Effect of terbutaline on mucociliary clearance in asthmatic and healthy subjects after inhalation from a pressurised inhaler and a dry powder inhaler.

BACKGROUND: beta Agonists have been shown to increase mucociliary clearance in some studies but not all. Whether the formulation of beta agonists affects mucociliary clearance is not known but may be important as the use of dry powder inhalers increases. METHODS: The effect of different methods of administration of inhaled terbutaline on mucociliary clearance and forced expiratory volume in one second (FEV1) was assessed in 10 patients with asthma and 10 healthy subjects. Terbutaline (1 mg) was administered through a metered dose inhaler with a spacer (Nebuhaler) or a dry powder inhaler (Turbuhaler), or both treatments were given, in a four way double blind, double dummy trial. Mucociliary clearance was measured by bronchoscintigraphy. RESULTS: Clearance of radioactivity from the lobar bronchi increased in the asthmatic patients by a median of 32% after terbutaline was given by metered dose inhaler and 55% after a combined dose of 2 mg from both inhalers (1 mg from each) compared with placebo but by only 9% after 1 mg of terbutaline was given by a dry powder inhaler. In the healthy subjects mucociliary clearance increased by 51% when terbutaline was given by a dry powder inhaler, by 66% when given by a metered dose inhaler, and by 66% when given by both inhalers combined. The effect of terbutaline on FEV1 was the same with each of the inhalers. CONCLUSION: Despite similar changes in FEV1 with the two formulations terbutaline increased mucociliary clearance significantly in asthmatic and healthy subjects when inhaled from a metered dose inhaler whereas when it was inhaled from a dry powder inhaler its effect was significant only in healthy subjects. The reason for the difference in asthmatic subjects is unclear, but may be associated with differences in the deposition of terbutaline.     

Acute effect of inhaled bradykinin on tracheobronchial clearance in normal humans.

BACKGROUND: Bradykinin, a nonapeptide that contributes as a mediator to the pathogenesis of asthma, may affect lung mucociliary clearance, as it has been shown to be a potent secretagogue in canine airways and in human nasal mucosa in vivo. To evaluate this possibility the effect of inhaled bradykinin on mucociliary clearance has been studied in 10 healthy volunteers. METHODS: Subjects attended the laboratory on two occasions to take part in tracheobronchial clearance studies using a non-invasive radioisotopic technique. Inhalation of radioaerosol was followed 30 minutes later by inhalation of either bradykinin (8 mg/ml) or vehicle placebo in a randomised, double blind fashion. After each inhalation the number of coughs was recorded. Whole lung radioactivity was measured every half hour for six hours with two collimated scintillation counters, and a tracheobronchial clearance curve was plotted for each subject on each occasion. RESULTS: Mucociliary clearance, expressed as the area under the tracheobronchial radioaerosol retention curve calculated for the first six hours (AUC0-6h), was greater in nine out of 10 subjects after inhalation of bradykinin than after placebo. The median values (range) for AUC0-6h were significantly reduced from 126% (78-232%)/h with placebo to 87% (51-133%)/h with bradykinin. CONCLUSION: It is concluded that acute exposure to inhaled bradykinin accelerates tracheobronchial clearance in normal human airways.     

Effect of inhaled 15-(s)-hydroxyeicosatetraenoic acid on tracheobronchial clearance in normal human airways.

15-(s)-Hydroxyeicosatetraenoic acid (15-HETE) is the predominant metabolite of arachidonic acid in normal and asthmatic human airways and a potent mucus secretagogue in canine and human airways. A study was carried out on the effect of inhaled 15-HETE on tracheobronchial clearance, measured for six hours by a radioaerosol technique, in 10 normal subjects. Subjects inhaled 80 nmol 15-HETE or the diluent (sodium phosphate buffer) on two occasions at least two weeks apart in a double blind and randomised fashion (20 minutes after radioaerosol inhalation. Tracheobronchial clearance after inhaled 15-HETE was almost identical to that after placebo for all measurements up to six hours. It is concluded that 15-HETE has no effect on tracheobronchial clearance in normal human airways and is unlikely to account for the impaired mucociliary clearance seen in asthma.     

