PRACTICAL THERAPEUTICS

Drugs 46 (5): 847-862, 1993

0012-6667/93/0011-0847/$08.00/0
© Adis International Limited. All rights reserved.

Clinical Pharmacology of Asthma

Implications for Treatment

Anthony 1. Frew and Stephen T. Holgate

University Medicine, Southampton General Hospital, Southampton, England

Contents
847 Summary
848 I. Changing Concepts of the Pathogenesis of Asthma
848 2. Drugs Used in the Treatment of Asthma
8-18 2.1 Anti-Inflammatory Agents
85 J 2.2 Bronchodilators
853 2.3 Other Drugs
854 2.4 Allergen Immunotherapy
855 3. Current Recommendations for the Management of Asthma
855 3.1 Allergen and Adjuvant Avoidance
855 3.2 Maintenance Therapy
857 3.3 Treatment of Deteriorating Asthma
857 3.4 Structured Management Plans
859 4. Conclusions

Summary
The past 10 years have seen three important changes in the philosophy of managing asthma.
First, histological studies using fibreoptic bronchoscopy have led to the recognition that asthma
is an inflammatory condition of the bronchial mucosa and is not simply caused by smooth muscle
spasm. Secondly, there has been some disenchantment with the long term use of regular
~2-adrenergic agonists as these agents do not appear to control bronchial inflammation and have
been associated with deaths from asthma. Thirdly, there has been a general shift away from
physician-centred management towards patient-oriented management plans.
These three separate strands have led to the development of regional and international consen-
sus documents that emphasise the use of regular anti-inflammatory treatment to control bronchial
inflammation and reduce symptoms. With the emphasis on finding the minimum amount of treat-
ment, several traditional anti-asthma medications have been downgraded in importance.
The introduction of self-management plans is to be welcomed, but it is important that these
new strategies for treating asthma are properly evaluated so that the benefits they confer can be
ascertained and maximised.
848
1. Changing Concepts of the
Pathogenesis of Asthma
Until quite recently asthma was generally re-
garded as a disease of airway physiology, in which
hypertrophy and increased contractility of bron-
chial smooth muscle was the dominant lesion (An-
tonissen et al. 1979; Heard & Hossain 1971). Over
the past few years it has become increasingly clear
that asthma is an inflammatory disease in which a
variety of triggers can lead to epithelial damage,
leucocyte infiltration and increased sensitivity of
the airways to a range of nonspecific stimuli (Kay
1991). Although bronchoconstriction is certainly
dependent on the contraction of smooth muscle,
intensive investigations have failed to reveal any
distinct abnormality of the muscle itself (Vincenc
et al. 1983). Most authorities now believe that the
muscular responses are a consequence of the epi-
thelial inflammatory process, rather than being the
primary element in asthma.
The root causes of airways inflammation remain
uncertain. In atopic individuals, allergen exposure
triggers the activation of airway mast cells. This
activation leads to release of a range of preformed
and newly generated bronchoactive and vasoactive
mediators, which in tum cause airway obstruction
and the recruitment of a mixed leucocyte infiltrate
(Beasley et al. 1989). The bronchospastic response
to allergen inflammation is commonly biphasic,
with an immediate or early phase response due to
the direct effects of mediators on bronchial smooth
muscle, and a prolonged or late phase response due
to mucosal oedema and cellular infiltration, 3 to 12
hours after inhalation. Other changes noted in his-
tological studies of mild asthma include shedding
of the airway epithelium, interstitial oedema, and
sub-basement-membrane deposition of collagen
(Jeffery et al. 1992). Similar histological changes
are found in intrinsic asthma (where there is no
defined external allergen) [Bentley et al. 1992b],
and in occupational asthma whether caused by high
or low molecular mass organic compounds (Bent-
ley et al. 1992a).
There is clearly more to asthma than just allergy,
in that many patients with allergic rhinitis and well
Drugs 46 (5) 1993
defined allergen sensitivity have no clinical evi-
dence of asthma (Britton 1992). Interest has fo-
cused on the role of inflammatory cells, such as
eosinophils, T cells, platelets and macrophages,
and on the protein mediators (cytokines) that these
cells elaborate when appropriately stimulated
(Djukanovic et al. 1990; Kay 1991). Our present
knowledge of the cell biology of asthma does not
permit us to draw any firm conclusion about the
pre-eminence of any particular cell type, cytokine
or other mediator class. However, our improving
understanding of the histology and pathophysiol-
ogy of asthma has allowed us to develop a more
rational approach to the treatment of asthma and to
use the available drugs in a more logical frame-
work.
2. Drugs Used in the Treatment of Asthma
Table I summarises the mode of action and rec-
ommended use of the drugs used in the treatment
of asthma.
2.1 Anti-Inflammatory Agents
2.1.1 Inhaled Corticosteroids
Following the clinical introduction of cor-
ticotrophin in 1949 and the development of syn-
thetic corticosteroids in the early 1950s, it was
soon realised that these agents were very effective
in the treatment of asthma (Bordley et al. 1949).
However, by the early 1960s it was clear that long
term use of oral corticosteroids was associated with
significant adverse effects, including the develop-
ment of iatrogenic Cushing's syndrome (Adinoff
& Hollister 1983; Smyllie & Connelly 1968).
