In order for medications to reach the lungs when using aerosol drug delivery devices, the proper particle size must be achieved. Particles >10 µm in diameter deposit in the mouth and pharynx and are subsequently swallowed. Particles from 5–10 µm deposit in the large bronchi and trachea. Those particles that reach the lower airways are 1–5 µm. Any particles <0.5 µm are exhaled. Delivery devices are designed to deliver adequate medication of the correct particle size in order to reach the lower airways.
Metered Dose Inhalers
MDIs have been the mainstay of delivery of asthma medications. Proper use with this mode of delivery has been an issue and the topic of many patient education sessions. Most of these products contain propellants known as chlorofluorocarbons (CFCs).CFC-propelled MDIs use up to three propellants including dichlorodifluoromethane, dichlorotetrafluoroethane, and trichloromonofluoromethane. Since CFCs contribute to the depletion of the earth’s ozone layer, other propellants such as hydrofluoroalkane-134a (HFA) in addition to other drug delivery devices, such as dry powdered inhalers (DPIs), have been developed.
Procedures for the proper use of metered dose inhalers (MDIs) are listed in TABLE 4. Inspiratory rate also plays a role in drug delivery— faster inspiration leads to greater delivery to the larger airways and less to smaller airways. To prevent this and other problems with patient technique, the use of a spacer devices with MDIs should always be advocated. All patients can benefit from the use of spacer devices in delivering increased amounts of medication to the small airways.
|Table 4 Metered Dose Inhaler Patient Directions|
|Proper Use of MDI: |
Nebulizers are often the easiest way to deliver inhaled medication because they do not require patient coordination other than normal breathing. They are most often used during an exacerbation of asthma or in children, especially when patients are unable to cooperate and use the MDI. Only about 10% of the medication dispensed in the nebulizer cup actually reaches the patient’s lungs. The remainder is either expired, swallowed, or left in the cup. Medications available for nebulization include quick-relief medications such as beta2 agonists and ipratropium. Also available for nebulization is the long-term controller cromolyn. Corticosteroids are not available for nebulization in the United States, although some products are available in Europe.
Two types of nebulizers exist on the market: the jet and the ultrasonic nebulizer. Conventional jet nebulizers deliver air from a compressor through a small opening known as a venturi. Various compressors deliver different rates of airflow. Flow can vary further depending on the type of nebulizer, disposable or reusable, used with the compressor. The dynamic flow of any compressor device should be tested with the delivery piece intended to be used with the compressor. Some delivery masks and mouthpieces may provide too much resistance for a given compressor and should not be used in combination. Patients should be made aware of this fact if they are having difficulty with their device.
Ultrasonic nebulizers are newer to the market and are usually lightweight, quieter, and easier to use. Ultrasonic waves vibrate the solution of medication resulting in aerosolization. Older models of these nebulizers were felt not to produce sufficient amounts of nebulized medication. However, newer models such as the Omron NE-U03V Micro Air have been tested against conventional nebulizers and appear to be effective in producing clinical outcomes similar to a jet nebulizer.
Jet nebulizers work by passing air through a venturi opening, drawing liquid up through feeding tubes and nebulizing the solution. While smaller particles, 1–5 µm in diameter, are inhaled by the patient, larger particles are caught on baffles and returned to the reservoir for renebulization. As mentioned previously, nebulizers were not considered to be very efficient in delivering drug; however, advances in nebulizer design have maximized medication delivery while eliminating medication waste. Types of nebulizers that deliver medication more efficiently include breath assisted devices and manual flow interrupters to help patients deliver drug with inspiration. Open vent nebulizers are available and shorten the duration of a treatment while delivering the same amount of medication.
Dry Powder Inhalers
Dry powdered inhalers (DPIs) deliver an active drug in powder form, lack propellants found in metered dose inhalers (MDIs), and are dependent on the inspiration of the user. Newer DPIs such as Pulmicort Turbuhaler and Serevent Diskus contain multiple doses of active drug in a reservoir or individual blister packs, respectively, that must be released prior to inhalation. When the patient inhales, the drug is aerosolized and passes through narrow channels in the inhaler mouthpiece that cause the drug to disperse or deaggragate into smaller particles. Some devices combine active drug with lactose, a commonly used excipient. However, lactose commonly deposits in the oropharnyx since the particle size is between 60–80 microns.
