339

Osmotic Release Oral Drug Delivery System of

Metoprolol in Hypertensive Asthmatic Patients
Pharmacodynamic Effects on /32-Adrenergic Receptors
Karin Bauer, Gerhard Kaik, Brigitte Kaik
Abstract This study investigated the effects of an osmotic
release oral drug delivery system of metoprolol on the changes
induced by cumulative doses of inhaled salbutamol on bronchomotor tone, skeletal muscle, and the circulatory system
after single (day 1) and multiple (day 7) dosing in 18 hypertensive asthmatic patients (forced expiratory volume in 1
second >50% predicted; diastolic blood pressure >90
mm Hg). The patients were given 14/190 mg metoprolol, 100
mg atenolol, and placebo once daily for a 7-day period each in
a randomized, double-blind, crossover design. At the estimated time of peak plasma concentrations, cumulative doses
of salbutamol (12.5, 37.5, 112.5, 412.5, 812.5, and 1612.5 fig)
were applied every 20 minutes. Specific airway conductance,
finger tremor amplitude, heart rate, and blood pressure were
registered at baseline and at each dose increment. The slopes
of the salbutamol dose-response curves of specific airway
conductance did not differ on day 1 (P>.05). On day 7,
atenolol caused a shift of the dose-response curves of specific
airway conductance to the right (P<.05), whereas metoprolol

was indistinguishable from placebo (P>.05). The median

cumulative salbutamol concentrations causing a 50% increase
in specific airway conductance were 416 and 384 jtg (days 1
and 7, respectively) for placebo, 594 and 444 jig for metoprolol, and 562 and 1419 ng for atenolol. The median cumulative
salbutamol concentrations causing a 35% increase in tremor
were 732 and 706 jig for placebo, 812 and 1213 /ig for
metoprolol, and 797 and 1323 jtg for atenolol. These results
demonstrate that single doses of metoprolol and atenolol
showed no differences in their effects on the ft-adrenergic
receptors of bronchial and skeletal muscle compared with
placebo. Multiple doses of metoprolol caused no measurable
bronchial ft-adrenergic receptor antagonism in contrast to
atenolol. Multiple doses of both ^-adrenergic receptor antagonists caused a measurable blockade of /Sj-adrenergic receptors of skeletal muscle. (Hypertension. \994\2A339-346.)
Key Words metoprolol receptors, adrenergic, beta
muscle, smooth, skeletal albuterol asthma

the drug at a constant hourly rate until 80% has been

released and then at a slower rate for the remaining
20% to provide relatively consistent release over a
24-hour period, avoiding unnecessary high peaks in
plasma concentrations.7"9
Clinical studies in healthy volunteers10 and asthmatic
patients 1112 showed that metoprolol oros produced less
bronchial ft-adrenergic receptor antagonism than
equivalent doses of atenolol and sustained-release metoprolol probably because of the relatively low, sustained
plasma concentrations provided by the oros formulation.10 However, no comparative data on the effects of
single and multiple doses of metoprolol oros on foreceptors have been published in hypertensive patients
with concomitant asthma. Various pathophysiological
mechanisms causing asthma as well as influences of
regular therapy are absent in healthy subjects. Therefore, our respective data on bronchomotor tone in
healthy subjects10 cannot be suggested without restriction to be identical with those in asthmatic hypertensive
patients.
The aim of this study was to compare the effects of
single and multiple doses of metoprolol oros on the
changes induced by cumulative doses of inhaled salbutamol on bronchial smooth muscle and skeletal muscle
and the circulatory system in hypertensive patients with
concomitant asthma. Atenolol and placebo were used
for comparison. The assessments were made after a
single dose on day 1 and after multiple dosing on day 7
of the respective treatment periods.

