Read the first part of this research: “Inhaled Glycopyrrolate and Atropine in Asthma Research“.
Changes in FEVX and sGaw throughout the study are summarized for each of the three aerosol treatments (Fig 1). Baseline pretreatment values for FEVi and sGaw were similar for each of the three aerosols. In subjects who received atropine, there was a significant increase in FEVX above baseline values (p<0.05) prior to the first exercise trial.
The sGaw was significantly elevated above baseline by both glycopyrrolate and atropine at this time. Prior to the second exercise period, both FEV! and sGaw were significantly elevated above baseline values in subjects receiving glycopyrrolate and atropine (p<0.05), but not placebo. Consequently, both glycopyrrolate and atropine beneficially affected resting airway function.
The initial exercise period produced significant decreases in FEVX and sGaw in all three treatment groups (p<0.05) when compared to their preexercise values. The absolute decline in these values did not vary significantly among the three groups. There was, however, a large variation among individual subjects. All subjects had more than a 20 percent fall in FEV1 with exercise after placebo inhalation, whereas two subjects receiving glycopyrrolate and one atropine had less than a 5 percent fall in FEV1 during the same time period.
The changes in sGaw paralleled those of FEV1. Similar changes were observed following the second exercise 90 minutes latei; but the bronchoconstrictive response was less severe. The decline in FEV1 was significantly less (p<0.05) in all groups with the second exercise compared to the first. This blunting of the bronchial response by repeated exercise was also reflected by similar smaller decreases in sGaw after atropine and glycopyrrolate but not after placebo.
After the first exercise period, values for FEVx in the glycopyrrolate and the atropine group, although decreased from preexercise levels, were higher than in the placebo group (p<0.05) (Fig 2). The values of sGaw in the glycopyrrolate and atropine groups were higher than the placebo group, but the difference did not reach statistical significance (p<0.08). After the second exercise period, FEV1 values in both the atropine and glycopyrrolate groups were greater than those in the placebo group (p<0.05) and did not differ significantly from predrug baseline values. At this point, FEVl and sGaw were also significantly higher with glycopyrro late compared to atropine (p<0.05).
A blunting of the bronchospastic response to exercise occurred in the second exercise period compared to the first. The FEV1 and sGaw values fell less after the second exercise period than after the first exercise period in all treatment groups (p<0.05). The one exception to this was that blunting did not occur in the placebo group with sGaw.
The heart rates of glycopyrrolate and placebo groups were similar during all periods (Fig 3). In contrast, atropine produced a significant increase in the resting preexercise heart rates when compared to the baseline value. With atropine, the heart rate increased by a mean of more than 40 percent prior to both exercise periods. The postexercise heart rates were similar among all three treatment groups. The side effects of moderate-to-severe dry mouth and flushing occurred in all subjects after atropine. Their incidence and severity differed significantly (p<0.01) from either placebo or glycopyrrolate. Exercise further intensified the symptoms of dry mouth and flushing produced by atropine. Jn contrast there was no significant difference in side effects between the glycopyrrolate and placebo inhalation groups.
Discussion
This study demonstrates that inhalation of glycopyrrolate and atropine produced signficant bronchodila-tion in subjects with a history of exercise-induced asthma. This bronchodilation was observed in subjects before exercise. With exercise, the same relative degree of bronchoconstricdon occurred after treatment with placebo, glycopyrrolate, and atropine. Because of the bronchodilation before exercise in the glycopyrrolate and atropine groups, airflow was better after exercise in the subjects receiving these drugs than in those receiving placebo. While atropine produced significant side effects, side effects of glycopyrrolate were minimal and indistinguishable from those of placebo.
Resting airway tone was decreased by glycopyrrolate and atropine before exercise as reflected by increases in sGaw. Similar results were found with FEVb except that 20 minutes after glycopyrrolate, FEV1 was not significantly elevated above baseline. Most likely this reflects the relatively slow onset of action of this rather long-acting drug. Previous observations have indicated that a minimum of 30 to 60 minutes elapsed before inhaled glycopyrrolate reaches its peak effect.
We found that the airflow following exercise with cold air was higher when our subjects received glycopyrrolate or atropine than when they received a placebo. Similar results have been noted in patients subjected to exercise alone after anticholinergic treatment; however, other investigators have found the responses to atropine highly variable in individual patients. Some observations Utilizing only cold air challenge noted higher airflow after anticholinergic treatment compared to placebo, while others using the same stimulus have reported no difference ip airflow between the same two groups. The observers who utilized the combined stimuli of cold air and exercise, as in this study, also noted a higher FEV1 in subjects who have received anticholinergics.
Our results indicated that this improved airflow following exercise and cold-air inhalation in subjects given anticholinergics results from drug-induced bron-chodilation prior to the exercise, not from direct blocking of the bronchoconstricdve response. The decreases in sGaw and FEV1 from the period before exercise to the period after exercise were similar in all treatment groups. Neither anticholinergic drug prevented the substantial fall in airflow. These data are consistent with most reports in the literature using either exercise, cold air, or both as a stimulus to induce bronchoconstriction.
We observed a smaller fall in FEV1 during the second exercise period than the first, characteristic of all three treatments. Several other investigators have noted this relatively refractory period lasting up to two hours to repeated exercise and have suggested that the duration of this period relates to the severity of the initial stimulus.
Glycopyrrolate was as effective as atropine in producing bronchodilation in our subjects. The increased heart rate, severe dry mouth, and flushing seen with atropine inhalation did not occur with glycopyrrolate. Similar large doses of ipratropium have been administered without side effects. These drugs appear to have the same potency relative to atropine; however, there are no data concerning the duration of action of ipratropium. Glycopyrrolate has a long duration of action compared to atropine, a factor which may further enhance its clinical utility. The effectiveness of glycopyrrolate in preserving postexercise pulmonary function results from preexercise bronchodilation, not specifically from blockade of the bronchoconstriction imposed by exercise in cold air. Because of the few side effects with inhalation and its long duration of action, glycopyrrolate may be a useful component of drug therapy in exercise-induced asthma and other variants of airwav disease responsive to anticholinergic therapy.
Ficure 1. Changes in FEV, and (sCaw) specific airway conductance during the entire study. Mean values are plotted for six subjects. Bars represent 1SEM.
Figure 2. Comparison of mean postexercise values for FEV1 and specific airway conductance with baseline pretreatment values. p<0.05 compared to pretreatment period; p<0.05 compared to postexercise placebo group; and p<0.05 compared to postexercise atropine group.
Figure 3. Heart rate changes with aerosol inhalation and exercise values are mean±SE for six subjects. p<0.05 denotes significant difference compared to placebo group.