Thorax 1994;49:771-774 771

Systemic effects of salbutamol and salmeterol in

patients with asthma Thorax: first published as 10.1136/thx.49.8.771 on 1 August 1994. Downloaded from

J A Bennett, E T Smyth, I D Pavord, P J Wilding, A E Tattersfield

Abstract action, to a higher relative dose, or to other Background - Knowing the extent of the actions is uncertain. The dose equivalence of systemic effects of a new P2 agonist relative salmeterol and salbutamol is still debated and is to an established drug is important for the an important issue in the context of the debate prediction and interpretation of side on the safety of 12 agonists.48 effects. A recent study in which the effect In our recent dose-response study in which of cumulative doses of salbutamol was the airway and systemic effects of single doses compared with single doses of salmeterol of salmeterol were compared with cumulative suggested that, weight for weight, salme- doses of salbutamol in subjects with asthma, terol may be up to 10 times more potent salmeterol was 8-10 times more potent than than salbutamol. This current study was salbutamol weight for weight.9 This study sug- designed to investigate further the dose gested that, for systemic effects at least, 50,g equivalence of salmeterol and salbuta- salmeterol is equivalent to approximately mol. 500 pg salbutamol. This estimate is higher than Methods - Twelve patients with mild that obtained from previous studies where dose asthma inhaled cumulative doses of pla- equivalence was determined from the effect of cebo, salmeterol 25, 50, 100, and 200pg, single doses of salmeterol and salbutamol on and salbutamol 100, 500, 1000, and 1000 pg lung function.10-2 on separate days at hourly intervals in a Our previous study was criticised because the randomised double blind crossover study. response to single doses of salmeterol was com- Changes in forced expiratory volume in pared with that of cumulative doses of salbuta- one second (FEVy), heart rate, plasma mol, different delivery devices were used for potassium concentration, systolic and salmeterol and salbutamol, and only one diastolic blood pressure were measured. measurement was made after salmeterol so that Dose was determined as the the peak effect may have been missed. We equivalence http://thorax.bmj.com/ dose ratio of salmeterol to salbutamol for therefore carried out a dose-response study to the 50% maximum reponse to salbuta- compare the effects of cumulative doses of mol. salmeterol and salbutamol on separate days, Results - No important changes occurred giving both drugs by a large volume spacer and in any measurements following placebo. making two measurements of airway and sys- Salmeterol and salbutamol caused a near temic effects after each dose and a third maximum increase in FEV, following the measurement after the final dose. first so for the dose the dose equivalence on October 2, 2021 by guest. Protected copyright. airway effects could not be estimated. Methods Heart rate increased and plasma potas- Twelve subjects (four women) aged 29-54 years sium concentration and diastolic blood with asthma but no other significant medical pressure decreased in a dose dependent problems were studied. All were lifelong non- manner following salmeterol and salbuta- smokers (nine subjects) or ex-smokers with a mol, with median dose equivalences for smoking history of less than five pack years. salmeterol compared with salbutamol of Subjects had a baseline forced expiratory 17-7, 7-8, and 7-6, respectively. volume in one second (FEVy) greater than 60% Conclusions - These results confirm that predicted and a rise in FEV, of at least 15% the systemic activity of salmeterol com- after inhalation of 400 jg salbutamol. All were pared with salbutamol is higher than taking an inhaled short acting 12 agonist as Respiratory would be expected from in vitro data, Medicine Unit, City required and 11 were taking a regular inhaled Hospital, particularly for heart rate. Whether this steroid (beclomethasone dipropionate or bude- Nottingham is because of the relatively high dose of sonide 400-1600 jg). Subjects gave informed NG5 1PB, UK salmeterol used or pharmacokinetic J A Bennett written consent and the study was approved by E T Smyth differences between the two drugs is the Nottingham City Hospital ethics commit- I D Pavord uncertain. tee. P J Wilding A E Tattersfield FEV, was measured by a dry bellows spiro- (Thorax 1994;49:771-774) meter (Vitalograph, Buckingham, UK) with the Reprint requests to: Dr J A Bennett. subject sitting, taking the best of two successive Received 12 November Salmeterol given in a dose of 50 jg twice daily measurements within 100 ml. Heart rate was 1993 provides more effective control of asthma measured over 60 seconds by palpation ox- the Returned to authors 7 January 1994 symptoms than salbutamol in doses of 200 jig radial pulse. Venous blood samples (10 ml) Revised version received and 400 gg four times daily in short term stud- were taken from a cannula in the forearm (But- 18 February 1994 Accepted for publication ies. '- The extent to which the better control terfly 21), placed in a lithium heparin bottle, 5 April 1994 with salmeterol is due to its longer duration of and centrifuged within 20 minutes of sampling 772 Bennett, Smyth, Pavord, Wilding, Tattersfield