Drug inhalation occurs when a patient takes a breath requiring minimal coordination for proper drug delivery. Dry powdered inhalers (DPIs) lack CFC propellants, which can be harmful to the environment and may cause further irritation to the throat and lungs. A limitation of DPIs is that a quick, deep inspiration (up to 60 L/min) is required compared to a slower inspiration with metered dose inhalers (MDIs) (requires <30 L/min). This may pose a problem for some patient populations such as young children or symptomatic asthmatics. TABLE 5 lists a comparison of MDIs to DPIs.
The Pulmicort Turbuhaler (AstraZeneca Pharmaceuticals) is a disposable, dry powder inhaler containing the corticosteroid budesonide. Budesonide is stored in a drug reservoir within the inhaler device. A circular knob on the bottom of the device is turned to release approximately 200 micrograms of drug onto a disk within the inhaler. When the patient inhales, the drug is pulled through a discharge funnel and is forced through small conical holes located in the mouthpiece. This generates high airflow resistance and deaggregates the powder to create an aerosol. Since the drug is not secure on the disk, exhalation prior to the inhalation of the drug may cause the powder to be blown out the opposite end of the inhaler. It is important for the user to hold the inhaler upright or in a horizontal position to prevent loss of the dose. A feature of this product is a low-dose indicator window. A red bar will appear in the dosing window when 20 doses remain.
The Pulmicort Turbuhaler deposits approximately twice the amount of budesonide in the lungs, compared to a CFC-propelled MDI (32% vs. 18%). Overall, systemic bioavailability is greater with the Turbuhaler, demonstrating that lung absorption accounts for the majority of systemic drug availability. When the Turbuhaler was compared to an MDI plus spacer, there were no differences in FEV1, asthma symptoms or urinary free cortisol levels (a measure of adrenal suppression) after 8 weeks of treatment. The occurrence of cortisol suppression after administration of 4 mg of budesonide (regular dose is 400–800 micrograms twice a day) was similar when budesonide was administered by Turbuhaler or MDI. There was significantly less cortisol suppression when the oral formulation was administered, confirming limited oral bioavailability.
|Table 5 Comparison of CFC-Propelled MDI and DPI Products|
|METERED-DOSE INHALERS||DRY-POWDER INHALERS|
|Aerosol generation dependent on propellants (mostly Freon)||Aerosol generation does not require any propellants|
|Requires coordination of actuation with inhalation||Relatively easy to administer since it is breath activated|
|With correct technique the lung deposition is 10%–15%||Lung deposition of the drug is similar to properly used metered dose inhalers (MDIs) (some studies: DPI>MDI)|
|No effect from humidity||High humidity conditions may result in clumping of the powder particles (in some DPIs), resulting in a decreased respirable dose|
|“Cold Freon effect” causing paradoxical bronchospasm||No Freon. Available in pure drug form|
|No dose indicators. Risk of continued use of empty inhaler||Newer multi-dose dry powdered inhalers (DPIs) have a window with dose indicator|
|Difficult to use in small children and elderly, unless attached to a spacer||Relatively easy to use in small children and elderly, since it is breath activated and requires little coordination|
|Future availability of MDI uncertain due to limitations||Freon-free. May replace MDIs in the future on Freon production (especially multidose DPIs)|
In conclusion, it appears that budesonide via a Turbuhaler may deliver up to twice the amount of drug in the lungs compared to a CFC-propelled MDI alone. In addition, there were no differences in overall asthma symptoms or systemic side effects in patients inhaling budesonide with an MDI plus spacer, making the Turbuhaler a good alternative to budesonide metered dose inhalers (MDIs).
Since the Turbuhaler requires a forceful inhalation, some patients may have difficulty with this device. Currently, there is evidence that children under the age of 5 have variable and unpredictable drug delivery to the lungs when using the Turbuhaler. The manufacturer recommends that this device should not be used in children under the age of 6.
