-
Pulmonary effects of long-term ,&blockade healthy subjects: Comparative study of metoprolol OROS
in
The effects on airway response of metoprolol OROS (oral osmotic) and three other long-acting /3-adrenoceptor blockers were studied. This was a placebo-controlled, randomized, five-period, single-blind, crossover trial in 15 healthy volunteers. Bronchial B-blockade was estimated as the displacement of the salbutamol bronchodilator response of specific airway conductance (SGAW) measured by whole-body plethysmography. Metoprolol OROS (14/1gO mg), slow-release (SR) metoprolol (208 mg), atenolol (100 mg), long-acting (LA) propranolol (160 mg), and placebo were given once daily for 7 days. Inhaled salbutamol was administered at peak drug levels in cumulative doses of 12.6 to 800 gg on day 5 and in a single dose of 400 gg on day 7. On day 5, salbutamol induced significant increases in SGAW in each treatment group. SGAW increased after the single dose of saibutamol on day 7 in all groups and then declined steadily. The highest values were found after placebo and metoprolol OROS, with smaller increases after SR metoprolol, atenolol, and LA propranolol, the latter showing ,the smallest increase. Therefore, it would appear that under steady-state conditions, &-bronchial receptors are least blocked by metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol. (AM HEART J 1990; 120:473.)
K. Bauer, MD,a S. Rakusan,
MD,b and G. Kaik, MD.a Vienna, Austria
Metoprolol, a cardioselective fi-adrenoceptor blocker, has been used for many years, mainly for the treatment of hypertension and angina pectoris.’ Recently, a metoprolol OROS (oral osmotic release system) tablet was developed to release metoprolol at a relatively constant rate, over an extended period of time, in a single daily dose.2y 3 The aim of the present study was to compare the bronchial &-blockade of metoprolol OROS and other long-acting P-blockers by studying the changes in ariway caliber in patients before and after administration of 82 stimulants. Airway response after inhalation of the &-adrenoceptor agonist was investigated by two different inhalation schedules.4y5 Bronchial P-blockade was measured as the displacement of the salbutamol bronchodilator response curve.5 The study was conducted in healthy subjects in a randomized single-blind crossover design. SteadyFrom BDivision of Pharmacology, varsity of Vienna Medical School; GmbH.
Department and bMedical
Reprint requests: Dr. K. Bauer, Division ment of Internal Medicine I, University Gasse 14, A-1090 Vienna, Austria. 4/O/21064
of Internal Department,
Medicine I, UniCIBA-GEIGY
of Clinical Pharmacology, of Vienna Medical School,
DepartLazarett-
state comparisons of metoprolol in two different formulations, and of propranolol, atenolol, and placebo were recorded on day 5 (after cumulative doses of salbutamol) and on day 7 (after a single dose of salbutamol) during each period of medication. METHODS
The study wascarried out in accordancewith the guidelines for investigations in healthy volunteers.6The protocol wasapproved by the university ethical review committee, and written informed consent was obtained in each case. Subject selection. Selection of healthy subjects was based on their medical history, smoking habits, physical examination, laboratory profile, electrocardiograms(EGG; standard 12-lead), chest x-ray examination, and pulmonary function. Subjectswho werehyperreactive in response to an inhaled irritant (acetylcholine) were excluded. In admitted subjects,inhalation of 400 rg of salbutamol from a metered-doseaerosolhad to increasespecific airway conductance (SGAW) by 30% or more.6-8Fifteen subjectswere enrolled, eight men and sevenwomen. They were all nonsmokers,their average age was 25 years (range 22 to 32 years), their height was172cm (range, 165to 182cm), and their weight was 70 kg (range 54 to 78 kg). Apparatus and measures. Airway resistance (RAW) and thoracic gasvolume (TGV) were measuredby a constant-volume whole-body plethysmograph (Bodytest, Gut 473
474
Bauer,
Rakusan,
and Kaik
American
August 1990 Heart Journal
I. Mean (*SD) specific airway conductance (L/set X cm HsO) before and 15 minutes after cumulative dosesof inhaled salbutamol in 15 healthy subjects after metoprolol OROS, slow-release(SR) metoprolol, atenolol, long-acting (LA) propranolol, and placebo
Table
Salbutamol Before
MetoprololOROS
0.155 * 0.029
SR metoprolol
0.161 kO.027
Atenolol
0.162 + 0.019
LA propranolol
0.160 kO.025 0.157 kO.023
Placebo
12.5
0.175 iO.026 0.180 kO.032 0.176 + 0.021 0.165
&0.019 0.186 20.022
75
300
400
800
0.209
0.263 kO.046 0.245 kO.037 0.221 izO.024 0.191 kO.027 0.263 kO.040
0.275 kO.045 0.268 io.037 0.247 10.033 0.196 kO.028 0.278 kO.037
0.271 20.048 0.271 + 0.039 0.231 io.035 0.233 kO.034 0.276 kO.037
25 0.188 r0.033
0.189 20.031 0.181 kO.020 0.170 kO.024 0.192 kO.026