etoprolol, introduced in 1975, has been described as an effective, well-tolerated, cardioselective ^-adrenergic receptor antagonist
without significant partial agonist activity used extensively in the treatment of hypertension and angina
pectoris.1"3 Its efficacy in the secondary prevention of
myocardial infarction and reduction of the incidence of
ventricular fibrillation,4 reinfarction, 3 and sudden
death4-6 has suggested cardioprotective properties.
The oral osmotic (oros) release drug delivery system
of metoprolol (Alza Corp) consists of an osmotically
active core, made up mainly of active drug, surrounded
by a semipermeable membrane.7 A small hole is drilled
through this membrane with a high-speed laser beam.
Osmotic pressure causes the passage of water into the
drug reservoir, resulting in a slow, continuous release of
active material. The oros system is designed to release
Received January 17, 1994; accepted in revised form June 1,
1994.
From the University of Vienna Medical School, Clinical Pharmacology, and the Kaiser Franz-Josef-Hospital, Department of
Internal Medicine 2, Vienna, Austria.
Presented in part at the 2nd International Symposium on Heart
Failure: Mechanisms and Management, Geneva, Switzerland, May
16-20, 1993.
Reprint requests to Karin Bauer, MD, University of Vienna
Medical School, Clinical Pharmacology, AKH-Ebene 6, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.
Correspondence to G. Kaik and K. Bauer, Reisnerstr. 35/16,
A-1030 Vienna, Austria.
O 1994 American Heart Association, Inc.

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340

Hypertension

TABLE 1 .

Vol 24, No 3

September 1994

Demographic Data, Pretrial Medication, and Bronchial Reversibility of 18 Hypertensive Asthmatic Patients
Bronchial Reversibility

Patient
1

Duration
Baseline
Asthma/
Blood
Sex/
Hyper- Therapy
sGaw,
Smoking Age, Height, Weight, tension, Before Pressure, FEV,, FEV,,%
1
1
mm Hg
Trial
m
Habits
L predicted s" k P a
kg
y
y
B-2, F,
67
165/110
49
F+l
1.72
M/ES
1.8
0.39
6/0.25
51

F/ES

54

M/NS

44

1.62

93

1.78

70

10/3

BU, T

3/1

BU, T

Postbronchodllator*
FEV,,%
change

sGaw, %
change

50

100

1.7

68

0.53

35

75

160/100

2.9

74

0.41

20

51

160/95

3.3

80

0.37

18

59

170/125

M/ES

40

1.77

72

9/2

B-2, F,
S

F/NS

44

1.64

62

6/0.5

B-1.S,
F+l

170/105

1.7

60

0.45

58

160

M/NS

50

1.78

90

4/0.5

B-1.S

165/100

2.8

75

0.45

25

66

12

F/NS

53

1.58

95

6/1

B-1, F

160/100

1.7

70

0.52

29

69

16

F/NS

53

1.61

87

7/0.25

B-2, F

170/100

1.8

72

0.57

38

66

150/105

1.8

60

0.43

50

74

17

F/NS

42

1.67

70

4/0.5

BU, F,
F+l, I

18

M/NS

54

1.71

89

3/3

B-2, T

150/105

2.4

72

0.47

21

74

19

F/ES

50

1.65

60

7/4

B-1.F

170/105

1.8

66

0.44

38

61

21

M/ES

53

1.73

76

10/1

B-1.S

160/100

2.7

77

0.48

22

66

23

M/NS

48

1.60

80

6/4

B-1.F,
F+l

160/115

2.1

70

0.56

39

50

24

M/ES

56

1.78

71

3/0.5

B-2, S

170/110

2.1

60

0.40

38

97

25

M/ES

47

1.78

76

7/1

BU, T

180/110

3.0

78

0.51

36

50

26

F/NS

48

1.72

100

4/3

B-2, F, I

160/115

1.9

63

0.53

26

77

27

M/NS

41

1.84

74

5/1

B-1.S, I

160/105

3.3

76

0.44

18

38

B-1.F,
F+l

180/110

2.0

55

0.42

60

61

2.27

68.17

0.47

34.50

71.89

0.14

1.97

0.01

3.15

6.34

28

M/ES

48

1.73

86

7/0.5

Mean

48.56

1.70

78.78

5.94/1.50

164.44/
106.39

SEM

1.14

0.01

2.76

0.53/0.31

1.98/1.71

FEV, indicates forced expiratory volume In 1 second; sGaw, specific airway conductance; NS, never smoker; ES, exsmoker (>5
years); B, beclomethasone diproplonate (B-1, 1200 jig/d; B-2, 1500 njgld;); BU, budesonlde (800 nfl/d); F. fenoterol (prn); I,
Ipratropiumbromlde (prn); F + l , combination metered dose aerosol (pm); S, saibutamol (prn); and T, terbutaline (pm).
*30 Minutes after inhalation of 400 /xg saibutamol (4 puffs) from a metered dose inhaler.

Methods
Full written informed consent was obtained from all patients
after approval of the local hospital ethics committee.

