Br. J. clin. Pharmac. (1983), 15, 695-700

EFFECTS OF TERBUTALINE SULPHATE AEROSOL ON RESPONSE AND MUCOCILIARY CLEARANCE IN PATIENTS WITH MILD STABLE J.R.M. BATEMAN*, D. PAVIA, N.F. SHEAHAN, S.P. NEWMAN & S.W. CLARKE Department ofThoracic Medicine, Royal Free Hospital, Pond Street, London NW3 2QG

1 Ventilatory function and whole lung mucociliary clearance have been assessed in 10 patients with mild stable asthma following of 1 mg of the ,8-adrenergic receptor agonist terbutaline sulphate (Bricanyl, Astra Pharmaceuticals) from a metered dose inhaler (MDI). 2 Compared to placebo inhalation, terbutaline produced marked bronchodilatation (mean percent- age increase in FEV1 14%, P < 0.01). 3 Mucociliary clearance (measured by the in vivo radioaerosol technique) was assessed on three occasions-control, followed by placebo or terbutaline studies in a double-blind, cross-over manner. 4 Particles were removed from the lung at a similar rate in all three studies. The mean (± s.e. mean) percentage of aerosol retained in the after 6 h was 58 + 5%, 57 + 5% and 57 + 4% for control, placebo and drug studies respectively. 5 It is concluded that terbutaline sulphate, given as a 1 mg acute dose, does not enhance mucociliary clearance in mild stable asthmatics, although it produces marked bronchodilatation.

Introduction Methods ,8-adrenergic receptor agonists are intended primarily Study design to relieve bronchospasm in patients with reversible airways obstruction. These substances may have Ten patients (six male, four female) clinically diag- valuable additional effects however, including in- nosed as having mild stable asthma were investigated. hibition of mediator release (Sorenby, 1975) and the All patients had demonstrated previously an increase enhancement of transport. Terbutaline of ' 15% in the forced expiratory volume in 1 second sulphate is a typical /3-adrenoceptor agonist in that it (FEV1) following bronchodilator inhalation. All has a powerful bronchodilator action when given by a were taking bronchodilator aerosols on a regular variety of routes (Freedman, 1971; Koch, 1972; basis, but none was taking oral or inhaled corti- Michaelson et al., 1978). It selectively stimulates AR- costeroids. The mean age of the patients was 44 (s.e. adrenoceptors in the bronchial tree, whilst having mean 5) years; the mean weight 79 (s.e. mean 4) kg little or no effect upon cardiac A-adrenoceptors. and the mean height 1.69 (s.e. mean 0.03) metres. Terbutaline enhances tracheal mucus velocity when Mean (± s.e. mean) tobacco consumption was 19 + 6 given subcutaneously to patients with airways ob- pack-years. Two patients were non-smokers, five ex- struction (Mossberg et al., 1976a; 1976b) and to smokers and three current smokers. healthy subjects (Camner et al., 1976). However, the In all, each patient performed five studies on five effect of terbutaline on mucus transport when separate days at least 48 h but not more than 1 week administered via a pressurized metered dose inhaler apart. In the first two studies, bronchodilator response (MDI) is largely unknown. We have investigated the to either 1 mg terbutaline sulphate aerosol (Bricanyl, acute effects upon both bronchodilator response and Astra Pharmaceuticals) or placebo aerosol was lung mucociliary clearance of a 1 mg dose ofterbutaline assessed in a double-blind cross-over manner. Five of sulphate, given from an MDI to patients with mild the patients were given terbutaline and five patients stable asthma. given placebo during the first of these two studies. Mucociliary clearance was measured during the third, *Present address: Derby Chest Clinic, 93 Green Lane, fourth and fifth studies. In the third study, a control Derby DE1 1RX mucociliary clearance measurement was performed. 0306-5251 83 '0600-6950 $02.00 © 1983 Blackwell Scientific Publications 696 J.R.M. BATEMAN, D. PAVIA, N.F. SHEAHAN, S.P. NEWMAN & S.W. CLARKE

