- Email: [email protected]
A comparative double-blind study of the bronchodilator effects and side effects of inhaled fenoterol and terbutaline administered in equipotent doses
Br. .I. Dis.
Chest
(1982)
76,
341
A COMPARATIVE DOUBLE-BLIND STUDY OF THE BRONCHODILATOR EFFECTS AND SIDE EFFECTS OF INHALED FENOTEROL AND TERBUTALINE ADMINISTERED IN EQUIPOTENT DOSES B. J. GRAY, The
Chest
Unit,
King’s
College
M. HI. FRAME Hospital Astra
AND
Medical School Pharmaceuticals,
J. F. COSTELLO and Ltd
the
Clinical
Trials
Department,
Summary
Increasing doses of fenoterol and terbutaline were administered by inhaler to 12 stable asthmatics in a double-blind crossover trial. 1OOpg doses of fenoterol were shown to be equal in potency to 25O~g doses of terbutaline, as measured by increases in forced expiratory volume in the first second (FEVr) and specific airways conductance (sGaw). FEVr and sGaw remained significantly greater than pretreatment levels up to five hours after both drugs and terbutaline showed a significantly greater effect on FEV, than fenoterol after four hours suggesting a small but significantly longer duration of activity. Fenoterol used at the dosage of 100 lg per puff (half the standard commercially available dose of 2OOpg per puff) caused significantly more cardiac effects than terbutaline, as measured by the magnitude and duration of increases in heart rate, and the incidence of reported palpitations.
Introduction Both terbutaline and fenoterol are highly active p-adrenergic agonists. When given by metered dose aerosol they produce rapid and sustained bronchodilatation in patients with reversible airflow obstruction (Ericksson & Lindgren 1978; Sackner & Silva 1978; Anderson et al. 1979). The importance of using equipotent doses of inhaled P-agonists, when assessing their relative efficacy, duration of activity and incidence of side effects has been stressed (Freedman 1972; Madsen et al. 1979) and Heel et al. (1978) showed that the dosages used in past trials have varied widely, with confusing and often conflicting results. In this study, we have established equipotent dosages of inhaled terbutaline and fenoterol, in terms of comparable increases produced in the forced expiratory volume in the first second (FEVr) and specific airways conductance (sGaw) in
B. J. Gray, M. H. Frame and J. F. Costello stable asthmatic patients. By using a wide dose range, it has been possible to compare accurately the duration of activity and assess the side effects of terbutaline and fenoterol.
Patients and Methods Patients Twelve stable asthmatic patients (seven female, five male) attending the Asthma Clinic at King’s College Hospital took part in the trial. The mean age was 33 years (range 18-62 years). All patients had previously shown at least a 20% increase in FEVt after inhaled o-agonist, and all were taking inhaled P-agonist regularly (salbutamol, eight; terbutaline, two; fenoterol, one; and orciprenaline, one). In addition seven patients were taking inhaled beclomethasone, four inhaled disodium cromoglycate, seven oral aminophylline and two oral prednisolone (5 mg and 7.5 mg daily). The patients gave informed consent for the study, and permission was obtained from the Ethics Committee, King’s College Hospital. Procedure The trial design was double blind with crossover of active terbutaline and fenoterol inhalers between study days. Standard metered dose aerosols were used delivering 1OOpg of fenoterol hydrobromide (WB Pharmaceuticals) per puff, or 250 /..tg of terbutaline sulphate (Astra Pharmaceuticals) per puff. Before each study day the patients were asked to discontinue their usual inhaled &agonist for the preceding 12 hours and oral aminophylline for the preceding 36 hours. Patients on oral or inhaled steroids or inhaled disodium cromoglycate were allowed to continue on these agents in unaltered doses throughout the study. The patients attended on three days, approximately five days apart. On the first day, the patients were instructed in the routine of the study and baseline FEVt was measured. They were then given placebo inhalers (containing propellant only) in a cumulative dose of 7 puffs (1 + 2 + 4) puffs of both at 15 minute intervals. FEVr was measured after each dose, to assess whether any bronchoconstriction resulted from the inhalation of propellant mixtures. On study days 2 and 3, the procedure was similar. Each patient was allowed to rest quietly for 30 minutes after arriving. Baseline values for FEVi (vitalograph), blood pressure, pulse rate, thoracic gas volume and airways resistance (Collins Whole Body Plethysmography, Warren E Collins, Inc) were measured. From the plethysmographic data, specific airways conductance (sGaw) was calculated (Dubois et al. 1956). The patients were randomly allocated two inhalers on each of days 2 and 3. One inhaler contained either terbutaline or fenoterol, the other inhaler was a placebo containing propellant only. The allocation was double blind, and the active inhalers were crossed over between days 2 and 3 so that each patient acted as his/her own control. Patients were not studied on day 3 unless the baseline FEVr on that day was within 15% of baseline FEVr on day 2. In the first part of the study a dose-response relationship was established in order to determine the equipotent dose of fenoterol and terbutaline. Patients took 1,2,4 and 8 puffs of each inhaler, active and placebo according to a previously constructed randomized code. Measurements of FEVi (best of three observations), heart rate and sGaw (best of three observations) were made every 15 minutes after each dose until a stable maximum response was recorded. Blood pressure was measured after the administration of the maximum dose. Cumulative doseresponse curves were constructed from these data. When a stable plateau had been reached after the maximum cumulative dose was given the patients were observed for a further five hours on each day to assess the duration of activity of each drug. Heart rate, FEVi and sGaw were measured every 30 minutes and blood pressure
Fenoterol
and Terbutaline:
Effects
of Equipotent
Doses
343
measured at the end of the study. The Student t-test for paired data was used to assess the significance of any differences in response to the two drugs. FEVr and sGaw are expressed as mean maximum percentage increases over pretreatment values and plotted against the log cumulative dose. Heart rate is expressed as mean maximum increase in beats per minute over pretreatment values. To assess duration of activity, FEVr and sGaw are expressed as mean percentage of maximum response and heart rate as mean increase over pretreatment value at each point. All numerical results are expressed as mean value +standard error of the mean (SEM).
