Beta Adrenergic Agonists*

Harold S. Nelson, COL, MC, USA

Betaprincipal
adrenergic agonists and theophylline are the
bronchodilators employed in the treat-
nucleotide-sensitive regulator protein occurs. This
combination then activates the third component, ade-
ment of bronchial asthma. During the last decade, the nylate cyclase, which converts ATP to cyclic
clinical usefulness of theophylline has been enhanced
EPHEDRINE:
by the availability of serum theophylline determina-
tions and sustained release fOrmulations. Beta adre-
nergic bronchodilators were initially somewhat
eclipsed in the United States by these improvements
in theophylline therapy. Now, however, with the CATECHOLAMINE$:
introduction of selective and long lasting adrenergic
agents, appreciation of their role in the treatment of
bronchial asthma is increasing. Selection of the appro-
priate adrenergic bronchodilators is more complex
~. ~2
than the use of theophylline because of the greater [Pt'IIEPH~ I NE CH3 H
variety of available agents and routes of administra-
.-CH3
tion, because of the special problems related to proper ISOPIIIOTERNOL CH
'CH3
H
techniques of aerosol therapy, and because of the
development of beta adrenergic tolerance or subsen- ... CH3
I S0E THARIN CH Cz "!I
sitivity. 'C".,3
Recognition of receptors with differing sensitivity to
the naturally-occurring catecholamines began with
Alquist in 1948. He identified alpha receptors which
mediate predominantly excitatory responses and beta
receptors which mediate primarily inhibitory re-
sponses. Lands in 1967 further separated the beta NON-cATEOtOL ADRENERGIC IRONCHODI.AlORS:
RESORCINOLS :
receptors on the basis of their relative responsiveness
OH OM
to epinephrine and norepinephrine into beta~> modu-
lating excitatory responses of the heart and adipose oC~-CHz-NH-RI
tissue, and bet"at mediating the inhibitory responses OH
which include not only relaxation of bronchial, vascu- METAPROTERENOL
lar and uterine smooth muscle, but also inhibition of
secretory activity of a variety of cells including his- ,cH3
TERBUTALINE C 'CHJ
tamine release from mast cells, antibody production CH3
by lymphocytes and enzyme release by polymorpho- ,cH 3
nuclear leukocytes. FENOTEROL
CH'CHz O o H
The response to beta adrenergic stimulation is
mediated by three distinct structural units in the cell
membrane. First is a receptor with specificity of either OTHER :
the beta, or bet"at type. Upon occupation of this
receptor by an agonist, interaction with a quanine
ALBUTEROL

HlNCONH

O
OH /CH3
From the Allergy-Immunology Service, Fitzsimons Army Medical 1
Center, Aurora, Colorado. CA~BUTEROL OH CH- CHz - NH- C~H3
The opinions or assertions contained herein are the private views of CH3
the author and are not to be construed as official or as reflecting the
views of the Department of the Army or the Department' of FIGURE 1. The structural relationships of the adrenergic bron-
Defense. chodilators.

CHEST I 82 I 1 I July, 1882 I Supplement 338

3'5'adenosine monophosphate (cAMP) which in tum
modulates most of the beta adrenergic responses .
Epinephrine was first used as a bronchodilator in
1910, followed in 1924 by the introduction of
ephedrine into Western medicine. In 1941, with the
introduction of isoproterenol, a drug free of alpha-
adrenergic stimulating properties, began the system-
atic development of adrenergic bronchodilators with
selective and long lasting effects (Fig 1). Changes in
the isoproterenol structure involved one of two ap-
proaches. First was modification in the catechol nu-
cleus which consists of a phenolic ring with hydroxyl
groups in the 3 and 4 position. By either changing the
position of the hydroxyl groups to the third and fifth
carbons or by substituting another chemical group fur
the hydroxyl on the third carbon, the compound is no
longer a catecholamine and, therefOre, no longer
susceptible to degradation by the enzyme catechol-0-
methyl-transferase (COMT). Increased selectivity fur
the betas receptor can be achieved by increasing the
size of the side chain adjacent to the nitrogen atom.