Ltd., Basle, Switzerland). For evaluation of airway caliber, SGAW (liters per secondtimes centimeters HsO) wasused. SGAW isthe reciprocal of RAW corrected by TGV; a mean value wascalculated from nine consecutivemeasurements. The provocative cumulative doseof salbutamol (micrograms) required to causea 35% increasein SGAW from baseline(PD 35 SGAW) was determined for each subject and eachmedi&tion.5 Heart rate (radial pulse/minute) and blood pressurewere recorded in a sitting position immediately after measurementof lung function. Drugs. The metoprolol OROS 14/190 tablet used has a zero-order releaserate of 14 mg/hr and a total metoprolol fumarate content of 190 mg (equivalent to 200 mg of immediate-releasemetoprolol tartrate). Standard preparations of the other @-blockerswere designed for once-daily oral administration. To facilitate comparison,dosingwas arranged so that the time of peak plasmaconcentration (t,,,) was between 7 PM and 9 PM. This then coincidedwith the time of lung function testing. The doseof eachdrug and the time betweeningestion and start of the lung function tests were asfollows: metoprolol OROS, 14/190mg, 12 hours post dose;slow-releasemetoprolol, 200mg, 5 hourspost dose;atenolol, 100mg, 3 hours post dose;long-acting propranolol, 160mg, 12 hours post dose;and placebo, 3 hours post dose. Salbutamol, a /3z-adrenoceptoragonist used for symptomatic bronchodilation,‘j was administered by metereddoseaerosolsdelivering 12.5 and 25 pg per puff (AerosolService AG, Mbhlin, Switzerland) and by a commercially available metered-doseaerosoldelivering 100 Mgper puff (Allen and Hanbury Ltd., England). To improve drug delivery in situ, a 10 cm spacerwas used. Study procedures. The study wascarried out in a controlled, randomized (Latin-square), five-period crossover, single-blind design,with eachmedication period separated by 1 week. On day 5 of eachperiod, after determination of baseline values, salbutamol inhalations were administered at 20minute intervals in increasingdoses:12.5,25,75,300,400,
(pg)
so.035 0.206 kO.031 0.201
k 0.019 0.190 kO.030 0.214 20.025
and 800pg. All measureswere repeated after eachsalbutamol inhalation (between 15 and 20 minutes). On day 7 of each period, after determination of baseline values, a singledoseof 400 pg of salbutamolwasgiven. All variables were monitored after 15 and 30 minutes and after 1, 2, 3, 4, and 6 hours. Pharmacokinetics. Venous blood sampleswere drawn on day 1 (before the start of medication), on day 3 (at ha-J, on day 5 (at t,,, = before, and 1 and 2 hours after salbutamol inhalation), and on day 7 (at t,, = before, and 1,2, and 6 hours after salbutamol). The plasmaconcentrations of metoprolol, atenolol, and propranolol were determined by high-performance liquid chromatography.g-12 Side effects. All subjects were observed, questioned, and scored for unwanted side effects (score: 0 = none, 1 = mild, 2 = moderate, 3 = severe)on all days of eachperiod, including those when no salbutamol was given. Safety and tolerability. Clinical investigation, ECG, and laboratory tests were repeated after each period of drug administration. Statistical analysis. All data analyzed were arithmetic means and standard deviations. Statistical analysis was performed on SGAW (peak value, area under the plasma concentration/time curve [AUC], AUC to baseline,and PD 35), heart rate, and blood pressureby analysisof variance. RESULTS Specific
airway conductance (SGAW). The mean baseline values of SGAW before salbutamol did not differ significantly between medication groups on
day 5 and on day 7 or between these days (Tables I and II). On day 5 the cumulative doses of salbutamol produced a continuous increase in SGAW that was statistically significant in all groups (p < 0.001) (Table I, Fig. 1). After placebo and each of the two metopro101 preparations, SGAW curves were practically identical and reached the highest values recorded.
Volume Number
120 2
Pulmonury effects of metoprolol OROS
475
II. Mean ( + SD) specific airway conductance (L/set X cm HzO) before and 0.25 to 6 hours after a single doseof inhaled salbutamol (400 pg) in 15 healthy subjectstreated with metoprolol OROS, slow-release(SR) metoprolol, atenolol, long-acting (LA) propranolol, and placebo Table
Hours
Metoprolol SR metoprolol Atenolol LA propranolol Placebo
OROS
Before
0.25
0.5
1
2
3
4
6
0.161 + 0.021 0.159 + 0.024 0.160 2 0.020 0.160 + 0.023 0.159 i 0.022
0.259 iz 0.032 0.223 ? 0.041 0.222 + 0.024 0.200 + 0.028 0.255 + 0.037
0.265 * 0.033 0.243 * 0.041 0.227 f 0.024 0.217 + 0.027 0.265 + 0.036
0.257 IL 0.030 0.242 k 0.033 0.230 + 0.027 0.212 zk 0.026 0.257 t 0.036
0.254 + 0.033 0.236 * 0.035 0.218 + 0.025 0.201 iz 0.029 0.253 + 0.036
0.242 * 0.031 0.226 E!z0.035 0.203 k 0.024 0.187 + 0.029 0.241 kO.036
0.224 t 0.029 0.210 kO.032 0.184 + 0.024 0.170 k 0.026 0.222 * 0.033
0.198 t 0.027 0.192 f 0.031 0.171 + 0.026 0.160 ? 0.023 0.197 * 0.028
--
