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Eur Respir J
1993, 6, 204-210
A comparison of the cardiovascular and metabolic effects of
formoterol, salbutamol and fenoterol
P. Bremner, K. Woodman, C. Burgess, J. Crane, G. Purdie, N. Pearce, R. Beasley
A comparison of the cardiovascular and metabolic effects of formoterol, salbutamol
and fenoterol. P. Bremner, K. Woodman, C. Burgess, J. Crane, G. Purdie, N.
Pearce, R. Beasley.
ABSTRACT: The cardiovascular and metabolic effects of the long-acting ~2 agonist formoterol were compared with those of salbutamol, fenoterol and placebo in 12 healthy volunteers, using a randomised, double-blind, cross-over
design.
On the study days, the subjects inhaled either formoterol (24 jlg), salbutamol
(400 jlg), fenoterol (400 jlg) or placebo, at 30 min intervals for five doses. Heart
rate (HR) total electromechanical systole (Q-8 21) (a measure of inotropy), the
corrected QT interval (QTc), systolic and diastolic blood pressure, plasma glucose and plasma potassium (K•) were measured prior to drug administration,
10 min after each inhalation and at 30 min intervals for 3 h after the last inhalation. All of the active agents significantly increased HR, QTc and plasma
glucose, and decreased Q-8 21, diastolic blood pressure and plasma K• compared
to placebo. Fenoterol had a significantly greater maximum effect on HR, QTc
and Q-8 21 than either salbutamol or formoterol. Formoterol and fenoterol
caused a similar maximum reduction in plasma K+, greater than that due to
salbutamol.
We conclude that formoterol is a more selective ~2 -agonist than fenoterol, and
has similar cardiovascular effects to salbutamol when inhaled repeatedly by normal volunteers.
Eur Respir J., 1993, 6, 204-210.
The long-acting beta-agonist formoterol may offer
clinical advantages over established shorter-acting
bronchodilators [1]. It has a considerably longer duration of bronchodilator action [2, 3], and results in
prolonged protection from bronchoconstriction induced
by provoking stimuli such as methacholine [4], or exercise [5]. In patients with unstable asthma, regular
twice daily use of formoterol results in greater control, with reduced requirement for rescue bronchodilator medication, and improved protection against
nocturnal asthma than the use of regular salbutamol or
terbutaline [6, 7].
In addition to clinical efficacy, it is important that
the safety profile of any new bronchodilator drug is
also investigated in detail, particularly when one considers that epidemics of asthma mortality followed the
introduction and widespread use of isoprenaline forte
in a number of countries in the 1960s [8] and, more
recently, of fenoterol in New Zealand in the 1970s [9].
Although the mechanisms by which isoprenaline and
fenoterol increase the risk of death, compared with
other beta-agonist drugs, have yet to be established,
one possibility is that it relates to the greater adverse
extra-pulmonary effects when inhaled repeatedly in
high doses by asthmatic patients during a severe attack [ 10].
Dept of Medicine, Wellington School of
Medicine, Wellington, New Zealand.
Correspondence: C. Burgess
Dept of Medicine
Wellington School of Medicine
PO Box 7343 Wellington South
Wellington
New Zealand.
Keywords: beta 2 agonists
cardiovascular effects
glucose
potassium
Received: May 14 1992
Accepted after revision September 18
1992.
This study was supported by a grant
from Ciba Geigy Ltd.
In vitro, formoterol has been shown to be at least
as beta 2 -adrenoceptor selective as salbutamol and
terbutaline [11, 12]. Preliminary clinical studies have
suggested that the cardiovascular effects of the recommended doses of fmmoterol are similar to those observed with equipotent doses of salbutamol [2, 3, 13,
14]. These studies cannot simply be extrapolated to
the clinical situation (where these drugs are used in
acute severe asthma), as either insensitive measures of
cardiovascular responses were undertaken, or small
doses of the beta-agonist drugs were used.
It is well-recognized that asthmatic patients may
self-administer very high doses of their inhaled betaagonist drugs in a severe asthma attack; doses well in
excess of those recommended by the manufacturers or
their physicians [15, 16]. For example, in a recent
study of the drug use by asthmatic patients prior to
hospital admission, about 30% of the patients had
taken more than 45 puffs of their beta-agonist inhaler
during the 24 h prior to admission [15]. Furthermore,
recent guidelines of the British Thoracic Society have
recommended that in a situation of life-threatening
asthma, treatment be commenced immediately with
20-50 puffs of a metered dose inhaler, given by multiple actuations of 5 puffs at a time [17].
