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Cardiac and Pulmonary Effects of Therapy with Albuterol and Isoproterenol
Cardiac and Pulmonary Effects of Therapy with Albuterol Thomas L. Whitsett,
and Isoproterenol
M.D.,-00 and Carl V. Manion, M.D.f
This study evaluated the cardiac and pulmonary effects of administering multiple inhaled doses of albuterol, isoproterenol sulfate, and placebo in ten patients with rever sible obstructive disease of the airways. The pulmonary effects of therapy with albuterol were similar in magnitude
to those of isoproterenol but lasted longer. The inotropic and chronotropic effects of therapy with isoproterenol were greater than those of albuterol. It appears that albu terol has ,) -adri'iu-r^ii-selectivity over a wide range of dosages and is an effective bronchodilator drug.
Tnhalation •¿ dilator *
clear that the absence of chronotropic effects of a drug does not preclude the possibility of positively inotropic activity. Only one study in humans has evaluated the inotropic effects of oral therapy with albuterol, and although the results suggested the effects were "clinically insignificant,"14 some in
of isoproterenol and other bronchodrugs, using a Freon propellant, is
common among patients with reversible obstructive disease of the airways. This method of treatment usually produces a rapid but transient relief of bronchospasm and has been associated with cardiac stimulation. Because of the limited duration of action of iso proterenol and its potential for cardiac toxic effects, alternative drugs have been sought. One such drug, albuterol (marketed in other countries as salbutamol), may offer the advantages of a longer dura tion of action and a decreased cardiac effect com pared to isoproterenol;1"13 however, assessment of
crease in inotropic activity was observed. The struc tural formulas for isoproterenol and albuterol are shown in Figure 1. The purposes of this study were to correlate the cardiac and pulmonary effects of administering a broad range of dosages of albuterol and to compare them to administration of isoproterenol sulfate and a placebo in patients with reversible obstructive dis ease of the airways.
the cardiac effects in these studies was limited to determinations of blood pressure and heart rate, determinations which may be misleading, since it is
MATERIALSANDMETHODS Subjects
"From the Departments of Medicine and Pharmacology, Veterans Administration Hospital and the University of Oklahoma Health Sciences Center, Oklahoma City. "Associate Professor of Medicine and Pharmacology. tAssistant Professor of Medicine and Pharmacology. Manuscript received November 16; revision accepted Febru ary 14. Reprint requests: Dr. Whitsett, Department of Medicine, University Health Sciences Center, PO Box 26901, Oklahoma City 73190
Ten male patients with reversible obstructive disease of the airways (range of ages, 18 to 61 years) were entered into a randomized double-blind crossover study of three treat ments. Reversible obstruction of the airways was defined by at least a 20 percent increase in the one-second forced expiratory volume (FEV,) measured 15 minutes after ad ministration of 0.15 mg (two inhalations) of aerosol isopro-
ALBUTEROL HOCH2 CH3 CH
CH,
.NHC
CH.,
I CH3
OH
ISOPROTERENOL
CH3 NH-
CH CH,
FIGURE 1. Structural CHEST, 74: 3, SEPTEMBER,1978
formulas of albuterol
and isoproterenol.