After atenolol, and even more after propranolol administration, SGAW increased more slowly, attaining lower peak values even after higher doses of salbutamol. Evaluation by PD 35 SGAW resulted in a median value of 117 for placebo, 97 for metoprolol OROS, 150 for slow-release metoprolol, 363 for atenolol, and 1295 for long-acting propranolol, respectively. There was no statistically significant difference between placebo and both preparations of metoprolol. The differences between metoprolol OROS and the other active drugs were statistically significant (p < 0.05). The differences between slow-release metoprolol and the other active drugs were also statistically significant (p < 0.05). Comparisons of atenolol and longacting propranolol with placebo and the active drugs showed all differences to be statistically significant @ < 0.05). On day 7 the single dose of salbutamol increased SGAW within the first hour 0, < O.OOl), followed by steady falls in SGAW in all groups (Table II, Fig. 2). The highest values were found after placebo and metoprolol OROS administration, there being no significant difference between these two curves. After slow-release metoprolol, atenolol, and long-acting propranolol were administered, the increase in SGAW was less marked, the difference between metoprolol and atenolol (p < 0.05) being about equal to that between atenolol and propranolol (p < 0.05). Heart rate and blood pressure. The mean heart rate before salbutamol administration was practically identical in all medication groups on days 5 and 7. After the administration of the active drugs, heart rate levels were lower than after placebo administration. No substantial difference was observed between days 5 and 7 of each period. On day 5, after the two
Ill. Mean ( + SD) peak plasmaconcentrations of metoprolol OROS, slow-release(SR) metoprolol, atenolol, and long-acting (LA) propranolol in 15healthy subjectson days 5and7 Table
Day Metoprolol
5
Day
7
OROS
(nmol/L)
363 + 154
316 + 168
685 k 228 1.31 ? 0.38
883 k 249 1.52 k 0.51
SR metoprolol
(nmol/L) Atenolol (rmol/L) LA propranolol b.mol/U
0.144
-+ 0.032
0.137
f 0.037
highest doses of salbutamol in the placebo period, heart rate increased by a mean of 10 beats/min. There was no change in heart rate on day 7. The mean systolic blood pressure before salbutamol administration was slightly lower after the active drugs were given on days 5 and 7 than after placebo was administered. Salbutamol caused no change on either day during placebo or the active drug periods. Plasma concentrations. The plasma concentrations revealed good compliance, although the individual values showed considerable variation (Table III). Side effects. After the highest doses of salbutamol, tremor, palpitations, and unrest were occasionally reported, their incidence being greater after placebo than after active drug administration. All side effects were graded’ as mild, and they disappeared within minutes. Twelve of the volunteers reported dyspnea on exertion after the &blockers were administered; this was least after metoprolol OROS, rather more pronounced after long-acting propranolol, and most
476
Bauer, Rakusan, and Kaik
American
August 1990 Heart Journal
0.300: s
- - - - Metoprolol OROS ... ‘. . . SR Metoprolol -. . -. Atenolol LA Propranolol Placebo
0.275
*; s E 0
0.250
1
;I:;:#
-~~~~~~~
0.150-
0.0
1.0 Salbutamol
0.5
1. Mean specific airway conductance (L/set (log-transformed) in 15 healthy subjects.
Fig.
0.300
0.275
X
----- Metoprolol OROS I........... -..-.. -
-
SR Metoprolol Atenolol LA Propranolol Placebo
0.250
0.225
0
1
2 Hours
3 After
4 Salbutamol
5
2. Mean specific airway conductance (L/set HxO) before and after a single dose of salbutamol(400 in 15 healthy subjects.
Fig.
*..”
6
X
cm fig)
marked after slow-release metoprolol and atenolol were given. Safety and toleration. No other adverse clinical, laboratory, or ECG changes were observed. DISCUSSION
Previous attempts have been made to assess the level of &-blockade and cardioselectivity in healthy subjects. Peak expiratory flow rate or forced expiratory volume in one second (FEV1) at rest and after exercise have been shown to be occasionally
1.5 (pg)
2.0
2.5
t 3.0
cm H20) in response to increasing doses of salbutamol
reduced to a greater extent by noncardioselective drugs, but the results have not been satisfactory.13-lg Evaluation of changes in airway caliber induced by additional application of a ,&agonist (isoproterenol hydrochloride, salbutamol) and by use of a more sophisticated technique of measurement (body plethysmography) have produced more satisfactory results. * In most studies, application of the P-blocker alone caused no detectable change in FEVi or SGAW.5-7* 15s20-23Comparison of our preliminary selection test SGAW values with the baseline values measured on days 5 and 7 of each medication period revealed that giving each @-blocker alone did not change the SGAW in healthy subjects; it did not even permit the effect of these agents on bronchi to be qualitatively assessed in accordance with other findings.? After salbutamol inhalation, SGAW varied according to the ,&blocker. After administration of noncardioselective long-acting propranolol, the SGAW doseresponse curve was displaced to the right, whereas after the cardioselective drugs, the SGAW response more or less followed the course of placebo. With the highest doses of salbutamol, the only differences that could be detected were between placebo and slow-release metoprolol and between placebo and atenolol. No difference was found between metoprolol OROS and placebo. PD 35 SGAW findings were in good agreement with the findings in a previous study in which *References
4, 5, 7, 15, and 20 to 22.
TReferences
4, 5, 7, 15, and 20 to 23.