at 3000 revs/min for 15 minutes. Plasma potas- remained in the department until symptoms sium concentration was measured by flame settled and heart rate had fallen below photometry (Olympus AU5000, Olympus Op- 1 10 beats/minute. tical Company, Eastleigh, UK). Subjects were studied at the same time of day Thorax: first published as 10.1136/thx.49.8.771 on 1 August 1994. Downloaded from on three occasions separated by at least seven DATA ANALYSIS days. Inhaled 12 agonists and caffeine contain- Analysis of variance was used to compare base- ing drinks were withheld for 12 hours before line measurements of FEVy, heart rate, plasma each visit. Following a 30 minute rest baseline potassium concentration, and blood pressure; measurements ofheart rate, blood pressure, and symptoms were compared by the Fisher exact FEV1 were made, and blood was taken for probability test. plasma potassium assay. Subjects were then Individual values for dose equivalence were given increasing doses of placebo, salmeterol calculated by plotting the response to each dose (25, 50, 100, and 200pg) or salbutamol (100, of salmeterol and salbutamol on a log dose- 500, 1000, and 1000 jg) by metered dose response curve and drawing a line of regression inhaler at hourly intervals according to a ran- through the linear part of the curve taking the domised, double blind, double dummy, cross- last three readings. Dose equivalence was over design. Doses of salmeterol, salbutamol, measured at 50% of the maximal effect seen and placebo other than the first dose were with salbutamol by comparing the dose of sal- administered using a large volume spacing de- butamol and salmeterol required to achieve this vice (Volumatic). At each visit two identical effect. Individual dose equivalences were not metered dose inhalers (active or placebo) were normally distributed and are described as used, patients receiving one, two, four, and median and interquartile range. eight puffs from one inhaler and one, five, 10, Since the earlier doses of salbutamol may not and 10 puffs from the other. The first inhaler have been effective at the time of administration was active on the salmeterol day giving doses of of the final dose because of its shorter duration 25, 50, 100, and 200 rg, and the second inhaler of action, we also calculated a minimum dose was active on the salbutamol day giving doses of equivalence assuming that at the time of each 100, 500, 1000, and 1000 gg. Two, four, or five drug administration only 50% of the preceding puffs were activitated into the spacer before two dose was active. This gave a cumulative dose inhalations; for higher doses this was repeated range of 100, 500, 1250, and 1500 jig for salbu- on a second occasion. Patients held their breath tamol. for 10 seconds after each inhalation. Each drug The log dose-responses for the two drugs dose was administered over a period of three were tested by analysis of variance to determine minutes. Further measurements were taken at whether they deviated from parallelism.'3

15 and 60 minutes after each dose in the same The generalised interactive modelling http://thorax.bmj.com/ order as at baseline, and a final set of measure- (GLIM) statistical package was used for statist- ments was taken 120 minutes after the last dose ical analysis. of drug. The maximum change after each dose was used in the analysis. The study was stopped if symptoms became troublesome or if the Results heart rate rose above 140 beats/minute. Patients All patients completed all three dose-response studies. There were no significant differences in