CARDIACANDPULMONARYEFFECTSOFALBUTEROL ANDISOPROTERENOL251
terenol sulfate from a metered-dose dispenser (MedihalerIso). Patients were excluded from the study if they had diabetes mellitus, hypertension, or cardiovascular, hepatic, hematologic, renal, or neurologic disease. Patients entered the study after meeting the criteria for acceptance and signing a form giving informed consent. Design of the Study This double-blind crossover study evaluated each of five sequentially administered doses of albuterol, isoproterenol, and placebo. On separate days, each dose was given by inhalation from identical looking containers designed to de liver either albuterol (86/xg as the base), isoproterenol sul fate (79^g as the base), or placebo (propellant only). Completion of each treatment involved receiving one, two, four, six, and eight inhalations of albuterol, isoproterenol, and placebo. Patients were instructed to hold their breath at full inspiration following each dose. Xo attempt was made to regulate the rapidity of inhalation. The time between inhala tions was not controlled but \vas approximately 20 seconds. The order of administration was randomized at each level. Intolerance to a dose was defined as either a heart rate of 120 beats per minute or an increase of 40 percent in the heart rate. When either occurred, a higher dose of that treatment was not administered. On each morning of study, patients reported to the labora tory in a fasting state and were allowed only water until completion of that day's evaluation. They received no bronchodilator drugs for at least 12 hours prior to each day of study or during the controlled observations. In order to qualify for each dose of a drug under study, each patient underwent spirometric studies, and the FEV, had to be less than 81 percent of the value obtained following the original screening challenge with isoproterenol. Measurements Before (zero time) and at 1, 5, 10, 15, 30, 60, 90, and 120
minutes after completion of the last inhalation, the following measurements were obtained: (1) blood pressure; (2) heart rate; (3) preelection period; (4) electrocardiogram; (5) forced vital capacity (FVC); (6) FEV,; and (7) mean forced expiratory flow during the middle half of the FVC (FEF25-75?). The preejection period was measured with a multichannel recorder (Elema-Schiinander Mingograph) by simultaneously recording the ECG, phonocardiogram, and contour of the carotid pulse at 100 mm/sec. Derived calcula tions of the preejection period and heart rate were the average values taken from ten consecutive beats, as previous ly described.'"1 Blood pressure was measured by an auto matic blood pressure recorder (Arteriosonde-Rocom). Measurements of pulmonary function were taken from records of the best of two consecutive forced expiratory maneuvers recorded on a Stead-Wells spirometer (Collins). The FEF25-753? at zero time was used to measure end-points for the forced expiratory flow after administration of the drug, so that all measurements of forced expiratory flow were at isovolume.'" Analysix of Data Values for observations at one and five minutes and for those at 10 and 15 minutes were averaged to reduce the amount of data. A three-way analysis of variance was per formed, with testing for effects due to times and treatments and subjects. Although the percentage of change has been used for graphic presentation of the results, statistical analysis was performed on the raw data. A compilation of the mean and standard error of both raw data and the percentage of change for each dose, along with the results of the corre sponding statistical tests for the data on pulmonary function (FEV,, FVC, and FEF25-75$) and the cardiovascular data (preejection period, blood pressure, and heart rate) may be obtained from the National Auxiliary Publication Service.t JAddress requests to Microfiche Publication, 400 Park Ave nue South, New York 10016.
Table 1—Data on Patients before and IS Minutes after Inhalation of 0.15 nig of Isoproterenol Sulfate
L/secBefore1.070.330.740.701.530.580.911.652.100.911.050.17 Patient, Age (yr)1,
(Percent)*2.52
(Percent)**3.18
(Percent)*4.87
(Percent)**5.41
Period, msec971101011151269912
352,
(57)0.95
(26)1.20
(89)2.31
(11)3.10
(85)0.62
493,
(27)1.57
(26)2.10
(52)2.56
(34)3.22
(88)2.06
(34)1.24
(58)1.24
(26)1.65
(178)1.24
(42)3.10
(29)4.21
(33)4.13
(77)2.31 (51)1.11
544,575,246,617,248,559,4710, (47)0.87 (27)2.48 (56)0.87
(25)1.24
(79)1.40
(-2)1.98
(29)1.86
(42)2.43
(35)2.97
(41)3.63
(91)2.06
(46)2.06
(31)2.97
(62)2.97
(22)4.75
(126)2.97
(59)3.51
(44)4.21
(64)2.10
(60)5.49
(180)3.84
(93)2.23
(20)3.22
(44)4.99
(5)5.32
(83)2.23
18MeanSEFEV,,Before (47)1.89
(44)2.49
(87)2.96
(7)3.87
(145)2.04
(49)0.27
(33)0.33
(60)0.42
(24)0.44
(110)0.29
(6)LAfter 'Percentage *'Percentage
(3)FVC,Before
(7)LAfter
(6)FEF25-75%,
(14)Preejection
of predicted value. of increase after inhalation.
252 WHITSETT, MANION
CHEST,74: 3, SEPTEMBER, 1978
RESULTS Ten subjects began this study, and eight com pleted all 15 sessions. Subject 1 did not receive six and eight inhalations of isoproterenol because his heart rate rose to 165 beats per minute after four inhalations. Subject 7 failed to receive eight inhala tions of isoproterenol because six inhalations caused a heart rate of 135 beats per minute.