Increasing the bulk in this position also makes the drug
resistant to degradation by monoamine-oxidase
(MAO) and further prolongs its action.
SPECIFIC BETA ADRENERGIC
BRONCHODILATORS
Epinephrine is still the drug of choice fur treatment
of acute anaphylaxis where a combination of alpha and
beta adrenergic properties are desirable. It is still
employed in the treatment of severe asthma, and
several recent studies have confirmed the efficacy of
injections of 0.25 mg (0.01 mglkg in small children)
repeated at 15 to 20 minute intervals in the treatment
of patients with acute bronchoconstriction. The princi-
pal alternative to epinephrine in the United States is
terbutaline.
Even befure the development of the newer adre-
nergic drugs, ephedrine was seldom employed alone.
It has demonstrable but relatively weak bronchodilat-
ing properties, its use is frequently associated with
side effects, and as a single agent it probably has little
place in the modem bronchodilator armamentarium.
The combination of ephedrine and aminophylline
enjoyed many years of popularity, and it has been
repeatedly demonstrated that the combination pro-
duces greater bronchodilation than either component
alone. Furthermore, the two components comple-
ment each other since initially ephedrine contributes
more to the bronchodilator effect, then, as subsen-
sitivity develops to ephedrine, theophylline blood
levels rise and the aminophylline becomes the princi-
pal contributor to the overall bronchodilator action. In
both acute and chronic comparisons, the combination
tablets have been roughly equivalent to the oral
selective betas agonists and it has been suggested that
34S
there remains a role fur this fixed combination medica-
tion in the treatment of patients who require only a
mild bronchodilator.
Isoproterenol is a potent but nonselective and short-
acting bronchodilator. Cardiac stimulation is usually
not a problem with one or two metered doses, but
becomes evident if the dose is increased. Iso-
proterenol is clearly unsuited fur maintenance bron-
chodilator therapy or prophylactic use prior to exercise
because of its brief duration of peak effect. The rapid
onset of bronchodilator action does provide prompt
relief of symptoms in most patients. However, in view
of the proven superiority of the newer beta adrenergic
agonists, there would appear to be little justification,
other than habit, for the continued use of iso-
proterenol.
Isoetharine was the first widely employed drug
which clearly had increased affinity for the betas
adrenoceptors. Although it has slightly longer dura-
tion of action due to resistance to MAO, its pattern of
bronchodilation closely resembles that of iso-
proterenol, and its use would also appear limited to
rapid relief of acute attacks of bronchoconstriction.
When repeated dosing is required, its decreased
cardiac stimulation is an advantage.
By virtue of a shift of the hydroxyl groups to the third
and fifth carbons on the benzene ring, metaproterenol
is not susceptible to inactivation by COMT and can,
therefOre, be administered orally. The bulk of the side
chain is unchanged from that of isoproterenol and, as
might be expected, metaproterenol does not differ
significantly from isoproterenol in its relative cardiac
and bronchial potency. 1 Furthermore, since meta-
proterenol is still susceptible to MAO, its duration of
action is somewhat shorter than the selective betas
adrenergic agonists whether administered orally or by
inhalation. u Because of this shorter duration of action,
metaproterenol is not as well suited fur either mainte-
nance bronchodilator therapy or fur prevention of
exercise-induced bronchoconstriction unless the activ-
ity will be completed within two hours .