Results The trial was completed by all 12 patients. The first day measured the changes in FEVl after taking cumulative doses of both placebo inhalers containing propellant only. After a cumulative dose of 7 puffs, there was a mean fall (* SE) in FEVl of 3 .l + 3.8% which was not statistically significant.
0 Terbutaline
0.25mg
0 Fenoterol
O.lmg LOG
CUMULATIVE
0.75mg
1.75mg
3.75mg
0.3mg
0.7mg
1,Smg
DOSE
Fig. 2. Log dose-response curves, comparing increases in FEVt (‘SE) after terbutaline with those after fenoterol. There was no significant difference in response (P> 0.05) between terbutaline and fenoterol at any dose level
Dose-response
analysis
In Fig. 1 the mean maximum percentage increases in FEV, after fenoFEV1. terol and terbutaline, are plotted against the log cumulative doses. Both drugs produced significant mean increases in FEVr over mean baseline values after the first dose (fenoterol 31.7-+ 6.6% P< 0.001, terbutaline 30.4+ 8.4% PC 0.005). There were no significant differences in the mean maximum FEVl increases 28
B. J. Gray, M. H. Frame and J. F. Costello
344
produced after a cumulative dose of 1,3, 7 or 15 puffs of fenoterol or terbutaline. The mean maximum peak response was not significantly different after the maximum dose of each drug; for fenoterol it was 68.7 -+9.3% and for terbutaline 71.5 + 11.1% (P > 0.5). In Fig. 2 the mean percentage increases in sGaw are plotted against the sGaw. log cumulative doses of terbutaline and fenoterol. As with FEVl both agents produced significant mean maximum increases in sGaw after the first dose (fenoterol63.4+ 19.6% P< 0.01, terbutaline 65 _+15.8%P < 0.005). The responses to terbutaline and fenoterol in terms of mean maximum percentage increase in sGaw, were not significantly different at any dose levels. 220200 B =:
180-
t 160 iz 9 g
140-
f +
120-
z 2 &
5 9
loo-
40' 0-k l Terbutaline
' 0.25mg
0.75mg
1.75mg
3.75mg
0 Fenoterot
O,lmg
0.3mg
0.7mg
1.5mg
I
LOG
CUMULATIVE
I
DOSE
Fig. 2. Log dose-response curves, comparing increases in sGaw (5 SE) after terbutaline to those after fenoterol. There was no significant difference in response (P> 0.05) between terbutaline and fenoterol at any dose level Heart rate. The mean baseline valu& for heart rate before fenoterol was administered was 85 + 2.4 beats per minute, and before terbutaline was administered 84 + 2.4 beats per minute; the difference was not significant (P > 0.5). The mean maximum increases in heart rate after fenoterol and terbutaline are shown in Table I. There was a small increase in mean maximum heart rate after the first dose of terbutaline (2.4 beats per minute +_1.3 P > 0.05) and a significant and larger increase in mean maximum heart rate after the first dose of fenoterol (6.3 beats per minute+- 1.4 P< 0.001). The mean maximum increase in heart rate after fenoterol was higher at all dose levels than after terbutaline. This difference reached statistical significance after 1, 7 and 15 puffs of fenoterol compared with the equivalent of terbutaline (Table I).
0.1 0.3 0.7 1.5
mg mg mg mg
Cumulative fenoterol
(1 puff) (3 puffs) (7 puffs) (15 puffs)
dose
I.
Increase
63 10.8 15.3 25
k * + +
1.4 2.3 2.5 3.1
Mean maximum increase in heart rate (+ SE) beats per minute fenoterol
Table
< < < <
0.001 0.001 0.001 0.001
P
in heart
following
0.25 0.75 1.75 3.75
mg mg mg mg
dose
the
(1 puff) (3 puffs) (7 puffs) (15 puffs)
Cumulative terbu taline
rate
of
+ 13 +_ 1.7 9 +_ 1.7 15 + 3.3
2.4 6.5
< < < <
terbutaline
Mean maximum increase in heart rafe (‘SE) beats per minute terbu taline
administration
0.05 0.005 0.001 0.001
P
NS
and
3.9 4.3 6.3 10
_+ 1.3 * 2.3 _+ 1.9 * 3.3
Difference in mean maximum increase in heart rate (2 SE) beats per minute
fenoterol
< 0.05 NS < 0.01 < 0.02
P
346
B. J. Gray, M. H. Frame and J. F. Costello
Blood pressure. There was no significant difference from pretreatment systolic and diastolic blood pressure after taking fenoterol or terbutaline at maximum cumulative dose. Duration
of activity
The second part of the study consisted of assessing the duration of activity in terms of FEVr , sGaw, heart rate and blood pressure of the two drugs. FEV,. In Fig. 3 the mean FEVl expressed as a percentage of maximum response is plotted against time, every 30 minutes for five hours after maximum response.