baseline measurements of FEV,, heart rate, on October 2, 2021 by guest. Protected copyright. plasma potassium concentration, and systolic Table 1 Mean (SD) baseline values of heart rate, FEV,, plasma potassium concentration, and blood pressure on the three study days and diastolic blood pressure (table 1), and no important changes in any of these measure- Heart FEV, Plasma Systolic Diastolic rate (1) potassium BP BP ments were seen after placebo (table 2). None of (bpm) (mmoljl) (mm Hg) (mm Hg) the log dose-reponses for the two drugs was Salbutamol 69.8 2 74 3 98 121 79 found to deviate from parallelism (all p > 0 05). (106) (1-14) (021) (75) (52) Salmeterol 67.9 2 69 4 0 119 79 (10 1) (1 05) (0 28) (7 5) (7 2) CHANGE IN FEVy Placebo 663 268 40 119 78 There was a near maximal increase in FEVI (12-1) (1 05) (0 27) (8 1) (5-2) following the first dose of both salmeterol (0-42 1) and salbutamol (041 1) and progress- ively smaller increases after further doses (fig 1). The maximum increase was 0-621 and 0-571 Table 2 Mean (SE) maximal change in effect seen with salmeterol, salbutamol, and respectively (table 2). placebo for heart rate, FEV, plasma potassium concentration, and diastolic blood pressure Heart FEV, Plasma Diastolic CHANGE IN HEART RATE, PLASMA POTASSIUM, rate (1) potassium BP AND BLOOD PRESSURE (bpm) (mmol/l) (mm Hg) Salmeterol and salbutamol caused a largely Salbutamol 4 92 0 57 -0 41 -6.5 dose dependent increase in heart rate and fall in (2 21) (0 08) (0 06) (2 03) plasma potassium concentration and diastolic Salmeterol 15 08 0 62 - 0-52 - 8.83 blood pressure (fig 1). The median dose equiva- (2 36) (0 08) (0 10) (1-92) lence for salmeterol compared with salbutamol Placebo 1 83 0.05 -0-13 - 1 74 was 17 7 (interquartile range 9-2-21-8) for heart (245) (0.09) (0 12) (220) rate, 7 8 (interquartile range 3-7-10 7) for Systemic effects of salbutamol and salmeterol in patients with asthma 773

Figure I Mean (SE) plasma potassium concentration, and 7-6 (inter- change from baseline in I 0_ quartile range 2-7-19-4) for diastolic blood FEV,, heart rate, plasma El pressure. Systolic blood pressure did not potassium concentration, ffi -4 and diastolic blood change significantly after cumulative doses of pressure with increasing m either drug. Thorax: first published as 10.1136/thx.49.8.771 on 1 August 1994. Downloaded from doses of salmeterol (A) - 0E8 and salbutamol (assuming The minimum dose equivalence for sal- inCD a total cumulative dose of meterol compared with salbutamol calculated 2600 ,ugE- or a -12 from each dose administered and 50% of the minimal estimate assuming < 0.8 preceding dose was 12-2 for heart rate, 6-8 for a total cumulative dose of 1500 ug OL--O [see plasma potassium concentration, and 7-7 for methods]). 0.6 diastolic blood pressure. > 0.4 After the last dose of salbutamol the maximal ui effect on heart rate, FEVI, plasma potassium <02OL _ concentration, and diastolic blood pressure was seen after 20 minutes (fig 2). There was little further change at 60 minutes but by 120 E 2020 minutes there was a return towards baseline _. 15 values. With salmeterol the maximum effect a) 1010 had plateaued at 60 and 120 minutes after the 5 last dose. t a) 0 < -5_ SYMPTOMS 0.2 Tremor and palpitations were significantly more common following salmeterol (four and o E -0.2 three patients) and salbutamol (four and three EI patients) than placebo (0 and 0). Other side -V' effects included headache (three salmeterol,

< -0.6 three salbutamol, and three placebo), flushing -0.8 (one salbutamol), and wheezing (one placebo). L 10 100 1000 Dose (jg) Discussion The new long acting P2 agonist salmeterol is available for twice daily administration. Clinical

