2004 Philip Kittredge Memorial Lecture
`
`The Inhalation of Drugs: Advantages and Problems
`
`Joseph L Rau PhD RRT FAARC
`
`Inhalation is a very old method of drug delivery, and in the 20th century it became a mainstay of
`respiratory care, known as aerosol therapy. Use of inhaled epinephrine for relief of asthma was
`reported as early as 1929, in England. An early version of a dry powder inhaler (DPI) was the
`Aerohalor, used to administer penicillin dust to treat respiratory infections. In the 1950s, the
`Wright nebulizer was the precursor of the modern hand-held jet-venturi nebulizer. In 1956, the first
`metered-dose inhaler (MDI) was approved for clinical use, followed by the SpinHaler DPI for
`cromolyn sodium in 1971. The scientific basis for aerosol therapy developed relatively late, follow-
`ing the 1974 Sugarloaf Conference on the scientific basis of respiratory therapy. Early data on the
`drug-delivery efficiency of the common aerosol delivery devices (MDI, DPI, and nebulizer) showed
`lung deposition of approximately 10 –15% of the total, nominal dose. Despite problems with low
`lung deposition with all of the early devices, evidence accumulated that supported the advantages
`of the inhalation route over other drug-administration routes. Inhaled drugs are localized to the
`target organ, which generally allows for a lower dose than is necessary with systemic delivery (oral
`or injection), and thus fewer and less severe adverse effects. The 3 types of aerosol device (MDI,
`DPI, and nebulizer) can be clinically equivalent. It may be necessary to increase the number of MDI
`puffs to achieve results equivalent to the larger nominal dose from a nebulizer. Design and lung-
`deposition improvement of MDIs, DPIs, and nebulizers are exemplified by the new hydrofluoroal-
`kane-propelled MDI formulation of beclomethasone, the metered-dose liquid-spray Respimat, and
`the DPI system of the Spiros. Differences among aerosol delivery devices create challenges to patient
`use and caregiver instruction. Potential improvements in aerosol delivery include better standard-
`ization of function and patient use, greater reliability, and reduction of drug loss. Key words:
`aerosol, metered-dose inhaler, dry powder inhaler, nebulizer, MDI, DPI.
`[Respir Care 2005;50(3):367–
`382. © 2005 Daedalus Enterprises]
`
`Introduction: The Inhalation of Drugs for
`Respiratory Disease
`
`The use of inhaled and aerosolized medications for treat-
`ment of diseases of the respiratory tract has a long history
`in medical therapy. Inhalation therapy for asthma and other
`
`Joseph L Rau PhD RRT FAARC is Professor Emeritus, Department of
`Cardiopulmonary Care Sciences, Georgia State University, Atlanta, Geor-
`gia.
`
`This article is based on a transcript of the 20th Annual Philip Kittredge
`Memorial Lecture delivered by Joseph L Rau PhD RRT FAARC at the
`50th International Respiratory Care Congress, in New Orleans, Louisi-
`ana, on December 6, 2004.
`
`Correspondence: Joseph L Rau PhD RRT FAARC, 2734 Livsey Trail,
`Tucker GA 30084. E-mail: joerau@comcast.net.
`
`complaints had a traditional place in Ayurvedic medicine,
`whose origins date back 4,000 years.1 In 17th-century
`Ayurvedic literature there are instructions for smoking an
`anticholinergic preparation from the Datura group of herbs
`for asthma or cough with dyspnea.1 Inhaled Datura for
`asthma was recorded in 1802 in Britain, and in 1797 a
`Philadelphia physician, Samuel Cooper, experimented with
`Datura stramonium preparations.1 Asthma cigarettes (Fig.
`1) (which contained stramonium leaves and had atropine-
`like effects), along with powders and cigars, were widely
`used in the 19th century as “fuming asthma remedies.”1,2
`Medications have also been added to boiling water to al-
`low inhalation.
`Muers reports that the word “nebuliser” was defined in
`1874 as “an instrument for converting a liquid into a fine
`spray, especially for medical purposes.”3 Seeger’s fire-
`powered steam nebulizer was advertised in Geo. Tiemann
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`IPR2021-00406
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`THE INHALATION OF DRUGS: ADVANTAGES AND PROBLEMS
`
`Fig. 1. Methods of inhaling formulations of stramonium, an atropine-like compound with anticholinergic effects, used in the 19th century.