Inhaled beclomethasone was introduced in
1970, and inhaled corticosteroids rapidly estab-
lished a position in the second line treatment of
asthma (Medical Research Council 1979). Sub-
sequent clinical experience led physicians to use
increased doses of inhaled corticosteroids. This in
tum resulted in the realisation that inhaled cortico-
steroids could be used as a first line treatment sup-
plemented with inhaled bronchodilators, instead of
prescribing regular bronchodilators as the first line
agent and only introducing inhaled corticosteroids
Clinical Pharmacology of Asthma
Table I. Summary of drugs used in the treatment of asthma
Drug Mode of action
Sodium cromoglycate (cromolyn Anti·inflammatory
sodium) and nedocromil sodium
Corticosteroids Anti·inflammatory
~2·Agonists Bronchodilator
short·acting
long·acting
Anticholinergics Bronchodilator
Xanthines Bronchodilator, weak anti· Oral/rectal
inflammatory
if the bronchodilator was insufficient to control
symptoms.
During the 1980s, studies confirmed that in-
haled corticosteroids can reduce nonspecific bron-
chial hyper-responsiveness (Clarke 1982; Jenkins
& Woolcock 1988; Kerrebijn et al. 1987; Kraan et
al. 1985; Wempe et al. 1992) and are more effective
than regular inhaled bronchodilators in providing
long term symptomatic relief.
Further support for the use of inhaled cortico-
steroids in all forms of asthma has come from the
recognition that asthma is an inflammatory condi-
tion that can be treated with anti-inflammatory
agents (British Thoracic Society 1990; Djukanovic
et al. 1992; Laitinen et al. 1992; van Bever & Ste-
vens 1992). With this transition to the use of in-
haled corticosteroids as first line drugs came rec-
ognition of the need to educate patients (and
medical staff) in the distinct roles of corticoste-
roids and bronchodilators and in the appropriate
use of inhalers (Frew & Macfarlane, 1982).
Problems with inhaled corticosteroids include
local adverse effects, chiefly hoarseness and can-
didiasis, caused by deposition of aerosol in the oro-
pharynx (Toogood et al. 1980). These problems
can largely be circumvented by use of a spacing
device (spacer inhalers) [Toogood et al. 1984]. Lo-
849
Route of administration Recommended use
Inhaled Maintenance therapy
Inhaled Maintenance therapy
Oral In exacerbations or as maintenance
therapy in severe asthma
Parenteral Maintenance therapy in severe asthma
Inhaled/oral As required
Inhaled/oral Maintenance therapy, especially for
noctumal symptoms
Inhaled As required or maintenance therapy,
especially in acute exacerbations
Maintenance therapy
Parenteral In severe exacerbations
cal adverse effects are also said to be less evident
when dry powder inhalers are used.
Systemic adverse effects from inhaled cortico-
steroids are a topic of considerable current interest
(Balfour 1985; Konig 1988; Wolthers & Pederson
1991). With conventional inhalers 85 to 90% of
each dose is swallowed, and some of this is then
absorbed from the gut. At dosages of beclo-
methasone or budesonide exceeding 1 mg/day in
adults (>400 ~g/day in children) this leads to bio-
chemically detectable impairment of adrenal re-
sponsiveness to corticotrophin. This absorption is
not sufficient to induce Cushing's syndrome, but
would suggest that additional corticosteroids
should be given during severe illnesses. Spacer de-
vices significantly reduce systemic absorption and
should always be used at steroid dosages over 1
mg/day.
In practice, patients with severe chronic asthma
are going to receive oral corticosteroids for any
exacerbation, so this is more of a theoretical than
a practical problem. However, concerns have been
raised about the possible effects of inhaled steroids
on growth rates in children with asthma receiving
high (or even moderate) dosage treatment with in-
haled steroids (Graff-Lonnevig 1979). The newly
introduced inhaled steroid fluticasone offers the
850
theoretical advantage of much lower bioavailabil-
ity via the gut while retaining efficacy in the air-
ways, and represents one of a new generation of
topically active drugs (Boner & Piacentini 1993;
Wolthers & Pederson 1993).
Compliance with therapy can be difficult in long
term use, especially if patients feel well controlled.
Prescribing twice-daily administration of inhaled
corticosteroids can be helpful in securing compli-
ance.
2.1.2 Sodium Cromoglycate and
Nedocromil Sodium
Sodium cromoglycate (cromolyn sodium) was
discovered as part of a systematic search for agents
that inhibit the degranulation of mast cells. Early
experimental studies tended to confirm the view
that sodium cromoglycate was effective in the
treatment of asthma through an effect on mast
cells, since it was able to block exercise-induced
asthma and both the early and late phase responses
to allergen inhalation (Booij-Noord et al. 1971;
Breslin et al. 1980).
Sodium cromoglycate is particularly active in
prevention of seasonal allergic asthma in children
and young adults (Murphy & Kelly 1987; Patel
1971; Petty et al. 1989). Since its clinical introduc-
tion in 1967 it has proved a very valuable agent in
this group of patients, but is usually less effective
in older patients or in patients whose asthma is not
allergic in character. Sodium cromoglycate has to
be taken by inhalation and has a relatively short
duration of action, requiring administration every
3 or 4 hours (Altounyan 1980). It reduces bronchial
responsiveness, but in this respect it is less effec-
tive than inhaled corticosteroids (Cockcroft &
Murdock 1987; Lowagen & Rak 1985; Stafford et
al. 1984; Svendson et al. 1987).
Attempts to develop other mast cell stabilising
agents were largely fruitless until the discovery of
nedocromil sodium. In the course of this research
and development, many questions were raised
about the mechanism by which sodium cromogly-
cate is effective in asthma (Murphy & Kelly 1987).