Terbutaline, albuterol, fenoterol and carbuterol are
selective betas adrenergic bronchodilators and to date
there is little evidence that any one is more selective
fur bet~ receptors than the others . All these drugs are
effective orally and by inhalation. All are long-acting
by any route of administration. All are largely free of
direct cardiac stimulation in doses employed clinically;
however, all share the same dose-limiting side ef-
fects-tremor and tachycardia. Both of these side
effects are directly related to betas receptor stimula-
tion. Stimulation of betas receptors in skeletal muscle
causes tremor and betas stimulation of the smooth
muscle in blood vessels supplying skeletal muscles
results in decreased peripheral resistance, leading to
reflex tachycardia and increased cardiac output.
Advances In Asn11ment and Therapy of Asthma
 80 TERBUTAUNE
o--o Subcutaneous
-Oral
.-- - ... Aerosol
80
0.25 mg
80 120 180 240
1111E IN MINUTES
Routes of Administration
Figure 2 compares the onset and duration of bron-
chodilation and the relative doses required when the
same drug, terbutaline, is administered by mouth, by
injections, and by inhalation. 4
The catecholamines, epinephrine, isoproterenol
and isoetharine, are too rapidly degraded by CO MT to
be effective by mouth. Even noncatecholamine adre-
nergic bronchodilators undergo significant conjuga-
tion and inactivation in the gut wall and liver, so the
oral dose is quite large. When specific betas agonists,
such as albuterol or terbutaline, are given by mouth,
the peak effect is usually achieved in two to four hours,
and bronchodilation persists for four to six hours. In a
study by Wilson et al5 in which the bronchodilator
response to terbutaline was monitored during a year of
therapy, the mean response to a 5 mg oral dose was an
increase in FEV1 of 23 percent, while 25 mg of
ephedrine, in the same study, produced a mean
increase in FEV1 of only 12 percent.
While on theoretical grounds terbutaline should be
superior to epinephrine for parenteral use, compara-
tive studies employing conventional doses have not
clearly shown an advantage in the incidence of side
effects or in the magnitude or duration ofbronchodila-
tion. The report by Pang and colleagues6 suggests that
terbutaline may be employed in considerably larger
doses than would be considered with epinephrine.
They administered up to 0.04 mglkg at ten to IS-
minute intervals in children with status asthmaticus.
One ten-year-old patient received a total of 10.2 mg
over a period of three and three-quarter hours. Nine of
the ten children, all refractory to aminophylline and
conventional doses of epinephrine, responded to .this
regimen. This study suggests that the dosage schedule
FIGURE 2. Changes in fOrced expiratory
volume in one second (FEV J fOllowing
three different routes of administration of
300 terbutaline. (Dulfano MJ, Glass P. Ann
Allergy 1976; 37:357, by permission)
recommended for terbutaline may not fully exploit its
betas selectivity.
The advantage of administration of beta adrenergic
bronchodilators by inhalation is evident in Figure 2.
The onset is rapid, the bronchodilation produced is
prolonged, and the therapeutic ratio of bronchodila-
tion to side effects is greatly increased over the other
routes of administration.
By inhalation, the catecholamines isoproterenol and
isoetharine, produce maximal bronchodilation by five
to 15 minutes, following which the effect progressively
declines and is usually undetectable between one and
two hours following administration. The non-
catecholamine beta adrenergic agonists are only
slightly less rapid in onset, with 75 percent of max-
imum effect attained by five minutes, peak bron-
chodilation is attained between 30 and 90 minutes, and
there is little loss of effect until after four hours.
An unresolved question is the proper aerosol dose
for the selective betas adrenergic agonists. When these
drugs are given orally, the occurrence of side effects
generally limits the dose to one producing consider-
ably less than maximal bronchodilation. This con-
straint does not exist when these agents are inhaled,
since side effects are rarely experienced with normally
recommended doses. Some investigators have re-
ported that maximal bronchodilator effect is achieved
with doses of the selective betas agonists which are
even less than those ordinarily employed. It is likely
that these reports can be credited to a failure to
appreciate that bronchodilation is related to the log of
the dose (Fig 3), and if the dose is plotted arith-
metically, there will be an apparent asymptote. Three
observations may be made from Figure 3, which shows
the dose response to aerosolized terbutaline delivered
by metered dose inhaler, IPPB, and compressor pow-
CHEST I 82 I 1 I July, 1982 I Supplement 35S

. - ISOPIDTllliiCIL .I 1
II - Tl.UTAUil .IH a _.TliiUTAUil Ua 1Y CW
- Tl.UTAL .HD a - TliiUTAUil 1.5& IY . , .