10
PLACEBO
•¿ ui u. 50 ISOPROTERENOL 40
Baseline Data 30
The clinical data from each patient are found in Table 1. There was an average increase in FEVi of 33 percent (range, 20 to 44 percent) following in halation of isoproterenol. Analysis of variance con firmed the consistency of each individual's FEVi at
20
10
zero time. Thus, we concluded that pulmonary func tion was comparable at the beginning of each ses sion. ALBUTEROL
Pulmonary Effects
40
The effects of each dose of placebo, isoproterenol, and albuterol on FEVi are shown in Figure 2. No statistically significant changes in FEVi were seen after administration of placebo. Dose-related in creases in FEVi were seen after inhalation of iso proterenol and albuterol. No differences were seen in the onset of the effect, but the duration of action was longer after inhalation of albuterol. Although the peak effects occurred at five minutes and at 60 minutes for isoproterenol and for albuterol, respec tively, there were no significant differences in the absolute response. The observations at all periods of time following inhalation of each dose of albuterol were significantly (P < 0.05) different from the corresponding baseline measurement. The increases in FEF25-75% and FVC were similar to those ob served for FEVi. Cardiovascular Effects Following inhalation of isoproterenol, there was a transient dose-related increase in heart rate, fol lowed by a progressive slowing (Fig 3). Inhalation of the placebo appeared to produce a dose-related slowing in heart rate, but this was not confirmed by analysis of variance. The slight increase in heart rate observed after six and eight inhalations of albuterol was not statistically significant. The peak effect on the heart rate after inhalation of the highest dose of albuterol was comparable to the lowest dose of iso proterenol. Administration of six and eight inhala tions of isoproterenol produced a decrease in diastolic pressure (8 to 10 mm Hg) that lasted 30 minutes or less. There were no changes in blood pressure reCHEST,74: 3, SEPTEMBER, 1978
30
- 20 UJ
u.
10
5
10*15
30
Time Post Dosing
60
90
120
(minutes)
FIGURE2. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in FEVr Values are means of data from ten patients. Asterisks indicate P < 0.05, com paring each observation to baseline value.
lated to the administration of albuterol or placebo. Variations in the preejection period occurring af ter inhalation of placebo were generally within the range of ±7percent (Fig 4). The shortening of the preejection period seen after inhalation of isopro terenol was related to the dose. The peak effect occurred at five minutes after inhalation and repre sented a decrease in the preejection period of 5 to 15 percent. The effect was dissipated by 30 minutes after administration. Inhalation of albuterol also shortened the preejection period by 5 to 8 percent, produced a peak effect at 15 minutes after inhala tion, and had a duration of effect of 30 minutes. The effects of inhalation of albuterol were not related to the dose. DISCUSSION This study has demonstrated that in patients with reversible obstructive disease of the airways, the
CARDIAC ANDPULMONARY EFFECTS OFALBUTEROL ANDISOPROTERENOL 253
pressure and heart rate.1'3-5'7-8-10"13 Such studies are insufficient, since /S-adrenergic stimulation of the heart may cause disproportionate effects on chronotropic and inotropic activity. In a previous report from this laboratory,14 the inotropic effect of oral therapy with albuterol was evaluated in patients with reversible obstructive disease of the airways. In that study, oral therapy with albuterol had a brief, clinically insignificant, positively inotropic effect at dosages of 4 and 6 mg. The current study has dem onstrated a small positively inotropic effect with large dosages of albuterol that was clinically incon sequential compared to therapy with isoproterenol. It was surprising that the peak inotropic effect seen at 10 to 15 minutes after administration, in the dosage of four to eight inhalations, did not coincide with the peak pulmonary effect. The duration of the positive-
PLACEBO
10 .
PLACEBO
a.
HI 0.
-10 10 ISOPROTERENOL
1«5
10'15
30
60
90
120
Time Post Dosing (minutes)
FIGURE3. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in heart rate (HR). Values are means of data from eight patients. Values for two in dividuals who developed tachycardia after inhalation of iso proterenol and did not receive higher doses were excluded from this illustration. Asterisks indicate P < 0.05, comparing each observation to baseline value.
cardiovascular and pulmonary effects of inhaled al buterol were different from those of inhaled isopro terenol. The maximal cardiopulmonary effects of inhalation of isoproterenol occurred by five minutes and immediately began to decrease. The peak pul monary effect of inhalation of albuterol did not occur until one hour after inhalation and had a rapid onset (80 percent in five minutes) with sustained action (80 percent in two hours). Thus, there was a stable response from five minutes to two hours after inhalation. This was contrasted to the relatively ab breviated effects of inhalation of isoproterenol. Most studies correlating cardiovascular and pul monary effects in humans have only measured blood 254 WHITSETT, MANION
£ ° 0. Ul
-10 -15 ALBUTEROL
Q. Ill o.
-10
1*5
10-15
Time Post
30 Dosing
60
90
120
(minutes)
FIGURE4. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in preelection period (PEP). Values are means of data from ten patients. Asterisks indicate P < 0.05, comparing each observation to baseline value.