In the fourth and fifth studies mucociliary clearance administration and radioaerosol inhalation was was assessed following administration of either 1 mg approximately 1 min. terbutaline sulphate aerosol (Bricanyl, Astra Phar- Immediately following radioaerosol inhalation, the maceuticals) or placebo aerosol in a double-blind initial topographical distribution of deposited particles cross-over manner. Patients refrained from taking in the right lung was measured using a rectilinear their prescribed for 12 h prior to gamma scanner (Dawson et al., 1971). The scanner commencement of all studies, for the duration of the recorded radioactivity in a series of vertical traverses bronchodilator response studies and during the initial of the right lung, each of width 2.5 cm. An aerosol 6 h recording period in mucociliary clearance studies. penetration index (API) was calculated as the All patients gave informed consent in writing, and quantity of radioactivity detected over the peripheral the investigations were approved both by the Ethical two-fifths of the lung compared to that recorded over Practices Committee of the Hospital and the the inner two-fifths (Thomson et al., 1975). Radioisotope Advisory Panel of the Department of Clearance of particles from the lungs was recorded Health and Social Security. using two diametrically opposed scintillation probes, one located anteriorly over the midsternum, and the Bronchodilator response studies other location posteriorly. Counts emanating from the chest were recorded immediately after radio- Patients inhaled either four puffs (1 mg) terbutaline aerosol inhalation and then at hourly intervals for 6 h. sulphate aerosol or four puffs of placebo aerosol These counts were corrected for background and which consisted of chlorofluorocarbons 11, 12 and radioactive decay. Patients returned after 24 h for a 114 with sorbitan trioleate surfactant (14mg ml-') but final measurement of chest radioactivity. The no active drug particles. Bronchodilator response was quantity of aerosol retained in the lungs after 24 h, assessed from simple spirometric tests. FEV, and corrected for background and radioactive decay, was forced (FVC) were measured using a taken to be alveolar deposition, on the assumption dry bellows spirometer (Vitalograph) and peak that those particles deposited on the conducting expiratory flow rate (PEFR) was measured using a airways had been removed by mucociliary clearance Wright peak flow meter. These tests were performed and productive coughing by that time. The number of prior to drug or placebo inhalation, and then 15, 30, coughs and expectoration of sputum was recorded 60 and 120 min later. Changes in maximal forced during the 6 h following radioaerosol inhalation. expiratory flow rate at 50% vital capacity (Vmax 50) were measured at 15 and 120 min post inhalation from Statistical analysis maximal expiratory flow-volume curves using an The data were not assumed to be normally distributed, Ohio 840 spirometer coupled to a Byrans X-Y and statistical significance was assessed by non- plotter. The highest of three technically acceptable parametric methods. The tests used were the readings was recorded at each time for each lung Wilcoxon rank sum test for paired data and the function test. Friedman analysis ofvariance by ranks (Siegel, 1956). Mucociliary clearance studies Results Whole lung mucociliary clearance was assessed using the in vivo radioaerosol technique which has already Bronchodilator response studies been reported more fully elsewhere (Thomson & Short, 1969). Patients inhaled in a controlled manner Inhalation of 1 mg terbutaline sulphate aerosol particles of polystyrene, firmly labelled with the resulted in marked bronchodilatation in the 10 gamma-emitting isotope 99rc. Inhalation, limited to asthmatic subjects throughout the 2 h recording a volume of450 ml, commenced at functional residual period. After 30 min, the mean (+ s.e. mean percent- capacity (FRC) and was followed by 3 s breath-holding age change in FEV, was 14 + 3% for terbutaline, and to allow particles to settle onto the airways at their -1 + 2% for placebo (P < 0.01). Similar changes furthest point of penetration. Inhaled flow rate was were noted for PEFR (drug 17 + 4%, placebo 0 + monitored by a pneumotachygraph. 