`
`and Co’s Surgical Instruments Catalogue in New York in
`1876.3 After the turn of the 20th century, newly discovered
`and isolated preparations of epinephrine and ephedrine
`began to supplant use of atropine-like substances such as
`stramonium.1
`
`Origins of Modern Aerosol Therapy
`
`In 1929, in England, Camps evaluated and recommended
`use of epinephrine via inhalation, and described “spraying
`it into the tracheobronchial tract.”4 In a 1948 publication,
`Benson and Perlman described the “spray method for ad-
`ministering epinephrine” as originating “with certain rel-
`atively obscure individuals in the Pacific Northwest” of
`the United States.5 They state that these individuals “ap-
`pear not to have contributed to the regular medical jour-
`nals, but have formed companies to produce a racemic
`brand of epinephrine and a fine nebulizer for administra-
`tion.”
`Benson and Perlman5 kept a record of 2,236 asthma
`patients in their practice, and reported that 48 of 648 users
`of oral spray epinephrine were fatalities (7.4%), while only
`22 of 1,588 non-users were fatalities (1.4%). Although not
`acknowledged by those authors, their results were early
`evidence that inhaled ␤ agonists alone will not control the
`sometimes fatal pulmonary inflammation of asthma. Their
`work presaged the subsequent debate over the potentially
`harmful effects of inhaled ␤
`2 agonists in asthma almost 50
`years later.6 The kit sold for inhaling epinephrine con-
`sisted of a bottle of 1:50 solution of racemic epinephrine
`and an all-glass nebulizer, which in all likelihood was the
`DeVilbiss No. 40 glass nebulizer (Fig. 2A), introduced for
`treatment of asthma in the 1930s.3,5
`The first real precursor to the modern T-piece plastic
`hand-held pneumatic nebulizer was the 1950s Wright neb-
`
`Fig. 2. A: The DeVilbiss No. 40 glass squeeze-bulb nebulizer. B:
`The Wright jet-venturi nebulizer, introduced in the late 1950s.
`
`ulizer (see Fig. 2B), made of Perspex, a shatter-resistant
`plastic used for fighter-plane canopies.3 This device used
`a combination of gas flow, precise venturi orifices, and
`baffles to produce aerosol particles more in the fine par-
`ticle range of 1–5 ␮m. The earlier DeVilbiss glass nebu-
`lizer and hand-bulb atomizers generated a wide range of
`particle sizes, and many of the particles were too large to
`reach the lower airways.3
`In 1944, Bryson et al published work on the introduc-
`tion of nebulized penicillin for treatment of respiratory
`infection.7 They described a mist formed by oxygen or air
`forced through aqueous solutions of the drug. Shortly there-
`after, in 1949, Krasno and Rhoads described the inhalation
`of penicillin dust for management of respiratory infec-
`tions, particularly sinusitis.8 Their inhalation device, known
`as the Aerohalor (Fig. 3), was produced by Abbott Labo-
`ratories. This was actually the first dry powder inhaler
`(DPI), and it used small cartridges of powdered penicillin
`
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`
`Fig. 3. The Aerohalor was an early dry powder inhaler, reported by
`Krasno and Rhoads,8 used for inhalation of penicillin dust to treat
`respiratory infections. (From Reference 2, with permission.)
`
`that fit into a rather modern-appearing clear plastic inhal-
`er.2,8 The advantages of aerosol drug delivery noted by
`Krasno and Rhoads remain those seen with aerosol ther-
`apy today: simplicity, low cost, little need for manipula-
`tion or instruction, no pain of injection, sustained localized
`action, and less local irritation than liquid nebulized pen-
`icillin.8
`
`Development of Modern Aerosol Delivery Devices
`
`One of the most interesting stories of drug-device im-
`plementation is the origin of the metered-dose inhaler
`(MDI), as described by Charles G Thiel.9 Thiel worked for
`Riker Laboratories, a subsidiary of Rexall Drugs and the
`company that developed the MDI. In 1955, Susie, a 13-
`year-old asthmatic, struggled with her squeeze-bulb neb-
`ulizer, and asked her father why she couldn’t get her in-
`haled medicine from a spray can, in the way in which
`hairspray is packaged. Susie was the daughter of George
`Maison, then President of Riker Laboratories. Apparently
`her father had also been frustrated with the fragile, easily
`breakable glass-bulb nebulizers. In the spring of 1955, a
`propellant (“FREON,” a trademark name for a certain mix-
`ture of chlorofluorocarbons 12 and 114), a metering valve,
`a glass vial device, and drug formulations of isoproterenol
`and epinephrine were investigated and assembled. In June
`of 1955, a clinical trial was conducted at the Long Beach,
`California, Veterans Administration Hospital by a Dr Karr.
