Aerodynamic Diameter (¡xm)
Figure 10.10 Dependence of deposition of particulates on particle size impact in the upper airways and are rapidly removed by mucociliary clearance. Smaller droplets which escape impaction in the upper airways, in the range 0.5 to 5 pm, are sufficiently large to deposit by sedimentation, while those below 0.5 p m are too small to sediment efficiently and migrate to the vessel walls by Brownian motion. The optimum diameter for pulmonary penetration has been determined by studies of the deposition of monodisperse aerosols to be 2 to 3 pm26. Smaller particles are exhaled before sedimentation can occur, although breath-holding can improve deposition in these cases. Extremely small aerosols, below 0.1 pm, appear to deposit very efficiently through Brownian diffusion to the vessel walls, but such fine aerosols are extremely difficult to produce.
Often the particle size does not remain constant as an aerosol moves from the delivery system into the respiratory tract. Volatile aerosols may become smaller through evaporation whereas hygroscopic aerosols may grow dramatically. The exact relative humidity within airways is not known, but particles produced from dry atmospheric aerosols have been found to double in diameter when the relative humidity is increased to 98%. Particle growth due to absorption of moisture does not appear to affect total drug deposition in the respiratory tract27.
Air in the deep branches of the lung has been estimated to contain around 40 g water per cubic metre. Most aerosol particles will absorb moisture to a degree that depends on temperature, relative humidity and the nature of the aerosol particle. The degree of saturation is also device dependent since aerosols formed by jet nebulizers may have a very low humidity, while ultrasonic nebulizers produce an aerosol with a much higher humidity.
Thermophoresis of particles has been reported to occur in the lung. This is a movement of droplets towards the cooler areas due to the more rapid Brownian motion in the warm areas. It is thought that this effect is small and short-lived in the lung, since the air in the deeper airways is rapidly brought to thermal equilibrium. Finally, electrostatic effects, in which the droplets are attracted to the vessel walls by virtue of a surface charge interaction, are thought to be unimportant in pulmonary delivery, due to the high humidity.
The delivery device largely influences the deposition of drug via the emitted particle size and velocity of the aerosol, as described above. Consequently it is important that the device emits a plume of particles in the 2-5 pm size band. A number of formulation factors may conspire to prevent this; for example the particles suspended in MDI propellants are generally aggregated, and it is assumed that they are disaggregated efficiently by the shear forces in the actuator. Poor formulation, for example a poor choice of surfactant in the suspension, may cause the particles to be irreversibly aggregated. A similar problem occurs in dry powder devices, in which the fine drug powder is often cohesive and may not readily disperse. In the Turbuhaler® (AstraZeneca) the particles are broken up by a spiral in the mouthpiece producing a high resistance to the patient's inspiratory flow28. The Turbuhaler® produces twice as many particles with diameters less than 4.7 micrometers than does the MDI with spacer. The Diskus® (GlaxoWellcome) is also a dry powder inhaler, but this device has a low resistance to inspiratory flow. Thus, it is a less efficient producer of respirable particles under 4.7 micrometers than an MDI plus a metal spacer device, or the Turbuhaler®. As a consequence, the Turbuhaler® DPI delivers 20% to 30% of drug to the lung, approximately twice as much drug as the equivalent dose in the corresponding MDI.
The average respiratory rate is approximately 15 breaths per minute with a tidal volume of about 500 ml and a residence time for tidal air of 3 seconds. A slowing of the respiratory rate increases the dwell time and retention of aerosol particles in the lung. Increasing the respiratory rate decreases dwell time, increases the turbulent flow and particle velocity. Severe turbulence retards the flow of gases into and out of the lung and results in premature deposition of the aerosol particles high into the respiratory tract since the collision rate with the walls is increased. Slowing inspiration and expiration minimizes turbulent flow. As a result deposition to the deep lung can be improved if the breath is held after actuation17.
The resting pressure within the trachea is equal to atmospheric pressure, but during inspiration the pressure may drop to 60 to 100 mm Hg below atmospheric pressure, creating the gradient responsible for the inward flow of the aerosol cloud. The flow into each segment of the lung may vary considerably according to the pressure differential across each passageway and its resistance. Increasing the pressure differential increases the flow and penetration by aerosols. Aerosol delivery with children is problematic due to compliance issues and smaller airways and lung volumes.
Inhaler technique is a common problem, particularly in the elderly. Pressurized metered-dose inhalers in particular can be difficult to administer properly. There are significant variables of inhaler technique, such as timing of actuation and inspiratory flow rate. In a study which assessed the use of seven common inhaler devices in 20 patients with chronic obstructive pulmonary disease, fourteen patients had a fault that would result in no drug delivery at some time during the study. The fault occurred at some point for each inhaler device29. These faults were most common with the Diskhaler®. Patients ranked the metered dose inhaler and Accuhaler highest for ease of use and preference. Even when the correct method of using an inhaler is taught to the patients, their technique declines within 1 hour after instruction.
Although a large volume of inhalation is desirable, a fast inspiratory flow rate is not. Marked differences in bronchodilator response occur in patients with known airway reactivity following inhalation of beta-adrenergic bronchodilators at a slow rate30. Bronchodilation was significantly reduced when the inhaled flow rate was increased to 80
L.min-1 from 25 L.min-1. The slow inhalation flow rate most likely allows the aerosol to penetrate more readily to the target receptor sites in the small, peripheral airways. Most asthmatic patients, however, tend to inhale too rapidly and pressurized inhalers in this group were used at peak inspiratory flow rates ranging from 50 L.min-1 to 400 L.min-1 31. A period of breath-holding increases the number of particles deposited in the lungs at their furthest point of penetration by the process of sedimentation. A new strategy to improve aerosol delivery to the lung involves devices that limit the inspiratory flow rate and increase inspiratory resistance. Examples of these devices are the Turbuhaler® or an inspiratory flow control device (IFCD) plus a metered-dose inhaler. Each is superior to drug delivery via a metered-dose inhaler plus the more common spacer device.
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