Patients
Twenty-eight stable asthmatic patients (outpatients, whites)
with concomitant essential hypertension but no other important disorders were recruited (Tables 1 and 2). Inclusion
criteria were an actual forced expiratory volume in 1 second
(FEV,) greater than 50% of the predicted value, a rise in FEV,
of at least 15% after inhalation of 400 /ig saibutamol applied
by a metered dose inhaler, and a diastolic blood pressure
greater than 90 mm Hg. Each patient had a normal electrocardiogram (ECG, 12-lead), a Holter ECG monitoring Lown
Grade 0-1, and a normal chest radiograph. Sixteen patients
met the criteria of mild hypertension defined by the 1993
guidelines for the management of mild hypertension with a
diastolic blood pressure between 95 and 105 mm Hg (Tables 1
and 2). 13 Eleven patients showed higher diastolic blood pressure values up to 115 mm Hg; patient 4 showed a diastolic

blood pressure of 125 mm Hg at the screening visit only.

Exclusion criteria were FEV, less than 50% of the predicted
value, angina pectoris, second- and third-degree heart block,
heart failure, bradycardia less than 50 beats per minute,
impaired renal or hepatic function, diabetes mellitus, pregnancy, lactation, or any known severe adverse reactions to
^-adrenergic receptor antagonists. Patients were excluded if
they had had an acute illness or an exacerbation of airflow
obstruction within 6 weeks before the start of the study. None
of the patients had a history of extrinsic asthma. Regular
medication consisted of bronchodilator therapy and regular
inhaled corticosteroids (1200 to 1500 fig beclomethasone
dipropionate daily or 800 fig budesonide dairy) (Tables 1 and
2). None of the patients was taking antihypertensive medications before the start of the study. All patients had to be
experienced in the use of all the equipment and inhalation
techniques.

Techniques
FEV, (best of three measurements) and specific airway
conductance (sGaw) were measured by a constant-volume

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Bauer et al
TABLE 2.

Metoprolol Oros in Hypertensive Asthmatics

341

Demographic Data, Pretrlal Medication, and Bronchial Reversibility of 10 Study Dropouts

Bronchial Reversibility

Duration
Baseline
Asthma/
Sex/
Hyper- Therapy
Blood
Smoking Age, Height, Weight, tension, Before Pressure, FEV,, FEV,,%
sGaw,
mm Hg
Patient
Trial
Habits
m
L predicted s" 1 kPa- 1
y
y
kg
B-1, F,
44
2
S, T
0.47
5/2
F/NS
1.70
70
82
145/100 2.1

Postbronchodllator*
FEV,,%
change

SGaw, %
change

38

89

F/NS

49

1.68

70

7/2

B-1.F

170/110

1.5

53

0.38

33

100

M/NS

60

1.75

80

11/1

B-2, F

150/100

2.1

63

0.39

42

107

10

F/NS

53

1.64

64

4/4

BU, S

150/105

1.9

73

0.61

21

54

160/100

1.9

76

0.57

36

80

11

F/ES

48

1.60

65

8/1

B-1.F,
F+l

13

F/NS

58

1.58

62

4/2

B-1, F

170/105

1.5

68

0.36

26

125

14

F/ES

51

1.58

58

5/0.25

B-2, F,
F+l

165/110

1.2

50

0.33

50

166

15

M/ES

58

1.68

82

3/1

B-1.S

170/110

1.9

61

0.42

42

80

20

M/NS

39

1.76

80

8/1

B-1.S

180/115

2.9

72

0.46

31

80

22

M/ES

52

1.68

109

4/0.25

BU, T

170/110

2.4

72

0.58

20

67

Mean

51.20

1.66

75.20

5.90/1.45

163.00/
106.50

1.94

65.80

0.46

33.90

94.80

SEM

2.08

0.01

4.72

0.80/0.35

3.59/1.67

0.15

2.79

0.03

3.06

10.16

Definitions are as in Table 1.