Effect of selective and non-selective beta blockade on pulmonary function and tracheobronchial mucociliary clearance in healthy subjects.

A controlled, double blind, crossover study was carried out to ascertain the effect of single doses of selective (100 mg atenolol) and non-selective (160 mg propranolol) beta blocker on pulmonary function and tracheobronchial mucociliary clearance. The study group comprised 12 healthy, young subjects. Adequate and comparable blockade was achieved with both drugs, the administration of which resulted in significantly lower pulse rates (at least up to eight hours after administration of the drug) and systolic blood pressures (three hours after drug administration) than were found with placebo. Small (of the order of 5%) but nevertheless statistically significant falls in FEV1 and forced vital capacity accompanied the administration of both beta blockers (but not the placebo) and were measurable up to eight hours after administration of the drug. Indices of pulmonary function had returned to normal by the next day. Peak expiratory flow and indices of small airways function remained unaltered after beta blockade. Mean tracheobronchial mucociliary clearance was depressed after administration of both beta blocking drugs, although the reduction was significant (p less than 0.05) only when propranolol was compared with placebo.     

Effect of temazepam on tracheobronchial mucus clearance.

BACKGROUND: Tracheobronchial clearance of mucus from the lungs is reduced during sleep and, usually, by the administration of opiates. It seemed possible therefore that temazepam, a widely used potent benzodiazepine, retarded clearance. METHODS: The effect of 10 mg temazepam on mucociliary clearance was studied in eight healthy volunteers, aged 18-50 (mean 30) years, in a randomised, placebo controlled, double blind, cross-over study. Six subjects were female and two male. Six were non-smokers and two were light current smokers. Clearance was assessed from the change in radio-activity in the lungs after inhalation of 5 microns diameter polystyrene particles, labelled with technetium-99m, under controlled conditions. RESULTS: Tracheobronchial clearance was reduced by 22% after temazepam by comparison with placebo during the first three hours after drug ingestion; this is the period when circulating drug concentrations are highest. CONCLUSION: Temazepam should be prescribed with caution in patients with impaired lung mucociliary transport.     

Effects of formoterol on histamine induced plasma exudation in induced sputum from normal subjects

BACKGROUND: A number of studies have shown that beta 2 agonists, including formoterol, inhibit plasma exudation induced by the inflammatory stimulus in animal airways. Whether clinical doses of beta 2 agonists inhibit plasma exudation in human bronchial airways is unknown. METHODS: In order to explore the microvascular permeability and its potential inhibition by beta 2 agonists in human bronchial airways a dual induction method was developed: plasma exudation induced by histamine inhalation followed by sputum induction by hypertonic saline (4.5%) inhalation. Sixteen healthy subjects received formoterol (18 micrograms) in a placebo controlled, double blind, crossover study. Sputum was induced on five occasions: once at baseline and four times after histamine challenge (30 minutes and eight hours after both formoterol and placebo treatments). Sputum levels of alpha 2-macroglobulin were determined to indicate microvascular-epithelial exudation of bulk plasma. RESULTS: Histamine induced plasma exudation 30 minutes after placebo was considerably greater than at baseline (median difference 11.3 micrograms/ml (95% confidence interval 0.9 to 90.0)). At 30 minutes after formoterol the effect of histamine was reduced by 5.1 (0.9 to 61.9) micrograms/ml compared with placebo. At eight hours histamine produced less exudation and inhibition by formoterol was not demonstrated. CONCLUSION: This study shows for the first time an anti-exudative effect of a beta 2 agonist in healthy human bronchial airways. Through its physical and biological effects, plasma exudation is of multipotential pathogenic importance in asthma. If the present findings translate to disease conditions, it suggests that an anti-exudative effect may contribute to the anti-asthmatic activity of formoterol.     

Effect of amiloride and saline on nasal mucociliary clearance and potential difference in cystic fibrosis and normal subjects.