Thus. while formoterol is currently recommended as
205
CARDIOVASCULAR AND METABOLIC EFFECTS OF BRONCHODILATORS
a twice daily preparation, it is essential that the cardiovascular effects are determined when it is taken in
doses considerably in excess of this recommendation.
The aim of this study was to determine the cardiovascular and metabolic responses to formoterol when
repeatedly inhaled in high doses, similar to those taken
by patients during acute asthma attacks. Comparison
was made with equivalent bronchodilator doses of the
selective beta2-agonist salbutamol and fenoterol, a less
selective betaragonist with similar cardiovascular
effects to those of isoprenaline when administered by
repeated inhalation to normal [18] or asthmatic subjects [19].
Subjects and methods
Twelve healthy, nonsmoking volunteers (4 male),
mean age 27 yrs were studied. All subjects had a
normal 12-lead electrocardiogram (ECG), and normal
routine biochemistry and haemotology. No medication
was taken throughout the study period, other than the
test drugs themselves. All subjects demonstrated the
ability to use a metered dose inhaler (MDI) correctly,
prior to entry in the study. The study design was
approved by the Wellington Area Health Board Ethics Committee and each subject gave written informed
consent before participation.
Subjects attended the laboratory on four occasions,
at least 3 days, but no more than 7 days, apart. On
arrival at 0800 h, after an overnight fast and abstinence from caffeine containing products, a cannula
was inserted into a forearm vein for removal of blood
samples. Subjects then rested supine for 10 min
after which two baseline recordings of systolic time
intervals, high speed surface ECG, blood pressure,
plasma potassium and blood glucose were made 10
min apart.
The subjects then inhaled five doses of either
formoterol (24 jlg), fenoterol (400 jlg), salbutamol
(400 jlg) or placebo, at 30 min intervals. These doses
were chosen because they were multiples of doses
which have been shown to provide an equivalent peak
bronchodilator effect in asthmatics [2, 3, 13, 20, 21].
Drugs were administered using a double-blind, doubledummy, randomized, cross-over design. Further
recordings were made 10 min after inhalation of each
dose of drug (10, 40, 70, 100 and 130 min), then at
30 min intervals after the last dose for a further
period of 3 h (150, 180, 210, 240, 270, 300 min).
The systolic time intervals were measured from
simultaneous high speed (100 mm·s· 1) photographic
recordings of the ECG, phonocardiogram and carotid
pulse trace. From these, total electromechanical systole (Q-S 2 I) was measured as described previously
[22], and corrected for heart rate using an equation
developed in our laboratory [23]. The QT interval was
measured as described previously from the ECG [18],
and corrected (QTc) for heart rate using the formula
of BAZETT [24]. Systolic and diastolic blood pressures
were measured automatically using a Hewlett Packard
78352A monitor. Plasma potassium was measured
using an Ionetics 310 electrolyte analyser, and plasma
glucose measured with a Hitachi 717 analyser using
a Boehringer Mannheim GOD-PAP 1040871 glucose
kit.
Statistical analysis
The differences in effects between the active agents
and placebo were compared at each time-point. As
the active agents are known to have different time
courses of action, the area under the dose-response
curves were also compared between the four treatments. The maximum mean effects of the three betaagonist drugs were also compared. Statistical analysis
was performed, using analysis of variance with group
(treatment order groups), subject (within-groups), treatment and time effects. The significance level was
adjusted for multiple comparisons, using Bonferroni's
inequality [25]. Thus, a value of p:=;0.0015 was considered significant when comparing the effects between
placebo and the active agents at the different time
points; p:=;O.Ol7 when comparing the maximum mean
change from baseline; and p:=;0.0083 when comparing
the area under the curve for each variable.
Results
There were no significant differences between the
subjects, baseline measurements on any of the four
study days (table 1).