`
`Fig. 4. The Medihaler-Epi was the original metered-dose inhaler for
`epinephrine. (From Reference 9, with permission.)
`
`The New Drug Application was filed on January 12, 1956,
`and consisted of a file only 13 mm thick— unheard of in
`today’s new-drug-submission-and-testing system. The
`drug-delivery device was approved by the Food and Drug
`Administration on March 9, 1956, and the Medihaler-Iso
`and the Medihaler-Epi were launched later that month. It
`is even more interesting that the original MDI of Medi-
`haler-Epi (Fig. 4) differs very little from the appearance
`and even function of current MDI devices. Following the
`release of the MDI, a DPI (the SpinHaler) for delivery of
`the anti-asthmatic drug cromolyn sodium was developed
`and approved. The article by Bell et al,10 describing and
`evaluating the SpinHaler, gave the following rationale for
`the new device:
`
`It is not generally realized that, with the pressurized
`aerosol. . . the administration of medication requires
`coordination of activation with the inspiratory cycle
`of respiration if variation in the quantity and site of
`drug deposition in the airways is to be minimized.10
`
`Bell et al10 noted a primary problem for optimal use of
`MDIs, namely, the difficulty for patients in activating the
`MDI while simultaneously beginning a slow deep inhala-
`tion. Because it was a breath-actuated device, the Spin-
`Haler relied on the force of a patient’s inspiratory flow to
`spin a small plastic propeller, thereby creating turbulent
`airflow through the device, and disaggregating drug pow-
`der from its carrier lactose particles (Fig. 5),11 which cre-
`ated a fine powder suitable for penetration to the lower
`airways. The SpinHaler was breath-actuated, so it elimi-
`nated the need to coordinate device actuation with patient
`inhalation (which is critical to effective MDI use).
`The problem of coordinating inhalation with MDI-ac-
`tuation, along with the high loss of drug in the oropharynx,
`which contributes to systemic adverse effects, ultimately
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`
`Fig. 5. The SpinHaler, a dry powder inhaler to deliver cromolyn sodium, reported in 1971 by Bell et al.10 (Based on data from Reference 11.)
`
`led to the development of spacer devices (add-on tubes
`with no valves) and holding chambers (extension tubes
`with 1-way inspiratory valves to contain the aerosol). This
`distinction in terminology between “spacer” and “holding
`chamber” is based on a presentation of Dr Myrna Dolo-
`vich at the Drug Information Association meeting on spacer
`devices in 1995.12
`In 1976, an early breath-actuated MDI system was de-
`veloped to simplify the coordination of actuation and in-
`halation, but the device required almost 50 L/min of in-
`spiratory airflow to operate.13 In 1978, Folke More´n
`investigated the effect of spacer tube design on delivery of
`pressurized MDI aerosols.14 Newman et al had also noted
`that a high proportion of the fast-moving and larger MDI
`aerosol particles deposit in the orophyarynx, not in the
`lungs.15 In 1981, Newman et al examined the deposition of
`MDI aerosol, using small (10-cm long) and large (750-
`mL) “extension” devices.16 Their results showed unchanged
`alveolar deposition, but initial oropharyngeal deposition
`was reduced from 82% with the MDI alone to 57% with
`the large-volume pear-shaped spacer.
`In 1982, at the conference of the American Association
`for Respiratory Care, held in New Orleans, Louisiana, Dr
`Martin Tobin graphically described the lack of patient co-
`ordination in using MDIs, and introduced the InspirEase
`drug delivery system for MDIs (Fig. 6).17 The advantages
`of this spacer device were its relatively small size, col-
`lapsibility, the presence of an airflow signal to warn of too
`high an inspiratory flow, the separation of MDI-actuation
`from inspiration, and reduced oropharyngeal drug loss.