Many drugs that are more potent than sodium
cromoglycate as mast cell stabilising agents have
Drugs 46 (5) 1993
proved to be totally ineffective in clinical treatment
of asthma (Stokes & Morley 1981). On the other
hand, sodium cromoglycate has been shown to
have a wide range of anti-inflammatory effects in
vivo and in vitro in assays relevant to asthma and
allergic inflammation (Diaz et al. 1984; Kimata et
al. 1991; Leung et al. 1986).
Nedocromil sodium has mast cell stabilising
properties similar to those of sodium cromoglycate
(Bruijnzeel etal. 1990; Moqbel et al. 1988), but has
also been found to act on nonadrenergic non-
cholinergic bronchoconstrictor neural mechanisms
(Ruggieri & Patalano 1989; Verleden et al. 1991).
In addition to being more potent than sodium
cromoglycate, it is effective in a wider range of
patients with asthma (Verleden et al. 1991).
Nedocromil sodium is effective in allergen and ex-
ercise provocation tests (Aalbers et al. 1991; Patel
& Albazzaz 1987), and has been found to be effec-
tive as a steroid-sparing agent in a proportion of
patients with nonallergic asthma (Bone et al. 1989;
Thomson 1989).
The steroid-sparing effect is unpredictable, but
within individuals it is usually consistent and
maintained. It is therefore logical to consider using
nedocromil sodium at an early stage in patients
with allergic asthma. It should also be considered
in patients with nonallergic asthma in whom an
increase in inhaled corticosteroids is being con-
templated (British Thoracic Society 1993; Brog-
den & Sorkin 1993).
The good safety profiles of nedocromil sodium
and sodium cromoglycate are also important fac-
tors in choosing this form of therapy. If nedocromil
sodium or sodium cromoglycate are going to be
effective the benefits of the drug are usually appar-
ent within 4 weeks (Altounyan 1980; Thomson
1989). After this time there is little purpose in con-
tinuing with either drug if no improvement has oc-
curred.
2.1.3 Oral Corticosteroids
Oral corticosteroids are extremely effective in
asthma, but their long term use is limited by their
typical Cushingoid adverse effects (Adinoff &
Hollister 1983; Smyllie & Connelly 1968). In cur-
Clinical Pharmacology of Asthma
rent clinical practice, oral corticosteroids have two
distinct roles: as short term (rescue) therapy, and
as maintenance treatment for a minority of se-
verely affected patients (table I).
Short courses of oral steroids are an important
component of any plan to control asthma. They
should be instituted rapidly at the onset of deterio-
ration and continued for at least 48 hours after im-
provement has been obtained. Typically, 30
mg/day is administered for 5 to 7 days. Tapering of
the dose is not necessary in patients who are not
receiving oral corticosteroids as maintenance ther-
apy.
If oral corticosteroids are required for long term
maintenance treatment, it is important to give the
lowest dosage that controls symptoms and to re-
view regularly the requirement for the drug. All
patients on oral corticosteroids should also be re-
ceiving high dose inhaled steroids as the effects of
oral and inhaled corticosteroids are additive.
2.2 Bronchodilators
2.2.1 ~2-Adrenergic Agonists
It has long been known that adrenaline (epi-
nephrine) relaxes bronchial smooth muscle and
that this effect is mediated through receptors dis-
tinct from those present on vascular smooth muscle
and cardiac muscle. Inhaled isoprenaline (iso-
proterenol) was widely used to treat asthma during
the 1960s and fell into disfavour only when a num-
ber of deaths from asthma were attributed to its use
(Stolley & Schinnar 1978). In retrospect, the evi-
dence against isoprenaline seems weak. Neverthe-
less, the development of ~2-adrenergic agonists
during the 1960s was a major advance in the treat-
ment of asthma. When used as oral preparations,
~2-agonist dosages are limited by sympathomi-
metic adverse effects. The introduction in 1969 of
inhaled preparations led to an improved quality of
life for many patients with asthma (Rebuck 1974).
Between 1970 and 1989, 8 different inhaled ~2-
adrenergic agonists were marketed in the UK. All
of these were relatively short-acting, with effective
durations of action between 3 and 5 hours. In ex-
perimental studies, they relax smooth muscle that
851
has previously been caused to contract by a wide
range of stimuli (i.e. allergens, sulphur dioxide, ex-
ercise, histamine, methacholine or osmotic stim-
uli). Preadministration of ~2-agonists partially pre-
vents allergen-induced release of inflammatory
mediators and protects against capillary leakage
induced by allergen exposure (Persson 1991).
In clinical practice, there is little to choose be-
tween the various short-acting ~2-agonists. The
major changes in ~2-agonist usage between 1970
and 1989 consisted of progressive modifications of
the dosage regimen and the introduction of new
inhaler devices. For most patients the pressurised
metered dose inhaler (MDI) has been an effective
source of relief, but for some patients the manipu-
lation and coordination of this device has proved
difficult, although breath-activated MDIs help in
this situation. Another factor that will clearly influ-
ence the use of MDIs is the phasing out of chloro-
fluorocarbons by 1995 under the Montreal Accord.
Dry powder delivery systems are likely to fill the
gap left by withdrawal of chlorofluorocarbon-pro-
pelled MDIs until new propellants have completed
toxicology testing.
A variety of devices have been used to improve
the effectiveness of dry powder delivery to the air-
ways. Among these the Rotahaler®, Diskhaler®
and Turbohaler® devices have all proved effective
in children and adults (Sears & Asher 1985). How-
ever, elderly patients and those with impaired man-
ual dexterity may find these devices difficult to
use.
