Until recently, the propellants used in pressurized MDIs were chlorofluorocarbons (CFCs) known as Freon compounds. Manufacture of Freon compounds has been discontinued because of their role in depletion of the stratospheric ozone layer (14).

Chlorine free aerosol hydrofluoroalkane (HFA) propellants (15,16) which do not contribute to stratospheric ozone depletion have been developed. Because the surfactants used to stabilize suspensions in CFC MDIs are not compatible with HFA propellants, ensuring suspension stability was a significant challenge in the development of non-CFC MDIs (17). HFAs generally appear to be safe and effective alternatives to CFC propellants (18,19), although they are not necessarily absolutely interchangeable. For example, beclomethasone dipropionate (BDP) is in solution in HFA propellant, whereas CFC formulations of BDP were suspensions (20). BDP is at least twice as potent with HFA propellants, and the BDP HFA aerosol properties are more favorable for airway deposition (21). However, no significant differences in bronchodilating effects have been reported comparing CFC and HFA albuterol inhalers (14,22,23).

Some HFA MDIs contain excipients such as ethanol. Breath alcohol levels up to 35 μg per 100 mL have been detected for up to 5 minutes after 2 puffs of albuterol HFA MDIs containing ethanol (24). Because the infrared spectrums of HFAs overlap with commonly used
anesthetic gasses, HFA propellants may cause erroneous readings in anesthetic gas-monitoring systems (25).

The Respimat Soft Mist inhaler (Boehringer Ingelheim Pharmaceuticals, Inc.—not available in the United States at this writing) is an MDI device which does not utilize pressurized propellants. It uses a spring-driven mechanism significantly differing from conventional pressurized MDIs in design ( Fig. 37.1) and output ( Fig. 37.2) (26).

The pressurized MDI is comprised of several components including active drug, propellants/excipients, metering valve, actuator, and container ( Fig. 37.3). Figure 37.4 shows a schematic diagram of the operation of an MDI. Prior to actuation, the propellant-drug formulation for the subsequent single dose is contained within the small metering chamber inside the MDI canister. During the actuation, the metering chamber briefly communicates with the atmosphere but is sealed off from the remainder of the formulation within the canister; at this time, the dose within the metering chamber exits the inhaler through the valve stem. Immediately after the dose is released, however, the valve blocks the connection of the metering chamber to the atmosphere but permits the chamber to communicate with the interior of the canister, allowing refilling of the metering chamber.

In most cases the active drug is not soluble in the propellant; therefore, micronized drug particles within the canister are in suspension rather than in solution. Shaking the canister prior to each actuation is essential to ensure that drug particles are re-suspended; otherwise, the aliquot of propellant that enters the metering chamber may not be a homogenous suspension and therefore may not contain the expected amount of drug. Inattention to shaking a budesonide MDI prior to actuation has been documented to result in a significant reduction in drug delivery to the airways (27). If the pause between shaking and actuation is excessive, the drug-propellant suspension will become inhomogeneous before it is drawn into the metering chamber. Several other details are important for proper use of an MDI. The canister must be held still and in the vertical position until the valve has completely returned to its resting position. Failure to do so may cause inconsistent dosing. The likelihood of such problems increases toward the end of canister life (28); this issue is less significant with the re-engineered HFA inhalers which provide improved dosing consistency. When a period of time elapses between actuations of an MDI, the suspension that entered the metering chamber at the time of last actuation may lose homogeneity, with some drug sticking to the walls of the metering chamber. When this occurs, the amount of drug delivered with the next dose actuation will be reduced (29,30), a phenomenon termed loss of prime. The patient may compensate for this by discarding the first 2 puffs prior to each use of MDI, a procedure termed priming the inhaler (30). Loss
of prime was a significant issue with CFC MDIs; it is less significant with HFA MDIs (31). Breath holding increases drug deposition in the airways. Greater bronchodilation is found with a 10-second pause compared with a 4-second pause, but a 20-second pause appears to produce no further benefit (32).

When an MDI is used without a holding chamber, the issue of whether the lips should be closed around the inhaler mouthpiece or instead held several centimeters from the open mouth (33,34) is open to debate. Comparisons between the two techniques have not shown consistent superiority of either technique over the other (32,35–37). Another issue relevant to optimal inhaler technique regards the lung volume at which inhalation begins. Although it has been proposed that inhalation from functional residual capacity yields improved results as compared with inhalation from residual volume (37), the difference is probably minor (39).

Many studies have documented the prevalence of errors in patients’ use of MDIs (40,41) (Table 37.3). Moreover, health care professionals often are not familiar with the details of appropriate use of the devices. Despite training, around 15% of individuals are not able to use inhalers properly without assistive devices. Of patients with initially inadequate technique who master proper technique with training, around 50% subsequently again develop significant deficiencies in technique over time (40). In patients with initially proper inhaler technique, 20% demonstrated incorrect usage at a later date. In addition to suboptimal response to treatment due to incorrect inhaler technique, there is significant direct economic loss as a result of wasted aerosol medication (41,42).