Advances in MDI and DPI Technology and

Enantiomer Preparations of Inhaled Drugs. There has been much interest in the differences in effects of enantiomers of many medications, and beta agonist adrenergic bronchodilators have received much attention. Evidence suggests that the (R)-enantiomer of albuterol is mainly responsible for bronchodilation while the (S)-enantiomer may stimulate airway reactivity. Data suggest, however, that after aerosol delivery, the systemic absorption for (R)-albuterol is faster than for (S)-albuterol and that, conversely, the lung retention of (S)-albuterol is longer, which may be detrimental [29]. The extent to which enantiomers will displace racemic preparations is not yet determined.

Generic Proliferation of Devices and Medications. The proliferation of new aerosol generators moves at a rapid pace. New MDI and nebulizer brands are introduced regularly. Even for those who watch this field, it is not unusual to hear a new, unfamiliar brand name regularly. One trend has been the move to generic MDIs and to over-the-counter availability. These are introduced in the literature by comparing them with well-known older devices. Often, documentation that generic brands or new devices are comparable to older ones is difficult to come by, so comparisons showing pharmacokinetic equivalency are useful [30]. One such, the Respimat, which is a multidose handheld nebulizer, appears to deliver more flunisolide to the lungs (9.9%) than does either an MDI (5.1%) or an MDI with spacer (7%) [31].

New CFC Substitutes for MDIs. The HFAs are rapidly replacing CFCs in MDIs. Numerous clinical studies have focused on documenting efficacy and safety. Some data suggest that the lung deposition fraction of beclomethasone dipropionate using HFA-134a MDI is much higher than that for CFC MDI [32]. The major reason for this difference is the particle size of the HFA aerosol, 1.1 mm, compared to the CFC aerosol, with a size of 3.5 mm. Evidence indicates that pulmonary deposition can be significantly influenced by HFA chosen and by actuator design. Lung deposition for fenoterol was significantly influenced by the actuator nozzle designed for HFA-134a [33]. The convenience of MDIs, in use since the 1950s, will ensure a major continuing role despite anticipated inroads by dry powder inhalers.

Inhalation Technique. Inhalation technique receives much attention even today. Proper use is important for MDIs and DPIs. Modifications of delivery techniques can greatly influence generator performance [34]. This report describes the performance differences among different aerosol-generating devices. Seemingly small differences in use technique, such as shaking the canister before each puff or failure to do so, can considerably affect puff dose [35]. Physicians, therapists, and patients are not well informed about these important techniques.

For MDIs, lung deposition can be enhanced by (1) gentle exhalation to residual volume rather than to functional residual capacity, (2) slow inhalation (10 L/min) rather that fast inhalation (50 L/min), and (3) breath hold of 10 sec rather than none at end of puff inhalation. These observations were based on measurement of urinary albuterol at 30-min postinhalation, which is considered to reflect lung delivery and to avoid gastrointestinal (GI) tract deposition [36]. The effect of inhalation flowrate through an aerosol device can greatly affect particle size, a factor that may explain in part the reduced deposition with suboptimal flowrates. Failure to quickly achieve optimal inspiratory flowrate via a budesonide Turbuhaler can result in an increase in size from < 6.6 microns to

45 microns [37]. For delivery of appropriately sized particles to peripheral airways, a slow inhalation flowrate may be best [38].

Inhalation Flowrate. The question of proper flowrate does not need further complication, but it seems children are different. Delivery to children may be different than for adults. This has been the subject of much deliberation over many years. Evidence indicates that an inhaled dose is higher with higher flowrates, which cannot be achieved by small children. However, some information indicates that while larger children, who have higher flowrates, inhale more budesonide via the Turbuhaler, a DPI, the deposition is similar when corrected for weight [39]. Some studies suggest that smaller children may actually achieve higher deposition when calculated on a body weight basis [40]. As with other use techniques, it is essential for all parties, physicians, therapists, and patients to know how to include flowrate control in care. MDI Inhalation Coordination. Both adults and children often have difficulty coordinating the inhalation effort with the timing of the aerosol puff. Evidence indicates considerable intra- and intersubject variability for the inhalation technique [41]. The historically reported deposition fraction into the lung is 5-10% at best. Considerable improvement has been described, using various techniques to improve timing. When uncoached subjects inhaled from an MDI, their deposition fraction is about one-third that achieved by patients taught proper technique (7.2% compared to 22.8%), while use of a breath-actuated MDI improved deposition (20.8%) over that of patients also taught proper technique [42]. Control of MDI firing to deliver the puff at optimal flowrate and time point after beginning inhalation also improves deposition. A device that does this (SmartMist) using conventional MDI canisters has been described, and it achieves approximately double the lung deposition [43]. The deposition fraction can be increased to 48% in adults using an inhalation-synchronized dosimeter, and further increased to 60% by controlling (slowing) inspiratory flow [44]. The problem of patient coordination with MDI use is much discussed.

Spacers. The efficacy of spacers for increasing pulmonary deposition and reducing oropharyngeal drug deposition is well documented [45]. Spacers offer the advantage of (1) particle size reduction by propellant evaporation and (2) reduction in cloud velocity, both reasons for the reduced oropharyngeal deposition and increased pulmonary deposition. Alternatively, spacers can cause particle loss by electrostatic precipitation. Application of antistatic agents or detergents improves the yield of inhalable particles [46] and can improve deposition from 25% to 200%. [47-49]. Metal spacers do not hold a charge and so do not affect deposition [50].

The way in which a spacer is used can also reduce delivery. Multiple puffs delivered to a spacer reduce availability [46,51], as does a delay between the dosing of the spacer and inhaling the dose from the spacer [46,47]. The lung dose of medication from an MDI via a large spacer is generally greater than that via a small spacer [52].

The importance of spacers and all techniques to improve delivery is relative. If the dose delivered "the old way" achieves maximum pharmacodynamic effect, improving delivery is moot [53]. This observation raises other questions about aerosol drug delivery, namely, the effective dose. It is likely that the "dose overkill" concept has been the reason for failure to show differences when some applications were compared. A new, refined device may not be more effective than an older one because the older one delivers such a large dose that, despite inefficiency, it is pharmacodynamically equivalent. At least one study shows no difference in protection from exercise-induced asthma by nedocromil sodium and by sodium cromoglycate via MDI, and use of a spacer did not change results [54].

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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