Volume Number
120 2
placebo, slow-release metoprolol, atenolol, and longacting propranolol were investigated. Comparison of the two salbutamol inhalation schedules inevitably revealed different SGAW curves, but the same conclusions about the effects of flzblockade on bronchi can be drawn from the displacement of these curves. The plasma P-blocker concentrations were in the expected therapeutic range for steady-state conditions.2* g-12y24-27The substantially lower @-blocker concentrations after metoprolol OROS administration may explain the difference in SGAW salbutamol response curves following metoprolol OROS and slow-release metoprolol administration. Single-dose studies of cardioselective P-blockers sometimes reveal little or no difference from placebo, though a dose-dependent difference has occasionally been reported.* Under the steady-state conditions employed in our studies, a marked shift of the SGAW salbutamol response curve to the right could be observed, especially after atenolol and slow-release metoprolol administration. This finding was confirmed by the results of a previous study.7 The results of this study indicate that under steady-state conditions, /32-adrenergic blockade is least with metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol, in that order. REFERENCES
1. Benfield P, Clissold SP, Brogden RN. Metoprolol. An update review of its pharmacodynamic and therapeutic efficacy, in hypertension, ischaemic heart disease, and related cardiovascular disorders. Drugs 1986;31:376-429. 2. Kendall MJ, Jack DB, Woods KL, Laugher SJ, Quaterman CP, John VA. Comparison of the pharmacodynamic and pharmacokinetic profiles of single and multiple doses of a commercial slow-release metoprolol formulation with a new OROS deliverv svstem. Br J Clin Pharmacol 1982:13:393-8. 3. Theeuwes F. Elementary osmotic pump. J Pharm Sci 1975; 641987-91. 4. Palminteri R, Kaik G. Time course of the bronchial response to salbutamol after placebo, betaxolol and propranolol. Eur J Clin Pharmacol 1983:24:741-5. 5. Tattersfield AE, Leaver DG, Pride NB. Effects of /3-adrenergic blockade and stimulation on normal human airways. J Appl Physiol 1973;35:613-9. 6. Kaik G. Bronchonasmolvtika und ihre klinische Pharmakologie. Mtinchen: Urban & Schwarzenberg, 1980. I. Kaik G, Bauer K, Brfiller W. Der Einfluss von Betaxolol, Atenolol, Metoprolol und Placebo auf die Salbutamol-induzierte Abnahme des Atemwegswiderstandes. Untersuchungen bei sesunden Probanden nach Einmal- und Mehrfachdosierung. Atemw-Lungenkrkh 1987;13:209-15. 8. Kaik G, Kaik B. Protective effect of various drugs in preventing an acetylcholine induced bronco-constriction, Respiration 1980;39(suppl 1):32-7.
Pulmonary effectsof metoprololOROS
477
9. Fitzgerald JD, Ruffin R, Smedstad KG, Roberts R, McAinsh J. Studies on the pharmacokinetics and pharmacodynamics of atenolol in man. Eur J Clin Pharmacol 1978;13:81-9. 10. Kendall MJ, John VA, Quaterman CP, Welling PG. A single and multiple dose pharmacokinetic and pharmacodynamic comparison of conventional and slow-release metoprolol. Eur J Clin Pharmacol 1980;17:87-92. 11. Leahey WJ, Neil1 JD, Varma MPS, Shanks RG. Comparison of the efficacy and pharmacokinetics of conventional propranolo1 and a long acting preparation of propranolol. Br J Clin Pharmacol 1980;9:33-40. 12. Lecaillon JB, Godbillon J, Abadie F, Gosset G. Determination of metoprolol and its alpha-hydroxylated metabolite in human plasma by high-performance liquid chromatography. J Chromatogr 1984;305:411-7. 13. Folgering HTM, Borm JFE, van Haaren RHLM. Metabolic aspects of maximal exercise performance after slow release metoprolol and after atenolol. Eur J Clin Pharmacol 1982; 23:283-8. 14. Fuller RW, Valiance PJT. Atenolol reduces blood pressure and FEVl in normal subjects. Br J Clin Pharmacol 1982;14: 445-6. 15. Gribbin HR, Mackay AD, Baldwin CJ, Tattersfield AE. Bronchial and cardiac beta-adrenoceptor blockade-a comparison of atenolol, acebutolol and labetolol. Br J Clin Pharmacol 1981;12:61-5. 16. Hutchinson PF, Harrison RN. Effect of acute and chronic beta-blockade on carbon dioxide sensitivity in normal man. Thorax 1980;35:869-72. 17. Kumana CR, Marlin GE, Kaye CM, Smith DM. New approach to assessment of cardioselectivity of beta-blocking drugs. Br Med J 1974;4:444-7. 18. Oh VMS, Kaye CM, Warrington SJ, Taylor EA, Wadsworth J. Studies of cardioselectivity and partial agonist activity in beta-adrenoceptor blockade comparing effects on heart rate and peak expiratory flow-rate during exercise. Br J Clin Pharmacol 1978;5:107-20. 19. Taylor EH, Trembath PW, Warrington SJ. Influence of environmental temperature and humidity on bronchial responses during assessment of selectivity of /%adrenoceptor antagonists in man. Br J Clin Pharmacol 1981;12:201-9. 20. Bauer K, Brunner-Ferber F, Distlerath LM, et al. Assessment of pulmonary P-blockade by L-653,328, a new a-selective fl-adrenoceptor antagonist. I. Healthy subjects. Respiration (In press). 21. Gribbin HR, Baldwin CJ, Tattersfield AE. Quantitative assessment of bronchial fl-adrenoceptor blockade in man. Br J Clin Pharmacol 1979;7:551-6. 22. Tattersfield AE, Harrison RN. Effect of P-blocker therapy on airway function. Drugs 1983;25(suppl 2):227-31. 23. Richardson PS, Sterling GM. Effects of fl-adrenergic receptor blockade on airway conductance and lung volume in normal and asthmatic subjects. Br Med J 1969;3:143-5. 24. Mason WD, Winer N, Kochak G, Cohen I, Bell R. Kinetics and absolute bioavailability of atenolol. Clin Pharmacol Ther 1979;25:408-15. 25. Regardh CG, Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 1980;5:557-69. 26. Routledge PA, Shand DG. Clinical pharmacokinetics of propranolol. Clin Pharmacokinet 1979;4:73-90. 9, Schaefer-Korting M, Kirch W, Axthelm T, Koehler H, MutY‘. schler E. Atenolol interaction with aspirin, allopurinol, and ampicillin. Clin Pharmacol Ther 1983;33:283-8.
