Isoproterenol acts directly on the smooth muscles, which are distributed throughout the large as well as small airways, by stimulating the cyclic AMP system resulting in bronchodilation. On the other hand, atropine dilates the airways by inhibiting parasympathetic nerve endings responsible for bronchoconstriction via cyclic GMP system. As the nerve supply is densest in the large airways, it is likely that the large airways are the major site of action of atropine. This is supported by the work of Chick and Jenne showing that atropine results in a greater dilatation of the large airways.
There are conflicting data on the major sites of action of isoproterenol. Some workers have shown that isoproterenol affects the large and small airways equally. Some have suggested that it dilates the large airways more than the small, while yet other workers show that it influences the small airways preferentially. All the above studies have been confined to the acute effects of isoproterenol and to subjects who were either normal or had bronchospasm for a short duration only. A difference in the responsiveness of the different segments of airways might have been responsible for the discrepancy in the results obtained by the different authors regarding the major site of action by isoproterenol.
Measurement of the density dependence of the maximum expiratory flow (D/MEF) by using two superimposed MEFV curves, one breathing air and the other breathing Helox, has been used for determining the major site of increase in airway resistance. Hutcheon et al reported that an increase in VisoV denoted a decrease in density dependence of the flow and was produced by shifting of the equal pressure point to the small airways. Despas et al described another method of measuring D/MEF by obtaining Vmaxso Helox/air, a decrease in which denotes a decrease in D/MEF and a peripheral movement of equal pressure point.
The mechanism of D/MEF has been discussed in detail elsewhere and only a brief discussion is needed here. Flow in the large airways is turbulent as opposed to that in the smaller airways where it is laminar. The turbulent flow is inversely proportional to the density of the gas being breathed while laminar flow is independent of that density. Furthermore, expiratory flow is determined by the events in the segment upstream from the equal pressure point (EPP) which is defined as the point where the lateral pressure inside the lumen of the airway equals the intrapleural pressure. Therefore, when Helox, a gas mixture with a density lower than air is breathed, the expiratory flow would be higher than when breathing air if the flow in the flow-determining upstream segment of the airways, ie peripheral to EPP, is turbulent. As turbulent flow occurs in the large airways, the EPP must exist in the large airways in the above instance. On the other hand, if no increase in the expiratory flow occurs on breathing Helox denoting independence of the expired flow from the density of the inhaled gas, the flow in the flow-determining segment must be laminar and the EPP in small airways. A decrease in the D/MEF would result from a shift of the EPP towards the small airways, ie peripherally, thereby making the flow in the flow determining segment laminar and independent of density. Shift of the EPP towards the large airways, or centrally, would result in an opposite effect, ie an increase in D/MEF.
In subjects showing an increase in D/MEF after isoproterenol (group 2), a relative increase in the resistance to turbulent flow due to a mouthward movement of the EPP must have occurred, so that the large airways contributed a relatively larger proportion of the total Raw (airway resistance) after bronchodilatation. It can be assumed that isoproterenol did not cause bronchoconstriction as the overall Raw had fallen. Then, an increase in the contribution of the resistance in the large airways to the total airway resistance must have resulted from a greater decrease in the resistance in the small airways compared to the large airways. This would seem to indicate a preferential bronchodilatation of the small airways with isoproterenol. Similarly, a group 1 response would denote an opposite set of events, ie a decrease in D/MEF after isoproterenol, peripheral movement of the EPP, a greater contribution of the small airway resistance to total airway resistance and a preferential dilatation of the large airways with isoproterenol. Thus, isoproterenol appears to result in a preferential dilatation of the large airways in group 1 and of small airways in group 2.
The apparent discrepancy in the preferred site of action of isoproterenol in groups 1 and 2 can be explained by a difference in the responsiveness of the small and large airways to the bronchodilator action of isoproterenol in the two groups. More severe disease in the large airways would lead to a relative resistance of the large airways to the bronchodilator effect of isoproterenol, and would thus be characterized by a group 2 response. Similarly, a group 1 type response could be attributed to the presence of more severe disease in the small airways. Dashe et al have shown that the predominant effect of isoproterenol depends mainly upon the responsiveness of the airways which is determined by, among other things, the severity of the bronchoconstriction in these airways. More severely or chronically involved segments of the airways respond the least to the effects of bronchodilators, and progressive diminution in the responsiveness of the airways with greater disease has been reported by Hume and Gandevia.