`The disadvantages were cost of an additional device to use
`an MDI, and the need to assemble the device. In fact, the
`original version required 2 different mouthpieces with MDI
`nozzle receptacles, to match different MDI drug canisters.
`
`Fig. 6. The InspirEase, an early spacer system to facilitate use of
`metered-dose inhalers and reduce oropharyngeal aerosol depo-
`sition.
`
`Subsequently in 1983, Dolovich et al reported the clin-
`ical evaluation of a simple “demand inhalation MDI aero-
`sol delivery system,” which was the early version of the
`AeroChamber from Monaghan Medical Corporation.18 This
`was a true holding chamber; that is, the chamber contained
`a 1-way inspiratory valve, so that aerosol was released
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`Table 1.
`
`Recommended Aerosol Studies, Listed in Order of Priority,
`From the 1974 Sugarloaf Conference on the Scientific
`Basis of Respiratory Therapy
`
`1. Determine regional deposition of nonhygroscopic stable aerosols, in
`both normal subjects and in patients with COPD
`2. Determine the effect of water vapor in patients with COPD
`3. Determine the physicochemical properties of bronchial secretions
`4. Conduct studies on bronchodilators
`5. Conduct studies on corticosteroids
`
`COPD ⫽ chronic obstructive pulmonary disease
`
`only when the patient inhaled from the chamber. Throat
`deposition (as measured with an aerosol radiolabeled with
`technetium) was reduced from 65% with the MDI alone to
`6.5% with the AeroChamber, in bronchitic subjects. The
`AeroChamber, a 145-mL cylinder, incorporated a rubber-
`ized opening into which fit the MDI’s mouthpiece actuator
`(or “boot”) regardless of MDI actuator shape. There was
`no need for different nozzle receptacles to accommodate
`different MDI drug nozzles. A vibrating reed warned users
`of excessive inspiratory airflow.
`
`The Need for Scientific Evidence
`With Inhaled Drug Delivery
`
`In the early 1970s there was little scientific or clinical
`evidence on the increasingly widespread and popular use
`of inhaled aerosols, especially with nebulization of a va-
`riety of agents. On May 2– 4, 1974, a landmark conference
`was held in Philadelphia, Pennsylvania, examining the sci-
`entific basis of respiratory therapy. The conference came
`to be called the “Sugarloaf Conference,” because of the
`site where it was held, and its proceedings were published
`in the December 1974 supplement of American Review of
`Respiratory Disease. The final report on aerosol therapy
`noted that there was a need for mathematical models of
`pulmonary distribution of aerosols, “with actual studies of
`deposition using various breathing patterns.”19 The report
`called for studies with both normal subjects and patients
`with chronic obstructive pulmonary disease. There was a
`call to determine “output characteristics of aerosol-pro-
`ducing devices,” including mass median diameter and dose
`delivered. Table 1 lists the recommended studies, in order
`of priority.
`The 1974 Sugarloaf Conference was followed 5 years
`later by the 1979 Conference on the Scientific Basis of
`In-Hospital Respiratory Therapy. The final report on aero-
`sol and humidity therapy again noted problems, including:
`difficulty in estimating or measuring the dose of a drug
`given via aerosol; lack of adequate information on parti-
`cle-size distributions produced by aerosol generators and
`nebulizers; failure of different nebulizers to provide a re-
`
`Fig. 7. Anterior scintigram showing distribution of radiolabeled aero-
`sol in the respiratory tract and stomach. The aerosol was delivered
`by an intermittent positive-pressure breathing device with a jet
`nebulizer. The lung deposition was 7.7%. (From Reference 21,
`with permission.)