Treatment with nebulised ~2-agonists is indi-
cated in acute exacerbations of asthma and in the
maintenance and treatment of a small proportion
of patients with asthma who require very high
doses or who are unable to benefit from the other
conventional devices. Specialist assessment, with
careful evaluation of spirometric response, should
be performed before long term nebulised ~2-agon­
ist therapy is commenced. Oral ~2-agonists can be
helpful in the management of chronic asthma, es-
pecially in patients with persistent nocturnal symp-
toms (Koeter et al. 1985), but their use is limited
by dosage-related tremor and agitation.
852
In the past, ~2-agonists were used 3 to 4 times
daily as first line maintenance treatment. However,
the current trend is to use them as required for short
term relief of bronchospasm. Both short term and
long term studies of ~2-agonist use in chronic
asthma have shown little or no influence on the
inflammatory process, with persistence of physio-
logical markers of inflammation such as nonspe-
cific bronchial hyper-reactivity (Kerrebijn et al.
1987; Kraan et al. 1985; Sears et al. 1990; Wempe
et al. 1992). Indeed, some advocate that the regular
use of this drug class leads to deterioration of
asthma (Sugiyama et al. 1992).
The long-acting ~2-agonists salmeterol and
formoterol were introduced to the UK in 1989 and
1990. These longer-acting ~-agonists have a
slower onset of action and do not provide 'first
aid' relief of bronchospasm. They are active as
mast cell stabilisers against inflammatory events in
the airways (Simons et al. 1992; Tattersfield 1992).
Their duration of effective action is between 8 and
15 hours and they can be valuable adjuncts to main-
tenance therapy, although their optimum place in a
long term management plan is yet to be agreed
(Crane et al. 1989).
The recent increase in the rate of deaths attrib-
uted to asthma has led some authorities to question
whether high dosage ~2-agonist therapy may in fact
be making some patients' asthma worse. There are
several difficulties in defining the true rate of death
from asthma, because of temporal trends in diag-
nostic labelling and the 1979 change in Interna-
tional Classification of Disease (ICD) coding. Ev-
idence from New Zealand and Canada specifically
implicating fenoterol in asthma deaths (Grainger et
al. 1991; Spitzer et al. 1992) has not met with uni-
versal agreement, largely because fenoterol was
prescribed preferentially to patients with severe
asthma and the preparation of fenoterol was more
potent, puff for puff, than other ~2-agonist inhalers
(Lipworth 1992; Tattersfield 1992).
Follow-up studies have indicated that long term
high dosage treatment with any ~2-agonist leads to
increased bronchial responsiveness and decreased
baseline lung function, and may de stabilise control
Drugs 46 (5) 1993
of asthma (Sears et al. 1990). However, ordinary
dosage regimens of salbutamol (albuterol) and ter-
butaline do not appear to cause these potential
problems, and patients receiving high dosages can
be protected by coadministration of inhaled corti-
costeroids (Crane et al. 1989; Lipworth 1992). At
present, the general view is that ~2-agonists may be
risky if used as high dosage maintenance treatment
without concurrent inhaled corticosteroids. There-
fore, all patients with asthma who require high dos-
age ~2-agonists should also receive inhaled corti-
costeroids (Lip worth 1992).
2.2.2 Xanthines
Xanthines have a long and honourable history
in the treatment of asthma, but their status has been
downgraded in recent years. Historically, it has
generally been considered that their principal
mode of action is through inhibition of phos-
phodiesterase, which maintains levels of intracel-
lular cyclic adenosine 5' -monophosphate and thus
relaxes bronchial smooth muscle. In addition, xan-
thines improve diaphragmatic contractility, which
may be useful in patients with chronic airflow ob-
struction (Aubier et al. 1989). Compared with ~2-
agonists, xanthines have only modest effects on
mediator release (Orange et al. 1971), on exercise-
induced asthma (McWilliams et al. 1984), or on
histamine-induced bronchoconstriction (duToit et
al. 1987; McWilliams et al. 1984). Xanthines do
not influence underlying bronchial responsiveness
(Du Toit et al. 1987).
The principal limitation in using xanthines is
their narrow therapeutic window (Andersson &
Persson 1980; Helliwell & Berry 1979). Although
xanthines are often prescribed without monitoring
the plasma drug concentration, it is necessary to
achieve a concentration of at least 10 mg/L for the
drug to be clinically effective. At 20 mg/L most
individuals will experience toxicity (tremor, nau-
sea and excitation of central nervous system) and,
in addition, some patients may experience nausea
despite having drug concentrations at the lower
end of the therapeutic range.
For these reasons, xanthines have largely been
relegated in the United Kingdom to third line status
Clinical Pharmacology of Asthma
except in the treatment of nocturnal asthma. In the
United States, xanthines have remained popular for
much longer. There are two main reasons for this
difference. First, salbutamol and other ~2-agonists
were not introduced into the US market until 1986.
Secondly, xanthines are cheap and are thus acces-
sible to many patients with asthma who cannot af-
ford to purchase recently introduced, perhaps more
expensive, medications.
Most xanthine preparations marketed today are
slow release formulations that are administered
once or twice daily. In addition, there is now a
wider range of tablet strengths, in recognition of
the need to tailor the dose to the individuals' phar-
macokinetic response.
In the UK, xanthines have been widely used in
the treatment of acute exacerbations of asthma.
There is no doubt that intravenous aminophylline
is an effective treatment for bronchospasm in acute
severe asthma, but it has been difficult to detect
whether it has any additional effect over and above
the response to inhaled ~2-agonists (Littenberg
1988; Self et a1. 1990; Wrenn et a1. 1991). The lat-
est study to compare aminophylline plus broncho-
dilators with bronchodilators alone found no dif-
ference in the spirometric response to emergency
treatment, but aminophylline did seem to be help-
ful in that patients who were treated with this drug
were able to leave hospital sooner than those who
did not receive aminophylline (Wrenn et a1. 1991).
