Theophylline and Fenoterol on Exercise-Induced Asthma Deliberations

Both theophylline and fenoterol were demonstrated to be effective bronchodilators when taken orally. The effects of theophylline have been shown by others to be dependent on serum drug levels, and in this study bronchodilation was significantly greater at mean serum levels of 12.5 ftg/ml than at levels of 6.1 ftg/ml. The bronchodilation shown in this study following 10 mg of fenoterol is similarly comparable to that in previous studies with this drug and to studies with other orally effective /3-adrenergic agonists.

The bronchodilatory effects of theophylline and fenoterol were clearly additive. The addition of a half-dose of fenoterol (5 mg) approximately doubled the pulmonary function changes seen following 130 mg of theophylline alone, so that bronchodilation was comparable to that seen with theophylline levels twice as high. Previous studies with other adrenergic agonists and theophylline preparations have shown partially additive effects. However, the protocol used in the present experiment differed slightly from that in previous studies, in that low-dose combinations were compared with single high doses. This approach allowed not only clearer demonstration of additive effects, but it was also possible to show that when 2.5 mg of fenoterol was given with low-dose theophylline, bronchodilation increased substantially, suggesting that the effects might even be synergistic.

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The effects of the two drugs (find on as modulators of exercise-induced asthma were not as clear. If the net effects of treatment (comparing pulmonary function before medication with function after exercise) are considered, it would appear that both fenoterol and theophylline had quite marked effects on exercise-induced asthma and that the effects are additive.

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However, any such conclusions overlook a major contribution of drug-induced bronchodilation that allowed subjects to begin exercise with more normal pulmonary function. Looking at exercise-induced asthma in isolation, as shown in Figure 3, it is apparent that none of the treatments actually had a marked effect on the pulmonary response to the challenge, and that the effects of combining halfdoses of the two drugs are not as great as those of a full dose of either drug alone.

The disparity between the significant effects of these drugs as bronchodilators and their lesser effects on exercise-induced asthma is similar to the results of other studies with oral doses of ^«adrenergic agonists. Anderson et al showed that comparable bronchodilation was produced by both a 5mg oral dose of salbutamol and a 250-^g inhaled dose, but that only the inhaled dose affected exercise-induced asthma. It was concluded that greater pulmonary concentrations are required to inhibit exercise-induced asthma than to effect bronchodilation. This conclusion is supported by other studies that show that ephedrine, a relatively weak adrenergic agonist, may produce significant bronchodilation without affecting exercise-induced asthma.asthmatic children

From the point of view of the asthmatic patient, it is the net effect of these drugs that is most easily appreciated. Pulmonary function abnormalities reflect symptomatic airflow obstruction, and treatment that most effectively limits the severity of obstruction might be viewed as the most effective, regardless of the mechanism of this limitation.

All three effective regimens—high-dose theophylline, 10 mg of fenoterol, or 130 mg of theophylline with 5 mg of fenoterol—were associated with significant toxicity. Although it might be anticipated that this combination of low doses of fenoterol and theophylline would reduce the dose-dependent side effects of each, such was not the case in this trial. Specific side effects did vary. Fenoterol, for example, was associated with cardiovascular and neurologic symptoms, while theophylline more frequently produced gastrointestinal distress.

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The tachycardia seen following oral fenoterol and other adrenergic agonists is of particular concern when these drugs are recommended for use before exercise, especially competitive athletics. Significant resting tachycardia suggests that there might be a greater cardiovascular risk during the exercise stress, and the significance of this risk has not yet been adequately studied. In the present study, heart rates and ECG (Electrocardiogram) tracings during exercise were not affected, even in the one subject whose heart rate before exercise was 124 beats/min. However, stress testing using more appropriate techniques for cardiovascular monitoring is necessary to evaluate adequately the effects. Until these effects are reported, the implication of risk remains, and oral adrenergic agonists cannot be said to be the treatment of choice.

The drugs of choice for the prevention of exercise-induced asthma are the inhaled adrenergic agonists, which are extremely effective in doses small enough to be without cardiovascular side effects. In addition, both cromolyn sodium and oral theophylline in appropriate doses are effective with less cardiovascular toxicity than found with oral doses of adrenergic agonists.

In summary, an orally effective adrenergic agonist and theophylline were found to have additive effects as bronchodilators, while their effects in preventing exercise-induced asthma were not significantly additive. Moreover, the frequency and severity of side effects increased with the combinations of the adrenergic agonist with theophylline, mitigating even their added value as bronchodilators.

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