Oral theophylline has recently fallen out of favor in the treatment of asthma because of its side effect profile and narrow therapeutic range. Ipratropium bromide is an inhaled anticholinergic drug used as a bronchodilator in patients with chronic obstructive pulmonary disease. Data suggest that ipratropium may be effective in the treatment of asthma and may produce an additive effect when it is combined with a beta agonist. However, ipratropium is not currently recommended as a first-line drug for asthma. Burki compared the efficacy and safety of oral theophylline in combination with ipratropium in patients with asthma.
The double-blind, placebo-controlled, crossover trial evaluated the effects of both drugs separately and in combination in 19 patients with asthma. The four test regimens evaluated in the study were as follows: theophylline tablets and two placebo inhalations from a metered-dose inhaler; theophylline tablets and two puffs (40 μg) of ipratropium; placebo tablets and two puffs of ipratropium; and placebo tablets and two placebo inhalations. The theophylline dosage ranged from 300 to 700 mg, depending on the optimal dosage to achieve a therapeutic blood level. Patients were excluded from the study if they were smokers, had a history of other systemic diseases or were taking oral steroids or cromolyn sodium.
Before the four regimens were evaluated, patients were seen on three separate screening days. On the first pretest day, a baseline measurement of forced expiratory volume in one second (FEV1) was obtained and was required to be 70 percent or less than the predicted normal value. An increase of at least 15 percent in the FEV1 also was required within 30 minutes of two isoproterenol inhalations. On the second pretest day, patients received two puffs of ipratropium, followed by spirometry at 30 and 60 minutes. On the third pretest day, patients were given 500 mg of theophylline orally, and spirometry was performed two and four hours after the dose. If the theophylline blood level was between 12 and 18 mg per dL, the subject was included in the study. If the level was subtherapeutic, the patient was evaluated again on a different day, and the theophylline dose was adjusted to obtain a therapeutic blood level.
Pre-study baseline spirometry values did not differ significantly, and the FEV1 increased significantly from baseline in response to isoproterenol, ipratropium and theophylline during the three pretest screening procedures.
Patients were then seen on four separate days for administration of the four test regimens. On each day, an electrocardiogram was obtained, baseline and post-test spirometry was performed and a serum theophylline level was measured. A total of 32 patients entered the study, but complete data were available in 19 (eight men and 11 women).
The FEV1 increased significantly after all three drug tests, with the increase occurring more rapidly with ipratropium alone than with theophylline alone. However, the combination of theophylline and ipratropium produced the greatest increase in FEV1 (3.0 L compared with 2.48 L for ipratropium and 2.61 L for theophylline). The effect persisted over a longer period of time with administration of ipratropium and theophylline together as opposed to either agent alone.
No significant side effects occurred in response to the drug and placebo combinations. A significant increase in the heart rate was noted three to five hours following all three drug tests, but the rate did not differ significantly among the drug tests.
The author concludes that since the proposed mechanisms of action of theophylline and ipratropium are different, the bronchodilator effect of this combination is likely to be additive, which would explain the greater increase in FEV1 when the drugs were administered together. In addition, the combination of theophylline and ipratropium did not result in increased side effects or tachycardia. The author notes that this combination may be a reasonable alternative in patients who cannot tolerate the side effects of beta agonists or when tachyphylaxis to the beta agonists is suspected.
editor's note: This small but interesting study provides further efficacy data on the use of ipratropium in patients with asthma. Ipratropium is often given in combination with albuterol in patients admitted to the hospital because of acute exacerbations of asthma. The synergistic effect with theophylline makes clinical sense, although the recently revised guidelines for the treatment of asthma still consider theophylline a third-line drug, making clinicians hesitant to use this agent in the majority of patients with asthma.—j.t.k.