BACKGROUND--Mucociliary clearance is an important component of pulmonary defence. Maximum clearance is thought to depend on an optimal depth of the sol layer, allowing the most efficient interaction between the cilia and the overlying mucus layer. Sodium absorption, the major ion transport in human airways, is thought to be important in the regulation of the depth of the sol layer. In the airways of patients with cystic fibrosis sodium absorption is increased and mucociliary clearance decreased. Amiloride, a sodium channel blocker, has been shown to improve pulmonary mucociliary clearance in patients with cystic fibrosis. However, its effects on nasal mucociliary clearance in either normal subjects or those with cystic fibrosis are unknown. A study was therefore performed to investigate whether nebulised amiloride improves nasal mucociliary clearance in normal or cystic fibrosis subjects. METHODS--Nasal mucociliary clearance was measured by the saccharin clearance technique in 12 normal subjects and 12 with cystic fibrosis. For the control study measurements were made on two consecutive days and the mean time for each subject averaged. For the drug study measurements were also made on two consecutive days, after administration of nasally nebulised amiloride or placebo (saline) in a double blind manner. Nasal potential difference was measured in eight patients with cystic fibrosis after the administration of amiloride or placebo to assess the efficacy of deposition and duration of action. RESULTS--Baseline values of mucociliary clearance were significantly faster in the normal subjects than in those with cystic fibrosis. In both groups mucociliary clearance was increased after both saline and amiloride, with no significant difference between either treatment. As previously reported, baseline nasal potential difference was significantly more negative in the subjects with cystic fibrosis. Amiloride significantly reduced the potential difference for at least 60 minutes in these subjects. CONCLUSIONS--Nebulised saline significantly improves nasal mucociliary clearance in both normal subjects and those with cystic fibrosis. Amiloride did not appear to exert any additional effects in either group of subjects, despite evidence of its efficacy of deposition.     

Comparison of nasal and tracheobronchial clearance by similar techniques in normal subjects.

Nasal and tracheobronchial mucociliary clearance have been compared in 10 healthy subjects. Nasal clearance was measured by monitoring the rate of removal of 2 microns diameter Teflon particles, labelled with 99mTc, which had been placed in the anterior part of the nose. Tracheobronchial clearance was measured with an objective radioaerosol technique, 5 microns diameter polystyrene particles being used. With these comparable techniques there was a close correlation between the nasal mucociliary clearance rate and both the area under the tracheobronchial clearance curve from 0 to 6 hours after radioaerosol inhalation (rs = -0.94, p less than 0.001) and the area under the tracheobronchial clearance curve from 0 to 2.5 hours after inhalation (rs = -0.79, p less than 0.01). The rate of clearance of small particles from the nose may thus be a useful guide to tracheobronchial clearance in healthy individuals.     

Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol.

Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.     

Effect of inhaled piriprost (U-60, 257) a novel leukotriene inhibitor, on allergen and exercise induced bronchoconstriction in asthma.

The leukotrienes, a group of oxidative metabolites of arachidonic acid, have potent pharmacological actions on human airways. We have investigated the effects of a leukotriene synthesis inhibitor, piriprost (U-60, 257) administered by inhalation on allergen and exercise induced bronchoconstriction in 12 subjects with allergic asthma. Subjects underwent diagnostic challenges with allergen and treadmill exercise to define the strengths of the stimuli required to reduce the FEV1 to about 25% of baseline (PS25). On separate study days subjects inhaled either piriprost 1 mg or vehicle placebo, followed 15 minutes later by the PS25 allergen or exercise. The FEV1 was measured at regular intervals before and after challenge up to 60 minutes. After allergen challenge in six subjects peak expiratory flow (PEF) was measured for the following 20 hours. When compared with placebo, inhalation of piriprost had no significant protective effect on the fall in FEV1 at any time point within 60 minutes of allergen or exercise challenge. In the four subjects with a documented late asthmatic reaction 2-12 hours after allergen challenge piriprost had no protective effect when compared with placebo. In the subjects who recorded PEF over 20 hours after allergen challenge there was no significant difference between piriprost and placebo. Piriprost was appreciably more irritant to the respiratory tract than was placebo. On the assumption that inhaled piriprost was bioavailable in the airways, this study casts doubt on any theory of a pivotal role for leukotrienes in the pathogenesis of acute exercise and allergen induced airway bronchoconstriction in asthma.     

Effect of oral bronchodilators on lung mucociliary clearance during sleep in patients with asthma.

