Studies in progress are investigating agents that may provide clinical advantages if delivered in aerosol form.

Aerosol therapy has been a form of drug delivery since the 19th century, when the use of medicated inhalations was considered a form of quackery.1 Much of it was, and individuals of that time would be surprised at the importance of this form of drug delivery today. An aerosol is a suspension of fine solid or liquid particles in gas, but this is a simple definition of a more complex process. Aerosol delivery of a pharmaceutical agent is designed to promote a systemic or direct clinical effect. Many issues must be evaluated in determining the usefulness of this mode of delivery in promoting a pharmacological response. These include stability of the pharmacological agent in an aerosol form, including the agent’s pharmacokinetic and pharmacodynamic properties; the delivery system for the agent; the particle size of the aerosol; and the patient’s ventilatory pattern and disease state. Studies in progress are investigating other agents that may provide clinical advantages if delivered in aerosol form.

Aerosol Therapy

Aerosol delivery of pharmacological agents to the lungs is designed to promote a direct clinical effect while producing a minimal adverse-effect profile. The administration of medications to the respiratory tract via aerosol is of proven efficacy. Several problems, however, can prevent this delivery method from succeeding with some pharmaceutical agents. The primary considerations, in this regard, are:

  • the accuracy and reproducibility of the inhaled dose,
  • the small amount of drug inhaled in relation to the dose placed in the aerosol delivery system,
  • the fear of allergic reactions within the respiratory system, and
  • the variability of drug transport into the systemic circulation.2 For an aerosol delivery system to be considered a major therapeutic success, the advantages and disadvantages of the delivery system must be addressed.

Basically, there are four types of delivery systems for drug aerosolization: metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), MDIs with spacers or holding chambers, and nebulizers (small volume nebulizers, large volume nebulizers, and ultrasounds). Each device provides advantages based on pharmacological or patient-based parameters. While MDIs are considered to be patient friendly, they have disadvantages, such as poor patient coordination of inspiration with device activation and variable degrees of oropharyngeal deposition of the drug. DPIs have been devised, but there are difficulties in handling and metering fine particles.3 Other concerns involve the removal of chlorofluorocarbons (CFCs) from pressurized asthma preparations because of their effect on the ozone layer. Antiasthma drugs are considered essential, and, at this moment, CFCs containing MDIs for commercial use have been banned since January 1996. Complete phaseout of CFCs for medical inhalers is targeted for 2005. The replacement of CFCs 11, 12, and 114 with agents such as tetrafluorethane and heptafluoropropane may prove difficult because of the physical-chemical properties of both agents 4; thus, other systems (such as precompression pumps or devices that can deliver medication in its pure form) would be ideal.

Nebulizers have also been shown to have limitations. A study has shown that only 1 percent to 10 percent of a drug placed in a nebulizer is delivered to the patient 2; this may be due to the great variability in drug delivery among devices and to patient-specific breathing patterns. Many assumptions were made in the past in predicting the effects of gravimetric changes, solute concentrations, and temperature fluctuations on nebulizer drug delivery. 1,5

A term that has received much attention in the delivery of pharmaceutical agents is inhaled mass. Hess et al 6 have determined that this term represents the mass of drug delivered to the patient (the end point of drug delivery) by an aerosol. This term is very useful because it avoids the assumptions of the past in predicting drug-delivery rates; it also takes into account the influence of the patient’s breathing pattern. Future studies of inhaled mass may provide better assessment of nebulizers and of quality control for such devices.

Future Agents-Antibiotics
Aerosol administration of antibiotics may provide an alternative for the treatment of patients with pulmonary infections because it permits direct, topical application of the agent to the target site of infection. Agents such as beta-lactams, polymyxins, and aminoglycosides have been shown to confer clinical benefits when administered by inhalation to cystic fibrosis patients.7

The aminoglycosides are a class of agents that has received much attention. Aminoglycosides are bactericidal antibiotics, used primarily in the treatment of gram-negative infections, that bind irreversibly to the 30S subunit of bacterial ribosomes, causing a misreading of the genetic code that leads to separation of the ribosome from messenger RNA and, as a result, cell death.

Aminoglycosides are primarily delivered intravenously; their killing mechanism is concentration dependent, and their administration is monitored using the analysis of serum levels (which may include a peak concentration after the intravenous dose is administered and trough concentration before the next dose is delivered). Peak concentrations reflect efficacy and trough concentrations reflect accumulation or toxicity. Each agent (amikacin, gentamicin, kanamycin, netilmicin, streptomycin, and tobramycin) has its own specific concentration levels for efficacy and toxicity, which is primarily seen as nephrotoxicity and/or ototoxicity.