c5 2 2 70 -f 0
1 60 0 Terbutaline
1 180
120 TIME
I 2LO
8 300
(MINS)
0 Fenoterol
Fig. 3. Decline in FEV, from mean maximum value plotted every 30 minutes (*SE) for 5 hours after terbutaline and fenoterol. From 240 to 300 minutes, terbutaline had a significantly greater activity than fenoterol (X: P < 0.01, 0: P < 0.005)
Values for FEV, declined steadily with time, for both terbutaline and fenoterol. There was no significant difference in the mean FEVr expressed as a percentage of maximum response until 240 minutes. At this point, the mean per cent maximum FEVr was significantly greater for terbutaline than for fenoterol, the mean difference being 4.5 + 1.6% (P < 0.01). This trend is continued at 270 and 300 minutes, the respective differences were 7.6 + 1.7%(P< 0.005) and 7.06 +_ 1.9% (PC 0.005). Thus, the effect of terbutaline in terms of FEV, was significantly greater than fenoterol between 240 and 300 minutes. sGaw. Fig. 4 shows sGaw expressed as apercentage of mean maximum response, plotted against time. sGaw shows a steady decline over the five hours of observation to 60.9 f 3.5% of maximum sGaw for fenoterol and 66 _+3.6% of maximum
Fenoterol
k Y E a
and Terbutaline:
Effects
of Equipotent
Doses
347
50 -
40 0
60
l
120
Terbutaline
TIME
180 (MINS
240
300
1
0 Fenoterol
Fig. 4. Decline in sGaw from mean maximum value plotted 5 hours after terbutaline and fenoterol. There was no significant and fenoterol at any point
every 30 minutes difference between
MEAN INCREASE IN HEART RATE OVER
0 Terbutaline 0 Fenoterol
PRE-TREATMENT RATE (Beats
per
Cumulatwe Dose
mini
(‘SE) for terbutaline
20 -
Terbutallne i Fenoterol
0 25
0 75
1.75
0 375mg
0 1
0 3
0 7
15mg
60
120 TIME
180
240
300
IMINS)
5. The effect of terbutaline and fenoterol on heart rate (k SE). The increase in heart rate was significantly greater after fenoterol than after terbutahne at the indicated significant levels. (ns: not significant, *:P< &05,&P< 0.03,x:Pc 0.02,&P< 0.005
Fig.
for terbutaline. There is no significant difference between the mean fall after fenoterol and the mean fall after terbutaline at any point on these curves. Heart rate. Mean increase in heart rate is plotted against time in Fig. 5. Mean heart rate after fenoterol administration is significantly higher than after terbuta-
348
B. J. Gray, M. H. Frame and J. F. Costello
line, at each point during the five hour observation period. At 150 minutes after terbutaline the mean increase in heart rate was not significantly greater than baseline (4.8 + 2.25 beats per min, P> 0.05). From 150 to 300 minutes after taking terbutaline mean heart rate was not significantly above baseline, while after taking fenoterol, mean heart rate remained significantly elevated until the end of the observation period at five hours (5.7 + 2.1 beats per minute P< 0.025). Side effects Palpitation. Six patients complained of palpitation within 10 minutes of taking the maximum cumulative dose of fenoterol (15 puffs), and one patient who also had palpitations after fenoterol complained of palpitation after taking the equivalent dose of terbutaline. The pulse rate in all six patients complaining of palpitations was greater than 100 beats per minute (mean 118 beats/min +_ 4.1 beats/min). Tremor. Three patients developed tremor after fenoterol, two after a cumulative dose of 8 puffs and one after a cumulative dose of 15 puffs. One patient developed tremor after a cumulative dose of 15 puffs of terbutaline. Discussion Large and rapid increases in FEVl and sGaw followed the administration of the lowest dose of both terbutaline and fenoterol (Figs 1 and 2), with further increases at each dose level. Heel et al. (1978) h ave reviewed the many combinations of dosages used in trials comparing fenoterol with other fl-adrenergic agonists. In this trial the doseresponse curves for FE& and sGaw show that terbutaline in a dose of 25Opg per puff is equipotent to fenoterol 1OOpg per puff. Anderson et al. (1979) and Petit and Roberts (1973) both showed that inhaled fenoterol had a longer duration of activity than terbutaline, but these studies did not attempt to define and use equipotent doses, and with the equipotent dosages used in the present study terbutaline had a small but significantly greater duration of activity than fenoterol. Carmichael et al. (1980) also found that terbutaline given by intermittent positive pressure breathing had a significantly longer duration of activity than fenoterol given by the same method. When given over longer periods terbutaline has been shown to have a more sustained effect than fenoterol (Trembath et al. 1979). Asthmatic patients given terbutaline by infusion and inhalation, even in relatively large doses, have few cardiovascular side effects (Thiringer & Svedmyr 1976). We have shown at all dose levels that there was a significantly smaller increase in heart rate after terbutaline than after fenoterol, even though the metered dose of fenoterol used was half the commercially available standard dose. The heart rate returned to baseline levels within two and a half hours of taking the maximum cumulative dose of terbutaline but remained significantly above pretreatment levels for the whole five hours after taking the equipotent dose of fenoterol.
