J. Aerosol Sci., Vol. 22, Suppl. I, pp. $813-$816, 1991. Printed in Great Britain.
0021-8502/91 $3.00+0.00 Pergamon Press plc
EFFECTS OF DISCOORDINATION UPON BRONCHODILATOR RESPONSE TO METERED DOSE INHALER A.F. WILSON, M.H. SCHECKER, H.S. NOVEY, S. SAVARIRAYAN and D.MUKAI
Department of Medicine, University of California Irvine, CA, U.S.A.
ABSTRACT Proper coordination of inhalation and MDI canister activation is an important determinant of availability of medication to airways and subsequent clinical response. We compared coordination of terbutaline and pirbuterol MDIs by evaluating clinical effects, deposition in a model of the human upper airway, rate of aerosol settling in a tank, and particle size distribution. The maximum clinical effects and least deposition in the upper airway occurred when both MDIs were activated at onset of inhalation. When MDIs were activated before inhalation, pirbuterol was less affected than terbutaline. Pirbuterol MDI aerosol is slightly smaller than terbutaline MDI aerosol. The results of this study strongly suggest that both clinical and airway model differences noted were due, at least in part, to smaller size of pirbuterol aerosol. KEYWORDS metered dose inhaler; coordination; aerosol size; airway model INTRODUCTION It is generally accepted that coordination of activation of canisters of metered dose inhalers (MDI) with onset of inhalation is essential to obtain full benefrt of released medication. Earlier, Newman et al (1981) compared bronchodilator potency of terbutaline MDI inhaled 3 seconds before, at onset of, and immediately after inhalation in 10 asthmatics. They found that, compared to canister activation which was well coordinated with onset of inhalation, efficacy was reduced moderately when activation preceded inhalation; efficacy was reduced greatly when activation was after the end of inhalation (table 1).
METHODS AND RESULTS We studied the effects of coordination in patients (clinical observations) and in a surrogate of the human upper airway (airway model experiments) and some physical $813
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characteristics of aerosol from terbutaline and pirbuterol MDIs (aerosol size experiments). Clinical Observations We studied effects of discoordination of pirbuterol MDI upon bronchodilator effect in 20 patients with mild to moderately severe asthma. !
This study of pirbuterol MDI utilized methods similar to those employed by Newman et al (1): Patients inhaled a full inspiratory reserve volume of air at a constant flow rate of 0.5 I/sec; inspiratory flow rate was monitored and timing of canister activation was controlled by enclosing MDI at one end of 3.5 cm diameter tubing enveloped by a cap and pierced by an external activation lever; the other end of the tubing was attached to a pneumotachygraph. Patients were able to observe their flow rates on a oscilloscope. Canister activation was accomplished by a technician; medication was inhaled only after flow rates were reproducible and correct.
Table 1 FEV1 60 mins after 1% (values normalized - % of onset) I%
from Newman et at (1981)
Our findings indicate that, while activation at end of inhalation reduced bronchodilator efficacy greatly and after inhalation almost completely, activation 3 seconds prior to inhalation had very little effect (table 1). Airway Model Experiments To help explain the observed differences between previously reported results with terbutaline and current observations with pirbuterol, we investigated some physical properties of these MDIs. The ability of aerosol generated by MDIs to traverse an anatomically accurate silastic model of the human upper airway (from teeth to trachea) was measured under conditions simulating the human experiments. An analytical ventilator was used to convey humidified air at body temperature through the upper airway model; at the appropriate phase of ventilation, MDI was activated; released aerosol that did not deposit in the upper airway was collected in a water trap at the end of the surrogate trachea (Wilson et al, 1991). Pirbuterol and terbutaline were contrasted under the three coordination conditions utilized in the human experiments. The contents of the water trap were analyzed by ultraviolet spectrophotometry. The results of these experiments are summarized in table 2.
Discoordination and bronchodilator response
Table 2 Aerosol in Surrogate Trachea (values normalized - % of onset) I%
Comparison of the data in tables 1 and 2 indicate that there was a remarkable similarity between the pattern of bronchodilatation in asthmatics and the pattern of aerosol traversing the upper airway model for 2 coordination modes - onset and 3 second prior activation - for both MDIs. We presume that the differences between the experimental details of our end of inhalation experiments and those of Newman et al (1981) explain the divergent observations for this coordination mode; in our experiments, canisters were activated at the end of the breath while in the experiments of Newman et al (1981) canisters were activated immediately after completion of inhalation. Aerosol Size Experiments Next, we assessed MMD and settling velocity of these MDIs. For these measurements, we utilized a 113 cm long cylindrical tank of 30 cm diameter with conical fittings on both top and bottom (Wilson et al, 1991). Pirbuterol and terbutaline MDIs were activated at the upper opening of this structure and particles were monitored by optical means (Climet 208, Redlands, CA, USA and Canberra Multichannel Analyzer series 30, Medden, CT, USA). The volume of the chamber was 63 1and the sampling rate of the optical analyzer was 7 I/min. We recorded the distribution of particle size at 16 minutes (table 3).
Table 3 Distribution of Aerosol Size Ilm
% of total
% of total
It is evident from the data in table 3 that pirbuterol MDI particles are, in general, smaller than terbutaline particles.
DISCUSSION AND CONCLUSIONS We conclude that substantially less pirbuterol particles settle in the mouth than terbutaline particles in the 3 seconds of preinhalation non-flow state and, hence, more aerosol is available for inhalation into intrathoracic airways. We hypothesize that the smaller size
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distribution of pirbuterol aerosol is the most likely explanation of the greater upper airway deposition and clinical differences noted between terbutaline and pirbuterol MDIs. During the preinhalation nonflow state, particles should grow in the humid conditions of the upper airway. In this humid reservoir, particles should impact in relationship to their size and length of stay in the reservoir. Additionally, small particles which might normally be exhaled during the course of normal aerosol inhalation, may grow large enough during their longer stay in the humid conditions of the airways to be retained in the lower airways during inhalation. / One likely explanation for the smaller size of pirbuterol particles when compared to those of terbutaline is the higher vapor pressure of pirbuterol MDI. Moren (1985) demonstrated that higher MDI vapor pressure produces smaller particles. Wilson et al (1991) also noted a similar phenomenon when canister vapor pressure was increased by raising temperature. Other factors which might play a role include metering chamber size and mass of medication and surfactant released at each activation.
REFERENCES Moren,F. (1985). Int. J. Pharmacol. 1__.213-218. Newman, S.P., Pavia, D. and S.W. Clarke (1981). Eur. J. Resp. Dis. 62. 3-21. Wilson, A.F., Mukai, D.S. and J.J. Ahdout (1991). Amer. Rev. Resp. Dis. 143. 1034-1037.
ACKNOWLEGDEMENT The authors wish to thank Bob Schultz of 3M Pharmaceuticals for useful discussions.