trials suggest that patients with asthma are http://thorax.bmj.com/ Figure 2 Mean (SE) I 4 better controlled by a twice daily dose of 50,g change from baseline in E salmeterol than by four times daily administra- heart rate, plasma E FEV,, OF tion of 200 gg and 400 jg salbutamol.1-3 The potassium concentration, a- extent to which this beneficial effect of sal- and diastolic blood m 0c meterol is the result of a higher relative dose, pressure with increasing -4 time following the last dose Co its longer duration of action, or other actions is of salmeterol (A) and Cn uncertain. Our recent study in which the re- salbutamol ( * ). -._ -8 sponse of cumulative doses of salbutamol was on October 2, 2021 by guest. Protected copyright. 0.7 r compared with non-cumulative doses of salme- terol suggested that higher dosage might be an 0.6 important factor since the dose equivalence of the two drugs on systemic measures was w between 8 and 10.9 These data imply that 50 jig .< 0.5jF of salmeterol twice daily would be roughly equivalent to 400-500 gig salbutamol up to four 0.4L hourly. This may be important if the use of 16 high doses of 02 agonists is causally associated E 12 with an increased risk of death.8 One criticism raised of our previous study 8 CU was that only one measurement was made after 4 each dose of drug and that the maximum drug effect may have been missed. In the present study measurements were made 20 and 60 -4 minutes after each dose with a further measure- o _ ment 120 minutes after the last dose. After the final dose of salmeterol there was little dif- Z -0.2 ference in the effects seen at 60 and 120 El T minutes. With salbutamol the maximum effect El was seen at 20 minutes following the final dose + -0.4 I with a gradual decrease in effect at 60 and 120 minutes. These results suggest that we had -0.6 measured the maximum effects of both drugs 20 60 20 after each dose. The responses to both sal- Time (min) meterol and salbutamol in our study are very 774 Bennett, Smyth, Pavord, Wilding, Tattersfield similar to those seen in other studies. temic effects, salmeterol is 7-17 times more Maconochie et al found a similar increase in potent than salbutamol. Further work is needed heart rate (16 beats/min) and fall in plasma to determine whether this is a result of pharma- potassium concentration (0-45 mmol/l) follow- cokinetic differences or differences in dose. ing a single 400 1tg dose of salmeterol in normal Whatever the mechanism, the difference Thorax: first published as 10.1136/thx.49.8.771 on 1 August 1994. Downloaded from subjects'4 to that seen in our study with cumu- between the two in their propensity to increase lative doses (total dose 375 fig). The magnitude heart rate may be relevant to the concerns about of change for all measurements following mortality with salmeterol compared with salbu- cumulative doses of salbutamol was similar to tamol which have been raised in the recent that seen in our previous studies.9 15 post-marketing surveillance study.23 We were unable to estimate the dose equi- We thank Mr A Wisniewski and Mrs J Williams for help with valence of salbutamol and salmeterol for the the study and Mrs S Pacey for randomisation and coding of the airway effects since a near maximum response drugs. was achieved with the lowest dose of both drugs. The dose equivalence for fall in plasma 1 Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol and potassium concentration and diastolic blood salbutamol in asthmatic patients. Am Rev Respir Dis 1990;142:571-5. pressure was 7-8, which agrees closely with 2 Pearlman DS, Chervinsky P, LaForce C, Seltzer JM, South- estimates from our previous study; the dose ern DL, Kemp JP, et al. A comparison of salmeterol with albuterol in the treatment of mild-to-moderate asthma. N equivalence for heart rate was greater at 17 7. It Engl J Med 1992;327:1420-5. is possible that the dose equivalence is an over- 3 Lundback B, Rawlinson DW, Palmer JBD. Twelve months comparison of salmeterol and salbutamol as dry powder estimate since the doses of salbutamol may not formulations in asthmatic patients. Thorax 1993; 48: be truly cumulative because of its shorter 148-53. 4 Cheung D, Timmers MK, Zwinderman AH, Bel EH, Dijk- duration of action. Any effect this might have man JH, Sterk PJ. Long term effects of a long-acting P2- on our estimate of dose equivalence would have adrenoceptor agonist, salmeterol, on airway responsiveness in patients with mild asthma. N Engl J Med 1992;327: been small - for example, assuming the final 1198-203. dose of salbutamol to be 1500 (50% of the 5 Crane J, Platt A, Jackson R, Ball M, Pearce N, Burgess C, et g.g al. Prescribed fenoterol and death from asthma in New penultimate dose and the final dose) rather than Zealand, 1981-83: case-control study. Lancet 1989;i: 2600 (the total dose) would reduce the dose 917-22. gig 6 Pearce N, Grainger J, Atkinson M, Crane J, Burgess C, equivalence for heart rate from 17 7 to 12 2. Culling C, et al. Case-control study of prescribed fenoterol The greater systemic effects of salmeterol and death from asthma in New Zealand, 1977-81. Thorax 1990;45: 170-5. relative to salbutamol in vivo may be due to 7 Grainger J, Woodman K, Pearce N, Crane J, Burgess C, increased systemic bioavailability, increased Keane A, et al. Prescribed fenoterol and death from asthma in New Zealand, 1981-87: a further case-control study. dose, or differences in ,B receptor selectivity. Thorax 1991;46:105-11. The dose equivalence for systemic P2 mediated 8 Spitzer WO, Suissa S, Ernst P, Horwitz RI, Habbick B, Cockcroft D, et al. The use of 0-agonists and the risk of effects, such as the fall in serum potassium J death and near death from asthma. N Engl Med http://thorax.bmj.com/ levels, are higher than would be expected from 1992;326:501-6. 9 Smyth ET, Pavord ID, Wong CS, Wisniewski AFZ, Wil- studies in vitro where salmeterol is approxim- liams J, Tattersfield AE. Interaction and dose equivalence ately five times more potent than salbutamol on of salbutamol and salmeterol in patients with asthma. BMJ 1993;306:543-5. a weight for weight basis. 16 17 This suggests that 10 Ullman A, Svedmyr N. Salmeterol, a new long acting , the systemic dose for salmeterol is high com- adrenoceptor agonist: comparison with salbutamol in adult asthmatic patients. Thorax 1998;43:674-8. pared with salbutamol. Whether this is because 11 Bierman CW, Kemp JP, Cuss FM. Dose-response study of of the high dose administered or differences in salmeterol, a new long acting beta2 agonist. Thorax systemic availability is difficult to determine 1989;44:850P.