Fenoterol
and Terbutaline:
Effects
of Equipotent
Doses
349
Half the patients complained of palpitation after taking the maximum cumulative dosage of fenoterol, compared with one patient who had palpitations following the equipotent dose of terbutaline. These results show significantly more cardiovascular effects from fenoterol and suggest that terbutaline has greater fiz-adrenergic receptor specificity in accord with previous pharmacological studies (Persson & Johnson 1970; O’Donnell & Wanstall 1974). Many methods of expressing and analysing data obtained when comparing the effects of different fi-adrenergic agonists on asthmatics have been proposed (Madsen et al. 1979). We have expressed our results as mean percentage changes from fixed reference points, either mean pretreatment values or mean maximum response. It is generally agreed that the expression of changes in measured indices in relative terms (such as percentage change from baseline) is preferable to the expression of results as absolute changes (Minette 1970; Kerridge 1977). However with a small degree of within-subject variation (less than 15% variation in pretreatment FEVl between study days in this trial) Racoveau et al. (1971) have argued that data can be accurately expressed either as absolute or relative values.
Acknowledgements We wish to thank Astra Pharmaceuticals and WB Pharmaceuticals, who supplied trial material, and the technical staff, Chest Unit, King’s College Hospital, for their help during the study. We would also like to thank Maggy Gleeson for secretarial assistance.
References Anderson, G., Wilkins, E. & Jariwalla, A. G. (1979) F enoterolin asthma.Br. J. Dir. Chest 73, 81. Carmichael, J., Bloomfield, P. & Crompton, G. K. (1980) Comparison of fenoterol and terbutaline administered by intermittent positive pressure breathing. BY. J. Dis. Chest 74, 268. Dubois, A. B., Botelho, S. Y. & Comroe, J. H., Jr. (1956) A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J. din. Invest. 35, 327. Eriksson, N. E. & Lindgren, S. B. (1978) The rapidity of bronchodilatation; a comparison of isoprenaline, terbutaline, and rimiterol. Stand. J. resp. Dis. 59, 30. Freedman, B. J. (1972) Trial of terbutaline aerosol in the treatment of asthma, and acomparison of its effects with those of a salbutamol aerosol. Br. J. Dis. Chest 66, 222. Heel, R. C., Brigden, R. N., Speight, T. M. & Avery, G. S. (1978) Fenoterol: a review of its pharmacological properties and therapeutic efficacy in asthma. Drugs 15, 3. Kerridge, D. F. (1977) Statistics for clinical trials in asthma. In Methods in Clinical Trials in Asthma. Proceedings of a British Thoracic and Tuberculosis Society Meeting, ed. J, E. Stark and J. V. Collins. BY. J. Dis. Chest 71, 227. Madsen, B. W., Tandon, M. K. & Paterson, J. W. (1979) Crossover study of the efficacy of four p2 sympathomimetic bronchodiIator aerosols. Br. J. din. Pharmacol. 8, 75. Minette, A. (1970) Spirometric study of the bronchodilating effects of hydroxyphenyl orciprenaline (Th:l165a) in various forms, in a group of 125 coal miners suffering from bronchospasm. Respiration 27, 276.
B. J. Gray, M. H. Frame and J. F. Costello 0 ‘Donnell, S. R. & Wanstall, J. C. (1974) Potency and selectivity in vitro of compounds related to isoprenaline and orciprenaline on 0 adenoreceptors in the guinea pig. BY. J. Pharmacol. 52,407. Persson, H. & Johnson, B. (1970) A dual preparation technique for studying the differentiation of effect of sympathomimetic agents on heart and tracheal muscle. Acta. med. stand. Suppl. 5.2, 21. Petit, J. M. SC Roberts, M. (1973) Comparison des effets bronchodilatateurs de l’inhalation d’aerosols dhydroxphknylorciprdnaline et d’autres agents P-adrdnergiques. Rev. Me’d. Likge.
28,
288.
Racoveau, U. C., Stanescu, D. C., Manicatide, M. & Stroescu, V. (1971) The bronchodilator effects of orciprenaline and salbutamol. A double-blind study. Postgrad. med. J. Suppl. 47, 83. Sackner, M. A. & Silva, G. (1978) Effects of terbutaline aerosol in reversible airways obstruction. Chest 73, 802. Thiringer, G. & Svedmyr, M. (1976) Comparison of infused and inhaled terbutaline in patients with asthma. Stand. J. resp. Dis. 57, 17. Trembath, P. W., Greenacre, J. K., Andersson, M., Dimmock, S., Mansfield, L., Wadsworth, J. & Green, M. (1979) Comparison of four weeks’ treatment with fenoterol and terbutaline aerosols in adult asthmatics. J. Allergy Clin. Immunol. 63, 395.