Pulmonary effects of long-term ,&blockade healthy subjects: Comparative study of metoprolol OROS
in
The effects on airway response of metoprolol OROS (oral osmotic) and three other long-acting /3-adrenoceptor blockers were studied. This was a placebo-controlled, randomized, five-period, single-blind, crossover trial in 15 healthy volunteers. Bronchial B-blockade was estimated as the displacement of the salbutamol bronchodilator response of specific airway conductance (SGAW) measured by whole-body plethysmography. Metoprolol OROS (14/1gO mg), slow-release (SR) metoprolol (208 mg), atenolol (100 mg), long-acting (LA) propranolol (160 mg), and placebo were given once daily for 7 days. Inhaled salbutamol was administered at peak drug levels in cumulative doses of 12.6 to 800 gg on day 5 and in a single dose of 400 gg on day 7. On day 5, salbutamol induced significant increases in SGAW in each treatment group. SGAW increased after the single dose of saibutamol on day 7 in all groups and then declined steadily. The highest values were found after placebo and metoprolol OROS, with smaller increases after SR metoprolol, atenolol, and LA propranolol, the latter showing ,the smallest increase. Therefore, it would appear that under steady-state conditions, &-bronchial receptors are least blocked by metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol. (AM HEART J 1990; 120:473.)
K. Bauer, MD,a S. Rakusan,
MD,b and G. Kaik, MD.a Vienna, Austria
Metoprolol, a cardioselective fi-adrenoceptor blocker, has been used for many years, mainly for the treatment of hypertension and angina pectoris.’ Recently, a metoprolol OROS (oral osmotic release system) tablet was developed to release metoprolol at a relatively constant rate, over an extended period of time, in a single daily dose.2y 3 The aim of the present study was to compare the bronchial &-blockade of metoprolol OROS and other long-acting P-blockers by studying the changes in ariway caliber in patients before and after administration of 82 stimulants. Airway response after inhalation of the &-adrenoceptor agonist was investigated by two different inhalation schedules.4y5 Bronchial P-blockade was measured as the displacement of the salbutamol bronchodilator response curve.5 The study was conducted in healthy subjects in a randomized single-blind crossover design. SteadyFrom BDivision of Pharmacology, varsity of Vienna Medical School; GmbH.
Department and bMedical
Reprint requests: Dr. K. Bauer, Division ment of Internal Medicine I, University Gasse 14, A-1090 Vienna, Austria. 4/O/21064
of Internal Department,
Medicine I, UniCIBA-GEIGY
of Clinical Pharmacology, of Vienna Medical School,
DepartLazarett-
state comparisons of metoprolol in two different formulations, and of propranolol, atenolol, and placebo were recorded on day 5 (after cumulative doses of salbutamol) and on day 7 (after a single dose of salbutamol) during each period of medication. METHODS
The study wascarried out in accordancewith the guidelines for investigations in healthy volunteers.6The protocol wasapproved by the university ethical review committee, and written informed consent was obtained in each case. Subject selection. Selection of healthy subjects was based on their medical history, smoking habits, physical examination, laboratory profile, electrocardiograms(EGG; standard 12-lead), chest x-ray examination, and pulmonary function. Subjectswho werehyperreactive in response to an inhaled irritant (acetylcholine) were excluded. In admitted subjects,inhalation of 400 rg of salbutamol from a metered-doseaerosolhad to increasespecific airway conductance (SGAW) by 30% or more.6-8Fifteen subjectswere enrolled, eight men and sevenwomen. They were all nonsmokers,their average age was 25 years (range 22 to 32 years), their height was172cm (range, 165to 182cm), and their weight was 70 kg (range 54 to 78 kg). Apparatus and measures. Airway resistance (RAW) and thoracic gasvolume (TGV) were measuredby a constant-volume whole-body plethysmograph (Bodytest, Gut 473
474
Bauer,
Rakusan,
and Kaik
American
August 1990 Heart Journal
I. Mean (*SD) specific airway conductance (L/set X cm HsO) before and 15 minutes after cumulative dosesof inhaled salbutamol in 15 healthy subjects after metoprolol OROS, slow-release(SR) metoprolol, atenolol, long-acting (LA) propranolol, and placebo
Table
Salbutamol Before
MetoprololOROS
0.155 * 0.029
SR metoprolol
0.161 kO.027
Atenolol
0.162 + 0.019
LA propranolol
0.160 kO.025 0.157 kO.023
Placebo
12.5
0.175 iO.026 0.180 kO.032 0.176 + 0.021 0.165
&0.019 0.186 20.022
75
300
400
800
0.209
0.263 kO.046 0.245 kO.037 0.221 izO.024 0.191 kO.027 0.263 kO.040
0.275 kO.045 0.268 io.037 0.247 10.033 0.196 kO.028 0.278 kO.037
0.271 20.048 0.271 + 0.039 0.231 io.035 0.233 kO.034 0.276 kO.037
25 0.188 r0.033
0.189 20.031 0.181 kO.020 0.170 kO.024 0.192 kO.026
