There is now considerable evidence that nocturnal asthma represents an exaggeration of the normal diurnal variation in airway caliber. There is a degree of resting cholinergic tone present in human airways. Since asthmatic subjects show an exaggerated bronchoconstrictor response to cholinergic agonists, it is possible that increased cholinergic tone at night might contribute to nocturnal asthma.
There may be several possible mechanisms for the increase in cholinergic effects at night. There may be an increase in central vagal drive, and some evidence for this is provided by the increase in cardiac parasympathetic tone at night, as reflected by bradycardia and a lengthened sinus arrhythmia gap. There may also be an increased parasympathetic drive to the airways at night, since the reduced heart rate and increased sinus arrhythmia gap are closely correlated with the fall in PE F. Vagal tone may be enhanced by reflex activation, due to stimulation of afferent receptors in airways, possibly because of increased release of inflammatory mediators or because of esophageal acid reflux, which may occur at night. A third possible mechanism may be an increase in efferent cholinergic effects brought about by the fall in circulating epinephrine at night.
The most direct way of testing the hypothesis that cholinergic mechanisms contribute to nocturnal bron-choconstriction is to measure the protective effect of an anticholinergic drug given in an effective dose at night. In a recent study, ipratropium bromide was found to be more effective than inhaled albuterol in preventing the early morning fall in PEF, but no placebo period was included in this study, and therefore the true effect of the anticholinergic drug is uncertain. Anticholinergic drugs have the advantage of longer duration of bron-chodilatation, compared with ^-adrenergic agonists, and effective bronchodilatation over eight to ten hours suggests that they may be effective overnight. Oxitropium bromide is a recently developed anticholinergic agent which has a similar bronchodilator effect and duration of action to ipratropium bromide. Since both ipratropium bromide and oxitropium bromide are competitive antagonists of acetylcholine, it is possible that, while able to reverse resting cholinergic tone, they may be less effective at preventing increases in cholinergic bronchoconstriction. This consideration may be particularly relevant when considering protection against increased vagal tone at night. In a previous study, we have shown that oxitropium protects against methacholine challenge for over six hours and so should be effective against increases in cholinergic tone which may occur overnight.
In the present study, 400μLg of oxitropium bromide administered at night significantly reduced the early morning all in PEF, but closer analysis of the data indicated that some pattents had responded, whereas others were unaffected by the therapy. In many previously reported studies, some patients are protected by anticholinergic drugs against challenge, whereas others have derived no benefit. Thus, in a study of hyperventilation-induced bronchoconstric-tion, approximately 50 percent of the patients were protected by ipratropium bromide, with the remainder being unaffected despite a dose of ipratropium which had a large protective effect against cholinergic challenge. Similarly, in the present study, 50 percent of the patients responded in a dose-dependent manner to oxitropium bromide, whereas the remainder were unaffected, even by the higher dosage. As in previous studies, we were unable to identify any clinical features which distinguished responders from nonresponders.
Our results indicate that cholinergic mechanisms contribute to nocturnal and early morning asthma in some patients and that inhaled anticholinergic therapy may have some protective effect if given in an adequate dosage; however, the protective effect is small, and there was no significant improvement in symptoms, although most “responders” preferred oxitropium to placebo. As the response was dose-related, it is possible that higher doses might be more effective. Patients with chronic obstructive pulmonary disease usually respond significantly better than asthmatic subjects to anticholinergic therapy, and, since these patients also frequently have a worsening of symptoms at night and in the early morning, they may be particularly helped by inhaled anticholinergic drugs at night. In asthmatic patients, who usually respond less well, it may be useful to add inhaled anticholinergic therapy at night when more conventional therapy, such as regular inhaled steroids or slow-release theophylline at night, have not effectively controlled nocturnal symptoms.
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