BACKGROUND: Lung mucociliary clearance rates are reduced during sleep in patients with asthma. Methylxanthines and beta 2 agonists have been shown to enhance rates of lung mucociliary clearance. This study examined whether oral slow release bronchodilators may also have an effect on this clearance mechanism during sleep in patients with asthma. METHODS: Nine patients with asthma with a mean(SE) age of 65(5) years and percentage predicted forced expiratory volume in one second (FEV1 of 61(9)% participated in a double blind, placebo controlled, within subject crossover study to assess the effect of two weeks of treatment with salbutamol (Volmax; 8 mg twice daily) or theophylline (Phyllocontin; 350 mg twice daily) on lung mucociliary clearance during sleep. Lung mucociliary clearance rates were measured by a radioaerosol technique. RESULTS: The observation period for radioaerosol clearance was approximately 0.3 hours before sleep, 6.0 hours during sleep and 0.6 hours after sleep. Mean mucociliary clearance rates for theophylline, placebo and salbutamol before sleep were: 39, 39, and 32%/hour respectively; during sleep: 11, 10, and 9%/hour respectively; and after sleep: 39, 32, and 35%/hour respectively. CONCLUSION: During sleep lung mucociliary clearance in stable asthma was reduced, which is in agreement with the group's previous findings. Treatment with controlled/slow release oral bronchodilators had no effect on this reduced rate of clearance associated with sleep.     

Effect of ipratropium bromide on mucociliary clearance and pulmonary function in reversible airways obstruction.

The effects of (a) regular use for one week and (b) a single dose of a synthetic anticholinergic (ipratropium bromide) on lung mucociliary clearance and as a bronchodilator was ascertained in a controlled, double-blind, cross-over study in 12 patients with reversible airways obstruction (mean increase in FEV after isoprenaline: 17% range 10-50%). Two puffs from a metered dose inhaler of either placebo (propellants only) or drug (40 microgram) were administered four times a day for one week (regular use), and mucociliary clearance was measured, by radioaerosol tracer, at the end of each treatment period and after a control period in which no treatment was given. On the mornings of the measurements after the placebo and drug periods one final dose (single dose) of ipratropium (40 microgram) or placebo was given 2.5 hours before the start of the test. There was no statistically significant difference between the three mean mucociliary clearance curves (control, placebo, and drug) for the group; however, there was a significantly greater penetration towards the periphery of the lung of the tracer in the test after drug administration compared with the other two. This increased penetration was attributed to bronchodilatation caused by the drug. Ipratropium bromide does not appear to impair mucociliary clearance, and it acts an effective bronchodilator.     

A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung

Thomson, M. L., Pavia, D., and McNicol, M. W. (1973).Thorax, 28, 742-747. A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung. The effect of guaiphenesin (administered as Robitussin¹) on mucociliary clearance has been assessed in 15 subjects from the rate of removal from the lung of previously inhaled radioactive tracer particles. The guaiphenesin was compared with a positive control preparation consisting of the guaiphenesin vehicle only in two double-blind crossover trials. The first trial examined eight aged `healthy' volunteer subjects and the second trial examined seven chronic bronchitic patients. Sequential gamma counts were made from the whole lung by scintillation counters for 6 hours after inhalation and the chest was also scanned rectilinearly. In the first 5 hours after inhalation the mean rate of removal of particles and therefore of secretions was faster after guaiphenesin than after the control preparation. This difference was not statistically significant in the healthy volunteers but achieved significance (P <0·05) in the chronic bronchitic patients. Lung scans after inhaling the tracer aerosol indicated that on average the initial penetration of the particles into the lung was similar in the guaiphenesin and control runs. The faster clearance after guaiphenesin was unlikely to be due to bulk movements of mucus caused by coughing since the mean frequency of coughing during the experiment was somewhat less after the drug.     

Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency.

