Conclusion
Despite great improvement in inhalation drug delivery systems, cough is
still a limiting adverse effect affecting patients’ compliance and
treatment efficacy as it would reduce the delivered dose. Cough is an
important symptom of many respiratory diseases so it may be difficult to
distinguish it from the adverse effects caused by the inhalation
product. The underlying disease that cause cough and bronchoconstriction
may also affect particle deposition and inhalation effort by the
patient. Airway acclimatisation and the individual’s response to cough
stimulants are also important factors. Since cough can be due to so many
confounding factors via direct or indirect effect of the stimulants, one
cannot simply make general statements such as powder aerosols being more
likely to cause cough than nebulized formulations, or vice versa, even
for the same drug molecule. Well-controlled clinical studies
specifically designed to address cough would be necessary to identify
the underlying cause for cough encountered in patients during aerosol
treatment.
In the airways, chemicals may stimulate Aδ or C fibres by changing the
acidity, osmolarity, or by directly activating the receptors. The cough
receptors in diseased lungs are highly sensitised and can be stimulated
easier compared to those in healthy people. Large particles may
stimulate the punctate-sensitive cough receptors in large airways and
trigger the expiratory reflex. Controlling the particles size of the
formulation to <5 µm is necessary for minimising cough so that
the particles deposit in the deep lung, where cough receptors are
absent. However, such an approach
would need to take into account the site of therapeutic action. Besides
particle size, the form of the aerosol, the dose, solid state of the
drug, type of excipients, concentration, and pH and tonicity of the
formulation should be considered to avoid causing cough. Higher doses of
drugs and/or excipients can increase the risk of cough if the inhaled
compounds can activate the cough receptors. Air flow characteristics
through the inhaler device must be optimised to achieve the maximum
aerosol performance and minimum airway irritation due to unwanted
particle
deposition. At the same time, the inhaler should be sufficiently simple
for patients to operate correctly. Figure 3 summarises these factors in
the design and use of inhalation products to avoid causing coughs.