Delivering inhaled corticosteroids to patients
BMJ 1999; 318 doi: https://doi.org/10.1136/bmj.318.7181.410 (Published 13 February 1999) Cite this as: BMJ 1999;318:410
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EDITOR - In their recent editorial, O’Callaghan et al highlight several
important points regarding inhaled corticosteroid use.1 We agree the type
of device used to deliver the corticosteroid may significantly alter the
respirable dose. Use of a large volume spacer confers several advantages,
including reducing the risk of oral candidiasis by reducing oropharyngeal
deposition and obviating coordination problems using pressurised metered
dose (pMDI) inhalers alone. Nevertheless, we wish to clarify two
important statements made by the authors.
Firstly, it is incorrect to state that spacer use with a pressurised-
metered dose inhaler (pMDI) does not affect the dose delivered to the
airway. In vitro impactor data with budesonide using an anatomical child
throat has shown the 750ml Nebuhaler™ plastic spacer to produce an
increase in the respirable fraction (as % of nominal dose ex-valve) from
8% to 27%, and from 20% to 40% using an adult anatomical throat. 2 In vivo
charcoal block pharmacokinetic work by Thorsson et al in healthy adults
demonstrated pulmonary bioavailability was increased from 18% to 36% with
use of a large volume spacer with budesonide pMDI. 3
Secondly, O’Callaghan and Barry imply that spacer use is associated
with a reduction in hypothalamo-pituitary-adrenal suppression. This may
be the case for beclomethasone, due to its low degree of hepatic first-
pass for the swallowed fraction (60-70%), but should not be extrapolated
to other corticosteroids such as budesonide (90% first-pass) or
fluticasone (99% first-pass). Systemic bioactivity is determined by the
sum of oral and lung bioavailability. For corticosteroids with a high
degree of hepatic first-pass, total bioavailability is determined
primarily by lung absorption 4. Therefore, the two-fold greater lung
delivery afforded by spacer use will translate into a similar increase in
systemic bioactivity and potential for adverse systemic effects. For
example, Toogood et al showed that adding a large volume spacer to
budesonide pMDI produced a two fold increase in the potency ratio for anti
-asthmatic efficacy which was mirrored by a similar increase in the
potency ratio for systemic bioactivity. 5 Furthermore, we have also
recently found that adrenal suppression with fluticasone pMDI is increased
by two-fold when used in conjunction with a large volume spacer
(unpublished data). This highlights that the use of a spacer may
represent a two-edged sword in terms of determining the overall
therapeutic ratio.
Dr Owen. J. Dempsey,
Clinical research fellow,
e-mail : o.dempsey@dundee.ac.uk,
tel : 01382 660111 ext 33452
Dr Andrew M Wilson,
Clinical lecturer,
e-mail : a.m.wilson@dundee.ac.uk,
tel :01382 660111 ext 32587
Prof Brian J Lipworth,
Professor of Allergy & Respiratory Medicine,
e-mail : b.j.lipworth@dundee.ac.uk,
tel : 01382 632983 (direct)
REFERENCES
1. O’Callaghan C, Barry P. Delivering inhaled corticosteroids to
patients BMJ 1999;318:410-411.
2. Berg E. In vitro properties of pressurized metered dose inhalers with
and without spacer devices. J Aerosol Med 1995;8 (Suppl 3):3-11.
3. Thorsson L, Edsbacker S. Lung deposition of budesonide from a
pressurized metered-dose inhaler attached to a spacer. Eur Respir J
1998;12:1340-1345.
4. Lipworth BJ. Pharnacokinetics of inhaled drugs. Br J Clin Pharm
1996;42:697-705.
5. Toogood JH, Baskerville J, Jennings B, Lefcoe NM, Johansson S.. Use of
spacers to facilitate inhaled corticosteroid treatment of asthma. Am Rev
Respir Dis 1984;129:723-729.
Competing interests: No competing interests
Systemic side effects of inhaled corticosteroids
EDITOR - A recent editorial considered the clinical importance of
systemic side effects from inhaled corticosteroids.1 The authors drew
attention to the difficulty in assessing data from clinical trials in
which the inhaled dose is highly dependent on the specific delivery
device(s) used and may bear little resemblance to the prescribed dose. We
concur with the central tenet of the article but would like to point out
that even an estimation of the "dose to the lung" does not directly equate
to systemic steroid exposure.
Systemic exposure to corticosteroids will be the product of the dose
absorbed from the lung plus the dose swallowed and absorbed from the
gastrointestinal tract (following deposition in the oropharynx and
clearance of drug from the lung by the mucociliary escalator). Drug
absorption from both oral and pulmonary sites of absorption will depend on
the amount of drug delivered from the device, but will then be subject to
a number of further factors which will complicate any approximation of
systemic exposure. For example, we recently found that fluticasone
absorption is affected by the extent of the mucus layer in vitro. Our
unpublished data show that fluticasone is well absorbed across in vitro
models of the intestinal and airway epithelium, but that the absorption
rate is reduced by 25-35% compared to control by a two-fold increase in
mucus secretion.
Measurement of drugs in plasma following inhalation often poses
difficulties because of low concentrations. Systemic exposure following
inhalation is inherently variable and although the delivery device will be
a major determinant, the contribution of other factors should not be
underestimated. Other factors include the particle size distribution of
the aerosol, regional aerosol deposition, the physicochemical properties
of the drug, formulation excipients, mucus secretion, mucociliary
clearance and presystemic drug metabolism. In turn these factors will be
determined by variables such as the pharmaceutics of the aerosol,
respiratory physiology and disease, environmental pollution and infection.
In conclusion, side effect profiles cannot be reliably interpreted without
accurate measurement of systemic corticosteroid exposure.
Ben Forbes Lecturer in pharmaceutics
Nageen Hashmi Research student
Gary Martin Reader in pharmaceutics
Department of Pharmacy
King's College London
Manresa Road
London SW3 6LX
1. O'Callaghan C, Barry P. Delivering inhaled corticosteroids to
patients: if side effects are so important, why are we so ignorant of the
dose inhaled? BMJ 1999;318:410-1 (13 February).
Competing interests: No competing interests