Chest
(1982)
76,
341
A COMPARATIVE DOUBLE-BLIND STUDY OF THE BRONCHODILATOR EFFECTS AND SIDE EFFECTS OF INHALED FENOTEROL AND TERBUTALINE ADMINISTERED IN EQUIPOTENT DOSES B. J. GRAY, The
Chest
Unit,
King’s
College
M. HI. FRAME Hospital Astra
AND
Medical School Pharmaceuticals,
J. F. COSTELLO and Ltd
the
Clinical
Trials
Department,
Summary
Increasing doses of fenoterol and terbutaline were administered by inhaler to 12 stable asthmatics in a double-blind crossover trial. 1OOpg doses of fenoterol were shown to be equal in potency to 25O~g doses of terbutaline, as measured by increases in forced expiratory volume in the first second (FEVr) and specific airways conductance (sGaw). FEVr and sGaw remained significantly greater than pretreatment levels up to five hours after both drugs and terbutaline showed a significantly greater effect on FEV, than fenoterol after four hours suggesting a small but significantly longer duration of activity. Fenoterol used at the dosage of 100 lg per puff (half the standard commercially available dose of 2OOpg per puff) caused significantly more cardiac effects than terbutaline, as measured by the magnitude and duration of increases in heart rate, and the incidence of reported palpitations.
Introduction Both terbutaline and fenoterol are highly active p-adrenergic agonists. When given by metered dose aerosol they produce rapid and sustained bronchodilatation in patients with reversible airflow obstruction (Ericksson & Lindgren 1978; Sackner & Silva 1978; Anderson et al. 1979). The importance of using equipotent doses of inhaled P-agonists, when assessing their relative efficacy, duration of activity and incidence of side effects has been stressed (Freedman 1972; Madsen et al. 1979) and Heel et al. (1978) showed that the dosages used in past trials have varied widely, with confusing and often conflicting results. In this study, we have established equipotent dosages of inhaled terbutaline and fenoterol, in terms of comparable increases produced in the forced expiratory volume in the first second (FEVr) and specific airways conductance (sGaw) in
B. J. Gray, M. H. Frame and J. F. Costello stable asthmatic patients. By using a wide dose range, it has been possible to compare accurately the duration of activity and assess the side effects of terbutaline and fenoterol.
Patients and Methods Patients Twelve stable asthmatic patients (seven female, five male) attending the Asthma Clinic at King’s College Hospital took part in the trial. The mean age was 33 years (range 18-62 years). All patients had previously shown at least a 20% increase in FEVt after inhaled o-agonist, and all were taking inhaled P-agonist regularly (salbutamol, eight; terbutaline, two; fenoterol, one; and orciprenaline, one). In addition seven patients were taking inhaled beclomethasone, four inhaled disodium cromoglycate, seven oral aminophylline and two oral prednisolone (5 mg and 7.5 mg daily). The patients gave informed consent for the study, and permission was obtained from the Ethics Committee, King’s College Hospital. Procedure The trial design was double blind with crossover of active terbutaline and fenoterol inhalers between study days. Standard metered dose aerosols were used delivering 1OOpg of fenoterol hydrobromide (WB Pharmaceuticals) per puff, or 250 /..tg of terbutaline sulphate (Astra Pharmaceuticals) per puff. Before each study day the patients were asked to discontinue their usual inhaled &agonist for the preceding 12 hours and oral aminophylline for the preceding 36 hours. Patients on oral or inhaled steroids or inhaled disodium cromoglycate were allowed to continue on these agents in unaltered doses throughout the study. The patients attended on three days, approximately five days apart. On the first day, the patients were instructed in the routine of the study and baseline FEVt was measured. They were then given placebo inhalers (containing propellant only) in a cumulative dose of 7 puffs (1 + 2 + 4) puffs of both at 15 minute intervals. FEVr was measured after each dose, to assess whether any bronchoconstriction resulted from the inhalation of propellant mixtures. On study days 2 and 3, the procedure was similar. Each patient was allowed to rest quietly for 30 minutes after arriving. Baseline values for FEVi (vitalograph), blood pressure, pulse rate, thoracic gas volume and airways resistance (Collins Whole Body Plethysmography, Warren E Collins, Inc) were measured. From the plethysmographic data, specific airways conductance (sGaw) was calculated (Dubois et al. 1956). The patients were randomly allocated two inhalers on each of days 2 and 3. One inhaler contained either terbutaline or fenoterol, the other inhaler was a placebo containing propellant only. The allocation was double blind, and the active inhalers were crossed over between days 2 and 3 so that each patient acted as his/her own control. Patients were not studied on day 3 unless the baseline FEVr on that day was within 15% of baseline FEVr on day 2. In the first part of the study a dose-response relationship was established in order to determine the equipotent dose of fenoterol and terbutaline. Patients took 1,2,4 and 8 puffs of each inhaler, active and placebo according to a previously constructed randomized code. Measurements of FEVi (best of three observations), heart rate and sGaw (best of three observations) were made every 15 minutes after each dose until a stable maximum response was recorded. Blood pressure was measured after the administration of the maximum dose. Cumulative doseresponse curves were constructed from these data. When a stable plateau had been reached after the maximum cumulative dose was given the patients were observed for a further five hours on each day to assess the duration of activity of each drug. Heart rate, FEVi and sGaw were measured every 30 minutes and blood pressure
Fenoterol
and Terbutaline:
Effects
of Equipotent
Doses
343
measured at the end of the study. The Student t-test for paired data was used to assess the significance of any differences in response to the two drugs. FEVr and sGaw are expressed as mean maximum percentage increases over pretreatment values and plotted against the log cumulative dose. Heart rate is expressed as mean maximum increase in beats per minute over pretreatment values. To assess duration of activity, FEVr and sGaw are expressed as mean percentage of maximum response and heart rate as mean increase over pretreatment value at each point. All numerical results are expressed as mean value +standard error of the mean (SEM).