2%, P < 0.01), and the change in FVC was also Immediately prior to radioaerosol inhalation, significantly (P < 0.01) enhanced after terbutaline FEV1, FVC and maximum mid-expiratory flow rate inhalation. Changes in Vm., 50 after terbutaline (MMEF) were assessed using a Vitalograph inhalation were also greater than those after placebo spirometer, and PEFR using a Wright peak flow inhalation, but these differences did not attain meter. In the drug and placebo runs, four puffs of statistical significance. Baseline FEV, values were either terbutaline sulphate (Bricanyl, Astra Phar- similar on the 2 study days, being 2.70 1 (s.e. mean maceuticals) or placebo were then administered from 0.34 1) on the terbutaline day and 2.86 1 (s.e. mean an MDI. The time interval between drug or placebo 0.35 1) on the placebo day. EFFECTS OF TERBUTALINE SULPHATE AEROSOL 697

Mucociliary clearance studies The clearance of radioactive particles from the lungs is shown in Figure 1. The quantity of radioactive particles remaining in the lungs is plotted against time as a percentage of the amount initially present. There 60, were no significant differences between control, 50- placebo and drug studies in the amount of aerosol '40- retained in the lungs at any time up to 24 h after radioaerosol inhalation. After 6 h, the mean (± s.e. mean whole lung retention of radioaerosol was 58 + 5%, 57 ± 5% and 57 + 4% for control, placebo and 10. drug studies respectively. Mean (+ s.e. mean) 1 2 3 4 5 6 24 alveolar deposition, as indicated by the 24 h whole Time (h) lung retention, was 39 + 4%, 40 + 5% and 44 + 6% for the three studies. This indicated that mucociliary Figure 2 Acute effect of inhaled terbutaline sulphate (1 mg) on tracheobronchial clearance in 10 patients with clearance was unaltered by terbutaline compared mild stable asthma. Group mean retention of deposited either to placebo or to the control study. radioaerosol in tracheobronchial zones is plotted as a percentage of the initial count. U control, * placebo, A terbutaline.

and the volume of expectorated sputum did not vary significantly among the three studies (Table 2). The number of coughs was greatest in the placebo study, although the wet weight of sputum produced was least. Sputum was expectorated by two patients in control and drug studies and by only one patient in the placebo study. The initial topographical distribution of radio- aerosol in the lungs was expressed in terms of the 3 4 aerosol penetration index (API). In the control Time (h) study, API was 0.54 ± 0.05 (mean + s.e. mean), but fell significantly to 0.34 + 0.05 (P < 0.01) in the Figure 1 Acute effect of inhaled terbutaline sulphate placebo study and to 0.43 + 0.05 (P < 0.02) in the (1 mg) on whole lung mucociliary clearance in 10 patients with mild stable asthma. Group mean retention of terbutaline study. This finding indicates a more deposited radioaerosol in the whole lung is plotted as a central deposition pattern within the lungs for both percentage ofthe initial count. U control, * placebo, A placebo and drug studies. There was no significant terbutaline. difference between API in the placebo study and API in the drug study. The data shown in Figure 1 were replotted by sub- tracting the 24 h retention of radioaerosol (alveolar deposition) and expressing the remaining radio- Table 1 Mean (t s.e. mean) ventilatory function prior to As radioaerosol inhalation in 10 patients with mild stable activity as tracheobronchial clearance (Figure 2). asthma. Mean percentage predicted values are shown in the in the case of whole lung clearance, there were no parentheses. significant differences between control, placebo and drug studies. Tracheobronchial retention at 6 h was Control Placebo Terbutaline 32 + 7 (mean + s.e. mean)%, 28 + 7% and 23 + 6% study study study. respectively. Ventilatory function, measured prior to radio- FEV1 (1) 2.86 + 0.35 2.76 + 0.35 2.93 ± 0.36 aerosol inhalation was similar for each of the three (90%) (87%) (92%) clearance studies, there being no significant differences FVC (1) 3.70 + 0.45 3.75 ± 0.44 3.83 ± 0.45 in FEV1, FVC, PEFR and MMEF (Table 1). Flow (95%) (96%) (98%) rate of inhaled radioaerosol also varied little on each PEFR (1 min-') 427 + 35 423 + 35 438 + 36 study day, being 27 + 1 (mean + s.e. mean) 1 min-', (86%) (85%) (88%) 27 + 2 1 min-m and 29 + 2 1 min-I for control, placebo MMEF ( s-') 2.51 + 0.43 2.38 + 0.47 2.49 + 0.40 and drug studies respectively. The number of coughs (69%) (65%) (68%) 698 J.R.M. BATEMAN, D. PAVIA, N.F. SHEAHAN, S.P. NEWMAN & S.W. CLARKE