.I .2 .3 .I .7 1.1 U U U Ul.U .D
CIIIIIIUTM liSE U
FrcURB 3. Comparison rX changes In FEV1 with repeated doses rX
iloproterenol 0.1 mg. terbutaline O.li5 mg. and terbutaline 0.25 mg
via pressurized canister aerosol, and terbutaline 1.5 mg aerosolized
via COMPand IPPB. (Weber Rw, Petty WE, Nelson HS. JAllergy
Clin lmmuno) 1979; 63:116, by permission.)
ered nebulizer. First, there is no advantage to IPPB
over the pressure nebulizer; second, six to eight times
as large a stated dose must be employed with either
nebulizer compared to the freon-propelled inhaler for
the same degree ofbronchodilation (and, therefore, for
the same amount of deposition in the lungs); and
finally, the bronchodilator response continued up to
the maximum doses which were tested. 7 These curves
were generated by administering doses at 20-minute
intervals and constructing a cumulative dose response
curve. The same results have been obtained in a large
group of patients given individual doses of albuterol of
increasing size on separate days. In that study there
was a linear bronchodilator response to the maximum
dose of eight inhalations from a metered dose inhaler
or 15 mg by IPPB. Side effects were not encountered
with the metered dose inhale~; but were seen with
increasing frequency at the higher doses by IPPB.
Despite obvious advantages in the ratio of bron-
chodilation to side effects with administration of beta
agonists by inhalation, there are other factors which
should be considered before embracing aerosols as the
exclusive route of administration. When the drug is
given by mouth or injected, only the most unusual
circumstances will prevent the drug from reaching the
adrenergic receptors in the lung. By inhalation, how-
ever, especially with the freon-propelled device, care-
ful coordination between actuation and breathing,
slow inhalation, and breathholding are required for
optimal or even predictable results. A number of
recent surveys have documented the frequency of
patient error in using these devices. In one survey of
30 regular users of metered-dose inhalers, 14 made
major errors, most commonly inhaling completely
prior to actuating the device, and second most com-
monly actuating the device and holding the breath
without inhaling. 8 Difficulty with use of inhalers is
encountered most commonly, but not exclusively in
the young and old. Another reason for caution in
relying solely on aerosol therapy is the potential for
abuse of this form of treatment especially by teen-
agers.
Another consideration in reliance on aerosol admin-
istration for bronchodilator therapy is the uncertainty
of the penetration of aerosols into the peripheral
airways. There is no doubt that in stable asthmatic
patients, properly inhaled beta-adrenergic agonists
II
can penetrate small airways, since they have been
demonstrated to decrease frequency dependence of
compliance. Also in a study in patients with acute
severe asthma aerosolized albuterol administered by
tight-fitting mask relieved paradoxic pulse more effec..
tively than did intravenous albuterol, while causing far
less cardiac stimulation. 9 On the other hand, it would
not be surprising if inhaled medication failed to
penetrate uniformly the distal airways in this disease
which is characterized by mucus plugging and uneven
distribution of inspired air even in relatively
asymptomatic patients. There are studies which lend
support to this concern. They show that for the same
degree ofdilation of large airways, parenterally-admin-
istered drug produced greater dilation of small airways
than did the same drug by inhalation. 10
Because of evidence suggesting more effect on
peripheral airways with oral medication, Thiringer
and Svedmyr11 have suggested that a proper approach
to the chronic use of adrenergic bronchodilators in
patients requiring continuous therapy would be to
employ oral therapy with aminophylline, a beta ago-
nist, or both in doses which do not cause troublesome
side effects and, if significant symptoms persist, to
employ the inhaled beta adrenergic agonists on a
regular basis.