Table 1. - Baseline values in the 12 subjects prior
to treatment
Placebo Formoterol Salbutamol Fenoterol
HR bpm
Q-S) ms
QTc ms
SBP mmHg
DBP mmHg
K mmoJ.l·1
Glue. mmoJ.l· 1
64
(1.7)
490
(4.2)
360
(8.1)
124
(2.9)
70
(2.6)
3.80
(0.09)
4.40
(0.16)
63
(2.6)
489
(4.9)
363
(5.9)
122
(3.5)
70
(3.2)
3.90
(0.11)
4.40
(0.12)
66
(2.2)
492
(4.0)
362
(6.4)
128
(3.1)
72
(2.5)
3.90
(0.10)
4.50
(0.1 5)
63
(2.7)
491
(5.0)
359
(6.1)
124
(3.1)
69
(2.6)
3.90
(0.09)
4.60
(0.13)
Data are mean and SEM in parenthesis. HR : heart rate;
Q-S 21: total electromechanical systole; QTc: the corrected
QT interval; SBP: systolic blood pressure; DBP: diastolic
blood pressure; K: plasma potassium; Glue: plasma glucose.
Comparison between active drugs and placebo
For all the measurements (apart from diastolic blood
pressure), fenoterol showed the earliest changes (figs,
I and 2). The effects due to formoterol and fenoterol
were significantly greater than placebo, for a longer
P. BREMNER ET AL.
206
Area under the dose response curve (AUC)
duration, than those due to salbutamol. (table 2). Unlike formoterol and fenoterol, salbutamol did not significantly increase systolic blood pressure.
The AUCs for the various responses are shown in
table 4. All of the drugs had significantly greater
effects than placebo when comparing the AUCs, except for the comparison of systolic blood pressure between placebo and salbutamol, where there was no
difference.
Fenoterol had greater overall cardiovascular effects,
as measured by heart rate, Q-SJ and the QTc interval, than formoterol. Both fenoterol and formoterol
had a greater hypokalaemic effect than salbutamol.
The differences between formoterol and salbutamol,
with respect to heart rate, Q-SJ, and glucose, probably relate to the more prolonged action of formoterol,
because the mean maximum effects of the two drugs
were similar for these indices.
Comparison between the active drugs
As the drugs have different durations of effect (figs,
1 and 2), we compared the maximum mean effect,
which in most instances followed the last dose (table
3). There were no differences between the drugs on
diastolic or systolic blood pressure. For all other cardiovascular measurements, fenoterol had greater maximum effects than formoterol and salbutamol. Both
fenoterol and formoterol had a greater hypokalaemic
effect than salbutamol.
30
E
20
(f)
E
0..
.0
;;N
a: 10
:::r::
0
a
~
-10
0
100
200
10
0
-10
-20
-30
-40
-50
-60
300
15
Ol
10
:::r::
E
E
c...
ro
(/)
5
0
-5
-10
0
200
100
Time min
300
0
Time min
100
200
300
Time min
Fig. 1. - Effect of treatment on heart rate (HR), total electromechanical systole (Q-S 2 I) and systolic blood pressure (SBP), measured as
the change from baseline (drug was administered at 0, 30, 60, 90 and 120 min . o: placebo; • : fenoterol; •: salbutamol; o: fonnoterol.
70
0.5
50
en
E
~
~
0
c
E
30
a
~
10
-10
-0.5
0
100
200
300
-1.5
0
100
200
300
Fig. 2. - Effect of treatment on plasma potassium (K) and QTc interval, measured as change from baseline (drug was administered at
0, 30, 60, 90 and 120 min. o: placebo; •: fenoterol; •: salbutamol; o: fonnoterol.
Table 2. - The time-points at which there were statistically significant differences
between placebo and the beta-agonist drugs*
Fenoterol
HR bpm
Q-S 21 ms
QTc ms
SBP mmHg
DBP mmHg
Plasma K mmol·l' '
Plasma glue mmol·f·'
All time points
All time points
40-300 min
40-130, 240 min
40-70, 130-180 min
All Lime points
40-240 min
Forrnoterol
70-300 min
40-300 min
100-210, 270-300 min
100-150 min
40-70 min
70-300 min
70-300 min
Salbutamol
70-240 min
40-240, 300 min
70-150 min
Nil
40-70, 150 min
40-300 min
40-210 min
*: value of p~0.0015 was considered significant when comparing the effects between placebo
and the active agents at the different time points. For abbreviations see legend to table I.