A new formulation of tobramycin solution for inhalation has been found safe and effective for use in cystic fibrosis patients with Pseudomonas aeruginosa infections.8 Aminoglycosides traditionally provide poor penetration into pulmonary secretions, and higher peak concentrations are usually needed to maximize their clinical effect. Topical pulmonary administration by aerosolization would provide direct application to the site of action, improving clinical efficacy while minimizing ototoxicity and nephrotoxicity.

Heparin is traditionally used as an anticoagulant for the prophylaxis and treatment of venous thrombosis; it has also been shown to prevent the bronchoconstriction response in subjects with exercise-induced asthma (EIA). In addition, it has been shown to inhibit histamine release mediated by immunoglobulin E in isolated mast cells. Garrigo et al 9 compared the antiasthma activity of inhaled heparin in exercise-induced asthma with that of cromolyn sodium. Heparin inhibited the bronchoconstriction response to exercise 58 percent, 78 percent, and 67 percent (P <.05) when nebulized 15 minutes, 1 hour, and 3 hours before exercise, respectively, and cromolyn attenuated the response with equally efficacy (P<0.05). These data demonstrated that inhaled heparin prevents exercise-induced asthma for up to 3 hours and is as effective as cromolyn. Since data are limited on the use of aerosolized heparin, these data do support the need for further randomized, controlled studies to determine whether this agent has a role in preventing exercise-induced asthma.

Budesonide is a intranasal glucocorticoid or steroid used in the management of symptoms of seasonal or perennial allergic rhinitis. The mechanism responsible for the anti-inflammatory action of this agent is unknown. It has, however, a wide range of inhibiting activities on multiple cell types (mast cells, eosinophils, and lymphocytes) and mediators (histamine, cytokines, and leukotrienes) involved in allergic and nonallergic inflammation. This class of agents has been used in other pulmonary disorders associated with inflammation, including asthma and croup. Nebulized budesonide has been shown to control asthma symptoms while eliminating the need for oral corticosteroids, 10 to reduce the symptoms of acute bronchiolitis or prevent postbronchiolitis wheezing, 11 and to decrease the rate of hospitalization for children with croup. 12

These studies involved different clinical end points and results, based upon study objectives. Nebulized budesonide is expected to receive Food and Drug Administration approval as a nebulized solution during 1999.

Cyclosporine is a cyclic polypeptide immunosuppressant traditionally indicated for prophylaxis against organ rejection in kidney, liver, lung, and heart transplantation. The agent is administered via oral or intravenous routes, and its blood concentration is monitored as an indication of its efficacy or toxicity. Its exact mechanism of action is unknown, but is related to its ability to inhibit the T-lymphocytes that are considered mediators of organ rejection and chronic inflammation.

Based upon its proposed effects, cyclosporine has been used in various clinical trials in an aerosol form, both as rescue therapy for refractory acute rejection in lung-transplantation patients who were unresponsive to conventional therapy and as an experimental treatment for asthma. Studies of its use as an aerosol in patients who have undergone lung transplantation found an improvement in pulmonary function parameters 13 and the histologic resolution of rejection within 3 months of the initiation of therapy. 14

Cyclosporine has also been shown to decrease symptoms and to allow a steroid-sparing effect in asthma patients. 15 Based upon its effects on refractory pulmonary rejection and its suppression of proinflammatory mediators, cyclosporine may have a high potential for delivery as an aerosol. Early clinical results are promising, but larger, randomized, multicenter trials are needed before cyclosporine can be considered an effective treatment for refractory acute rejection in lung-transplantation patients or a primary or adjunctive treatment in patients with asthma.

A problem seen in insulin users involves patient compliance with the need for frequent subcutaneous injections. In response, a new device has been designed to deliver a pharmacological agent as a powder. The powder is sealed in blister packs that are inserted into an inhaler approximately 6 inches long. Pumping the device forces air into the chamber, breaking open the powder pack. As the patient inhales deeply, the drug is delivered; then, a second volume of air forces the remainder of the drug into the lungs.

Although the inhaler’s manufacturer is developing agents for osteoporosis and a1-antitrypsin deficiency, insulin for inhalation will probably be the first preparation of this type to reach the marketplace. Inhaling insulin is not as efficient as injecting it, but preliminary results are extremely promising. 16,17

Other Agents
Other pharmacological agents that have been investigated in preliminary studies of administration by aerosolization include amphotericin B, morphine, prostacyclin, amiloride, and interferon-g. 18-20 Many studies have been performed using human and animal subjects, and preliminary findings show that some of these agents seem promising for future human application (because of a better understanding of aerosol dynamics and of the physical and chemical properties of pharmaceutical agents). The aerosol route may, indeed, provide a better alternative for patients due to its ease of medication delivery, its lower adverse-effect profile and, possibly, its ability to improve medication compliance.