CHEST,74: 3, SEPTEMBER, 1978
ly inotropic response was considerably less than the duration of the pulmonary effect. Both of these ob servations for albuterol demonstrate widely dis parate dose-response curves separating the cardiac and pulmonary responsiveness. The effect of four to eight inhalations of isoproterenol was a decrease of 17 msec in the preejection period. This response was approximately 50 percent less than the effect of an intravenous infusion of 2.5/ug of isoproterenol per minute17 and was equiva lent to an infusion of dopamine at 4ju.g/kg/min18 or to 1.2 mg of deslanoside (Cedilanid-D).15 Inha lation of the higher doses of isoproterenol had an equivalent inotropic and chronotropic effect. The effects of therapy with albuterol on blood pressure and heart rate were similar to those in previous reports and appear to be clinically desir able. Although the effects of inhalation of isopro terenol on blood pressure and heart rate were small, these effects could be detrimental to certain patients. ACKNOWLEDGMENT: We thank Mr. Robert Murphree and Mr. Ken Brooks for their technical assistance and Ms. Barbara Million, Ms. Gloria Guthrie, and Ms. Nancy Hoshaw for their secretarial assistance.
7 8
9
10
11
12 13 14
REFERENCES 1 Riding WD, Chatterjee SS, Dinda P: Clinical trial of a new /3-adrenergic stimulant in asthma. Br J Clin Pract 23:217-219, 1969 2 Tattersfield AE, McNicol MW: Salbutamol and isopro terenol: A double-blind trial to compare bronchodilator and cardiovascular activity. N Engl J Med 281:13231326, 1969 3 Warrell DA, Robertson DG, Howes J, et al: Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. Br Med J 1:65-70, 1970 4 Paterson J\V: Human pharmacology: Comparison of in travenous isoprenaline and salbutamol in asthmatic pa tients. Postgrad Med J (suppl) 47:38-39, 1971 5 Choo-King YFJ, Parker SS, Grant IWB: Response of
CHEST,74: 3, SEPTEMBER, 1978
6
15
16 17
18
asthmatics to isoprenaline and salbutamol aerosols admin istered by intermittent positive pressure ventilation. Br Med J 4:465-468, 1970 Streeton JA: Salbutamol: A double-blind crossover trial. Med J Aust 2:1184-1187, 1970 Chatterjee SS, Perry AE: Salbutamol: Clinical application as pressure-packed aerosol. Postgrad Med J (suppl) 47: 53-55, 1971 Minette A: Ventilatory results and side-effects of sal butamol given by different routes in coalminers with reversible bronchoobstruction. Postgrad Med J (suppl) 47:55-61, 1971 Tala E, Kellomaki L, Pylkas A: Double-blind comparison of isoprenaline, orciprenaline and salbutamol aerosols in patients with asthma. Postgrad Med J (suppl) 47:61-63, 1971 Conolly ME, Warrell DA, Howes JA, et al: A comparison of the cardiorespiratory effects of isoprenaline and sal butamol in patients with bronchial asthma. Postgrad Med J (suppl) 47:77-81,1971 Bianco S, Kamburoff PL, Prime FJ: Comparison between the bronchodilator and cardiovascular effects of inhaling 0.5 mg rimiterol (Pulmadil) and 0.2 mg salbutamol. Curr Med Res Opin 3:30-35, 1975 Murray AB, Hardwich DF, Pirie GE, et al: The effects of pressurized isoproterenol and salbutamol in asthmatic children. Pediatrics 54:745-756, 1974 Sillett RW, Dash CH, McNicol MW: Comparison of salmefamol with salbutamol aerosols in asthmatics. Eur J Clin Pharmacol 9:277-280, 1976 Whitsett TL: Albuterol and ephedrine in patients with reversible obstructive airway disease. Ann Allergy 38:416421, 1977 Harris WS, Schoenfeld CD, Weissler AM: Effects of adrenergic receptor activation and blockage on the sys tolic preejection period, heart rate and arterial pressure in man. J Clin Invest 46:1704-1714, 1967 Petty TL: Intensive and Rehabilitative Respiratory Care. Philadelphia, Lea and Febiger, 1971 Ahmed SS, Levinson GE, Schwartz CJ, et al: Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man. Circulation 46:559571, 1972 Whitsett TL, Goldberg LI: Effects of levodopa on systolic preejection period, blood pressure, and heart rate during acute and chronic treatment of Parkinson's disease. Cir culation 35:97-106,1972
CARDIAC ANDPULMONARY EFFECTS OFALBUTEROL ANDISOPROTERENOL 255
and Isoproterenol
M.D.,-00 and Carl V. Manion, M.D.f
This study evaluated the cardiac and pulmonary effects of administering multiple inhaled doses of albuterol, isoproterenol sulfate, and placebo in ten patients with rever sible obstructive disease of the airways. The pulmonary effects of therapy with albuterol were similar in magnitude
to those of isoproterenol but lasted longer. The inotropic and chronotropic effects of therapy with isoproterenol were greater than those of albuterol. It appears that albu terol has ,) -adri'iu-r^ii-selectivity over a wide range of dosages and is an effective bronchodilator drug.