Since there was no difference between the two
groups in their spirometric improvement, it is not
immediately clear how aminophylline might be ex-
erting this beneficial effect.
2.2.3 Anticholinergic Agents
Part of the bronchoconstriction seen in asthma
appears to be due to the influence of parasympa-
thetic activity mediated through the vagus nerve.
Anticholinergic drugs can counteract this and can
be effective additions in the treatment of asthma.
Anticholinergic treatment seems to be particu-
larly effective in acute exacerbations of asthma and
may be more useful in the treatment of older pa-
tients with asthma rather than younger patients
(Calverley 1992; Ullah et a1. 1981). Two anticho-
853
linergic agents are commercially available for use
in asthma, ipratropium bromide and oxitropium
bromide. Both drugs have similar modes of action
and are equally efficacious when used in equiva-
lent dosages. Both drugs are poorly absorbed and
hence are free from systemic adverse effects
(Laitinen & Poppius 1986; Pavia et a1. 1979).
The principal difference between the two drugs
is their duration of action, with ipratropium bro-
mide having a more rapid onset of action and a
shorter duration of action. As a result, ipratropium
bromide is often administered 4 times a day
whereas oxitropium bromide need be given only
twice daily. Ipratropium bromide is also available
as a nebuliser solution; when used thus, it is usually
administered together with a ~2-agonist. Nebulised
ipratropium bromide is usually given twice daily,
even if the ~2-agonist is being given more fre-
quently. As with nebulised ~2-agonist treatment,
the decision to use nebulised anticholinergics
should be guided by formal evaluation of spiromet-
ric response to the drug.
2.3 Other Drugs
2.3.1 Histamine HI-Receptor Antagonists
In the past, it was widely believed that mast cell
degranulation was the central pathophysiological
event in asthma. Histamine is a major component
of mast cell granules, and it therefore seemed log-
ical to test the effects of histamine antagonists in
asthma. Careful clinical trials of conventional Hl-
histamine receptor antagonists showed some bron-
chodilation and protection against histamine inha-
lation, and to a lesser extent protection against the
immediate effects of allergen challenge (Albazzaz
& Patel 1988; Phillips et a1. 1984); there is, how-
ever, little or no beneficial effect in clinical asthma.
Following the development of new nonsedating
antihistamines, there have been several trials of
high dosage antihistamine treatment in asthma.
Evaluation of these newer agents is complicated by
the fact that several of the drugs have additional
modes of action. For example, loratidine is a
leukotriene antagonist, cetirizine inhibits eo sino-
854
phil migration, and oxatomide stabilises mast cells
(De Vos 1989; Redier et al. 1992).
In high dosage (120mg daily), terfenadine has
been shown to have a small beneficial effect on
peak flow rates in a group of patients with allergic
asthma (Rafferty & Holgate 1989). To date, the evi-
dence remains somewhat inconclusive and the use
of antihistamines to treat asthma should remain
confined to clinical trials in research centres.
2.3.2 J(etott(en
Ketotifen is an orally active antihistamine
which has been widely marketed as a specific an-
tiallergic agent for use in asthma. Worldwide it is
one of the largest selling agents, although its sales
in Western Europe have been much weaker. Pla-
cebo-controlled double-blind studies have shown
no effect ofketotifen upon bronchial hyper-respon-
siveness and only limited efficacy in clinical
asthma, at least in adults (Loftus & Price 1987).
2.3.3 Other Mediator Antagonists
A number of specific mediator antagonists are
currently undergoing development. These include
antagonists of sulphidopeptide leukotrienes and
antagonists of platelet-activating factor. Early
studies have shown effective inhibition of bron-
choconstriction induced by the relevant mediator,
and limited effects in certain models of human
asthma (for example allergen challenge) [Lohman
& Halonen 1990; Rasmussen et al. 1992]. The ef-
ficacy of these agents in the treatment of clinical
disease has yet to be demonstrated.
2.3.4 Immunosuppressants and Troleandomycin
Although most patients with asthma respond
well to corticosteroids, there is a significant sub-
group who have clinical and biochemical evidence
of resistance to the effect of corticosteroids. These
patients require large dosages of corticosteroids to
achieve remission and are particularly prone to iat-
rogenic Cushing's syndrome (Alvarez et al. 1992;
Corrigan et al. 1991ab). In all settings where high
dosages of corticosteroids have to be used, physi-
cians are keen to try alternative agents that may
reduce the requirement for corticosteroids.
Drugs 46 (5) 1993
Early trials with the immunosuppressants
cyclophosphamide and azathioprine in asthma
proved singularly unsuccessful (Asmudsson et al.
1971; Hodges et al. 1971). More recently, evidence
has been presented indicating that methotrexate
has a beneficial effect in chronic severe asthma,
although the treatment has to be pulsed and fre-
quent liver biopsies are required to assess hepato-
toxicity (Mullarkey et al. 1988; Shiner et al. 1990).
Other adverse effects are also encountered, chiefly
haematological (Erzurum & Leff 1991).
Cyclosporin is an immunosuppressant that spe-
cifically acts on the T lymphocyte. Alexander et
al. (1992) used cyclosporin in a double-blind pla-
cebo-controlled trial and found a beneficial effect
on spirometry and medication requirements. Both
methotrexate and cyclosporin have significant po-
tential to cause systemic toxicity and require inten-
sive monitoring.