Despite the in vitro ciliotoxicity of tobacco smoke and the abnormal mucociliary clearance found in smoking related chronic bronchitis, studies of mucociliary clearance in healthy smokers have produced variable results. The nasal mucociliary clearance of saccharin and the in vitro nasal ciliary beat frequency were studied in healthy smokers and non-smokers. One of 29 smokers had a nasal mucociliary clearance time of over 60 minutes; in the remaining 28 the mean (SD) clearance time was 20.8 (9.3) minutes, which was significantly longer (p less than 0.001) than the mean time of 11.1 (3.8) minutes in 27 lifelong non-smokers. There was no significant difference between the mean nasal ciliary beat frequency of 10 smokers and 10 non-smokers. There were no significant differences in mean ciliary beat frequency or mean nasal mucociliary clearance time after 10 healthy non-smoking volunteers had smoked two cigarettes each, exhaling the smoke through their nostrils. Unless there is a prompt reversal of any ciliotoxic effect of tobacco smoke when cilia are removed for in vitro examination, the defective clearance seen in chronic cigarette smokers seems unlikely to be due to slowed ciliary beat frequency. It may be due to reduction in number of cilia or to change in the viscoelastic properties of mucus. The failure to detect any acute effect of tobacco smoke is in keeping with this hypothesis.     

Effect of the antitussive glaucine on bronchomotor tone in man

In view of the observation that the antitussive agent glaucine prevents histamine-induced bronchoconstriction in guinea pigs we investigated this agent for a possible peripheral action in man, using a new method for measuring changes in bronchomotor tone. The forced airflow oscillation method was used to determine respiratory resistance (Rrs) over a range of lung volumes (VL) in seven healthy supine subjects. Computer analysis of the hyperbolic relationship between Rrs and VL was used to determine the asymptotic resistance and yield estimates of lower airways conductance (Glaw). Specific lower airways conductance (sGlaw) was expressed as the slope of the linear plot of Glaw against VL and is a sensitive index of bronchomotor tone. After baseline measurements of sGlaw subjects received placebo or 60 mg glaucine orally according to a double-blind crossover protocol. Histamine, 500 micrograms, was inhaled 45 minutes later. Measurements of sGlaw were repeated every 10 minutes for two hours. Although there was a trend towards bronchodilatation after glaucine administration (sGlaw = 130% of baseline) there was no significant difference from the effect of placebo (sGlaw = 89% of baseline). After inhalation of histamine sGlaw fell to 26% of baseline after both glaucine and placebo (p less than 0.01). In a further study three subjects received glaucine and placebo according to an identical protocol except that the histamine was omitted. Again the increase in sGlaw failed to achieve significance. Glaucine does not affect the bronchoconstrictor response to histamine in man and there is no convincing evidence of an effect on resting bronchomotor tone.     

Increase in mucociliary clearance in normal man induced by oral high frequency oscillation.

Data on the effect on mucociliary clearance of oral high frequency oscillation is conflicting. By means of a technique to superimpose high frequency oscillation on tidal breathing, changes in mucociliary clearance during high frequency oscillation were studied in seven normal non-smokers by monitoring the clearance of inhaled radiolabelled aerosol from the lungs. After inhalation of 5 microns technetium 99m labelled particles under controlled conditions, whole lung clearance was monitored by scintillation counters half hourly for six hours with a final count at 24 hours, from which tracheobronchial deposition and clearance could be calculated. Control and high frequency oscillation studies were performed on separate days in random order. Oral high frequency oscillation was applied by a bass loudspeaker through a mouthpiece to superimpose sinewave oscillations (RMS input pressure 1.2 cm H2O, mean pressure zero) on normal breaths. On high frequency oscillation days 30 minutes of oscillation alternated with 30 min of rest. Between 3 and 4.5 hours mucociliary clearance with high frequency oscillation exceeded control by about 10% (p less than 0.05). The mean time taken to eliminate 90% of deposited radioaerosol from the tracheobronchial tree fell from 4 hours 50 minutes (range 1 h 52 min-6 h 50 min) during control to 3 hours 43 minutes (range 2 hr 28 min-5 hr 54 min) during the high frequency oscillation run (p less than 0.05). Possibly this comfortable, simple technique would be of therapeutic benefit to patients with chronic sputum retention and merits further investigation.     

Nifedipine enhances the bronchodilator effect of salbutamol.