Results The trial was completed by all 12 patients. The first day measured the changes in FEVl after taking cumulative doses of both placebo inhalers containing propellant only. After a cumulative dose of 7 puffs, there was a mean fall (* SE) in FEVl of 3 .l + 3.8% which was not statistically significant.
0 Terbutaline
0.25mg
0 Fenoterol
O.lmg LOG
CUMULATIVE
0.75mg
1.75mg
3.75mg
0.3mg
0.7mg
1,Smg
DOSE
Fig. 2. Log dose-response curves, comparing increases in FEVt (‘SE) after terbutaline with those after fenoterol. There was no significant difference in response (P> 0.05) between terbutaline and fenoterol at any dose level
Dose-response
analysis
In Fig. 1 the mean maximum percentage increases in FEV, after fenoFEV1. terol and terbutaline, are plotted against the log cumulative doses. Both drugs produced significant mean increases in FEVr over mean baseline values after the first dose (fenoterol 31.7-+ 6.6% P< 0.001, terbutaline 30.4+ 8.4% PC 0.005). There were no significant differences in the mean maximum FEVl increases 28
B. J. Gray, M. H. Frame and J. F. Costello
344
produced after a cumulative dose of 1,3, 7 or 15 puffs of fenoterol or terbutaline. The mean maximum peak response was not significantly different after the maximum dose of each drug; for fenoterol it was 68.7 -+9.3% and for terbutaline 71.5 + 11.1% (P > 0.5). In Fig. 2 the mean percentage increases in sGaw are plotted against the sGaw. log cumulative doses of terbutaline and fenoterol. As with FEVl both agents produced significant mean maximum increases in sGaw after the first dose (fenoterol63.4+ 19.6% P< 0.01, terbutaline 65 _+15.8%P < 0.005). The responses to terbutaline and fenoterol in terms of mean maximum percentage increase in sGaw, were not significantly different at any dose levels. 220200 B =:
180-
t 160 iz 9 g
140-
f +
120-
z 2 &
5 9
loo-
40' 0-k l Terbutaline
' 0.25mg
0.75mg
1.75mg
3.75mg
0 Fenoterot
O,lmg
0.3mg
0.7mg
1.5mg
I
LOG
CUMULATIVE
I
DOSE
Fig. 2. Log dose-response curves, comparing increases in sGaw (5 SE) after terbutaline to those after fenoterol. There was no significant difference in response (P> 0.05) between terbutaline and fenoterol at any dose level Heart rate. The mean baseline valu& for heart rate before fenoterol was administered was 85 + 2.4 beats per minute, and before terbutaline was administered 84 + 2.4 beats per minute; the difference was not significant (P > 0.5). The mean maximum increases in heart rate after fenoterol and terbutaline are shown in Table I. There was a small increase in mean maximum heart rate after the first dose of terbutaline (2.4 beats per minute +_1.3 P > 0.05) and a significant and larger increase in mean maximum heart rate after the first dose of fenoterol (6.3 beats per minute+- 1.4 P< 0.001). The mean maximum increase in heart rate after fenoterol was higher at all dose levels than after terbutaline. This difference reached statistical significance after 1, 7 and 15 puffs of fenoterol compared with the equivalent of terbutaline (Table I).
0.1 0.3 0.7 1.5
mg mg mg mg
Cumulative fenoterol
(1 puff) (3 puffs) (7 puffs) (15 puffs)
dose
I.
Increase
63 10.8 15.3 25
k * + +
1.4 2.3 2.5 3.1
Mean maximum increase in heart rate (+ SE) beats per minute fenoterol
Table
< < < <
0.001 0.001 0.001 0.001
P
in heart
following
0.25 0.75 1.75 3.75
mg mg mg mg
dose
the
(1 puff) (3 puffs) (7 puffs) (15 puffs)
Cumulative terbu taline
rate
of
+ 13 +_ 1.7 9 +_ 1.7 15 + 3.3
2.4 6.5
< < < <
terbutaline
Mean maximum increase in heart rafe (‘SE) beats per minute terbu taline
administration
0.05 0.005 0.001 0.001
P
NS
and
3.9 4.3 6.3 10
_+ 1.3 * 2.3 _+ 1.9 * 3.3
Difference in mean maximum increase in heart rate (2 SE) beats per minute
fenoterol
< 0.05 NS < 0.01 < 0.02
P
346
B. J. Gray, M. H. Frame and J. F. Costello
Blood pressure. There was no significant difference from pretreatment systolic and diastolic blood pressure after taking fenoterol or terbutaline at maximum cumulative dose. Duration
of activity
The second part of the study consisted of assessing the duration of activity in terms of FEVr , sGaw, heart rate and blood pressure of the two drugs. FEV,. In Fig. 3 the mean FEVl expressed as a percentage of maximum response is plotted against time, every 30 minutes for five hours after maximum response.