Ltd., Basle, Switzerland). For evaluation of airway caliber, SGAW (liters per secondtimes centimeters HsO) wasused. SGAW isthe reciprocal of RAW corrected by TGV; a mean value wascalculated from nine consecutivemeasurements. The provocative cumulative doseof salbutamol (micrograms) required to causea 35% increasein SGAW from baseline(PD 35 SGAW) was determined for each subject and eachmedi&tion.5 Heart rate (radial pulse/minute) and blood pressurewere recorded in a sitting position immediately after measurementof lung function. Drugs. The metoprolol OROS 14/190 tablet used has a zero-order releaserate of 14 mg/hr and a total metoprolol fumarate content of 190 mg (equivalent to 200 mg of immediate-releasemetoprolol tartrate). Standard preparations of the other @-blockerswere designed for once-daily oral administration. To facilitate comparison,dosingwas arranged so that the time of peak plasmaconcentration (t,,,) was between 7 PM and 9 PM. This then coincidedwith the time of lung function testing. The doseof eachdrug and the time betweeningestion and start of the lung function tests were asfollows: metoprolol OROS, 14/190mg, 12 hours post dose;slow-releasemetoprolol, 200mg, 5 hourspost dose;atenolol, 100mg, 3 hours post dose;long-acting propranolol, 160mg, 12 hours post dose;and placebo, 3 hours post dose. Salbutamol, a /3z-adrenoceptoragonist used for symptomatic bronchodilation,‘j was administered by metereddoseaerosolsdelivering 12.5 and 25 pg per puff (AerosolService AG, Mbhlin, Switzerland) and by a commercially available metered-doseaerosoldelivering 100 Mgper puff (Allen and Hanbury Ltd., England). To improve drug delivery in situ, a 10 cm spacerwas used. Study procedures. The study wascarried out in a controlled, randomized (Latin-square), five-period crossover, single-blind design,with eachmedication period separated by 1 week. On day 5 of eachperiod, after determination of baseline values, salbutamol inhalations were administered at 20minute intervals in increasingdoses:12.5,25,75,300,400,
(pg)
so.035 0.206 kO.031 0.201
k 0.019 0.190 kO.030 0.214 20.025
and 800pg. All measureswere repeated after eachsalbutamol inhalation (between 15 and 20 minutes). On day 7 of each period, after determination of baseline values, a singledoseof 400 pg of salbutamolwasgiven. All variables were monitored after 15 and 30 minutes and after 1, 2, 3, 4, and 6 hours. Pharmacokinetics. Venous blood sampleswere drawn on day 1 (before the start of medication), on day 3 (at ha-J, on day 5 (at t,,, = before, and 1 and 2 hours after salbutamol inhalation), and on day 7 (at t,, = before, and 1,2, and 6 hours after salbutamol). The plasmaconcentrations of metoprolol, atenolol, and propranolol were determined by high-performance liquid chromatography.g-12 Side effects. All subjects were observed, questioned, and scored for unwanted side effects (score: 0 = none, 1 = mild, 2 = moderate, 3 = severe)on all days of eachperiod, including those when no salbutamol was given. Safety and tolerability. Clinical investigation, ECG, and laboratory tests were repeated after each period of drug administration. Statistical analysis. All data analyzed were arithmetic means and standard deviations. Statistical analysis was performed on SGAW (peak value, area under the plasma concentration/time curve [AUC], AUC to baseline,and PD 35), heart rate, and blood pressureby analysisof variance. RESULTS Specific
airway conductance (SGAW). The mean baseline values of SGAW before salbutamol did not differ significantly between medication groups on
day 5 and on day 7 or between these days (Tables I and II). On day 5 the cumulative doses of salbutamol produced a continuous increase in SGAW that was statistically significant in all groups (p < 0.001) (Table I, Fig. 1). After placebo and each of the two metopro101 preparations, SGAW curves were practically identical and reached the highest values recorded.
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Pulmonury effects of metoprolol OROS
475
II. Mean ( + SD) specific airway conductance (L/set X cm HzO) before and 0.25 to 6 hours after a single doseof inhaled salbutamol (400 pg) in 15 healthy subjectstreated with metoprolol OROS, slow-release(SR) metoprolol, atenolol, long-acting (LA) propranolol, and placebo Table
Hours
Metoprolol SR metoprolol Atenolol LA propranolol Placebo
OROS
Before
0.25
0.5
1
2
3
4
6
0.161 + 0.021 0.159 + 0.024 0.160 2 0.020 0.160 + 0.023 0.159 i 0.022
0.259 iz 0.032 0.223 ? 0.041 0.222 + 0.024 0.200 + 0.028 0.255 + 0.037
0.265 * 0.033 0.243 * 0.041 0.227 f 0.024 0.217 + 0.027 0.265 + 0.036
0.257 IL 0.030 0.242 k 0.033 0.230 + 0.027 0.212 zk 0.026 0.257 t 0.036
0.254 + 0.033 0.236 * 0.035 0.218 + 0.025 0.201 iz 0.029 0.253 + 0.036
0.242 * 0.031 0.226 E!z0.035 0.203 k 0.024 0.187 + 0.029 0.241 kO.036
0.224 t 0.029 0.210 kO.032 0.184 + 0.024 0.170 k 0.026 0.222 * 0.033
0.198 t 0.027 0.192 f 0.031 0.171 + 0.026 0.160 ? 0.023 0.197 * 0.028
--