Ten male asthmatic volunteers each inhaled two puffs (200 micrograms) of salbutamol on two separate days 30 minutes after double blind oral administration of either 20 mg nifedipine or identical placebo. FEV1 was recorded before and at intervals for four hours after inhalation of salbutamol. Overall the FEV1 was significantly greater during the four hour period after premedication with nifedipine (p less than 0.025) and the difference between the effects of placebo and nifedipine was greatest four hours after salbutamol (p less than 0.005). These results suggest that nifedipine prolongs the bronchodilator action of salbutamol in vivo.     

Tracheobronchial mucociliary clearance in asthma: impairment during remission.

Tracheobronchial mucociliary clearance was measured in eight non-smoking patients with asthma in complete remission. The patients were symptom free and required no medication whatsoever for one to six months before assessment. Mucociliary clearance was measured with an objective, radioaerosol technique. For comparison, mucociliary clearance of eight non-smoking, healthy subjects with physical characteristics and pulmonary function similar to those of the asthmatics was also measured on two occasions. In their first assessment the healthy subjects inhaled the tracer radioaerosol under experimental conditions similar to those used for the asthmatics; in the second assessment they inhaled the radioaerosol rapidly to simulate the asthmatic pattern of deposition. Under similar experimental conditions the radioaerosol was deposited more proximally in the asthmatic subjects than in the normal subjects and the difference was statistically significant (p less than 0.01). When, however, the depth of radioaerosol lung penetration was similar in the two groups, there was evidence of a significantly (p less than 0.01) poorer mucociliary clearance six hours after radioaerosol inhalation in the asthmatic than in the healthy group. These findings raise the question whether asthma ever remits completely.     

Time course of bronchodilating effect of inhaled formoterol, a potent and long acting sympathomimetic.

BACKGROUND: Most of the currently available inhaled beta 2 agonists are short acting bronchodilators. The aim of this study was to compare the rate of onset and duration of the bronchodilating activity of formoterol and salbutamol. METHODS: Fourteen patients with reversible airways obstruction received placebo, 200 micrograms salbutamol, and 12, 24, and 48 micrograms formoterol from a metered dose inhaler, according to a double blind, randomised crossover design. Forced expiratory volume in one second (FEV1) and specific airways conductance (sGaw) were measured over 12 hours. RESULTS: Salbutamol and all doses of formoterol caused a significant and substantial increase in sGaw one minute after inhalation. The mean maximum increase in FEV1 was 58% (8%) after 200 micrograms salbutamol compared with 63% (11%), 62% (10%), and 74% (10%) after 12, 24, and 48 micrograms formoterol, respectively. The mean maximum increase in FEV1 occurred 57 (12) minutes after administration of salbutamol compared with 137 (16), 141 (21), and 161 (33) minutes after 12, 24, and 48 micrograms formoterol respectively. The bronchodilating effect of salbutamol did not differ from placebo after six hours. In contrast, the mean increase in FEV1 12 hours after 12 micrograms formoterol (26% (8%) of baseline) significantly exceeded the change after placebo. Tremor was recorded in four patients after 48 micrograms formoterol. CONCLUSION: Formoterol is a potent, fast acting bronchodilator with a long duration of action.     

Difference in pulmonary absorption of inhaled terbutaline in healthy smokers and non-smokers.

Pathophysiological studies have shown that the alveolocapillary transfer of small solutes is much faster in healthy smokers than in non-smokers. The effects of smoking on the pulmonary absorption of inhaled terbutaline were examined in normal subjects. Nine healthy smokers and 13 healthy non-smokers inhaled nebulised terbutaline and dry terbutaline powder on two study days. Plasma concentrations of terbutaline were measured up to 240 minutes after the inhalation. The plasma concentration of terbutaline rose much faster in smokers than in non-smokers, the mean time to peak terbutaline concentration being 17 minutes in the smokers and 50 minutes in the non-smokers. The peak plasma concentration was nearly twice as high in the smokers as in the non-smokers, being 21 mmol/l and 23 mmol/l for the dry powder inhalation and nebuliser respectively in the smokers and 12 mmol/l and 14 mmol/l in the non-smokers. It is concluded that smoking increases the rate of terbutaline absorption and the peak plasma concentration achieved. The rapid pulmonary absorption of terbutaline in smokers may affect the onset of action of the drug and the duration of its therapeutic effects.