Table 2 Mean (+ ss.e. mean) number of coughs and mean particles to the throat was presumably shorter than (± s.e. mean) wet weight of sputum expectorated during that in the control study, and similar to that in the first 6 h of mucociliiary clearance studies in 10 mild stable placebo study. asthmatics. Mucociliary clearance is impaired in subjects with Control Placebo Terbutaline obstructive airway disease (Pavia et al., 1980b), even study study study in patients with only mild asthma (Bateman et al., 1979). Many /8-adrenergic agents are capable of Coughs 13 t 5 29 t 18 10 ± 2 accelerating clearance in such patients towards more normal levels (Sackner, 1978). Salbutamol (Fazio & Wet weight Lafortuna, 1981) given from an MDI and clenbuterol of sputum (g) 0 .56 t 0.50 0.12 t 0.11 0.40 t 0.27 (Weiss et al., 1981) given orally, improve whole lung mucociliary clearance in subjects with chronic bronchitis, and tracheal mucus velocity may be Discussion increased in normal subjects by nebulized adrenaline and isoprenaline (Foster et al., 1976) and by These investigati(ons have shown that a 1 mg acute nebulized orciprenaline (Yeates et al., 1981). dose of terbutalirie sulphate aerosol, given from an Isoprenaline aerosol improves tracheal mucus MDI, does not eliicit an increase in mucociliary clear- velocity in anaesthetized dogs (Sackner et al., 1976). ance in patients with mild stable asthma, even though Terbutaline, given subcutaneously in a dose of 250,ug, this dose is sufficcient to produce marked broncho- was found to enhance lung mucociliary clearance in dilator response. The standard dose of terbutaline healthy subjects (Camner et al., 1976), in asthmatics aerosol is two piaffs (500 ,ug). Our findings are in (Mossberg et al., 1976a) and in chronic bronchitics agreement with those of a previous study from our with only moderate ventilatory impairment (Mossberg laboratory (Pavia;et al., 1980a) in which the adminis- et al., 1976b). The same dose of terbutaline given tration of two puffs of terbutaline four times daily for subcutaneously was found to enhance tracheal mucus 1 week producecd no enhancement of mucociliary velocity in patients with cystic fibrosis (Wood et al., clearance in patieints with chronic bronchitis. 1975) and chronic obstructive lung disease (Santa In the presenIt studies, drug or placebo was Cruz et al., 1974) although not in normal subjects. administered innmediately before radioaerosol Oral administration of 5 mg terbutaline enhanced the inhalation, in ord(er that any coughing associated with clearance of lung secretions both in bronchitic administration of drug or placebo should not result in subjects and in healthy volunteers (Konietzko et al., removal of radi(oactive particles from the lungs. 1975). Compared to the control study, aerosol penetration To date, no study has demonstrated an enhance- was significantly reduced in drug and placebo studies, ment of mucus clearance from terbutaline sulphate in possibly because of an initial bronchoconstrictor aerosol form. Terbutaline (250 ,ug) given sub- effect as a resulIt of inhaling chlorofluorocarbon cutaneously appears to have a potent effect on mucus propellants or s urfactant. A transient broncho- clearance in subjects with obstructive airways disease constrictor effect (duration approximately 1 min) was (Santa Cruz etal., 1974; Wood etal., 1975; Mossberg noted in asthmattic subjects who inhaled fenoterol etal., 1976a,b), but we did not find the same to be true aerosol (Nolte eta1., 1979). This effect was ascribed to of a 1 mg dose given as an aerosol. Our technique is, the cold propellarnt spray, since it was reversed when however, capable of detecting enhancement of clear- the drug itself beg:an to act. Sterling & Batten (1969) ance following administration of respiratory drugs. also noted transient (duration < More rapid clearance has been noted in subjects with 5 min) after inihalation of placebo pressurised obstructive airway disease given the mucolytic