c5 2 2 70 -f 0
1 60 0 Terbutaline
1 180
120 TIME
I 2LO
8 300
(MINS)
0 Fenoterol
Fig. 3. Decline in FEV, from mean maximum value plotted every 30 minutes (*SE) for 5 hours after terbutaline and fenoterol. From 240 to 300 minutes, terbutaline had a significantly greater activity than fenoterol (X: P < 0.01, 0: P < 0.005)
Values for FEV, declined steadily with time, for both terbutaline and fenoterol. There was no significant difference in the mean FEVr expressed as a percentage of maximum response until 240 minutes. At this point, the mean per cent maximum FEVr was significantly greater for terbutaline than for fenoterol, the mean difference being 4.5 + 1.6% (P < 0.01). This trend is continued at 270 and 300 minutes, the respective differences were 7.6 + 1.7%(P< 0.005) and 7.06 +_ 1.9% (PC 0.005). Thus, the effect of terbutaline in terms of FEV, was significantly greater than fenoterol between 240 and 300 minutes. sGaw. Fig. 4 shows sGaw expressed as apercentage of mean maximum response, plotted against time. sGaw shows a steady decline over the five hours of observation to 60.9 f 3.5% of maximum sGaw for fenoterol and 66 _+3.6% of maximum
Fenoterol
k Y E a
and Terbutaline:
Effects
of Equipotent
Doses
347
50 -
40 0
60
l
120
Terbutaline
TIME
180 (MINS
240
300
1
0 Fenoterol
Fig. 4. Decline in sGaw from mean maximum value plotted 5 hours after terbutaline and fenoterol. There was no significant and fenoterol at any point
every 30 minutes difference between
MEAN INCREASE IN HEART RATE OVER
0 Terbutaline 0 Fenoterol
PRE-TREATMENT RATE (Beats
per
Cumulatwe Dose
mini
(‘SE) for terbutaline
20 -
Terbutallne i Fenoterol
0 25
0 75
1.75
0 375mg
0 1
0 3
0 7
15mg
60
120 TIME
180
240
300
IMINS)
5. The effect of terbutaline and fenoterol on heart rate (k SE). The increase in heart rate was significantly greater after fenoterol than after terbutahne at the indicated significant levels. (ns: not significant, *:P< &05,&P< 0.03,x:Pc 0.02,&P< 0.005
Fig.
for terbutaline. There is no significant difference between the mean fall after fenoterol and the mean fall after terbutaline at any point on these curves. Heart rate. Mean increase in heart rate is plotted against time in Fig. 5. Mean heart rate after fenoterol administration is significantly higher than after terbuta-
348
B. J. Gray, M. H. Frame and J. F. Costello
line, at each point during the five hour observation period. At 150 minutes after terbutaline the mean increase in heart rate was not significantly greater than baseline (4.8 + 2.25 beats per min, P> 0.05). From 150 to 300 minutes after taking terbutaline mean heart rate was not significantly above baseline, while after taking fenoterol, mean heart rate remained significantly elevated until the end of the observation period at five hours (5.7 + 2.1 beats per minute P< 0.025). Side effects Palpitation. Six patients complained of palpitation within 10 minutes of taking the maximum cumulative dose of fenoterol (15 puffs), and one patient who also had palpitations after fenoterol complained of palpitation after taking the equivalent dose of terbutaline. The pulse rate in all six patients complaining of palpitations was greater than 100 beats per minute (mean 118 beats/min +_ 4.1 beats/min). Tremor. Three patients developed tremor after fenoterol, two after a cumulative dose of 8 puffs and one after a cumulative dose of 15 puffs. One patient developed tremor after a cumulative dose of 15 puffs of terbutaline. Discussion Large and rapid increases in FEVl and sGaw followed the administration of the lowest dose of both terbutaline and fenoterol (Figs 1 and 2), with further increases at each dose level. Heel et al. (1978) h ave reviewed the many combinations of dosages used in trials comparing fenoterol with other fl-adrenergic agonists. In this trial the doseresponse curves for FE& and sGaw show that terbutaline in a dose of 25Opg per puff is equipotent to fenoterol 1OOpg per puff. Anderson et al. (1979) and Petit and Roberts (1973) both showed that inhaled fenoterol had a longer duration of activity than terbutaline, but these studies did not attempt to define and use equipotent doses, and with the equipotent dosages used in the present study terbutaline had a small but significantly greater duration of activity than fenoterol. Carmichael et al. (1980) also found that terbutaline given by intermittent positive pressure breathing had a significantly longer duration of activity than fenoterol given by the same method. When given over longer periods terbutaline has been shown to have a more sustained effect than fenoterol (Trembath et al. 1979). Asthmatic patients given terbutaline by infusion and inhalation, even in relatively large doses, have few cardiovascular side effects (Thiringer & Svedmyr 1976). We have shown at all dose levels that there was a significantly smaller increase in heart rate after terbutaline than after fenoterol, even though the metered dose of fenoterol used was half the commercially available standard dose. The heart rate returned to baseline levels within two and a half hours of taking the maximum cumulative dose of terbutaline but remained significantly above pretreatment levels for the whole five hours after taking the equipotent dose of fenoterol.