*30 Minutes after Inhalation of 400 jig salbutamol (4 puffs) from a metered dose inhaler.

body plethysmograph (Jaeger Co). sGaw is the reciprocal of

airway resistance corrected for thoracic gas volume, and the
mean of five reproducible traces was used for analysis.14 All
values were corrected for body temperature, pressure, and
saturation. Finger tremor was measured by a previously validated method13 using a piezoelectric accelerometer (Zak Co)
taped to the terminal phalanx of the right middle finger with
the forearm supported and the hand outstretched. Tremor
amplitude was assessed as the sum of the integrated signals
over a period of 10 seconds; a mean value was calculated from
four consecutive measurements. Heart rate was assessed by
Holter ECG monitoring (Hewlett-Packard Co). Continuous
ambulatory readings of the ECG were made during the
assessment of the salbutamol dose response on days 1 and 7,
respectively. Blood pressure was measured with a standard
mercury sphygmomanometer, taking the first and the fifth
Korotkoff sounds as the systolic and diastolic values,
respectively.

Study Design
The study was carried out in a randomized, double-blind
(investigator blinded), three-period, crossover, placebo-controlled design with at least a 7-day washout phase between
treatment periods. To maintain Investigator blinding, medication was dispensed by a study coordinator, and patients were
instructed not to discuss their study medication with the
investigator conducting the clinical evaluations.

Drugs
Patients were given single daily doses of 14/190 mg metoprolol oros, 100 mg atenolol, or placebo over a 7-day treatment
period each. The oros system is identified by two numbers: the
first represents the release rate in milligrams per hour, and the
second represents the total milligram content of the drug in
the tablet. The 14/190 mg metoprolol oros tablet contains 190
mg metoprolol fumarate (equivalent to 200 mg metoprolol
tartrate) released at a rate of 14 mg metoprolol fumarate

hourly. The preparations supplied for oral administration were

of identical appearance and taste and were provided by
CIBA-GEIGY Ltd. Salbutamol was administered by specially
prepared metered dose aerosols delivering 12.5 and 25 fig per
puff (Aerosol Services AG) and by a commercially available
metered dose aerosol delivering 100 fig per puff (Glaxo
Operations).

General Procedure
Assessments were performed on days 1 and 7 of each
treatment period at the same time of day. The salbutamol dose
response started at the estimated time of peak plasma concentrations,8'16-17 that is, 12 hours after the dose for metoprolol
oros, 3 hours for atenolol, and 3 hours for placebo. During the
complete trial, inhaled ft-adrenergic receptor agonists were
allowed if necessary. No additional oral bronchodilators or
antihypertensive drugs were permitted. The dose of inhaled
steroids was kept constant throughout the study. The morning
dose was applied between 7 and 8 AM and the evening dose
between 8 and 9 PM. On study days the evening dose was given
after salbutamol dosing at 9 PM. All patients had to abstain
from inhaled /3-adrenergjc receptor agonists 12 hours before
each study day.
When the patients arrived, an ECG (12-lead) was recorded
and an ambulatory ECG monitor was attached. After 30
minutes of rest, postmedication baseline measurements of all
parameters were made. Dose-response curves were then constructed using six increasing doses of inhaled salbutamol as
follows: 12.5, 25, 75, 300, 400, and 800 tig, resulting in
cumulative doses of 12.5, 37.5, 112.5, 412.5, 812.5, and 1612.5
fig. Dose increments were made every 20 minutes. A 5-minute
period was scheduled for recording all parameters, and the
order of recording was sGaw, tremor, heart rate, and blood
pressure. Subjective effects were documented on all days of
each treatment period as well as at each dose increment of the
salbutamol dose response on days 1 and 7 as either spontaneously reported or reported after direct questioning, and these

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342

Hypertension

Vol 24, No 3 September 1994

TABLE 3. Effects of 0-Adrenerglc Receptor Antagonists and Placebo on Baseline Values Before Salbutamol Dose
Response In 18 Hypertensive Asthmatic Patients
Metoprolol oros, 14/190 mg

Placebo
Parameter

Day 1

sGaw, s~1 kPa"1

0.400.02

Atenolol, 100 mg

Day 1

Day"7

Day 1

Day7

0.380.02

0.400.03

0.360.01

0.390.02

0.390.02

67.721.83

65.392.53*

66.332.08

62.563.12*

75.671.76t:

72.332.24t

71.282.58*

Day 7

Tremor amplitude, cm s~2

72.442.93

78.563.54

Heart rate, bpm

86.062.65

87.332.18

SBP, mm Hg

159.172.07

156.672.29

75.112.16t
156.942.53

DBP, mm Hg

105.831.16

103.891.54

101.11 1.37*

156.392.01
97.781.41*

154.172.11
98.891.49*

151.942.03
96.671.81*

sGaw Indicates specific airway conductance; SBP, systolic blood pressure; and DBP, diastolic blood pressure. Values are
meanSEM.
*P<.01, tP<.001, *P<.0001 compared with placebo.
were graded as mild, moderate, or severe in nature. Routine
laboratory profiles were made before the patient entered the
trial and on day 7 of each treatment period. At the conclusion
of the study, a physical examination, ECG (12-lead), and
routine laboratory profile were repeated.
Statistical Evaluation
Data are presented as meanSEM. The area under the
curve (AUC) was determined for sGaw, tremor amplitude,
heart rate, and blood pressure using the log trapezoidal rule
method. The data were analyzed with an ANOVA model for a
three-period crossover design. Standard SPSS routines were
used to analyze data for normality of distribution and homogeneity of variances. To exclude carryover effects, tests for
treatment period interactions were performed. Dose-response
curves were constructed for each patient by plotting the
cumulative concentration (CC) of salbutamol against sGaw
and tremor amplitude. The cumulative concentration of salbutamol producing a 50% increase in sGaw (CQosGaw) and a
35% increase in tremor (CQjtremor) from postmedication
baseline was calculated by linear interpolation from the doseresponse curves for each patient and each treatment. As
salbutamol caused insufficient change from postmedication
baseline in some patients, the respective CC was set equal to
1613 fig (greater than the maximal CC of salbutamol) in these
cases. Because of a violation of the normality of distribution
and the variance homogeneity assumption of the CC data, a
nonparametric analysis (Wilcoxon rank sum test) with a Bonferroni a-adjustment was performed on the ranks of the CC
data. Holter ECG recordings were analyzed for heart rate,
ventricular ectopic beats, and supraventricular premature
beats. Values were considered to be significantly different at a
value of P<.05. Results were assessed by the SPSS+ software
package (SPSS Inc).

Results
The data of 18 patients could be subjected to analysis,
and the data of 10 patients had to be excluded (Tables
1 and 2). Six patients (patients 2, 3, 14, 15, 20, and 22)
discontinued prematurely for personal reasons not related to the trial medication but because of the timeconsuming study design. One patient (patient 11) acquired an upper respiratory tract infection during the
placebo treatment period. One patient (patient 6) experienced finger tremor and palpitations of moderate
degree during the salbutamol dose response on placebo
(day 1) and refused to continue. Two patients showed
an impairment of asthma during the washout period:
patient 10 after having finished the placebo and metoprolol treatment period and patient 13 after the metoprolol and atenolol phase. Patient 13 needed systemic
corticosteroids and oral ft-adrenergic receptor agonists

as additional treatment. Statistics on pretrial baseline

characteristics comparing the patients who completed
the study with those who dropped out revealed no
statistically significant differences between the groups
(P>.05) (Tables 1 and 2).
Effect of 0-Adrenergic Receptor Antagonists on
Postmedication Baseline
Table 3 shows postmedication baseline values for
each of the treatment periods. ANOVA showed no
difference between treatments for sGaw on day 1
(P>.05) and day 7 (P>.05) and for tremor on day 1
(P>.05). On day 7 mean postmedication baseline
tremor amplitude showed significantly lower values during both active drugs compared with placebo (P<.01).
On days 1 and 7 the active drugs showed significantly
lower postmedication baseline values compared with
placebo for heart rate (P<.001, /><.0001) and for
diastolic blood pressure (P<.01, P<.01), respectively.
For systolic blood pressure no significant differences
could be found (P>.05, P>.05).
Dose Response With Inhaled Salbutamol
There were highly significant linear dose-response
relations for sGaw (/><.0001) and tremor (P<.0001) on
days 1 and 7, respectively (Figs 1 through 3).
Specific Airway Conductance
The slopes of the salbutamol dose-response curves
did not differ on day 1 (P>.05), whereas on day 7
atenolol caused a marked shift of the dose-response
curve to the right (P<.05) (Fig 1). Analysis of A U C ^
revealed no significant difference between any of the
treatments on day 1 (P>.05). On day 7 the differences
between atenolol and placebo (P<.05) and those between atenolol and metoprolol oros (P<.05) were significant. The difference between placebo and metoprolol was not significant (P>.05). The comparison of
AUC.Q between days 1 and 7 of each treatment period
resulted in significant differences for atenolol only
(P<.01) (Fig 2).
Table 4 presents individual values of CQosGaw. The
median was 416 and 384 /xg (days 1 and 7, respectively)
for placebo, 594 and 444 /ig for metoprolol, and 562 and
1419 jig for atenolol. Statistical analysis on the ranks of
CGjosGaw revealed no significant differences between
the drugs on day 1 (P>.05); on day 7 atenolol differed

