Vol. 13 •Issue 3 • Page 24
New Asthma Drugs Target the Small Airways
Metered dose inhalers have long been the preferred method of medication delivery to the lung for patients with stable asthma. But these particle generators typically used chlorofluorocarbons (CFCs) to create a gas stream that carried the medication into the lung. Unfortunately, CFCs were well-known to be harmful to the planet’s ozone layer, and the Food and Drug Administration mandated the removal of CFCs from MDI preparations.
What was once an environmental concern has now ushered in a new era for asthma medications. Dry powder inhalers for asthma medications have reached the market along with new propellants such as hydrofluoroalkanes (HFA) that are used in pressurized MDIs.
THE ASTHMA CASCADE
The pathophysiology of asthma is a complicated cascade of biochemical events that leads to airway inflammation. Allergens, cold air and exercise are at the top. From here, cellular events unfold that involve eosinophils, neutrophils, basophils, mast cells and T-lymphocytes. These cells release chemical mediators that produce asthma’s characteristic airway swelling, bronchoconstriction and mucus secretion. Many mediators exist, including histamine, leukotrienes, interleukins, inflammatory cytokines and eotaxins.
The site of these pathological changes, the small airway, historically has been beyond the scope of traditional chest X-rays. But high-resolution computed tomography (HRCT) now provides images of airways as small as 1.5 mm to 2.0 mm. Studies using HRCT have shown, for example, that airways in the 2 mm to 4 mm range are the site of methacholine-induced bronchoconstriction.1
Air trapping and lung hyperinflation are typical sequela of airway narrowing, and HRCT also serves as a window for this process, allowing evaluation of regional ventilation over time.2
Other authors have examined resected lung tissue and transbronchial biopsy tissue to demonstrate more severe cellular inflammation and structural changes in small airways compared to large, central airways in patients with asthma.3 It’s also well-known that traditional pulmonary function tests characteristically will show a reduction in midflow rates (peak expiratory flow rate 25-75) during a forced vital capacity in patients with asthma. Clearly, the small airway is the site of pathology in this disease.
Taken collectively, these findings present a challenge for those treating asthma. First, one needs to deliver particles of medication directly to the small airway. To do this, very small particles, 2 microns to 4 microns, are needed. And second, because of the very large surface area of the small airways, a large percentage of particles penetrating the small airway must be deposited in the lung.
Consider inhaled corticosteroids (ICS). For many, they’re the mainstay of asthma treatment. ICS are anti-inflammatory agents that inhibit the production of inflammatory cytokines in the lung. Additionally, ICS seem to decrease the number of inflammatory cells — eosinophils, mast cells and lymphocytes — in the airway and surrounding mucosa. This interruption of the chemical cascade of inflammation results in the symptomatic relief experienced by millions of asthma patients who use ICS.
A very common ICS, beclomethasone diproprionate (BDP), now has been reformulated to incorporate HFA as its propellant. This new preparation also resulted in a change from a suspension of BDP (with the CFC propellant) to a solution with the HFA propellant. This change in formulation created a smaller particle size: 1.1 microns (HFA) vs. 3.5 microns to 4.0 microns (CFC) mass median aerodynamic diameter.4
Some have suggested that the smaller particle size might actually result in particle deposition in the alveoli without any beneficial effect. Others maintain that high concentrations of glucocorticoid receptors in the alveoli might actually benefit from a particle size of approximately 1 micron.5
Studies using radiolabeled HFA BDP demonstrated an approximate tenfold improvement in the amount of drug delivered to the airways compared to the CFC BDP. Additionally, the diffuse distribution pattern seen on the scintigraphic images of HFA BDP seems to reflect an improved distribution of the drug to the peripheral airways.6 Clinical studies support an improved response (FEV1) with the HFA formulation compared to the CFC preparation of BDP.7
Another ICS, HFA flunisolide hemihydrate, is being marketed as a replacement to its CFC counterpart. Again, clinical studies have shown the HFA preparation produces comparable improvement in lung function improvement compared to the CFC formulation, but the improvements noted for the HFA flunisolide occurred at roughly one-third of the dose needed for the CFC flunisolide.8 Cellular markers of inflammation (eosinophils, IL-5 and eotaxin) all were reduced in the peripheral airways after treatment with HFA flunisolide.
Both HFA preparations of beclomethasone and flunisolide are well-tolerated with minimal systemic absorption and minor local adverse effects, such as oropharyngeal candidiasis and dysphonia.
LEUKOTRIENE RECEPTOR ANTAGONISTS
The inflammatory cascade described above demonstrates another important pathway in producing airway inflammation and symptoms of asthma. Cysteinyl leukotrienes LTC4 and LTE4 are at least 100 times to 1,000 times more potent bronchoconstrictors than histamine, and they alter vascular permeability, induce mucus secretion, and hamper mucociliary clearance.
Their action on the small airway can be blocked by either inhibition of leukotriene production or by interfering with leukotriene binding to cellular receptors in the airway. Three oral leukotriene receptor antagonist products are currently available: Zafirlukast and montelukast block leukotriene receptor binding, and zileuton inhibits leukotriene formation.
These drugs are designated as second-line medications, but their potential is great for reducing the inflammatory response in the distal lung. Studies confirm the importance of these drugs in managing asthma, but results are mixed when compared to ICS.9
New formulations of ICS are rapidly changing the asthma therapy landscape. A novel class of drugs, leukotriene receptor antagonists, offers alternatives, but their story has yet to be told. We’re getting closer to the ideal drug that targets the biochemical cascade at the site of the injury: the small airway. These are exciting times in the treatment of this pervasive disease. n
Bakow is the manager of respiratory care and pulmonary diagnostics at the Penn State Milton S. Hershey Medical Center, Hershey, Pa.
For a list of references, please call Sharlene George at (610) 278-1400, ext. 1324, or visit www.Respiratory-care-sleep-medicine.advanceweb.com.