Tnhalation •¿ dilator *
clear that the absence of chronotropic effects of a drug does not preclude the possibility of positively inotropic activity. Only one study in humans has evaluated the inotropic effects of oral therapy with albuterol, and although the results suggested the effects were "clinically insignificant,"14 some in
of isoproterenol and other bronchodrugs, using a Freon propellant, is
common among patients with reversible obstructive disease of the airways. This method of treatment usually produces a rapid but transient relief of bronchospasm and has been associated with cardiac stimulation. Because of the limited duration of action of iso proterenol and its potential for cardiac toxic effects, alternative drugs have been sought. One such drug, albuterol (marketed in other countries as salbutamol), may offer the advantages of a longer dura tion of action and a decreased cardiac effect com pared to isoproterenol;1"13 however, assessment of
crease in inotropic activity was observed. The struc tural formulas for isoproterenol and albuterol are shown in Figure 1. The purposes of this study were to correlate the cardiac and pulmonary effects of administering a broad range of dosages of albuterol and to compare them to administration of isoproterenol sulfate and a placebo in patients with reversible obstructive dis ease of the airways.
the cardiac effects in these studies was limited to determinations of blood pressure and heart rate, determinations which may be misleading, since it is
MATERIALSANDMETHODS Subjects
"From the Departments of Medicine and Pharmacology, Veterans Administration Hospital and the University of Oklahoma Health Sciences Center, Oklahoma City. "Associate Professor of Medicine and Pharmacology. tAssistant Professor of Medicine and Pharmacology. Manuscript received November 16; revision accepted Febru ary 14. Reprint requests: Dr. Whitsett, Department of Medicine, University Health Sciences Center, PO Box 26901, Oklahoma City 73190
Ten male patients with reversible obstructive disease of the airways (range of ages, 18 to 61 years) were entered into a randomized double-blind crossover study of three treat ments. Reversible obstruction of the airways was defined by at least a 20 percent increase in the one-second forced expiratory volume (FEV,) measured 15 minutes after ad ministration of 0.15 mg (two inhalations) of aerosol isopro-
ALBUTEROL HOCH2 CH3 CH
CH,
.NHC
CH.,
I CH3
OH
ISOPROTERENOL
CH3 NH-
CH CH,
FIGURE 1. Structural CHEST, 74: 3, SEPTEMBER,1978
formulas of albuterol
and isoproterenol.