`
`producible dose; patients’ difficulty with MDIs in releas-
`ing the proper dose at the correct time; and the possibility
`that aerosol generators and nebulizers can be contaminated
`and act as sources of nosocomial infection.20
`
`Early Data on Modern Aerosol Devices
`
`Even before the 1974 Sugarloaf Conference, there were
`studies that began to provide scientific data and raise crit-
`ical questions about aerosol therapies. In 1973, Irwin Zi-
`ment published an article in RESPIRATORY CARE, entitled
`“Why Are They Saying Bad Things About IPPB?” [inter-
`mittent positive-pressure breathing] He offered his own
`unpublished data that with IPPB only 7.7% of radiolabeled
`saline was deposited in the lungs of a normal volunteer
`(Fig. 7).21 Although Ziment was concerned more with IPPB
`therapy than nebulizer therapy in that article, his data sup-
`ported the trend calling for quantitative scientific measure-
`ment of aerosol therapy, which was seen in the Sugarloaf
`Conference the following year.
`Further scientific evidence on aerosol therapy began to
`accumulate in the literature after the 1980 publication of
`the proceedings of the second conference on respiratory
`therapy. Stephen Newman et al published their classic and
`oft-referenced study on the disposition of aerosol drug
`from a pressurized MDI.15 Their measurement of 8.8%
`lung-deposition of the total MDI dose was similar to Zi-
`ment’s data from 1973 for IPPB/nebulizer delivery. In the
`study by Newman et al, 80% of MDI drug was lost to the
`oropharynx, and 9.8% was retained in the MDI mouth-
`piece-actuator (Fig. 8). These early studies began to alert
`clinicians to the relative inefficiency of aerosol delivery
`devices.
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`THE INHALATION OF DRUGS: ADVANTAGES AND PROBLEMS
`
`Fig. 8. Distribution of radiolabeled aerosol in the human respiratory
`tract, delivered via metered-dose inhaler with no add-on or spacer
`device. (Based on data from Reference 15.)
`
`The study I mentioned above, by Dolovich et al,18 con-
`cerning the early AeroChamber, showed that the large
`throat loss of drug from an MDI was reduced 10-fold with
`use of a valved holding chamber (Fig. 9). However, lung
`deposition was almost identical for the MDI alone (8.7%)
`versus the MDI with holding chamber (9.0%).18 An often
`overlooked aspect of that study is the improvement in
`peripheral lung deposition and the more uniform lung dep-
`osition with use of the holding chamber by the normal
`subjects, although this was not seen with the chronic bron-
`chitis subjects. Newman et al dramatically showed the
`transposition of aerosol loss in the throat using the MDI
`alone (⬎ 80%) with loss in the chamber using a spacer
`device (approximately 76%), based on ventilation scans
`using radiolabeled aerosol (Fig. 10).22 That study also noted
`that good technique with the MDI delivered 11.2% of the
`total dose to the lungs, and use of a spacer device in-
`creased this to 14.8%, which was a statistically significant
`difference, but may not be clinically important. Their data
`indicated that the spacer increased lung deposition for pa-
`tients with poor MDI technique.
`Data also became available that indicated that lung dep-
`osition with a nebulizer was roughly the same as that with
`an MDI. The classic study by Lewis and Fleming exam-
`ined the disposition of radiolabeled albumin in saline, in
`volunteers using an Inspiron Mini-Neb, and found that
`12% of the total dose reached the lungs (Fig. 11).23 This
`was not very different from the 9% lung-deposition that
`Newman et al had found with an MDI.15 In their study,
`Lewis and Fleming contrasted the disposition of the total
`aerosol dose using the nebulizer with the MDI data from
`Newman et al. Although lung deposition was approxi-
`mately the same with the 2 types of aerosol device, the
`largest loss of aerosol drug with the MDI was in the oro-
`pharynx (80%), whereas with the nebulizer, 66% of the
`
`Fig. 9. Difference in throat deposition of drug from a metered-dose
`inhaler (MDI) with and without a breath-actuated valved holding
`chamber (AeroChamber). (Based on data from Reference 18. Pho-
`tograph courtesy of Monaghan Medical.)
`
`loss was in the device itself. A relatively large percentage
`(20%) of the aerosol was lost to the ambient air, which is
`not surprising, given the nebulizer’s open-T-shape design
`and constant output of aerosol.
`In a more recent study, published in 1994, Newman et
`al measured total drug disposition with a DPI, the Spin-
`Haler.24 Lung deposition was 13% when volunteers
`achieved an inspiratory flow of 120 L/min (Fig. 12). Not
`surprisingly, since the DPI is “powered” by inspiratory
`flow, a lower flow rate of 60 L/min resulted in a lung
`deposition of only 6%—less than half of that with the
`higher flow rate.