12 Sandstrom T, Frederiksen B, Rosenhall L, Sandstrom B. on October 2, 2021 by guest. Protected copyright. without knowing the relative effect of the two Salmeterol - a lose response study with a long acting 02- agonist. Am Rev Respir Dis 1989;139:64A. drugs on the airways. Systemic effects of salbu- 13 Armitage P. Statistical methods in medical research. Oxford: tamol are largely due to the inhaled rather than Blackwell Scientific Publications: 1971. 14 Maconochie JG, Forster JK. Dose response study with high- the swallowed portion of the drug,'8 partly dose inhaled salmeterol in healthy subjects. Br J Clin because it undergoes first pass metabolism.'9 Pharmacol 1992;33:342-5. 15 Wong CS, Pavord ID, Williams J, Britton JR, Tattersfield The fate of the swallowed portion of salmeterol AE. Bronchodilator, cardiovascular, and hypokalaemic is unknown and it is possible that its greater effects of fenoterol, salbutamol, and terbutaline in asthma. Lancet 1990;336:1396-9. systemic effects are due to decreased first pass 16 Ball DI, Brittain RT, Coleman RA, Denyer LH, Jack D, metabolism. Differences in oropharyngeal or Johnson M, et al. Salmeterol, a novel, long-acting P2- adrenoceptor agonist: characterization of pharmacological lung deposition of the two drugs are unlikely to activity in vitro and vivo. BrJtPharmacol 1991;104:665-71. account for our findings as both drugs were 17 Butchers P, Cousins SA, Vardey CJ. Salmeterol, a potent and long acting inhibitor of the release of inflammatory and administered using the same delivery system. spasmogenic mediators from human lung. Br J Pharmacol Dose equivalence for heart rate was higher 1987;92:745. 18 Collier JG, Dobbs RJ, Williams I. Salbutamol aerosol causes than that of plasma potassium concentration. a tachycardia due to the inhaled rather than swallowed This finding was surprising as there is evidence fraction. Br J Clin Pharmacol 1980;9:273-4. 19 Morgan DJ, Paull JD, Richmond BH, Wilson-Evered E, that the chronotropic response to 1 agonists is Ziccone SP. Pharmacokinetics of intravenous and oral predominantly mediated,20 although some salbutamol and its sulphate conjugate. BrJ3 Clin Pharmacol P2 1986;22:587-93. effect cannot be excluded. In vitro salmeterol is 20 Lipworth BJ, Brown RA, McDevitt DG. Assessment of at least as 12 selective as salbutamol." 22 Our airways, tremor and chronotropic reponses to inhaled salbutamol in the quantification of beta-2 adrenoceptor findings suggest that salmeterol may be less P2 blockade. Br J7 Clin Pharmacol 1989;28:95-102. selective than salbutamol; alternatively, the 21 Ball DI, Coleman RA, Denyer LH, Nials AT, Sheldrick KE. In vitro characterisation of the beta2-adrenoceptor agonist, lipophilic nature of salmeterol may result in salmeterol. Br J Pharmacol 1987;88:591. more rapid absorption from the lung into bron- 22 Ball DI, Coleman RA, Denyer LH, Nials AT, Sheldrick KE. Bronchodilator of a mucosa a activity salmeterol, long acting P2- chial veins or the buccal and perhaps adrenoceptor agonist. Br J Pharmacol 1987;90:746. transient concentration at cardiac 23 Castle W, Fuller R, Hall J, Palmer J. Serevent nationwide higher P2 surveillance study: comparison of salmeterol with salbuta- receptors. mol in patients who require regular bronchodilator treat- In conclusion we have shown that, for sys- ment. BM7 1992;306:1034-7.