aerosols. Since the time between terbutaline or bromhexine (Thomson etal., 1974), hypertonic saline placebo administration and radioaerosol inhalation aerosol (Pavia etal., 1978) and aminophylline (Sutton was approximate]ly 1 min in the present study, any et al., 1981). It is possible that the dose of terbutaline bronchoconstricti[on produced by the metered dose administered in the present study, although twice the aerosols might stilllhave been present when the radio- normal therapeutic dose, was too low. The inhaled aerosol was inhalled. A reduced API suggests that route is inefficient in its delivery of drug to the lung, radioaerosol depc)sition was shifted away from small since only about 10% of the aerosol dose reaches the airways towards lI arger, more central, airways in both airways (Newman etal., 1981). Only 100,ug of a 1 mg placebo and drulg studies. Alveolar deposition as dose would therefore reach the bronchial tree, and assessed by the 24 h whole lung retention of radio- the surface concentration of the drug particles on the aerosol, was simiilar for control, placebo and drug airway mucosa would be correspondingly small, studies, however No enhancement of the rate of particularly in the peripheral regions of the lung. It is mucus clearance iwas noted in the terbutaline study, possible that terbutaline aerosol given in twice the even though the transit path of the radioactive normal therapeutic dose is insufficient to stimulate EFFECTS OF TERBUTALINE SULPHATE AEROSOL 6" mucus clearance, even though this dose is able to give studies), so that the mucociliary clearance measure- marked bronchodilatation. ment is averaged over both large and small conducting It is interesting to note that published studies which airways. If terbutaline enhances clearance in the most have demonstrated an enhancement of mucus trans- central airways only, then this might be more readily port following subcutaneous administration of detected by methods which primarily assess clearance terbutaline are those in which measurements were from these regions. Spektor etal. (1979) have reported confined entirely or primarily to central lung zones. that oral administration of 20 mg orciprenaline, an- The technique used by Wood et al. (1975) and by other /3-adrenoceptor agonist, enhanced tracheal Santa Cruz et al. (1974) involved the monitoring of mucus velocity in healthy non-smokers, but did not opaque Teflon discs which had been previously in- increase overall clearance of particles from the lungs. troduced into the trachea, and tracheal mucus However, Sadoul et al. (1981), using a radioaerosol velocity was calculated from the rate of movement of technique which monitored clearance primarily from the discs observed by X-ray screening. The technique large central airways, were unable to detect an increase employed by Camner et al. (1976) and by Mossberg et in clearance in chronic bronchitic subjects given orally al. (1976a,b) involved the inhalation and subsequent 7.5 mg terbutaline daily. clearance of 6 ,um diameter Teflon particles. Teflon In conclusion therefore, terbutaline sulphate has a density of 2.1 g cm-3 so that the aerodynamic aerosol, given as twice as usual therapeutic dose, does diameter of these particles was 6 x \/2. 1 ,um, i.e. 8.7 not enhance whole lung mucociliary clearance in mild Am. Particles of this aerodynamic size are very asthmatics, even though marked bronchodilatation susceptible to deposition in large central airways of was produced. The reason for this may well be dose- the lungs (Lippman & Albert, 1969) and relatively related, or may occur because terbutaline promotes few reach the more peripheral zones. Clearance of clearance primarily in more central lung regions only. these particles therefore reflects chiefly mucus trans- Further studies are indicated in order to investigate port in large central airways. Our radioaerosol has an this problem further. aerodynamic diameter of 5 ,um, and is delivered more uniformly to the lungs, (on average 41% of the particles This work was supported by Astra Pharmaceuticals Ltd. has not been cleared from the lungs after 24 h in these

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