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Bauer et al Metoprolol Oros In Hypertensive Asthmatics

100-1

343

100 T

DAY 1
80

80-

METOPROLOL OROS

UJ

a
z

(3

80-

o
40

a
CO

o-

20-

0-

100

1000

100

1000

100-1

100 n

DAY 7
LU

80-

80

UJ

o
<
o

SO

80-

40

|
20-

10

100

1000

SALBUTAMOL CUMULATIVE (ug)

Fra 1. Line graphs show specific airway conductance (sGaw)
response to cumulative concentrations of inhaled salbutamol
after pretreatment wfth 14/190 mg metoprolol oros (stars), 100
mg atenolol (triangles), and placebo (circles) in 18 hypertensive
asthmatic patients.

significantly from placebo (P<.05) and metoprolol

(P<.05).
Tremor Amplitude
Both active drugs caused a shift of the salbutamol
dose-response curve to the right, which was more
clearly and statistically significant on day 7 (P< .05) (Fig
3). Analysis of AUCJOTO, revealed no significant differences between treatments on day 1 (P>.05). On day 7
the difference between placebo and both /3-adrenergic
receptor antagonists was significant (P-c.OOOl), whereas
the active drugs did not differ from each other (P>.05).
The comparison of AUCm^, between days 1 and 7 of
each treatment period resulted in significant differences
for atenolol (P<.05).
CC^ tremor
The median values of CCjjtremor were 732 and 706
fig for placebo, 812 and 1213 fig for metoprolol, and 797
and 1323 fig for atenolol (Table 4). Statistical analysis
on the ranks of CCjjtremor showed no significant differences between the drugs on day 1 (P>.05). On day 7
the difference between placebo and atenolol (P<.05)
and that between placebo and metoprolol (P<.05) were
significant. No significant difference was observed between metoprolol and atenolol (P>.05).

Ul

o
<
9

20-

0-

tO

SALBUTAMOL CUMULATIVE (yg)

Fra 2. Une graphs show specific airway conductance (sGaw)
response to cumulative concentrations of inhaled salbutamol
after pretreatment with 14/190 mg metoprolol oros, 100 mg
atenolol, and placebo in 18 hypertensive asthmatic patients.
sGaw response on day 1 was opposed to that on day 7
(squares), separated for each treatment group.

Heart Rate and Systolic and Diastolic Blood Pressures

A CCyheart rate causing an increase in heart rate of
25 beats per minute could not be calculated because of
insufficient change from postmedication baseline within
our salbutamol dose range. No salbutamol dose-response relation could be obtained for systolic and
diastolic blood pressures.
Holier ECG Monitoring
There was no rise in supraventricular or ventricular
ectopic beats, and no important arrhythmias occurred
during the salbutamol dose response.

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344

Hypertension

Vol 24, No 3

September 1994

caused a difference in postmedication baseline lung

function before salbutamol inhalation, and the salbutamol dose-response curves were indistinguishable from
those with placebo. Another single-dose study in 12
asthmatic patients showed similar results in postmedication baseline sGaw after 14/190 mg metoprolol oros,
whereas after 100 mg atenolol postmedication baseline
sGaw was significantly lower than after placebo.12 In
that study single doses of both metoprolol oros and
atenolol blunted the salbutamol-induced A U Q c values, with no significant difference between the drugs.12
These conflicting results on the bronchial effects of
single doses of cardioselective ^-adrenergic receptor
antagonists indicate a different sensitivity to 0-adrenergic receptor antagonism in different groups of mild to
moderate asthmatic patients.11-12*18"20 Therefore, in the
treatment of hypertensive asthmatic patients, it would
seem sensible to avoid /3-adrenergic receptor antagonists, as alternative forms of antihypertensive therapy
are likely to be as effective and at least as well tolerated.13-21 In the treatment of ischemic heart disease,
however, /3-blockers may have specific advantages over
other classes of drugs, such as calcium antagonists and
nitrates.21

<

a.
o

o
2
<
<r
o

10

100

SALBUTAMOL

1000

CUMULATIVE

Fra 3. Une graphs show tremor response to cumulative concentrations of inhaled salbutamol after pretreatment with 14/190
mg metoprolol oros (stars), 100 mg atenolol (triangles), and
placebo (circles) In 18 hypertensive asthmatic patients.