`Figure 13 combines data from these well-done, land-
`mark studies into one graph that shows the disposition of
`aerosol drug with MDI, MDI-with-spacer, small-volume
`nebulizer (SVN), and DPI (SpinHaler). Figure 13 shows
`that these studies indicate lung deposition in the 10 –15%
`range for all the aerosol device types, although oropha-
`ryngeal loss, device loss, and exhalation loss differ mark-
`edly among the devices. The data clearly show that among
`these devices there was no important difference in effi-
`
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`Fig. 10. Patterns of radioaerosol distribution from a metered-dose inhaler alone (left) and a metered-dose inhaler with the InspirEase spacer
`(right). A ⫽ actuator. O ⫽ oropharynx. L ⫽ lungs. S ⫽ stomach. I ⫽ InspirEase. (From Reference 22, with permission.)
`
`Fig. 11. Left: Schematic of a generic constant-output jet nebulizer.
`Right: Drug disposition with the Inspiron Mini-Neb, measured with
`radiolabeled albumin suspended in saline. O-P ⫽ oropharyngeal.
`(Based on data from Reference 23.)
`
`ciency—if efficiency is interpreted as the percentage of
`total dose that reaches the lung.
`
`Advantages to Administering Drugs as Aerosols
`
`Given the problems with patient use of different aerosol
`devices and the relatively low fraction of total dose that
`reaches the lungs, critics could certainly argue against the
`use of inhaled aerosol drug therapy. It is unquestionably
`faster and possibly simpler to take a pill than to use an
`MDI, a nebulizer, or a DPI. Nonetheless, there are advan-
`
`Fig. 12. Drug disposition of cromolyn sodium from the SpinHaler
`at inspiratory flows of 60 L/min and 120 L/min. (Based on data
`from Reference 24.)
`
`tages to aerosol inhalation for treating airways diseases
`(Table 2). Inhaled aerosol therapy allows placing the drug
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`Fig. 13. Summary of drug disposition from the major types of
`aerosol delivery devices in clinical use. MDI ⫽ metered-dose in-
`haler. SVN ⫽ small-volume nebulizer. DPI ⫽ dry powder inhaler.
`(Data from multiple studies: MDI alone - Reference 15; MDI with
`spacer device - Reference 22; SVN - Reference 23; DPI - Refer-
`ence 24.)
`
`Table 2. Advantages of the Inhalation Route of Administration With
`Aerosolized Drugs in Treating Pulmonary Diseases
`
`Aerosol doses are generally smaller than systemic doses. For example,
`the oral dose of albuterol is 2–4 mg, whereas the inhaled dose is 0.2
`mg (via MDI) to 2.5 mg (via SVN).
`Onset of effect is faster with inhalation than with oral administration.
`For example, the onset of effect with oral albuterol is about 30 min,
`whereas inhaled albuterol takes effect within about 5 min.
`The drug is delivered directly to the target organ (lung), with
`minimized systemic exposure.
`Systemic adverse effects are less severe and less frequent with
`inhalation than with systemic drug delivery (injection or oral) (eg,
`less muscle tremor and tachycardia with ␤
`2-agonists; less
`hypothalamic-pituitary-adrenal suppression with corticosteroids).
`Inhaled drug therapy is painless and relatively comfortable.
`
`MDI ⫽ metered-dose inhaler
`SVN ⫽ small-volume nebulizer
`COPD ⫽ chronic obstructive pulmonary disease
`
`directly in the target organ, which reduces systemic expo-
`sure. This advantage is lost with the oral or parenteral
`(injection) route.
`Dulfano and Glass examined the effect of terbutaline on
`pulmonary function with the subcutaneous route, the oral
`route (tablets), and the aerosol route.25 The quickest and
`largest response in forced expiratory volume in the first
`second (FEV1) was with the inhaled route, followed by the
`subcutaneous route (Fig. 14). The slowest onset and small-
`est effect was seen with the oral route. In fact, a larger
`change in FEV1 occurred with 0.75 mg of inhaled terbutal-
`ine than with a 5.0-mg oral dose.
