropium bromide and again after a three-week course of inhaled salbutamol. After ipratropium bromide treatment, responses to low doses of salbutamol tended to be larger than after salbutamol treatment, but differences were not significant. Three hours after the last inhalation of salbutamol the FEV₁ was lower on days 1 and 42 than on day 21. We conclude that long-term inhalation therapy with ß₂-agonists in patients with COPD decreases the duration of the bronchodilation produced by the same agents but does not affect the peak response.

(Chest 1990; 97:280–84)

Section snippets

METHODS

Twelve patients were entered into the study, selected from a large pool of patients attending our pulmonary clinic. Selection criteria included a clinical diagnosis of COPD, a history of cigarette smoking, an FEV₁-value of less than 60 percent of predicted normal and less than 2 L, a TLC value of more than 80 percent of predicted normal and long-term regular therapy with inhaled ß₂-agonists. Exclusion criteria included any history suggestive of asthma, sputum or blood eosinophilia and an

RESULTS

Of 12 patients selected, one had an exacerbation of COPD during treatment with ipratropium bromide and was excluded. Baseline clinical data from the 11 patients who successfully completed the study are shown in Table 1. The average patient was elderly, had a significant smoking history, severe airway obstruction and hyperinflation.

Mean values of FEV₁, recorded during dose-response curves, are shown in Table 2. The heart rate did not change significantly during the dose-response curves and these

DISCUSSION

The results of this study demonstrated that in patients with severe COPD, therapy with inhaled salbutamol in the usual doses appeared to decrease the duration of the bronchodilation produced by the same agent, while the peak response remained relatively stable.

Stopping sustained-release theophylline for 12 h before study in the laboratory may not be long enough to drop the blood drug concentration to subtherapeutic levels. This probably did not affect the response to inhaled salbutamol. It has

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A randomized, double-blind, placebo-controlled clinical trial was designed to assess the safety, efficacy, and duration of the bronchodilation resulting from the addition of 500 μg of ipratropium bromide (Atrovent; Boehringer Ingelheim, CT) inhalation solution to standard small volume nebulizer treatments with 2.5 mg albuterol inhalation solution. A total of 195 patients (63% men, average age 64 years) with >10 pack-year smoking histories and stable, moderate-to-severe chronic obstructive pulmonary disease (COPD; forced expiratory volume in 1 second [FEV₁] 1.02 liter, 38.8% predicted) from eight university-affiliated chest clinics in seven U.S. cities were enrolled into the study. Asthma, rhinitis, and eosinophilia were exclusions, as was daily use of >10 mg of prednisone (or 20 mg on alternate days). There was a 2-week stabilization period during which the patients were instructed in the use of the small volume nebulizers, which they used three times daily with albuterol alone. They were asked to keep daily logs of peak flow rates, pulmonary symptoms, and additional medication usage. On their test day 1 the subjects came to the pulmonary function laboratory having been off theophylline for 24 hours and β₂-agonists for 12 hours and performed a baseline spirometry. They then received their morning small volume nebulizer treatment of albuterol to which was added either 500 μg of ipratropium bromide or a saline placebo. Spirometry was repeated at 15, 30, and 60 minutes, and then hourly for 8 hours. Subjects then took home a 2-week supply of albuterol and test drug for thrice daily use in their small volume nebulizer. They were evaluated for pulmonary symptoms and adverse effects every 14 days. The 8-hour spirometry was repeated on test day 43 and finally on test day 85. Primary data evaluated were the peak increase in FEV, and the area between the FEV₁ baseline value and the 8-hour FEV₁ curve. Similar calculations were made for forced vital capacity (FVC) and 25–75% forced expiratory flow (FEF_25–75%). On test day 1 the peak increase in FEV₁ for the ipratropium bromide+albuterol subjects was 26% greater than those on placebo+albuterol (p <0.003). The area under the 8-hour FEV₁ curve was 64% greater in those given ipratropium bromide on test day 1 (p <0.0002). Similar increases were seen in FVC and FEF_25–75%. The peak improvements in FEV_l and FVC with the addition of ipratropium bromide to albuterol were maintained on test days 43 and 85. Considering the safety and efficacy profiles of this combination, the data would suggest that ipratropium bromide inhalation solution should be considered first-line therapy for those patients with COPD requiring small volume nebulizer treatments.
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1995, The American Journal of Medicine
The β-agonist controversy: Impact in COPD
1995, Chest
The effect of increasing doses of β-agonists on airflow in patients with chronic airflow limitation
1993, Respiratory Medicine
Objective: To determine the increase in FEV₁ associated with increasing doses of inhaled terbutaline and salbutamol, the reproducibility of the increase in FEV₁, and the reproducibility of the associated optimal bronchodilator dose, in patients with chronic airflow limitation (CAL). Design: Double-blind, randomized, controlled trial examining spirometric response to cumulative doses of bronchodilators. Patients and Setting: Patients with clinical diagnosis of CAL, FEV₁ below 70% predicted, and FEV₁ to FVC ratio less than 0·7 after administration of bronchodilator recruited from secondary care respirology practices. Measures of outcome: The estimates of maximum and optimal bronchodilation, as well as the associated drug dosages, were established in each patient on three occasions (twice on terbutaline and once on salbutamol). The ‘optimal’ drug dose was defined as the lowest dose associated with an FEV₁ not exceeded by 50 ml on any other dose. Main results: Thirty-five patients completed the trial. FEV₁ improved from 0·93 to a maximum of 1·19 l with terbutaline (average of the two administrations) and from 0·95 l to 1·14 l with inhaled salbutamol (difference in increase in FEV₁ between terbutaline and salbutamol P=0·006). In less than 50% of cases administration of more than four puffs of bronchodilator resulted in FEV₁ increase by more than 50 ml. The average dose of salbutamol and terbutaline associated with optimal bronchodilation were 430 μg and 1160 μg respectively. Patients varied widely in the optimal dose. Estimates of optimal dose were not reproducible (intraclass correlation coefficient <0·5). Conclusion: Substantial incremental increase in FEV₁ in response to increasing doses of β-agonists beyond those commonly used in clinical practice is restricted to a minority of patients. Lack of reproducibility limits the clinical usefulness of establishing the optimal dose of β-agonist for a given patient.
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Supported by a grant from MRC Canada.

Manuscript received February 14; revision accepted June 1.

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Chest

Tolerance to ß2-Agonists in Patients with Chronic Obstructive Pulmonary Disease

Section snippets

METHODS

RESULTS

DISCUSSION

Lancet

Chest

Chest

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Lancet

Chest

Resistance to beta-adrenoceptors stimulants

Br J Clin Pharmacol

Airway and metabolic responsiveness to intravenous salbutamol in asthma: effect of regular inhaled salbutamol

Clin Sci

Airway response to salbutamol inhalations in normal, atopic and asthmatic subjects

Thorax

Clinical implications of drug-induced desensitization of the beta receptor after continuous oral use of terbutaline

J Allergy Clin Immunol

Tolerance to ß₂-Agonists in Patients with Chronic Obstructive Pulmonary Disease