However, the long term effects of a bronchodila-tor may be different from the acute effects. In reversible disease, as the airways regain responsiveness to bronchodilatation, the inherent preferential site of the action of a drug would, in the long run, assume a greater importance than the state of immediate responsiveness of a diseased segment of the airways.
A significant improvement in both large and small airways function might have resulted from either drug. It should be noted that the preceding discussion is concerned with a relative rather than an absolute change in Raw in large and small airways. For example, a subject could manifest a group 1 or group 2 response solely on the basis of whether or not an improvement in small airway function occurred after isoproterenol inhalation. But the relative change in Raw in small airways as compared to that in the large airways would be the same whether small airways fail to dilate and the large airways do, or both the large and small airways dilate but the large airways dilate relatively more than the small airways.
If isoproterenol and atropine act best at small airways and large airways respectively, then it can be predicted that maximum long term bronchodila-tion would be attained with atropine in group 2 subjects and with isoproterenol in group 1 subjects. The data presented suggest that there is at least a moderately greater improvement in FEVi and Vmax5o in response to atropine then to isoproterenol in those patients with an increase in density-dependence of the MEFV curve after inhaled isoproterenol. Conversely, isoproterenol appeared to produce a greater improvement in FEVi and Vmaxso than atropine in those patients whose density dependence decreases after isoproterenol. These results support the above concept.
Inasmuch as other medications given to the two groups, and the mode of administration of isoproterenol or atropine were identical, we assume that the effects of tolerance to sympathomimetic drugs, or difference in aerosol deposition, would be distributed equally and would not alter the overall conclusions. Other workers have shown that asthma induced by antigen challenge and exercise, as well as perennial asthma with marked seasonal variation, denote a relatively greater involvement of the central or larger airways and a better response to atropine (read article on our site). Asthma associated with chronic bronchitis, smoking, and recurrent respiratory infection has a large component of small airways involvement. In our study, group 2 subjects were characterized as having milder disease, greater reversibility, a higher incidence of reacting to known allergens, and a higher incidence of seasonal exacerbation in symptoms. However, none of these differences was significant, and the two groups were essentially similar in all respects. We examined these data in subjects responding best to isoproterenol and to atropine, and could not detect a difference between the two. The results agree with Altounyan who showed that clinical criteria, unfortunately, fail to predict the responses in patients to different drugs.
Atropine is known to result in diminished mucociliary clearance and drying of the respiratory tract mucosa. However, the side effects have been tolerable in most of the studies when using 0.05-0.1 mg/ kg of the drug. We observed a higher incidence of side effects using 0.08 mg/ kg of the drug taken four times daily by inhalation (Table 5), than in the other studies referred to above. In these studies, atropine was administered as a single dose, or for one or two days only. A study using atropine for one week used only a 1 mg dose four times a day. Atropine probably has a cumulative effect resulting in a higher incidence of side effects if used regularly for more than one or two days. When the dose of atropine was reduced to 0.04 mg/kg/body-weight, the side effects were mild or disappeared. It is difficult to say whether this resulted in a reduction of the bronchodilator effect also. Fully one-third of the subjects experienced no side effects with atropine in the full dose used in this study.
We conclude that atropine sulfate at a dose of 0.08 mg/kg body weight four times a day by inhalation results in a greater subjective and objective improvement than 2.5 mg isoproterenol by inhalation in about half (45 percent) the adult chronic asthmatic patients, and is preferred by them in spite of a high incidence of side effects. The subjects who respond better to atropine than to isoproterenol over a one-week period were characterized by an increase in D/MEF immediately after inhalation of isoproterenol. Therefore, a decrease in VisoV or an increase in Vmaxso Helox/ air after isoproterenol can be used as a diagnostic test to predict a better response to atropine than to isoproterenol, and in such subjects, the inhalation of atropine would be indicated. No other clinical or laboratory parameters distinguish between AR and IR, although the AR group have a higher incidence of identifiable allergies and seasonal exacerbation of symptoms. The results can be explained by atropine being more effective in subjects whose disease more severely affects the large airways.
Previously published articles:
Density Dependence of Expiratory Flow and Bronchodilator Response in Asthma
Research Concerning Expiratory Flow and Bronchodilator Response in Asthma
Outlet Concerning Expiratory Flow and Bronchodilator Response in Asthma