After atenolol, and even more after propranolol administration, SGAW increased more slowly, attaining lower peak values even after higher doses of salbutamol. Evaluation by PD 35 SGAW resulted in a median value of 117 for placebo, 97 for metoprolol OROS, 150 for slow-release metoprolol, 363 for atenolol, and 1295 for long-acting propranolol, respectively. There was no statistically significant difference between placebo and both preparations of metoprolol. The differences between metoprolol OROS and the other active drugs were statistically significant (p < 0.05). The differences between slow-release metoprolol and the other active drugs were also statistically significant (p < 0.05). Comparisons of atenolol and longacting propranolol with placebo and the active drugs showed all differences to be statistically significant @ < 0.05). On day 7 the single dose of salbutamol increased SGAW within the first hour 0, < O.OOl), followed by steady falls in SGAW in all groups (Table II, Fig. 2). The highest values were found after placebo and metoprolol OROS administration, there being no significant difference between these two curves. After slow-release metoprolol, atenolol, and long-acting propranolol were administered, the increase in SGAW was less marked, the difference between metoprolol and atenolol (p < 0.05) being about equal to that between atenolol and propranolol (p < 0.05). Heart rate and blood pressure. The mean heart rate before salbutamol administration was practically identical in all medication groups on days 5 and 7. After the administration of the active drugs, heart rate levels were lower than after placebo administration. No substantial difference was observed between days 5 and 7 of each period. On day 5, after the two
Ill. Mean ( + SD) peak plasmaconcentrations of metoprolol OROS, slow-release(SR) metoprolol, atenolol, and long-acting (LA) propranolol in 15healthy subjectson days 5and7 Table
Day Metoprolol
5
Day
7
OROS
(nmol/L)
363 + 154
316 + 168
685 k 228 1.31 ? 0.38
883 k 249 1.52 k 0.51
SR metoprolol
(nmol/L) Atenolol (rmol/L) LA propranolol b.mol/U
0.144
-+ 0.032
0.137
f 0.037
highest doses of salbutamol in the placebo period, heart rate increased by a mean of 10 beats/min. There was no change in heart rate on day 7. The mean systolic blood pressure before salbutamol administration was slightly lower after the active drugs were given on days 5 and 7 than after placebo was administered. Salbutamol caused no change on either day during placebo or the active drug periods. Plasma concentrations. The plasma concentrations revealed good compliance, although the individual values showed considerable variation (Table III). Side effects. After the highest doses of salbutamol, tremor, palpitations, and unrest were occasionally reported, their incidence being greater after placebo than after active drug administration. All side effects were graded’ as mild, and they disappeared within minutes. Twelve of the volunteers reported dyspnea on exertion after the &blockers were administered; this was least after metoprolol OROS, rather more pronounced after long-acting propranolol, and most
476
Bauer, Rakusan, and Kaik
American
August 1990 Heart Journal
0.300: s
- - - - Metoprolol OROS ... ‘. . . SR Metoprolol -. . -. Atenolol LA Propranolol Placebo
0.275
*; s E 0
0.250
1
;I:;:#
-~~~~~~~
0.150-
0.0
1.0 Salbutamol
0.5
1. Mean specific airway conductance (L/set (log-transformed) in 15 healthy subjects.
Fig.
0.300
0.275
X
----- Metoprolol OROS I........... -..-.. -
-
SR Metoprolol Atenolol LA Propranolol Placebo
0.250
0.225
0
1
2 Hours
3 After
4 Salbutamol
5
2. Mean specific airway conductance (L/set HxO) before and after a single dose of salbutamol(400 in 15 healthy subjects.
Fig.
*..”
6
X
cm fig)
marked after slow-release metoprolol and atenolol were given. Safety and toleration. No other adverse clinical, laboratory, or ECG changes were observed. DISCUSSION
Previous attempts have been made to assess the level of &-blockade and cardioselectivity in healthy subjects. Peak expiratory flow rate or forced expiratory volume in one second (FEV1) at rest and after exercise have been shown to be occasionally
1.5 (pg)
2.0
2.5
t 3.0
cm H20) in response to increasing doses of salbutamol
reduced to a greater extent by noncardioselective drugs, but the results have not been satisfactory.13-lg Evaluation of changes in airway caliber induced by additional application of a ,&agonist (isoproterenol hydrochloride, salbutamol) and by use of a more sophisticated technique of measurement (body plethysmography) have produced more satisfactory results. * In most studies, application of the P-blocker alone caused no detectable change in FEVi or SGAW.5-7* 15s20-23Comparison of our preliminary selection test SGAW values with the baseline values measured on days 5 and 7 of each medication period revealed that giving each @-blocker alone did not change the SGAW in healthy subjects; it did not even permit the effect of these agents on bronchi to be qualitatively assessed in accordance with other findings.? After salbutamol inhalation, SGAW varied according to the ,&blocker. After administration of noncardioselective long-acting propranolol, the SGAW doseresponse curve was displaced to the right, whereas after the cardioselective drugs, the SGAW response more or less followed the course of placebo. With the highest doses of salbutamol, the only differences that could be detected were between placebo and slow-release metoprolol and between placebo and atenolol. No difference was found between metoprolol OROS and placebo. PD 35 SGAW findings were in good agreement with the findings in a previous study in which *References
4, 5, 7, 15, and 20 to 22.
TReferences
4, 5, 7, 15, and 20 to 23.