`Grimwood et al found similar results. Both nebulized
`and inhaled-powder preparations of albuterol caused larger
`improvements in peak expiratory flow than did oral albu-
`terol tablets.26 In that study, the nominal (starting) dose of
`albuterol via nebulizer and via oral tablet was 4 mg, whereas
`the powder inhalation nominal dose (from a Rotahaler
`
`Fig. 14. Changes in forced expiratory volume in the first second
`(FEV1) with 3 different routes of administration for the bronchodi-
`lator terbutaline. Lower inhaled drug doses resulted in larger clin-
`ical response, measured by FEV1. The aerosol was from a me-
`tered-dose inhaler. (From Reference 25, with permission.)
`
`DPI) was only 400 ␮g— one tenth of the nebulizer or oral
`dose. The DPI had a stronger effect on peak expiratory
`flow than did the oral route, but the DPI’s effect was less
`than the nebulizer’s effect, almost certainly because of the
`lower DPI nominal dose. The DPI’s duration of action
`declined below that of the oral dose. Grimwood et al showed
`that different starting doses in aerosol devices can give
`different effects. If the 3 types of aerosol device studied
`(MDI, SVN, and DPI) are all equally efficient in deliver-
`ing 10 –15% of the nominal dose to the lungs, then it is the
`starting dose and not the type of device alone that can
`determine clinical response.
`Because the inhalation route puts the drug directly into
`the lung, there should be lower systemic drug levels and
`therefore less adverse effect. Thiringer and Svedmyr com-
`pared dose-response effects with terbutaline given intra-
`venously versus as an aerosol on lung function (FEV1),
`heart rate, blood pressure, and skeletal muscle tremor.27
`Table 3 shows that the cumulative highest dose of 0.34 mg
`terbutaline given via infusion resulted in greater adverse
`effects than did the cumulative 8.0-mg dose given via
`inhalation—a dose almost 24 times larger. All the differ-
`ences in adverse effects between the infused and inhaled
`routes were significant, except for muscle-tremor changes.
`
`Are Aerosol Devices Equivalent?
`
`Measurements of aerosol disposition with the different
`types of aerosol devices in use have shed light on com-
`parative performance. As seen previously in Figure 13, all
`of the aerosol devices in common use prior to the 1990s
`delivered around 10 –15% of the total starting dose to the
`lungs, so the MDI, MDI-with-spacer, SVN, and the DPI
`
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`THE INHALATION OF DRUGS: ADVANTAGES AND PROBLEMS
`
`Table 3.
`
`Comparison of Adverse Effects With Infused Versus
`Inhaled Terbutaline in Patients With Asthma*
`
`Heart rate (beats/min)
`Systolic blood pressure (mmHg)
`Diastolic blood pressure (mmHg)
`Tremor ratio†
`
`Infusion
`(0.34 mg)
`
`25 ⫾ 3
`8 ⫾ 6
`⫺17.1 ⫾ 1
`1.2 ⫾ 0.45
`
`Inhalation
`(8.0 mg)
`
`⫺0.7 ⫾ 2.2
`⫺4 ⫾ 4
`⫺3 ⫾ 1
`0.2 ⫾ 0.03
`
`*The changes listed are with the highest cumulative dose of terbutaline with each
`administration route.
`†The tremor ratio is the change over baseline. (Based on data in Reference 27)
`
`Table 4. Differences in Nominal (Starting) Doses Between MDI and
`Nebulizer Formulations for 4 Different Drugs
`
`MDI*
`
`Nebulizer
`
`Ratio
`(Nebulizer to MDI)
`
`Metaproterenol (mg)
`Albuterol (mg)
`Ipratropium (␮g)
`Cromolyn sodium (mg)
`
`1.3
`0.2
`40
`1.6
`
`15
`2.5
`500
`20
`
`11.5
`12.5
`12.5
`12.5
`
`*MDI (metered-dose inhaler) recommended dose
`MDI dose/actuation: metaproterenol 0.65 mg; albuterol 90 ␮g; ipratropium 18 ␮g; cromolyn
`sodium 800 ␮g
`
`are equally efficient. However, it is often overlooked that
`the starting, nominal dose in different types of device is
`not the same. Table 4 lists the nominal dose differences
`between MDIs and nebulizers for 4 different inhaled drugs.