CARDIACANDPULMONARYEFFECTSOFALBUTEROL ANDISOPROTERENOL251
terenol sulfate from a metered-dose dispenser (MedihalerIso). Patients were excluded from the study if they had diabetes mellitus, hypertension, or cardiovascular, hepatic, hematologic, renal, or neurologic disease. Patients entered the study after meeting the criteria for acceptance and signing a form giving informed consent. Design of the Study This double-blind crossover study evaluated each of five sequentially administered doses of albuterol, isoproterenol, and placebo. On separate days, each dose was given by inhalation from identical looking containers designed to de liver either albuterol (86/xg as the base), isoproterenol sul fate (79^g as the base), or placebo (propellant only). Completion of each treatment involved receiving one, two, four, six, and eight inhalations of albuterol, isoproterenol, and placebo. Patients were instructed to hold their breath at full inspiration following each dose. Xo attempt was made to regulate the rapidity of inhalation. The time between inhala tions was not controlled but \vas approximately 20 seconds. The order of administration was randomized at each level. Intolerance to a dose was defined as either a heart rate of 120 beats per minute or an increase of 40 percent in the heart rate. When either occurred, a higher dose of that treatment was not administered. On each morning of study, patients reported to the labora tory in a fasting state and were allowed only water until completion of that day's evaluation. They received no bronchodilator drugs for at least 12 hours prior to each day of study or during the controlled observations. In order to qualify for each dose of a drug under study, each patient underwent spirometric studies, and the FEV, had to be less than 81 percent of the value obtained following the original screening challenge with isoproterenol. Measurements Before (zero time) and at 1, 5, 10, 15, 30, 60, 90, and 120
minutes after completion of the last inhalation, the following measurements were obtained: (1) blood pressure; (2) heart rate; (3) preelection period; (4) electrocardiogram; (5) forced vital capacity (FVC); (6) FEV,; and (7) mean forced expiratory flow during the middle half of the FVC (FEF25-75?). The preejection period was measured with a multichannel recorder (Elema-Schiinander Mingograph) by simultaneously recording the ECG, phonocardiogram, and contour of the carotid pulse at 100 mm/sec. Derived calcula tions of the preejection period and heart rate were the average values taken from ten consecutive beats, as previous ly described.'"1 Blood pressure was measured by an auto matic blood pressure recorder (Arteriosonde-Rocom). Measurements of pulmonary function were taken from records of the best of two consecutive forced expiratory maneuvers recorded on a Stead-Wells spirometer (Collins). The FEF25-753? at zero time was used to measure end-points for the forced expiratory flow after administration of the drug, so that all measurements of forced expiratory flow were at isovolume.'" Analysix of Data Values for observations at one and five minutes and for those at 10 and 15 minutes were averaged to reduce the amount of data. A three-way analysis of variance was per formed, with testing for effects due to times and treatments and subjects. Although the percentage of change has been used for graphic presentation of the results, statistical analysis was performed on the raw data. A compilation of the mean and standard error of both raw data and the percentage of change for each dose, along with the results of the corre sponding statistical tests for the data on pulmonary function (FEV,, FVC, and FEF25-75$) and the cardiovascular data (preejection period, blood pressure, and heart rate) may be obtained from the National Auxiliary Publication Service.t JAddress requests to Microfiche Publication, 400 Park Ave nue South, New York 10016.
Table 1—Data on Patients before and IS Minutes after Inhalation of 0.15 nig of Isoproterenol Sulfate
L/secBefore1.070.330.740.701.530.580.911.652.100.911.050.17 Patient, Age (yr)1,
(Percent)*2.52
(Percent)**3.18
(Percent)*4.87
(Percent)**5.41
Period, msec971101011151269912
352,
(57)0.95
(26)1.20
(89)2.31
(11)3.10
(85)0.62
493,
(27)1.57
(26)2.10
(52)2.56
(34)3.22
(88)2.06
(34)1.24
(58)1.24
(26)1.65
(178)1.24
(42)3.10
(29)4.21
(33)4.13
(77)2.31 (51)1.11
544,575,246,617,248,559,4710, (47)0.87 (27)2.48 (56)0.87
(25)1.24
(79)1.40
(-2)1.98
(29)1.86
(42)2.43
(35)2.97
(41)3.63
(91)2.06
(46)2.06
(31)2.97
(62)2.97
(22)4.75
(126)2.97
(59)3.51
(44)4.21
(64)2.10
(60)5.49
(180)3.84
(93)2.23
(20)3.22
(44)4.99
(5)5.32
(83)2.23
18MeanSEFEV,,Before (47)1.89
(44)2.49
(87)2.96
(7)3.87
(145)2.04
(49)0.27
(33)0.33
(60)0.42
(24)0.44
(110)0.29
(6)LAfter 'Percentage *'Percentage
(3)FVC,Before
(7)LAfter
(6)FEF25-75%,
(14)Preejection
of predicted value. of increase after inhalation.
252 WHITSETT, MANION
CHEST,74: 3, SEPTEMBER, 1978
RESULTS Ten subjects began this study, and eight com pleted all 15 sessions. Subject 1 did not receive six and eight inhalations of isoproterenol because his heart rate rose to 165 beats per minute after four inhalations. Subject 7 failed to receive eight inhala tions of isoproterenol because six inhalations caused a heart rate of 135 beats per minute.