Volume Number
120 2
placebo, slow-release metoprolol, atenolol, and longacting propranolol were investigated. Comparison of the two salbutamol inhalation schedules inevitably revealed different SGAW curves, but the same conclusions about the effects of flzblockade on bronchi can be drawn from the displacement of these curves. The plasma P-blocker concentrations were in the expected therapeutic range for steady-state conditions.2* g-12y24-27The substantially lower @-blocker concentrations after metoprolol OROS administration may explain the difference in SGAW salbutamol response curves following metoprolol OROS and slow-release metoprolol administration. Single-dose studies of cardioselective P-blockers sometimes reveal little or no difference from placebo, though a dose-dependent difference has occasionally been reported.* Under the steady-state conditions employed in our studies, a marked shift of the SGAW salbutamol response curve to the right could be observed, especially after atenolol and slow-release metoprolol administration. This finding was confirmed by the results of a previous study.7 The results of this study indicate that under steady-state conditions, /32-adrenergic blockade is least with metoprolol OROS, followed by SR metoprolol, atenolol, and LA propranolol, in that order. REFERENCES
1. Benfield P, Clissold SP, Brogden RN. Metoprolol. An update review of its pharmacodynamic and therapeutic efficacy, in hypertension, ischaemic heart disease, and related cardiovascular disorders. Drugs 1986;31:376-429. 2. Kendall MJ, Jack DB, Woods KL, Laugher SJ, Quaterman CP, John VA. Comparison of the pharmacodynamic and pharmacokinetic profiles of single and multiple doses of a commercial slow-release metoprolol formulation with a new OROS deliverv svstem. Br J Clin Pharmacol 1982:13:393-8. 3. Theeuwes F. Elementary osmotic pump. J Pharm Sci 1975; 641987-91. 4. Palminteri R, Kaik G. Time course of the bronchial response to salbutamol after placebo, betaxolol and propranolol. Eur J Clin Pharmacol 1983:24:741-5. 5. Tattersfield AE, Leaver DG, Pride NB. Effects of /3-adrenergic blockade and stimulation on normal human airways. J Appl Physiol 1973;35:613-9. 6. Kaik G. Bronchonasmolvtika und ihre klinische Pharmakologie. Mtinchen: Urban & Schwarzenberg, 1980. I. Kaik G, Bauer K, Brfiller W. Der Einfluss von Betaxolol, Atenolol, Metoprolol und Placebo auf die Salbutamol-induzierte Abnahme des Atemwegswiderstandes. Untersuchungen bei sesunden Probanden nach Einmal- und Mehrfachdosierung. Atemw-Lungenkrkh 1987;13:209-15. 8. Kaik G, Kaik B. Protective effect of various drugs in preventing an acetylcholine induced bronco-constriction, Respiration 1980;39(suppl 1):32-7.
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9. Fitzgerald JD, Ruffin R, Smedstad KG, Roberts R, McAinsh J. Studies on the pharmacokinetics and pharmacodynamics of atenolol in man. Eur J Clin Pharmacol 1978;13:81-9. 10. Kendall MJ, John VA, Quaterman CP, Welling PG. A single and multiple dose pharmacokinetic and pharmacodynamic comparison of conventional and slow-release metoprolol. Eur J Clin Pharmacol 1980;17:87-92. 11. Leahey WJ, Neil1 JD, Varma MPS, Shanks RG. Comparison of the efficacy and pharmacokinetics of conventional propranolo1 and a long acting preparation of propranolol. Br J Clin Pharmacol 1980;9:33-40. 12. Lecaillon JB, Godbillon J, Abadie F, Gosset G. Determination of metoprolol and its alpha-hydroxylated metabolite in human plasma by high-performance liquid chromatography. J Chromatogr 1984;305:411-7. 13. Folgering HTM, Borm JFE, van Haaren RHLM. Metabolic aspects of maximal exercise performance after slow release metoprolol and after atenolol. Eur J Clin Pharmacol 1982; 23:283-8. 14. Fuller RW, Valiance PJT. Atenolol reduces blood pressure and FEVl in normal subjects. Br J Clin Pharmacol 1982;14: 445-6. 15. Gribbin HR, Mackay AD, Baldwin CJ, Tattersfield AE. Bronchial and cardiac beta-adrenoceptor blockade-a comparison of atenolol, acebutolol and labetolol. Br J Clin Pharmacol 1981;12:61-5. 16. Hutchinson PF, Harrison RN. Effect of acute and chronic beta-blockade on carbon dioxide sensitivity in normal man. Thorax 1980;35:869-72. 17. Kumana CR, Marlin GE, Kaye CM, Smith DM. New approach to assessment of cardioselectivity of beta-blocking drugs. Br Med J 1974;4:444-7. 18. Oh VMS, Kaye CM, Warrington SJ, Taylor EA, Wadsworth J. Studies of cardioselectivity and partial agonist activity in beta-adrenoceptor blockade comparing effects on heart rate and peak expiratory flow-rate during exercise. Br J Clin Pharmacol 1978;5:107-20. 19. Taylor EH, Trembath PW, Warrington SJ. Influence of environmental temperature and humidity on bronchial responses during assessment of selectivity of /%adrenoceptor antagonists in man. Br J Clin Pharmacol 1981;12:201-9. 20. Bauer K, Brunner-Ferber F, Distlerath LM, et al. Assessment of pulmonary P-blockade by L-653,328, a new a-selective fl-adrenoceptor antagonist. I. Healthy subjects. Respiration (In press). 21. Gribbin HR, Baldwin CJ, Tattersfield AE. Quantitative assessment of bronchial fl-adrenoceptor blockade in man. Br J Clin Pharmacol 1979;7:551-6. 22. Tattersfield AE, Harrison RN. Effect of P-blocker therapy on airway function. Drugs 1983;25(suppl 2):227-31. 23. Richardson PS, Sterling GM. Effects of fl-adrenergic receptor blockade on airway conductance and lung volume in normal and asthmatic subjects. Br Med J 1969;3:143-5. 24. Mason WD, Winer N, Kochak G, Cohen I, Bell R. Kinetics and absolute bioavailability of atenolol. Clin Pharmacol Ther 1979;25:408-15. 25. Regardh CG, Johnsson G. Clinical pharmacokinetics of metoprolol. Clin Pharmacokinet 1980;5:557-69. 26. Routledge PA, Shand DG. Clinical pharmacokinetics of propranolol. Clin Pharmacokinet 1979;4:73-90. 9, Schaefer-Korting M, Kirch W, Axthelm T, Koehler H, MutY‘. schler E. Atenolol interaction with aspirin, allopurinol, and ampicillin. Clin Pharmacol Ther 1983;33:283-8.
