The efficacy of anticholinergic drugs in preventing asthma induced by exercise, cold air, or both is controversial. While some studies have shown that bronchoconstriction following exercise could be inhibited by treatment with anticholinergic drugs, others have suggested that these agents have variable, inconsistent results. It has also been debated whether these drugs improve airflow after exercise or cold air inhalation by altering resting baseline airway tone or by actually blocking the bronchospasm precipitated by the exercise.
Relatively large doses of anticholinergics appear to be necessary to affect the response to exercise or cold air consistently in asthmatic subjects. Inhalation of large doses of atropine produces systemic manifestations of muscarinic blockade such as tachycardia, mental confusion, dry mouth, and blurred vision because of systemic absorption across mucosal surfaces. These undesirable side effects limit the widespread use of atropine.
Interest in anticholinergics as bronchodilators has recently been stimulated by the evidence that quaternary atropine derivatives such as ipratropium produce significant bronchodilation. These highly polar ammonium compounds are poorly absorbed across mucosal surfaces, and thus systemic effects are unlikely with drug inhalation. Glycopyrrolate is another such quaternary compound with anticholinergic properties similar to those of atropine, but with minimal cardiovascular, ocular, and CNS effects. The safety of glycopyrrolate has been established by nearly 20 years of clinical use orally to control gastric acidity and parenterally as an antisialogogue and an antimuscarinic during reversal of neuromuscular blockade. When inhaled by normal subjects in large doses, glycopyrrolate is at least twice as potent as atropine, on a molar basis, and produces significantly longer lasting bronchodilation. Studies have not been performed, however to test the effect of this drug in patients with airway disease.
The purpose of this study was twofold: first, to examine the effect of high doses of anticholinergics in exercise and cold air-induced asthma, and second, to compare the effectiveness and side effects of inhaled glycopyrrolate with that of atropine and placebo.
Methods
Subjects were six nonsmoking male volunteers between the ages of 18 and 33 years. All had a previous history of exercise-induced asthma and required prophylactic or therapeutic administration of oral or inhaled p-agonists for control of symptoms which were stable at the time of the study. Their airway reactivity was confirmed by a reproducible fall in FEV1 of at least 15 percent after each of two preliminary screening sessions of exercise. No subject was receiving cromolyn sodium or oral corticosteroids; one subject was receiving daily inhaled bedomethasone. Corticosteroids, theophylline, and antihistamines were excluded for 24 hours prior to testing; b-agonists were excluded for 12 hours prior to testing.
Glycopyrrolate, atropine, and placebo (normal saline solution) were administered in a randomized, double-blind fashion to each of the subjects. Concentrated solutions of glycopyrrolate meth-ylbromide (10 mg/ml) and atropine sulfate (20 mg/ml) were prepared by dissolving the crystalline compounds in 0.5N saline. Solutions were delivered to the airways by a Devilbiss 646 nebulizer attached to a dosimeter (Rosenthall-French, Model 2A, Laboratory for Applied Immunology, Inc) consisting of a source of compressed air at 20 psi and a solenoid valve. The valve was activated by inspiration and remained open, dispensing solution for about 0.6 second as subjects inhaled slowly from functional residual capacity to total lung capacity. The output of the nebulizers was checked by weighing on an analytical balance before and after delivery of five activated puffs. With 2.0 ml of solution in the nebulizer, each puff dispensed an average of0.0264 ml ± 0.0014 SE, so that subjects received approximately 1.32 mg±0.007 SE of glycopyrrolate and 2.64 mg ±0.014 SE of atropine.
Spirometry was performed using a Collins water seal spirometer (Collins 420). Airway resistance (Raw) and functional residual capacity (FRC) were measured by the method of Dubois and coworkers using a constant-volume body plethysmograph. Resistance was expressed as its reciprocal conductance (Caw) and divided by FRC to give specific conductance (sGaw). The mean values from ten satisfactory measurements were used in the results. Forced expiratory volume in one second (FEV1) and sCaw were determined before drug administration (baseline) and 20 minutes after drug administration (preexercise).
Exercise was performed 30 minutes after drug administration. Subjects exercised by running on a treadmill with a 5° incline at a speed of 8 kph for ten minutes. During the exercise, the subjects inhaled air cooled to — 2.09°C ±0.19(SE). Spirometry was performed at 1,3, and 5 minutes after the completion of exercise. Hie sGaw was determined immediately after spirometry. Values showing the greatest fall after exercise were used for comparisons. FEV, and sGaw were again determined before and after another exercise session repeated at 120 minutes after each aerosol administration. Heart rates were also determined at the time of each pulmonary function measurement At these times subjects were asked to assess the severity of the symptoms of dry mouth and flushing on a scale of 0 to 4, 0 being not present; 1 noticeable, 2 mild, 3 moderate, and 4 severe.
Differences among the three treatment groups were analyzed by one-factor analysis of variance. If F ratios indicated that the means differed significantly (p<0.05), modified paired t tests were utilized to isolate the differences.