`The nominal nebulizer dose is usually 11–12 times larger
`than the MDI dose. If MDIs and nebulizers both deliver
`10 –15% of the starting dose to the lung, then 11–12 times
`more drug reaches the lung with a nebulizer than with an
`MDI, all other factors being held constant, and assuming
`correct use of the devices. It is little wonder that anecdot-
`ally many clinicians have considered nebulizers more ef-
`fective than MDIs, especially in emergency use. However,
`Mestitz et al clearly showed that the lower-dose MDI can
`achieve as much clinical effect as the higher-dose nebu-
`lizer, by increasing the number of MDI puffs (Fig. 15).28
`In that study, 5 MDI puffs (1.25 mg) of terbutaline had the
`same FEV1 effect as a 2.5-mg nebulizer dose of terbutal-
`ine. Because the MDI nominal dose is usually lower than
`the corresponding nebulizer dose, it is often necessary to
`increase the number of MDI actuations to achieve clinical
`results equivalent to a nebulizer.
`Perhaps the clearest demonstration of the equivalence of
`MDIs, nebulizers, and DPIs was provided by Zainudin et
`al.29 Their study was unique in loading the same nominal
`dose of 400 ␮g of albuterol into an MDI, a nebulizer, and
`a DPI. As seen in Figure 16, the lung deposition was
`nearly identical among the 3 devices. The change in FEV1
`
`Fig. 15. Mean change in forced expiratory volume in the first sec-
`ond (FEV1) versus cumulative dose of terbutaline from a metered-
`dose inhaler (MDI) or from a jet nebulizer. More puffs from the MDI
`(250 ␮g per puff) were required to give equivalent responses to
`that from the larger 2.5-mg nebulizer dose. (From Reference 28,
`with permission.)
`
`Fig. 16. Lung deposition (white bars) and percent change in forced
`expiratory volume in the first second (FEV1, black bars) with me-
`tered-dose inhaler (MDI), dry powder inhaler (DPI), and small-vol-
`ume nebulizer (SVN), each using the same nominal dose of 400 ␮g
`of albuterol. (Based on data from Reference 29.)
`
`was somewhat higher for the MDI, and the authors attrib-
`uted that difference to patient variability. Nonetheless, such
`results suggest that we should expect similar clinical re-
`sults with similar starting doses. In comparing aerosol ther-
`apies, Mestitz et al stated that the clinical effect “is a
`reflection of the dose of bronchodilator administered and
`not the mode of administration.”28
`Raimondi et al clinically compared MDI-with-holding-
`chamber, SVN, and DPI in emergency-department treat-
`ment of 27 adult asthmatics whose FEV1 was ⬍ 30% of
`predicted. They administered 400 ␮g of albuterol via MDI-
`with-holding-chamber and via DPI (Rotahaler), and 5 mg
`via nebulizer.30 Despite the larger nominal dose with the
`nebulizer, there were no differences in FEV1 response over
`6 hours, or in other clinical variables, including numbers
`discharged and admitted.
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`THE INHALATION OF DRUGS: ADVANTAGES AND PROBLEMS
`
`Fig. 17. Deposition in the human respiratory tract with the hydrofluoroalkane (HFA) formulation and the chlorofluorocarbon (CFC) formu-
`lation of beclomethasone dipropionate (BDP). Lung deposition was better with HFA-BDP because of the ultrafine particle distribution of the
`HFA aerosol. (Adapted from Reference 36, with permission.)
`
`Changes in Aerosol Delivery Systems
`Beginning in the 1990s
`
`In 1987 the Montreal Protocol, which banned the use
`of chlorofluorocarbons (CFCs, often known by the brand
`name FREON) as pressurized propellants and refrigerants,
`catalyzed a number of changes in aerosol delivery sys-
`tems.31,32 That signal event, agreed to by the United
`States among others, stimulated a fresh look at the tech-
`nology of aerosol generators. The use of CFCs in MDIs
`was exempted under the Protocol as an “essential use,”
`until suitable alternatives for aerosol drug delivery could
`be developed. Hydrofluoroalkanes (HFA), which have
`similar physical and ch