10
PLACEBO
•¿ ui u. 50 ISOPROTERENOL 40
Baseline Data 30
The clinical data from each patient are found in Table 1. There was an average increase in FEVi of 33 percent (range, 20 to 44 percent) following in halation of isoproterenol. Analysis of variance con firmed the consistency of each individual's FEVi at
20
10
zero time. Thus, we concluded that pulmonary func tion was comparable at the beginning of each ses sion. ALBUTEROL
Pulmonary Effects
40
The effects of each dose of placebo, isoproterenol, and albuterol on FEVi are shown in Figure 2. No statistically significant changes in FEVi were seen after administration of placebo. Dose-related in creases in FEVi were seen after inhalation of iso proterenol and albuterol. No differences were seen in the onset of the effect, but the duration of action was longer after inhalation of albuterol. Although the peak effects occurred at five minutes and at 60 minutes for isoproterenol and for albuterol, respec tively, there were no significant differences in the absolute response. The observations at all periods of time following inhalation of each dose of albuterol were significantly (P < 0.05) different from the corresponding baseline measurement. The increases in FEF25-75% and FVC were similar to those ob served for FEVi. Cardiovascular Effects Following inhalation of isoproterenol, there was a transient dose-related increase in heart rate, fol lowed by a progressive slowing (Fig 3). Inhalation of the placebo appeared to produce a dose-related slowing in heart rate, but this was not confirmed by analysis of variance. The slight increase in heart rate observed after six and eight inhalations of albuterol was not statistically significant. The peak effect on the heart rate after inhalation of the highest dose of albuterol was comparable to the lowest dose of iso proterenol. Administration of six and eight inhala tions of isoproterenol produced a decrease in diastolic pressure (8 to 10 mm Hg) that lasted 30 minutes or less. There were no changes in blood pressure reCHEST,74: 3, SEPTEMBER, 1978
30
- 20 UJ
u.
10
5
10*15
30
Time Post Dosing
60
90
120
(minutes)
FIGURE2. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in FEVr Values are means of data from ten patients. Asterisks indicate P < 0.05, com paring each observation to baseline value.
lated to the administration of albuterol or placebo. Variations in the preejection period occurring af ter inhalation of placebo were generally within the range of ±7percent (Fig 4). The shortening of the preejection period seen after inhalation of isopro terenol was related to the dose. The peak effect occurred at five minutes after inhalation and repre sented a decrease in the preejection period of 5 to 15 percent. The effect was dissipated by 30 minutes after administration. Inhalation of albuterol also shortened the preejection period by 5 to 8 percent, produced a peak effect at 15 minutes after inhala tion, and had a duration of effect of 30 minutes. The effects of inhalation of albuterol were not related to the dose. DISCUSSION This study has demonstrated that in patients with reversible obstructive disease of the airways, the
CARDIAC ANDPULMONARY EFFECTS OFALBUTEROL ANDISOPROTERENOL 253
pressure and heart rate.1'3-5'7-8-10"13 Such studies are insufficient, since /S-adrenergic stimulation of the heart may cause disproportionate effects on chronotropic and inotropic activity. In a previous report from this laboratory,14 the inotropic effect of oral therapy with albuterol was evaluated in patients with reversible obstructive disease of the airways. In that study, oral therapy with albuterol had a brief, clinically insignificant, positively inotropic effect at dosages of 4 and 6 mg. The current study has dem onstrated a small positively inotropic effect with large dosages of albuterol that was clinically incon sequential compared to therapy with isoproterenol. It was surprising that the peak inotropic effect seen at 10 to 15 minutes after administration, in the dosage of four to eight inhalations, did not coincide with the peak pulmonary effect. The duration of the positive-
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FIGURE3. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in heart rate (HR). Values are means of data from eight patients. Values for two in dividuals who developed tachycardia after inhalation of iso proterenol and did not receive higher doses were excluded from this illustration. Asterisks indicate P < 0.05, comparing each observation to baseline value.
cardiovascular and pulmonary effects of inhaled al buterol were different from those of inhaled isopro terenol. The maximal cardiopulmonary effects of inhalation of isoproterenol occurred by five minutes and immediately began to decrease. The peak pul monary effect of inhalation of albuterol did not occur until one hour after inhalation and had a rapid onset (80 percent in five minutes) with sustained action (80 percent in two hours). Thus, there was a stable response from five minutes to two hours after inhalation. This was contrasted to the relatively ab breviated effects of inhalation of isoproterenol. Most studies correlating cardiovascular and pul monary effects in humans have only measured blood 254 WHITSETT, MANION
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FIGURE4. Effects of inhalation of placebo, isoproterenol, and albuterol on percentage of change in preelection period (PEP). Values are means of data from ten patients. Asterisks indicate P < 0.05, comparing each observation to baseline value.