Subsensitivity
Subsensitivity or tolerance is a diminished respon-
siveness which develops in many physiologic systems
when receptors are repeatedly exposed to increased
levels of their agonist either natural or administered.
With chronic administration, subsensitivity develops
to the beta adrenergic agonists and results in a reduced
bronchodilator response. This occurs over a period of
one to two weeks and requires a similar period of time
to reverse after the beta adrenergic drug has been
discontinued. In vitro studies of tissue from patients in
whom adrenergic subsensitivity has developed show
markedly decreased numbers of available beta-adre-
nergic receptors and a similarly diminished generation
ofcAMP from ATP on stimulation of adenylate cyclase.
Since adrenergic subsensitivity is caused by de-
creased receptor density, it is not specific for any
particular beta adrenergic agonist. Failure to com-
pletely exclude all adrenergic medication, oral and
Adloencee In A11111ment Mel Therapy ol Alllvna
inhaled, for two weeks prior to initiating drug studies marked in eight hours. Holgate et al14 induced adre-
has resulted in failure to detect the development of nergic subsensitivity in normal individuals with aero-
subsensitivity during many drug trials. solized albuterol (Table 1). Six hours following in-
What is the magnitude of the loss of the adrenergic travenous administration of 200 mg hydrocortisone,
bronchodilator response, and does it significantly their response to inhaled albuterol was restored to the
reduce the clinical effectiveness of these medications? original level. From the study by Weber et al11 (Thble 1)
Thble 1 summarizes some of the studies in which the it appears that low-dose alternate day and inhaled
development of adrenergic subsensitivity has been steroids, such as are ordinarily employed in the
reported. It is evident that adrenergic subsensitivity chronic treatment of patients with bronchial asthma,
occurs with both oral and aerosol therapy. In these are not sufficient to prevent the development of
studies, the peak FEY1 response declined by 14 to 58 adrenergic subsensitivity.
percent, and the duration during which the FEY1 Since patients with status asthmaticus have many
remained more than 15 percent above the baseline was reasons for poor response to beta adrenergic bron-
reduced even more, usually about 50 percent for long- chodilators, including mucosal edema and mucus
1\Cting bronchodilators. Once subsensitivity develops plugging, they would not be expected to respond as
to a particular dose, usually after one or two weeks, dramatically to corticosteroids as did the patients of
there is no further loss of bronchodilator effect with Ellul-Micallef and Holgate. Nevertheless, there is
continuing observation for up to 12 months. In most often a history of recent overuse of adrenergic bron-
patients, the beta agonists continue to be effective chodilators, particularly by aerosol, in patients seen in
bronchodilators even after subsensitivity has devel- emergency rooms, so an element of induced adre-
oped. Perhaps the importance of recognizing the nergic subsensitivity may exist as well. Awareness that
phenomenon of subsensitivity is to serve as a note of corticosteriods can restore adrenergic responsiveness
caution in assessing the findings ofsingle-dose studies, in as little as one hour provides an additional reason for
particularly if there is no information on preceding their prompt use in moderate doses in patients with
adrenergic therapy. Since the duration ofbronchodila- exacerbations of asthma not responding to normal
tion is reduced more than the peak, one should not adrenergic therapy.
expect patients to obtain the same prolonged bron- TnE RoLE oF BETA ADRENERGIC BRONCHODILATORS
chodilator effect during chronic administration that is IN THE TREATMENT OF AsTHMA
often reported in the literature. Inhaled beta adrenergic bronchodilators are the
Corticosteroids have been reported to restore beta treatment of choice for prompt relief of acute episodes
adrenergic responsiveness. Ellul-Micallef and Fench13 of wheezing and dyspnea no matter what has been the
identified ten stable asthmatic patients who failed to stimulus.