The macrolide antibiotic troleandomycin has
been tried as a steroid-sparing agent in asthma. Pre-
liminary studies showed promise (Zeiger et al.
1980), but in later work the drug was found to act
by increasing the effect of a given dose of pre-
dnisolone by altering steroid metabolism. This per-
mits a smaller oral dose of prednisolone, but does
not decrease the potential for adverse effects
(Szefler et al. 1982).
For the present, the use of methotrexate, cyclo-
sporin and troleandomycin remains a matter for ex-
perimental studies and cannot be recommended in
routine practice.
2.4 Allergen Immunotherapy
Specific desensitisation by injection of allergen
extracts has been widely used in the treatment of
allergic asthma (Bousquet et al. 1990; Lichtenstein
1978; Ohman 1989). Claims have also been made
that immunotherapy for allergic rhinitis may pre-
vent or reduce the development of allergic asthma,
and thus playa preventive role.
Many early trials of immunotherapy in allergic
disease were methodologically flawed, but recent
trials have confirmed that immunotherapy can be
successfully used to treat patients with severe al-
Clinical Phannacology of Asthma
lergic rhinitis that is resistant to conventional med-
ication (Varney et al. 1991). However, formal trials
of immunotherapy compared with optimum con-
ventional management of asthma have not yet been
performed. Such studies would be time consuming
and difficult to perform, but are nonetheless neces-
sary to establish the cost-benefit and risk-benefit
ratios of the respective treatment options.
It is important to note that patients with asthma
are at greater risk of adverse reactions from aller-
gen immunotherapy compared with patients with
allergic rhinitis without asthma. The incidence of
adverse reactions, the incidence of immunother-
apy-induced asthma, and the risk of death from
anaphylaxis, are all much greater in patients with
asthma (British Society for Allergy and Clinical
Immunology, 1993). Consequently, asthma is not
currently regarded as an indication for immuno-
therapy in the UK, although elsewhere many pa-
tients with asthma continue to receive desensitis-
ing injections. Similarly, coexistent asthma is a
relative contraindication for the use of immuno-
therapy to treat allergic rhinitis.
Future developments in allergen vaccines and in
the production of peptide epitope fragments may
improve the safety of this form of treatment and
permit a re-evaluation of the utility of immunother-
apy in asthma, but for the present immunotherapy
cannot be recommended as a routine treatment for
patients with asthma.
3. Current Recommendations for the
Management ofAsthma
Following recognition of the importance of al-
lergic factors and inflammation in the pathogenesis
of asthma, there has been a major change in the
philosophy of treating asthma. Regional and
international consensus documents have been de-
veloped that emphasise the use of regular anti-in-
flammatory treatment to control bronchial inflam-
mation and reduce symptoms. In addition, there
has been a general shift away from physician-cen-
tred management towards patient-oriented man-
agement plans.
855
3.1 Allergen and Adjuvant Avoidance
Since most asthma occurs in relation to atopy,
avoidance of factors known to increase or incite the
disease is worthwhile, especially when, as in occu-
pational asthma, a single sensitising agent has been
identified.
However, at present there is very little that can
be done to influence the process of sensitisation to
environmental allergens. There is clear evidence
that high levels of house dust mite exposure in
childhood are associated with increased sensitisa-
tion rates (Sporik et al. 1990). However, other fac-
tors associated with high levels of house dust mite
allergens, including socioeconomic status, paren-
tal smoking and diet, all interact with genetic sus-
ceptibility to lead to the development of sensitisa-
tion and asthma (Dannaeus 1984; Ehnert et al.
1992).
Where environmental allergens have been im-
plicated, it is logical to reduce exposure if this is
practicable. Clear benefits have been demonstrated
in children who have been removed from homes
with high dust mite exposure, by transfer either to
high altitude (Boner et al. 1985) or to hospitals
with special environmentally controlled units
(Platts-Mills et al. 1982).
3.2 Maintenance Therapy
Inhaled ~2-agonists remain the first line drug for
patients with very infrequent symptoms or symp-
toms provoked solely by exercise. Where symp-
toms occur daily or occur often at night, or if daily
~2-agonist treatment has become necessary, pa-
tients should take prophylactic medication, usually
in the form of inhaled corticosteroids.
Sodium cromoglycate and nedocromil sodium
are worth trying as an initial step in prophylactic
medication, especially at the milder end of the dis-
ease spectrum, although they are generally more
effective in children than in adults.
In patients taking prophylactic medication,~2-
agonists should be used as required to relieve bron-
chospasm but are not generally needed regularly.
 00
Clinical ieatures Therapy (NB. must include patient education about prevention ,n additIOn to VI
Outcome 0\
pretreatment" I symptom control) 1 I
• Short-acting
Step 1
inhaled
Mild asthma
jl2-agonist pm
• Intenmllent brief Control of asthma
(not more often
symptoms « l-2Iweek)
than 3 timas/Week)
• < 1-2 noctumal • Minimal (ideally no)
• Inhaled sodium
symptoms/month chrome symptoms
cromoglycate or
• Asymptomatic between • Minimal (infrequent)
short-acting
ePisodes ep,sodes
I\?-agonlst
• PEFR or FEV, > 80% of • No emergency vlslls
belore exercise
predicted values and • Minimal need for inhaled
or allergen
vanability < 20% jl2-agonlsts
exposu,e
• No limitation ot activities
.. Controillot achieved
(including exercise)
• Inhaled • Short-acting Inhaled • (Near) normal PEFR
corticosteroid Ilz-agonlst (pm, up to and circadian variation
(200-500~g 3-4 lomas dally) <20%
daJiy, inc, to • Minimal (or no) adverse
Steps2end3 400-75OI-'g effects from medication
Moderate asthma daily,t +.