Side Effects
No serious adverse effects were reported. Some patients reported fatigue, headache, heartburn, nervousness, and mild agitation during the treatment periods.
Salbutamol-related adverse effects of mild to moderate
degree were restlessness, tremor, palpitations, and
headache.
Overall Tolerabllity and Drug Safety
No other clinical, electrocardiographic, or laboratory
adverse experiences were found.

Discussion
The results of the present study demonstrate that
single doses of metoprolol oros showed no measurable
influence on ft-adrenergic receptors of bronchial
smooth muscle and skeletal muscle in our hypertensive
asthmatic patients. Multiple doses of metoprolol oros
caused no measurable bronchial ft-adrenergic receptor
antagonism but did cause a measurable blockade on
ft-adrenergic receptors of skeletal muscle.
Effects on ft-Adrenergic Receptors of Bronchial
Smooth Muscle
Single doses of both 14/190 mg metoprolol oros and
100 mg atenolol had no measurable influence on bronchial /Jj-adrenergic receptors in our hypertensive asthmatic patients. Neither metoprolol oros nor atenolol

Therapeutically used, ^-adrenergic receptor antagonists are mainly administered over a prolonged period
of time, so we compared the effects of metoprolol oros
on ft-receptors after a single dose on day 1 with those
after repeated doses on day 7. Multiple doses of metoprolol oros caused no measurable bronchial /Sradrenergic receptor antagonism in our patients. In contrast,
atenolol resulted in a clear shift of the sGaw doseresponse curve to the right. These results are in keeping
with findings in healthy volunteers, in which multiple
doses of 14/190 mg metoprolol oros resulted in sGaw
dose-response curves indistinguishable from those with
placebo; the order of bronchial ^-adrenergic receptor
antagonism was placebo = 14/190 mg metoprolol
oros<200 mg slow-release metoprolol<100 mg
atenolol < 160 mg long-acting propranolol.10
Effects on ft-Adrenergic Receptors of
Skeletal Muscle
To assess ft-adrenergic receptor antagonism on ftreceptors of skeletal muscle, we investigated the
changes on finger tremor amplitude. After single doses
of metoprolol and atenolol, postmedication baseline
tremor values and tremor response to salbutamol
showed no differences compared with placebo. Multiple
doses of both ^-adrenergic receptor antagonists shifted
the tremor dose-response curve to the right. These
results clearly demonstrate a separation of the ftadrenergic receptor antagonism of metoprolol oros on
ft-receptors of different tissues, with the effect on
bronchial smooth muscle being less than that for skeletal muscle.
Quantification of ft-Adrenergic
Receptor Antagonism
Evaluation of the CC of inhaled salbutamol causing a
certain relevant change in sGaw and tremor amplitude
demonstrates a quantitative approach of ft-adrenergic
receptor antagonism on ft-receptors of different tissues,
although the interindividual variation was relatively
high.15-22 After pretreatment with placebo, the median

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Bauer et al Metoprolol Oros in Hypertensive Asthmatics

345

TABL 4. Individual Cumulative Salbutamol Concentrations Causing a 50% Increase in sGaw and 35% Increase In
Tremor Amplitude
Placebo
Gaw
Patient

