© 2005 American Thoracic Society doi: 10.1164/rccm.2507002
Bigger May Be BetterTargeted ß2-Agonist TherapyNational Heart & Lung Institute, Hammersmith Hospital, Imperial College, London, United Kingdom ß2-Agonists remain the most important inhaled bronchodilators and provide rapid symptom relief for many patients. More than thirty years after their introduction, short-acting, inhaled, selective ß2-agonists remain the mainstay bronchodilators for asthma, chronic obstructive pulmonary disease, and airway obstruction of all etiologies. They act principally on smooth muscle ß2-adrenoceptors, which are widely distributed throughout the human bronchial tree, though the highest density of ß2-receptors is in alveolar regions (1). ß2-Agonists are among the most prescribed drugs worldwide, and the metered dose (polydisperse) aerosol inhaler remains the most popular device. Nevertheless, aspects of their use remain controversial (2). The relationship between ß–adrenoceptor haplotype and acute and chronic pharmacodynamic (bronchodilator) response is complex (3). The article by Usmani and colleagues in this issue of the Journal (pp. 704–712) adds important contributions to our understanding of ß2-agonists and bronchodilation in asthma (4). This novel study explores in detail the relationship between albuterol monodisperse aerosol particle size, total and regional lung deposition, bronchodilator response, and, to a lesser extent, systemic effects. This is a careful, rigorous (eight randomized plus three additional visits) study employing a well-validated system to produce monodisperse aerosols. It adds to the available literature in confirming the authors' earlier finding (5) that uniform 6-µm albuterol particles gave greater bronchodilation than smaller particles (1.5 or 3 µm). It has long been known that very small (submicron) particles are mainly inhaled and re-exhaled (6). Larger particles (> 8 µm) mainly impact in more proximal airways and deposit in the oropharynx. In asthma, ß2-agonists are logically targeted at the main smooth muscle containing conducting airways, generations 0–16 (7). Previous studies examining bronchodilation in asthma (8, 9) using monodisperse aerosols concluded that 1.5–2.8-µm particles were optimally effective, but technical differences relating to the aerosol generation and delivery are likely to account for the discrepancies with the present study. These current findings contradict much received wisdom that smaller particles (< 5 µm) are more effective, and may prompt a rethink among inhaler device manufacturers. The present study nicely demonstrates a dose–response to monodisperse albuterol and confirms that very low doses (around 30 µg) are very effective, in fact slightly more effective than the standard 200-µg dose delivered as two puffs from a polydisperse aerosol inhaler. While it can be argued that ß2-agonists, in general, have such a wide therapeutic ratio that accurately targeting deposition is academic, the same may not be true for other drugs. For example, anything that reduces the dose of an inhaled steroid by accurately targeting delivery would surely be seen as beneficial. The new evidence is that regional lung deposition of albuterol (previously inferred from particle size and slower flow rate of inspired aerosol and now measured scintigraphically) determines bronchodilator response in asthma. Total lung and peripheral deposition were increased with the 1.5-µm particle aerosol (higher penetration index), but more was expired and the bronchodilator response was reduced for the same dose. Inhalation of aerosol at faster flow rates (> 60 L/min) decreased total lung, peripheral, central, and intermediate deposition for 6-µm particles and produced significantly reduced bronchodilation. However, slightly greater central deposition, with unaltered total lung deposition, apparently resulted in less bronchodilation than with a slow inhalation for the 3-µm particles. There was no correlation of total lung dose or regional deposition and either particle size or bronchodilation. As the authors acknowledge, the limitations of planar two-dimensional scintigraphic imaging did not allow them to accurately determine central (and intermediate) deposition of albuterol (because of alveolar counts included in these regions). They infer that the monodisperse nature of the aerosol defines the airway, as 1.5-µm particles identify alveolae and 6-µm particles conducting airways. Presumably, in the intermediate case of the 3-µm particles, this may explain the apparent discrepancy outlined above. More sophisticated techniques such as positron emission tomography or single photon emission computed tomography would have advantages in imaging the localization of particles, but have practical problems. Theoretical mathematical modeling of the data would be of interest and should be performed. The study does not tell us about effects of alveolar deposition of small particles of albuterol, but increased systemic absorption, which was not reflected in side effects because of the very low doses, could have been determined by urinary albuterol measurement (10), which would have been of interest. Regional ventilatory inhomogeneity was present at baseline, but was not monitored. In this and the authors' previous study (5), the failure of FEF25–75 and FVC as potential measures of small airway effects is disappointing and questions the value of these measurements in this situation. This paper highlights the usefulness of monodisperse aerosols as tools with wide applications. Excluding patient performance in the use of inhalers, the most important factors determining effect include particle size, total lung deposition, regional deposition, distribution of aerosol delivery, and target site(s). This has largely been defined for ß2-agonists in mild, stable reversible asthma, but remains to be determined for other conditions and for other drugs. This is a precedent for future studies with other asthma drugs, where it is currently more difficult to show clinically important pharmacodynamic effects and dose–response. It has clear implications for the delivery of future drugs, such as inhaled insulin and other protein molecules, but also for new antiinflammatory agents. It is also fundamental to the design and manufacture of the ever-increasing profusion of inhaler devices and expanding interest in more sophisticated, microchip-controlled, "smart," hand-held nebulizer technologies. FOOTNOTES Conflict of Interest Statement: P.W.I. has received monies for speaking at conferences, lecturing to physicians and Advisory Boards from GlaxoSmithKline (GSK), AstraZeneca, and Pfizer. He has received grants from GSK and Pfizer. REFERENCES
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