• > 1-2 exacerbationsiweek n9Cessary)b t
• Activity and sleep affected or
• Noctumal symptoms • Sodium
(> 21monlh) cromoglycate
N B:Once sustained
• Almost daily need for or nedocromil
Inhaled 1l2-agonist control achieved , a
~ Control not achieveo' step-down reduction in
• PEFR or FEV, 60-80% ot
• Inhaled • Sustained release • Short-acting therapy may be carefully
predicted values and
ParTlcutarly corticosteroid theophyll,ne inhaled jl2-agonlst considered (to identity
variability 20-30%
for nocturnal (800-1oool-'g or (pm. up to 3-4 minimum Iherapy required
symptoms darly)b • Oral jl2-agonist Umes daily) to maintain control)
+ or
1+
I • long-acting inhaled
1l2-agomst (esp. tor
I nocturnal symptoms)"
J.. Control nol achieved
• Inhaled • Sustained release • Oral corticosterOid • Short-acting
Step 4 Best possible results
corticosteroid theophylline (alternate day or Inhaled
Severe asthma • leasl symptoms
(800-1oool'g andlor single daoly dose) ll2-agonist
• Frequent exacerbations • least need tor
daily)b • Oraljl2-agonist (pm, up to
• Continuous symploms inhaled Ilz-agonlst
or 3-4 times
• Frequent nocturnal • least limitation of
+ • long-acting inhaled
+1 daily)
symptoms activities
I
1+,
jl2-agonist (esp.
• Activities timited • Best PEFR with least
tor nocturnal symptoms) .
• PEFR Or FEV, < 60% of corcadian variation
with or withoul I
predicted values and ill Least adverse effects
• Short-acting inhaled , I t1
variability> 30""- I
trom medication
!lz-agonist once daily" I
~to
c Adis Ime rnational Ud
~
Flg_ 1. Treatment protocol illustrating a stepwise approach to the management of chronic asthma (after International Concensus Report on the Diagnosis and Management of
""
'--
Asthma 1992); a , one or more features may be present - assign patient to most severe grade in which any feature is present; b, inhaled corticosteroid dose refers to
---.....v.
'0
beclomethasone dipropionate; C, consider inhaled anticholinergic (e.g. iprotropium bromide). Abbreviations: FEV 1 = forced expiratory volume in I second; PEFR = peak
~
expiratory flow rate; pm =as required; inc =increase.
Clinical Pharmacology of Asthma
In more severe cases of asthma, and in patients
who do not respond fully to prophylactic medica-
tion, the dosage of inhaled corticosteroids should
be increased until control is obtained. Break-
through symptoms at night are an important indi-
cation of inadequate maintenance treatment and
should be regarded as an indication for an increase
in prophylactic medication and not simply as an
indication for long-acting bronchodilators. Never-
theless, long-acting bronchodilators are useful ad-
ditions to the therapeutic regimen in patients
whose nocturnal symptoms persist despite high
dosages of prophylactic medication.
The inhaled long-acting· bronchodilators (sal-
meterol and formoterol) represent an important ad-
vance in controlling nocturnal symptoms without
systemic adverse effects, but oral long-acting bron-
chodilators (slow release preparations of salbut-
amol and terbutaline, or the long-acting ~-agonist
bambuterol) remain useful second line agents.
Slow release xanthines are a useful alternative to
these long-acting ~2-agonists, although achieving
a therapeutic concentration without toxicity can be
more difficult.
3.3 Treatment of Deteriorating Asthma
Once they recognise a deterioration in their con-
dition, patients should increase their inhaled corti-
costeroids without delay. In many instances this
may be sufficient to abort an attack. If the exacer-
bation continues, a short course of oral pred-
nisolone or prednisone will be required (30 mg/day
for 5 to 7 days) together with increased use ofbron-
chodilator medication as required. With such short
courses of prednisolone, it is not necessary to re-
duce the dosage gradually (adrenocortical suppres-
sion does not occur with courses of less than 14
days). If airway obstruction responds poorly to
conventional inhaled bronchodilators, nebulised
bronchodilators may be helpful in avoiding the
need for hospital admission.
Antibiotics are not usually appropriate, but are
indicated if the sputum is green or brown, indicat-
ing probable bacterial infection. If deterioration
continues or there is failure to improve on standard
857
therapy, referral to hospital is appropriate for inten-
sive monitoring and treatment. Detailed guidelines
for assessment and management of asthma in the
acute sector have been published (British Thoracic
Society 1990b).
3.4 Structured Management Plans
Over the past 5 years, several organisations
have issued guidelines to assist physicians in a log-
ical choice of medication (British Thoracic Society
1990a, 1993; International Consensus Report
1992; Thoracic Society of Australia and New Zea-
land 1989). The central philosophy of all manage-
ment plans is to define each patient's optimum lung
function, to adjust maintenance treatment in a
structured strategic plan, and to devise a per-
sonalised written management plan that allows the
patient to adjust their medication to deal with ex-
acerbations and deteriorations.
The strategic plan guides the physician or spe-
cialist nurse in decisions on long term maintenance
treatment, based on objective measurements of dis-
ease activity, and provides structured guidelines
for increasing or adding medication. In addition,
the plans offer guidance on stepping down medi-
cation once control has been achieved, so that the
minimum maintenance medication can be defined
and long term adverse effects kept as infrequent as
possible. A treatment algorithm based on a struc-
tured plan for the management of chronic asthma
(International Consensus Report 1992) is illus-
trated in figure 1.