respond to inhaled isoproterenol. Following intra- Although exercise-induced bronchoconstriction can
venous infusion of 40 mg prednisolone, eight of the ten be prevented by therapy with cromolyn, theophylline
became responsive to isoproterenol. There was some or oral beta adrenergic agonists, it is most conve-
effect evident after one hour and it was even more niently and effectively prevented with the least num-
18ble 1-~ cf S~ willa Long-term Admlniltration cf &14-~ BronclaotUliJtora
8-Adren Route Change in Peak Change in Duration c:A
Author Washout Admin Drug Duration Bronchodilator Response Bronchodilator Response
Nelson 11 yes oral albuterol 1 week FEV 1 ~20% >6 hr to5 hr
12 weeks FEVI~~
Jenne 13 inhaled oral terbutaline 2 weeks FEVIH4%
allowed
Holgate1 yes aerosol albuterol 4 weeks SGawi54%
Plummer14 inhaled oral fenoterol 3 months but not signif
FEV 1 ~31% tFEV1>15% 5 hr to 3\11 hr
allowed oral ephedrine tFEV1>15% 2 hr to \II hr
Chervinsky11 aerosol metaproterenol 2 months SignlftFEV1 4 hr .. 2 hr
isoproterenol SigniftFEV1 3 hr .. 5 min
1hwtlein17 aerosol terbutaline 6weeks FEVIUiO%
Brandon11 aerosol fenoterol 3 months tFEV1 15% 4 hr .. 2 hr
aerosol isoproterenol tFEV1 15% 1 hr .. 20 min
Miller yes oral fenoterol 6weeks Reduced FEV1 signi~at 2+3 hr
terbutaline FEV1 signi~at 2,3+4 hr
Bransoomb10 yes aerosol fenoterol 3 months FEV 1 ~31% FEV1above baseline 6 hr .. 3 hr
Van ArsdeJII yes oral fenotero! 3 months significant reduction
We be..- yes aerosol terbutaline 3 months FEV 1 ~37% FEV1>15% 4 hr .. 2 hr
-infOrmation not given

CHEST I 82 I 1 I July, 1882 I Supplement 378

her of side effects by inhalation of a long-acting
adrenergic bronchodilator shortly before beginning
exercise.
The relative role of beta adrenergic agonists and
theophylline for chronic bronchodilator therapy is not
established. A recent study by Rachelefsky and co-
authors.. on the use of oral albuterol in children clearly
demonstrated that symptom scores, pulmonary func-
tion, and need for additional medication can all be
significantly improved by oral adrenergic therapy
alone in tolerated doses. Smith and colleagues111 com-
pared inhaled terbutaline four times daily with max-
imum therapeutic doses of theophylline in a group of
adult asthmatic patients. Pulmonary function tests
performed regularly at home were not significantly
different while on either of the drugs alone, but were
significantly better when both drugs were taken to-
gether. It is evident that beta adrenergic bronchodila-
tors are possible alternatives as well as additions to
long-term theophylline therapy. Further studies will
be necessary to determine which are the most effective
drug regimens for patients requiring continuous treat-
ment.
The role of beta-adrenergic bronchodilators in the
emergency treatment of acute, severe episodes of
bronchial asthma has been clarified by several recent
studies. The response to repeated doses of injected
epinephrine or inhaled short-acting beta agonists has
been compared to conventional loading doses of
aminophylline followed by continuous infusion. The
studies are in agreement that the response to adre-
nergic bronchodilators by either route was equal and
either was superior to aminophylline.111.rr The addition
of aminophylline to the adrenergic agonists provided a
modest but usually significant additional bronchodila-
tor effect. rr- These studies suggest that the impor-
tance of aminophylline in the emergency room treat-
ment of asthma may have been overemphasized in
recent years, leading to underutilization of what has
now been proven to be the more important component
of the treatment, the adrenergic bronchodilators.
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