Role of the RCP
Advances in technology in both the application of respiratory care and the development of aerosol drug delivery will expand the present role of the RCP. The future practitioner will need a thorough understanding of newer pharmaceutical agents-including their mechanisms of action, doses, frequencies of administration, adverse effects, and drug-drug and drug-disease interactions-to improve the delivery of pharmaceutical care. The need to know these specifics for only the handful of agents traditionally administered by the RCP (b-agonists, mucolytics, mast-cell stabilizers, corticosteroids, and anticholinergics) may expand to include opioids, a-1 proteinase inhibitors, insulin, antibiotics, antifungals, growth hormone, and immunosuppressive agents.

Changes in the biotechnology of drug delivery are inevitable, and it is the role of each RCP to improve his or her knowledge of new pharmaceutical agents and expand it over the years to come.

Michael J. Cawley, PharmD, RPh, RRT, CPFT, is assistant professor of clinical pharmacy at the Philadelphia College of Pharmacy/University of the Sciences in Philadelphia and clinical pharmacist at the Nathan Speare Regional Burn Treatment Center, Crozer Chester Medical Center, Upland, Pa.

1. Anderson PJ. Respiratory drug delivery. Chest. 1997;111:1155-1156.
2. Kohler D. Aerosols for systemic treatment. Lung. 1990;168(suppl):677-684.
3. Ganderton D. General factors influencing drug delivery to the lung. Respir Med. 1997;91(suppl A):13-16.
4. Ajache JM. Problems raised by the reformulation of inhalers after the removal of chlorofluorocarbon (CFC) propellants [in French]. Ann Pharm Fr. 1997;55:62-68.
5. Smaldone GC. Aerosolized drug delivery in the 90s. Chest. 1996;110:316-317.
6. Hess D, Fisher D, Williams P, Pooler S, Kacmarek RM. Medication nebulizer performance. Effects of diluent volume, nebulizer flow and nebulizer brand. Chest. 1996;110:498-505.
7. Smith Al, Ramsey B. Aerosol administration of antibiotics. Respiration. 1995;62(suppl 1):19-24.
8. Prescribing information: TOBI, Tobramycin Solution for Inhalation. Seattle, Wash: PathoGenesis Corp; 1997.
9. Garrigo J, Danta I, Ahmed T. Time course of the protective effect of inhaled heparin on exercise-induced asthma. Am J Respir Crit Care Med. 1996;153:1702-1707.
10. Oyulana BA, Varma N, Bullock A, Higenbottam T. High dose nebulized steroid in the treatment of chronic steroid-dependant asthma. Respir Med. 1992;86:105-108.
11. Richter H, Seddon P. Early nebulized budesonide in the treatment of bronchiolitis and the prevention of postbronchiolitic wheezing. J Pediatr. 1998;132:849-853.
12. Johnson DW, Jacobson S, Edney P, Hadfield P, Mundy M, Schuh S. A comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup. N Engl J Med. 1998;339:498-503.
12. Iacono AT, Smaldone GC, Keenan RJ, et al. Dose-related reversal of acute lung rejection by aerosolized cyclosporine. Am J Respir Crit Care Med. 1997;155:1690-1698.
13. Keenan RJ, Zeevi A, Iacono AT, et al. Efficacy of inhaled cyclosporine in lung transplant recipients with refractory rejection: correlation of intragraft cytokine gene expression with pulmonary function and histologic characteristics. Surgery. 1995;118:385-391.
14. Floreani AA, Rennard SI. Experimental treatments for asthma. Curr Opin Pulm Med. 1997;3:30-341.
15. BusinessWeek ONLINE. Available at: Accessed February, 1998.
16. BusinessWeek ONLINE. Available at: Accessed September, 1998.
16. Dubois J, Bartter T, Gryn J, Pratter M. The physiologic effects of inhaled amphotericin B. Chest. 1995;108:750-753.
17. Watson NW, Taylor KM, Joel SP, Slevin Ml, Eden OB. A pharmacokinetic study of sublingual aerosolized morphine in healthy volunteers. J Pharm Pharmacol. 1996;48:1256-1259.
18. Olschewski H, Walmrath D, Schermuly R, Ghofrani AH, Grimminger F, Seeger W. Aerosolized prostacyclin and Iloprost in severe pulmonary hypertension. Ann Intern Med. 1996;124:820-824.
19. Everard ML, Devadason SG, Sunderland VB, LeSouef PN. An alternative aerosol delivery system for amiloride. Thorax. 1995;50:517-519.
20. Condos R, Rom W, Schluger NW. Treatment of multidrug-resistant pulmonary tuberculosis with interferon-gamma via aerosol. Lancet. 1997;349:1513-1515.