CHEST,74: 3, SEPTEMBER, 1978
ly inotropic response was considerably less than the duration of the pulmonary effect. Both of these ob servations for albuterol demonstrate widely dis parate dose-response curves separating the cardiac and pulmonary responsiveness. The effect of four to eight inhalations of isoproterenol was a decrease of 17 msec in the preejection period. This response was approximately 50 percent less than the effect of an intravenous infusion of 2.5/ug of isoproterenol per minute17 and was equiva lent to an infusion of dopamine at 4ju.g/kg/min18 or to 1.2 mg of deslanoside (Cedilanid-D).15 Inha lation of the higher doses of isoproterenol had an equivalent inotropic and chronotropic effect. The effects of therapy with albuterol on blood pressure and heart rate were similar to those in previous reports and appear to be clinically desir able. Although the effects of inhalation of isopro terenol on blood pressure and heart rate were small, these effects could be detrimental to certain patients. ACKNOWLEDGMENT: We thank Mr. Robert Murphree and Mr. Ken Brooks for their technical assistance and Ms. Barbara Million, Ms. Gloria Guthrie, and Ms. Nancy Hoshaw for their secretarial assistance.
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REFERENCES 1 Riding WD, Chatterjee SS, Dinda P: Clinical trial of a new /3-adrenergic stimulant in asthma. Br J Clin Pract 23:217-219, 1969 2 Tattersfield AE, McNicol MW: Salbutamol and isopro terenol: A double-blind trial to compare bronchodilator and cardiovascular activity. N Engl J Med 281:13231326, 1969 3 Warrell DA, Robertson DG, Howes J, et al: Comparison of cardiorespiratory effects of isoprenaline and salbutamol in patients with bronchial asthma. Br Med J 1:65-70, 1970 4 Paterson J\V: Human pharmacology: Comparison of in travenous isoprenaline and salbutamol in asthmatic pa tients. Postgrad Med J (suppl) 47:38-39, 1971 5 Choo-King YFJ, Parker SS, Grant IWB: Response of
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asthmatics to isoprenaline and salbutamol aerosols admin istered by intermittent positive pressure ventilation. Br Med J 4:465-468, 1970 Streeton JA: Salbutamol: A double-blind crossover trial. Med J Aust 2:1184-1187, 1970 Chatterjee SS, Perry AE: Salbutamol: Clinical application as pressure-packed aerosol. Postgrad Med J (suppl) 47: 53-55, 1971 Minette A: Ventilatory results and side-effects of sal butamol given by different routes in coalminers with reversible bronchoobstruction. Postgrad Med J (suppl) 47:55-61, 1971 Tala E, Kellomaki L, Pylkas A: Double-blind comparison of isoprenaline, orciprenaline and salbutamol aerosols in patients with asthma. Postgrad Med J (suppl) 47:61-63, 1971 Conolly ME, Warrell DA, Howes JA, et al: A comparison of the cardiorespiratory effects of isoprenaline and sal butamol in patients with bronchial asthma. Postgrad Med J (suppl) 47:77-81,1971 Bianco S, Kamburoff PL, Prime FJ: Comparison between the bronchodilator and cardiovascular effects of inhaling 0.5 mg rimiterol (Pulmadil) and 0.2 mg salbutamol. Curr Med Res Opin 3:30-35, 1975 Murray AB, Hardwich DF, Pirie GE, et al: The effects of pressurized isoproterenol and salbutamol in asthmatic children. Pediatrics 54:745-756, 1974 Sillett RW, Dash CH, McNicol MW: Comparison of salmefamol with salbutamol aerosols in asthmatics. Eur J Clin Pharmacol 9:277-280, 1976 Whitsett TL: Albuterol and ephedrine in patients with reversible obstructive airway disease. Ann Allergy 38:416421, 1977 Harris WS, Schoenfeld CD, Weissler AM: Effects of adrenergic receptor activation and blockage on the sys tolic preejection period, heart rate and arterial pressure in man. J Clin Invest 46:1704-1714, 1967 Petty TL: Intensive and Rehabilitative Respiratory Care. Philadelphia, Lea and Febiger, 1971 Ahmed SS, Levinson GE, Schwartz CJ, et al: Systolic time intervals as measures of the contractile state of the left ventricular myocardium in man. Circulation 46:559571, 1972 Whitsett TL, Goldberg LI: Effects of levodopa on systolic preejection period, blood pressure, and heart rate during acute and chronic treatment of Parkinson's disease. Cir culation 35:97-106,1972
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