CARDIOVASCULAR AND METABOLIC EFFECTS OF BRONCHODILATORS
207
Table 3. - Maximum change from baseline for the extrapulmonary effects of
the four treaments
Placebo
Formoterol
Salbutamol
Fenoterol
-2.7 (1.6)
16.7 (2.7)
12.8 (3.3)
29.8 (3.9)
240
130
150
130
A
8
B
-7.6 (2.4)
-35.5 (3.9)
-31.5 (2.6)
Q-S 2I ms
-53.8 (4.0)
270
130
130
130
Time
8
8
A
32.5 (5.2)
7.1 (3.0)
40.2 (8.4)
61.4 (7 .6)
QTc ms
130
Time
130
130
130
8
8
A
-0.2 (2.2)
3.0 (2.2)
12.3 (2.7)
9.2 (1.9)
SBP mmHg
40
40
130
130
Time
A
A
A
-8 .3 (1.6)
-3.6 (1.5)
-9.5 (2.1)
-9.4 ( 1.5)
DBP mmHg
240
70
Time
130
100
A
A
A
-0.08 (0.07)
-1.13 (0.07)
-0.96 (0.09)
-0.55 (0.06)
K mmoH·'
210
180
300
Time
130
A
A
8
0.09 (0.15)
1.28 (0.22)
0.76 (0.10)
0.99 (0.18)
Glue mmol.f"'
300
Time
lOO
180
lOO
A
A
A
Data are mean and SEM in parenthesis. #; time at which maximum effect occurred;
A, B: different letters on any particular line denote that those means are significantly
different (i.e. A is significantly different to B); these relate only to the active drugs.
For abbreviations see legend to table I.
Heart rate bpm
Time mins#
Table 4. -
AUC for the extra ulmonary effects of the four treatments
Placebo
Salbutamol
Fenoterol
Formoterol
-8.2
56.7
37.0
104.0
D
c
8
A
-19.3
Q-S 2I ms·h·'
-136.0
-105.1
-179.1
D
c
8
A
20.1
QTc ms·h·'
93.8
219.6
135.9
c
8
8
A
-7.9
SBP mmHg·h·'
29.5
3.1
35.6
8
A
8
A
-29.3
-4.4
-34.2
-30.5
DBP mmHg·h·'
A
8
A
A
0.29
-2.91
-1.75
-3.86
K mmol·h·l·'
D
c
8
A
-0.51
4.23
2.35
Glue. mmol·h·l·'
2.72
c
B
A
A
A, B, C, D : Different letters on any particular line denote that these means are significantly different (i.e. A is significantly different to B, C and D etc.) for that measurement.
A UC: area under the dose-response curve, 0-300 min . For further
abbreviations see legend to table 1.
HR bpm·h·'
Discussion
In this study, we have shown that repeated inhalation of formoterol in doses considerably in excess of
those recommended, resulted in lesser inotropic,
chronotropic and electrophysiological effects than
fenoterol, despite equivalent systemic beta2 -receptor
effects. Formoterol behaved like salbutamol with
regard to its speed of onset and potency on the
cardiovascular system, and, as would have been
expected, these effects were of greater duration.
The primary variable chosen for comparison between
the different bronchodilator drugs in this study was
change in electromechanical systole, a sensitive and
specific measure of inotropic response [26]. When
measured 10 min after each dose the fall in Q-S 21 with
formoterol was similar to that with salbutamol, although the effect of salbutamol declined more rapidly,
208
P. BREMNER ET AL.
due to its shorter duration of action. In contrast, the
maximum inotropic effect of formoterol was considerably less than that due to fenoterol. This difference
occurred despite the cumulative dose response design
employed, which effectively "biased" the results
against formoterol, due to its longer duration of action.
The chronotropic effect of fenoterol was about twice
that of formoterol and salbutamol. The chronotropic
response to beta-agonist drugs is considered to be
mediated, in part, by both beta 1- and beta2 -receptors,
due to both direct cardiac stimulation and reflex
mechanisms secondary to stimulation of presynaptic
beta2-receptors [27, 28]. The finding in this study of
equivalent effects on diastolic blood pressure with
formoterol and fenoterol would suggest that the difference in chronotropic response is due to differences
in direct cardiac stimulation.