These structured plans have gained ready accep-
tance with hospital specialists and general practi-
tioners and have undoubtedly led to a more logical
approach to the management and treatment of pa-
tients with asthma. Benefits in terms of reducing
mortality from asthma have not yet materialised,
but it is perhaps too early to expect to see any such
effect.
Day-to-day management of asthma is devolved
to the patient by providing them with a means of
monitoring lung function (peak flow meter) and
written advice on the actions to be taken if their
lung function deteriorates by a given degree. One
858
important benefit of the structured management
plan is the sense of control over their disease that
many patients with asthma now feel. The existence
of international guidelines has also made it easier
for patients to obtain courses of oral corticosteroids
to keep at home and use when their asthma deteri-
orates rather than having to wait for an appoint-
ment with their physician.
Three areas of concern have been raised in rela-
tion to asthma self-management plans. The first
and most important of these is the increased use of
inhaled corticosteroids in the paediatric age group.
In the majority of cases, this is a good result from
the adoption of the structured guidelines in that
prior to the development of management plans
many children with asthma went undiagnosed or
undertreated. However, the widespread use of po-
tent corticosteroids has raised questions about the
effects of systemic absorption on bone growth. In-
deed, there is clear evidence that inhaled cortico-
steroids do reduce long bone growth in children, at
least over the short term (Graff-Lonnevig 1993;
Wolthers & Pedersen 1991, 1993). The degree of
growth suppression observed in these short term
studies cannot be extrapolated to long term treat-
ment, and previous long term experience of inhaled
corticosteroids suggests that while that growth
may be retarded or temporarily suspended, final
height will be achieved with minimal influence
from inhaled corticosteroids.
It must also be recognised that chronic untreated
asthma has an adverse effect on stature. If potent
inhaled corticosteroids are needed to control
asthma, it is likely that using these drugs will lead
to a better quality of life and greater final stature
than not using them and leaving asthma to run un-
checked (Balfour 1985; Boner & Piacentini 1993).
In this respect, the newly developed inhaled corti-
costeroid fluticasone appears to be a notable ad-
vance in that it is not significantly absorbed from
the gastrointestinal tract and has less influence than
beclomethasone on short-term growth rates (Wol-
ther & Pedersen 1993).
The second area of concern is the 'medicalisa-
tion' of patients who previously were managing
Drugs 46 (5) 1993
perfectly well without a self-management plan. It
is clear that some patients prefer to cope with their
asthma by ignoring it and do not want to be re-
minded that they have a chronic disease by having
to complete peak flow records every day and mon-
itor their disease. At the same time, self-assessment
without objective measures of lung function is un-
satisfactory as patients often fail to recognise per-
sistent airflow limitation and undertreat them-
selves (Tschopp & Turner 1984). Clearly, the
psychological impact of a self-management plan is
an important component of its general accept-
ability. If a patient has very mild asthma and re-
quires only occasional ~2-agonists it seems reason-
able to allow some flexibility in adherence to the
self-management plan. It is, nevertheless, useful
for these patients to have a peak flow meter so that
they can monitor themselves during exacerbations
and make recordings prior to clinic attendance so
that an objective assessment oftheir disease sever-
ity can be made.
Finally, there is a small but significant group of
patients in whom exacerbations can occur with ra-
pidity and little warning ('brittle asthma'). These
patients may be perfectly stable over a period of
weeks and then suddenly develop catastrophic
bronchospasm. Regular peak flow monitoring is
not able to detect the onset of exacerbation in suf-
ficient time for standard interventions to be effec-
tive and prevent hospital admission. Such patients
are usually well known to the local hospital re-
spiratory service and require frequent hospital ad-
mission to assess and control their exacerbations.
Having recognised such a patient, a written man-
agement plan and a peak flow meter are still useful
tools in managing their asthma, but it is unlikely
that the standard management plan will be appro-
priate to their particular needs (British Thoracic
Society 1993).
The main purpose behind structured manage-
ment plans is to effect an improvement in the mor-
bidity and mortality associated with asthma. While
this is an entirely worthy aim, it is vital that this
hope is translated into practice. Over the next few
years the impact of management plans on morbid-
Clinical Pharmacology of Asthma
ity and mortality will need to be assessed formally
and, where appropriate, adjustments may need to
be made to existing recommendations.
4. Conclusions
Considerable progress has been made over the
past 10 years in defining the changes in the cellular
and molecular biology of the bronchial mucosa
that occur during asthma. This progress has led to
an increasing recognition of the importance of anti-
inflammatory treatment in the control of asthma.
Dosages of anti-inflammatory drugs should be ad-
justed stepwise to achieve control and establish the
minimum level of maintenance therapy.
Bronchodilator treatment is now generally pre-
scribed as required rather than on a regular basis.
This stems from the realisation that f32-adrenergic
agonists do not control inflammation and may have
adverse effects on asthma morbidity and mortality.
The development of international and regional
guidelines has facilitated the translation of these
changes from specialist clinics into general medi-
cal practice. The development of self-management
plans has encouraged physicians to empower their
patients by allowing them discretion in adjusting
their medication according to their spirometric per-
formance. It is important that these major changes
in the management of asthma are properly evalu-
ated so that benefits are maximised and risk-bene-
fit ratios optimised.
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Southampton, Faculty of Medicine, University Medicine, Level
0, Centre Block, Tremona Road, Southampton S09 4XY,
England.