Irritant Activity

Ramifying within and beneath the epithelium of the central airways are nerves that serve a sensory function and that may be characterized on the basis of their structure, physiology, and susceptibility to stimulation by chemical substances. The two most important (as far as inhaled substances are concerned) are irritant (rapidly adapting receptors) and afferent C-fibers. Impulses received from either nerve type are processed in the central nervous system and results in centrally mediated changes in respiratory rhythm and depth (coughing or sneezing and rapid, shallow breathing), airway smooth muscle tone (bronchoconstriction), and mucus secretion [124]. Airborne substances, such as chemically inert dusts, cigarette smoke, and irritant aerosols (e.g., citric acid, capsaicin, histamine), stimulate sensory nerves to produce an irritant effect, characterized by the previously mentioned physiological changes [124]. This central reflex arc is responsible for the bronchoconstrictor action of nonspecific stimuli (e.g., dust and smoke) and, in addition, may contribute to the bronchoconstrictor action of pharmacological agents, such as histamine. In asthma and other pulmonary diseases, increased sensitivity of sensory nerves to irritants has been proposed as a mechanism by which the airways become hyperresponsive. In the context of aerosol administration, this process has important ramifications, in that a therapeutic agent may actually induce a bronchospastic episode should it prove to stimulate airway sensory nerves, i.e., act as an irritant. Cromolyn administration as an inhalable powder initially induced coughing, wheezing, and, in some instances, bronchospasm, which are actions emanating from an effect on sensory nerve endings. Reformulation as an inhalable solution obviated these problems. Interestingly, a component of therapeutic action of the cromones, such as cromolyn and nedocromil, may rest in their ability to diminish the sensitivity of airway sensory nerves to irritant stimuli [125,126].

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