Fenoterol
and Terbutaline:
Effects
of Equipotent
Doses
349
Half the patients complained of palpitation after taking the maximum cumulative dosage of fenoterol, compared with one patient who had palpitations following the equipotent dose of terbutaline. These results show significantly more cardiovascular effects from fenoterol and suggest that terbutaline has greater fiz-adrenergic receptor specificity in accord with previous pharmacological studies (Persson & Johnson 1970; O’Donnell & Wanstall 1974). Many methods of expressing and analysing data obtained when comparing the effects of different fi-adrenergic agonists on asthmatics have been proposed (Madsen et al. 1979). We have expressed our results as mean percentage changes from fixed reference points, either mean pretreatment values or mean maximum response. It is generally agreed that the expression of changes in measured indices in relative terms (such as percentage change from baseline) is preferable to the expression of results as absolute changes (Minette 1970; Kerridge 1977). However with a small degree of within-subject variation (less than 15% variation in pretreatment FEVl between study days in this trial) Racoveau et al. (1971) have argued that data can be accurately expressed either as absolute or relative values.
Acknowledgements We wish to thank Astra Pharmaceuticals and WB Pharmaceuticals, who supplied trial material, and the technical staff, Chest Unit, King’s College Hospital, for their help during the study. We would also like to thank Maggy Gleeson for secretarial assistance.
References Anderson, G., Wilkins, E. & Jariwalla, A. G. (1979) F enoterolin asthma.Br. J. Dir. Chest 73, 81. Carmichael, J., Bloomfield, P. & Crompton, G. K. (1980) Comparison of fenoterol and terbutaline administered by intermittent positive pressure breathing. BY. J. Dis. Chest 74, 268. Dubois, A. B., Botelho, S. Y. & Comroe, J. H., Jr. (1956) A new method for measuring airway resistance in man using a body plethysmograph: values in normal subjects and in patients with respiratory disease. J. din. Invest. 35, 327. Eriksson, N. E. & Lindgren, S. B. (1978) The rapidity of bronchodilatation; a comparison of isoprenaline, terbutaline, and rimiterol. Stand. J. resp. Dis. 59, 30. Freedman, B. J. (1972) Trial of terbutaline aerosol in the treatment of asthma, and acomparison of its effects with those of a salbutamol aerosol. Br. J. Dis. Chest 66, 222. Heel, R. C., Brigden, R. N., Speight, T. M. & Avery, G. S. (1978) Fenoterol: a review of its pharmacological properties and therapeutic efficacy in asthma. Drugs 15, 3. Kerridge, D. F. (1977) Statistics for clinical trials in asthma. In Methods in Clinical Trials in Asthma. Proceedings of a British Thoracic and Tuberculosis Society Meeting, ed. J, E. Stark and J. V. Collins. BY. J. Dis. Chest 71, 227. Madsen, B. W., Tandon, M. K. & Paterson, J. W. (1979) Crossover study of the efficacy of four p2 sympathomimetic bronchodiIator aerosols. Br. J. din. Pharmacol. 8, 75. Minette, A. (1970) Spirometric study of the bronchodilating effects of hydroxyphenyl orciprenaline (Th:l165a) in various forms, in a group of 125 coal miners suffering from bronchospasm. Respiration 27, 276.
B. J. Gray, M. H. Frame and J. F. Costello 0 ‘Donnell, S. R. & Wanstall, J. C. (1974) Potency and selectivity in vitro of compounds related to isoprenaline and orciprenaline on 0 adenoreceptors in the guinea pig. BY. J. Pharmacol. 52,407. Persson, H. & Johnson, B. (1970) A dual preparation technique for studying the differentiation of effect of sympathomimetic agents on heart and tracheal muscle. Acta. med. stand. Suppl. 5.2, 21. Petit, J. M. SC Roberts, M. (1973) Comparison des effets bronchodilatateurs de l’inhalation d’aerosols dhydroxphknylorciprdnaline et d’autres agents P-adrdnergiques. Rev. Me’d. Likge.
28,
288.
Racoveau, U. C., Stanescu, D. C., Manicatide, M. & Stroescu, V. (1971) The bronchodilator effects of orciprenaline and salbutamol. A double-blind study. Postgrad. med. J. Suppl. 47, 83. Sackner, M. A. & Silva, G. (1978) Effects of terbutaline aerosol in reversible airways obstruction. Chest 73, 802. Thiringer, G. & Svedmyr, M. (1976) Comparison of infused and inhaled terbutaline in patients with asthma. Stand. J. resp. Dis. 57, 17. Trembath, P. W., Greenacre, J. K., Andersson, M., Dimmock, S., Mansfield, L., Wadsworth, J. & Green, M. (1979) Comparison of four weeks’ treatment with fenoterol and terbutaline aerosols in adult asthmatics. J. Allergy Clin. Immunol. 63, 395.