It is important to consider what effect these cardiac
changes could have in the clinical situation of acute
severe asthma. The combination of an increase in
heart rate and inotropy would lead to a marked increase in myocardial oxygen consumption, which
might be deleterious in the clinical situation of hypoxaemia. Beta-agonist drugs can also lead to a worsening of hypoxaemia due to changes in ventilation
perfusion relationships within the lung [29], and may
lead to a reduction in subendocardial blood flow [30].
Furthermore, both severe hypoxia [31], and hypercapnia [32], per se can cause marked inotropic and
chronotropic effects.
Beta-agonist induced prolongation of the QTc interval is mediated in part by cardiac beta2 stimulation,
in addition to that due to the reduction in plasma
potassium [33]. Although the significance of this
electrophysiological effect is uncertain, QTc prolongation of the magnitude seen in this study has been
shown to increase the risk of ventricular arrhythmias,
particularly in the situation of an increase in heart rate
[34]. The maximum increase in QTc observed with
formoterol was similar in magnitude to that of
salbutamol, but considerably less than that due to
fenoterol.
Both formoterol and fenoterol had a greater maximum hypokalaemic effect than salbutamol, indicating
greater potency at the beta2 -receptor in the doses used
in this study. However this should not be confused
with greater therapeutic efficacy of these agents.
When inhaled in the same relative doses, formoterol,
fenoterol and salbutamol lead to similar maximum
increases in forced expiratory volume in one second
(FEV 1) or peak flow [2, 3, 13, 20, 31]. This confirms previous observations [35] that the maximum
bronchodilator effects of beta-agonists are achieved at
considerably lower doses than the maximum hypokalaemic effects, reflecting airway and systemic beta2receptor responses [36], respectively.
The finding of no difference in the maximum hypokalaemic effect between formoterol and fenoterol, in
the face of major differences between their cardiovascular effects, sheds light on the possible mechanism
of fenoterol's greater effect on the heart. The most
likely explanation for these findings is that fenoterol
has greater intrinsic cardiac beta 1-receptor activity than
formoterol, as its inotropic and chronotropic effects are
considerably greater than formoterol, at doses that result in similar systemic beta2 -receptor effects. This
high degree of in vivo beta2 selectivity of formoterol
is consistent with in vitro studies [37]. The differences in cardiovascular responses between fenoterol
and salbutamol cannot be accounted for solely on the
basis of a lower degree of beta 2 selectivity of
fenoterol. They are also likely to relate to the greater
beta 1 - and beta2-receptor potency and intrinsic activity of fenoterol, effects which have been demonstrated
both in vitro [38, 39] and in vivo [40].
Although we have proposed that the cardiovascular
changes noted in this study are primarily due to stimulation of myocardial beta-receptors, an alternative
explanation could be that they are due to inhalation
of high doses of freons from inhalers. However this
is unlikely for a number of reasons. Firstly, freons
alone tend to cause depression of chronotropic, inotropic and dromotropic responses [41]. This was not
evident in this study, and the changes seen with placebo are consistent with previous studies in our laboratory, where no cardioactive substance or freon had
been given [42]. Secondly, it has been shown that
freons are cleared very rapidly from the circulation and
would necessitate much more frequent administration
than the half-hourly dosing given in this study to produce cardiovascular effects [43]. Lastly, although
freons have been shown to potentiate the arrhythmogenic effects of adrenaline when given under conditions of hypoxia and hypercapnia, no such potentiation was seen with isoprenaline [44], suggesting
that more selective agents may be less likely to demonstrate this toxicity. Furthermore, our subjects did
not have hypoxia and/or hypercapnia, a usual
prerequisite to demonstrate freon cardiotoxicity with
sympathomimetrics. Therefore, we do not believe that
freons played any role in the cardiovascular effects
demonstrated in this study.
We conclude that formoterol is a more selective
beta2 -agonist than fenoterol, having a lower degree of
cardiac effect despite equivalent systemic beta2 effects.
However, when inhaled in the relative cumulative
doses of 120 vs 2,000 11g, formoterol had greater beta2receptor effects than salbutamol. With the recent demonstration of equivalent maximum bronchodilator effect
with 12 11g, as compared with 24 11g, of formoterol
in both children [14] and adults [13], our results would
suggest that this lower dose may be more appropriate
for use in clinical practice.
Acknowledgements: The authors thank
H. Bark and M. Gordon for secretarial assistance.
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