Day 1

Metoprolol oros, 14/190 mg

Tremor

Day 7

Day 1

Day7

s Gaw

Tremor

sGaw
Day 1

Atenolol, 100 mg

Day7

Day 1

Day 7

Day 1

Tremor

Day 7

Day 1

Day 7

370

101

897

676

217

162

797

709

744

1412

698

>1612

377

426

1177

1304

1380

317

1180

1285

320

217

984

1366

400

394

339

525

679

1612

688

786

1283

>1612

631

>1612

744

387

927

935

636

>1612

785

1132

1612

1430

909

1420

432

435

777

665

721

467

901

746

1070

>1612

655

1012

240

372

612

679

219

331

812

1412

221

>1612

729

1612

12

360

247

741

795

1107

342

1186

>1612

437

1000

1102

812

16

1352

301

1160

1148

620

122

1422

866

570

406

1162

758

17

319

457

394

612

679

590

955

1164

268

1118

826

1142

18

277

273

594

785

285

>1612

741

949

1002

1355

588

1281

19

320

370

326

525

562

422

624

793

444

1426

595

749

21

1212

>1612

746

655

650

1212

812

1360

341

712

1283

>1612

23

542

328

608

734

569

336

946

1079

554

>1612

769

>1612

24

821

698

1452

1172

491

351

>1612

1285

245

1308

1079

>1612

25

268

381

367

574

218

301

662

1262

650

>1612

592

1241

26

432

1021

412

772

619

599

1186

>1612

800

1449

885

787

27

543

>1612

934

803

412

764

737

>1612

290

794

1235

>1612

28

1063

189

724

677

300

550

738

1479

950

>1612

681

798

Mean

559.55

533.66

732.61

779.77

575.77

650.22

929.05

1174.77

655.61

1239.16

855.72

1258.66

SEM

80.01

103.71

75.10

52.76

71..47

119.16

64.60

73.34

93.56

103.67

55.15

83.54

18

18

18

18

17

15

18

18

12

16

16

13

sQaw Indicates specific airway conductance. Salbutamol concentrations are in micrograms.

salbutamol CC inducing a 50% increase in sGaw was

about half the CC inducing a 35% increase in tremor
amplitude. These results are in keeping with previous
findings that a plateau level of the inhaled salbutamol
dose-response curve for sGaw occurred with lower
concentrations of inhaled salbutamol than for systemic
effects such as tremor and heart rate because of exposure of airways /J-adrenergic receptors to high local
concentrations of inhaled salbutamol compared with
the low plasma salbutamol levels in the periphery.15-23
After pretreatment with multiple doses of both active
drugs, ft-adrenergic receptor antagonism on skeletal
muscle resulted in significantly higher CC values of
salbutamol compared with those after placebo or the
respective single doses. These findings may be due to
the fact that ft-adrenergic receptor sensitivity may be
changed after prolonged exposure to ^-adrenergic receptor antagonists.
After pretreatment with single and multiple doses of
metoprolol oros, CQosGaw was comparable to that
after placebo. In contrast, multiple doses of atenolol
resulted in remarkably higher salbutamol concentrations for CQosGaw. These results may be explained by
the fact that the most crucial parameter for the negative
effect of ^-adrenergic receptor antagonists on the airways is the peak plasma concentration.1018 Therefore,
the consistent drug delivery of the oros system, which

avoids high peak plasma concentrations and provides

smooth plasma concentrations, may be an advantage in
the pharmacodynamic effects of /J-adrenergic receptor
antagonists.
^-Adrenergic receptor antagonists without any cardioselectivity are contraindicated in asthmatic patients
because of their bronchoconstrictive effect.24-26 Selective ^!-adrenergic receptor antagonists have been
shown to cause less pronounced bronchoconstriction 2735 and were thought to be less dangerous in
patients with concomitant asthma.36 Especially those
^-adrenergic receptor antagonists with enhanced / 3 r
selectivity such as bisoprolol19 and those with partial
ft-agonist activity such as dilevatolol37 or celiprolol38
were considered to have advantages over conventional
/3-blockers such as atenolol in some patients with concomitant asthma.21
Conclusions
Although metoprolol oros had no measurable influence on bronchomotor tone in our asthmatic hypertensive patients, the presence of systemic effects on ftreceptors of skeletal muscle could be demonstrated. As
sensitivity to /J-adrenergic receptor antagonists differs
from asthmatic to asthmatic dependent on the balance
of various pathophysiological mechanisms, the lack of a
measurable bronchial ft-antagonism of metoprolol oros

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346

Hypertension

Vol 24, No 3

September 1994

obtained in our stable asthmatic patients should not be

interpreted as a relevant aspect of drug safety applicable to all asthmatic hypertensive patients. As there are
several other groups of antihypertensive agents from
which to choose, it must be concluded that both cardioselective /J-adrenergic receptor antagonists, atenolol
and metoprolol oros as well,- are contraindicated for
antihypertensive treatment in patients with concomitant
asthma.
Acknowledgment
We thank CIBA-GEIGY, Basel, Switzerland, for providing
the drugs.

16.
17.
18.

19.
20.

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Osmotic release oral drug delivery system of metoprolol in hypertensive asthmatic patients.
Pharmacodynamic effects on beta 2-adrenergic receptors.
K Bauer, G Kaik and B Kaik
Hypertension. 1994;24:339-346
doi: 10.1161/01.HYP.24.3.339
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 1994 American Heart Association, Inc. All rights reserved.
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