The Serevent Diskus (GlaxoWellcome) is a disposable, disk-shaped inhaler containing a long-acting, beta2 selective agonist, salmeterol xinafoate and a lactose excipient in a dry powder form. Fifty micrograms of salmeterol are packaged in individual blister foil packs protecting the drug from clumping when exposed to humidity or excess moisture. The blisters are contained on a long strip, which is coiled in the inhaler. When the inhaler is primed, the strip lid is peeled back from the blister pack and the drug is available for inhalation. Each inhaler provides one month’s supply or 60 doses of salmeterol. The product has a dose counter located on each inhaler to assist patients in recognizing the need for refills.
Numerous studies have been performed to assess the efficacy of the Serevent Diskus. The device showed similar improvement in FEV1 compared to the Serevent MDI after 12 weeks in adult patients with mild-moderate asthma symptoms. Both devices demonstrated a decrease in daily albuterol use and nocturnal awakenings and an increase in asthma-free symptom days when compared to placebo. In pediatric patients (ages 3–11) with exercise-induced asthma, there was no decrease in FEV1 after exercise when treated with Serevent Diskus. In addition, there was no difference in FEV1 in patients taught to inhale at low (30 L/min) or high flow rates (60 L/min). Therefore pediatric patients who may not be able to achieve high flow can benefit from this device. Both these studies reported no significant drug-related side effect with these products.
The Serevent Diskus has been shown to provide adequate asthma control when compared to the MDI. It has also demonstrated adequate prevention of exercise-induced asthma in pediatric patients between the ages of 3–11 when used at both low and high flow-rates. Currently, it is FDA approved for children 4 years of age and older.
Inhaler technique can be difficult to master, particularly for small children and the elderly. Spacer devices help improve drug delivery by improving overall patient technique. National guidelines recommend spacer use for those >4 years of age or < or = to 4 years of age with a face mask. Spacers are also recommended for those patients on medium- and high-dose inhaled corticosteroids. Extensive education and reinforcement upon repeat visits is essential to ensure proper drug delivery. Studies have shown single instruction to be inadequate to master the techniques required.12 Kamps and colleagues demonstrated comprehensive instruction with repeated reinforcement at the pharmacy and in clinical trial settings greatly improved performance compared to single instruction by a general practitioner.
Various spacers may deliver variable amounts of medication. Barry and associates investigated the in vitro output of medication from seven such devices. Spacer devices do vary in volume, with some devices as low as 60 mL and others as high as 800 mL. Their data revealed large spacer devices deliver more medication than do smaller devices.
Spacer devices, although designed to improve overall drug delivery, do have limitations. Factors such as multiple actuations of the inhaler into the spacer, static electricity build-up and delaying inhalation can decrease bioavailability of inhaled medications through the spacer. To decrease static build-up, patients should be instructed to wash their spacer device with soapy water. Multiple actuations into the spacer should be discouraged and patients should be instructed that delaying inhalation may decrease drug delivery. Education on the proper spacer device, optimal use, and proper care is essential for patients utilizing these devices.
Peak Flow Meters
Peak flow meters (PFMs) are designed to assist patients in monitoring and managing asthma symptoms. Peak flow reading averages are available based on patient age, sex, and height. However, it is best to determine a patient’s personal best to guide future monitoring and treatment. Patients should be instructed to record peak flows twice daily for approximately two weeks to determine their personal best reading in this time frame. Proper use of the PFM includes placing the indicator at zero, standing up, taking a deep breath, placing the lips tightly around the mouthpiece, and blowing as fast and hard as possible. This procedure should be repeated three times and the best reading recorded.
Once the patient knows his/her personal best, future asthma exacerbations can be monitored and treated based on this value. Zone systems have been established to guide therapy and are based on the stoplight system of green, yellow, and red. The green zone is 80%–100% of the personal best and represents good control. Readings 50%–80% of the personal best represents the yellow zone. Patients may require medication adjustments including increases in long-term controller uses such as inhaled corticosteroids. The red zone represents readings less than 50% of the personal best. If patients reach their red zone they will need emergency treatment. However, frequent monitoring of peak flows during exacerbations can allow for interventions and medication adjustments to avoid a trip to the emergency room.