DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 36–4
Side Effects of Inhaled Corticosteroids
Local side effects
Dysphonia
Oropharyngeal candidiasis
Cough
Systemic side effects
Adrenal suppression and insufficiency
Growth suppression
Bruising
Osteoporosis
Cataracts
Glaucoma
Metabolic abnormalities (glucose, insulin, triglycerides)
Psychiatric disturbances (euphoria, depression)
Pneumonia
needed to control the asthma, and by use of a large-volume spacer to
reduce oropharyngeal deposition.
Several systemic effects of inhaled steroids have been
described and include dermal thinning and skin capillary fragility
(relatively common in elderly patients after high-dose inhaled
steroids). Other side effects, such as cataract formation and osteoporosis,
are reported but often in patients who are also receiving
courses of oral steroids. There has been particular concern about the
use of inhaled steroids in children because of growth suppression
(Pedersen, 2001). Most studies have been reassuring that doses ≤400
μg/day have not been associated with impaired growth; on the
contrary, there may even be a growth spurt as asthma is better controlled.
There is some evidence that use of high-dose ICS is associated
with cataract and glaucoma, but it is difficult to dissociate the
effects of ICS from the effects of courses of oral steroids that these
patients usually require.
ICS may have local side effects due to the deposition of inhaled
steroid in the oropharynx. The most common problem is hoarseness
and weakness of the voice (dysphonia) due to atrophy of the vocal cords
following laryngeal deposition of steroid; it may occur in up to 40% of
patients and is noticed particularly by patients who need to use their
voices during their work (lecturers, teachers, and singers). Throat
irritation and coughing after inhalation are common with MDI and
appear to be due to additives because these problems are not usually
seen if the patient switches to a DPI. There is no evidence for atrophy
of the lining of the airway. Oropharyngeal candidiasis occurs in ~5%
of patients. There is no evidence for increased lung infections, including
tuberculosis, in patients with asthma. Growing evidence suggests
that high doses of ICS increase the risk of pneumonia in patients with
COPD (Singh et al., 2009); although this is reported with high doses of
fluticasone propionate, a similar increase in pneumonia has not been
found with budesonide, which may be explained by its lower systemic
effects (Sin et al., 2009).
It may be difficult to extrapolate systemic side effects of corticosteroids
using data from normal subjects. In asthmatic patients,
systemic absorption form the lung is reduced, presumably because
of reduced and more central deposition of the inhaled drug in more
severe patients (Brutsche et al., 2000; Harrison et al., 2001); most of
the inhaled drug deposits in larger airways, thereby limiting effects
in the smaller airways where inflammation is also found, especially
in patients with severe asthma. Corticosteroid MDIs with HFA propellants
produce smaller aerosol particles and may have a more
peripheral deposition, making them useful in treating patients with
more severe asthma.
Therapeutic Choices. Numerous ICS are now available
including beclomethasone dipropionate (QVAR), triamcinolone,
flunisolide (AEROBID), budesonide (PULMICORT,
others), fluticasone hemihydrate (AEROSPAN), fluticasone propionate
(FLOVENT), mometasone furoate (ASMANEX), and
ciclesonide (ALVESCO). All are equally effective as antiasthma
drugs, but there are differences in their pharmacokinetics:
Budesonide, fluticasone, mometasone, and
ciclesonide have a lower oral bioavailability than
beclomethasone dipropionate because they are subject
to greater first-pass hepatic metabolism; this results in
reduced systemic absorption from the fraction of the
inhaled drug that is swallowed (Derendorf et al., 2006)
and thus reduced adverse effects. At high doses (>1000 μg),
budesonide and fluticasone propionate have less systemic
effects than beclomethasone dipropionate and triamcinolone,
and they are preferred in patients who need
high doses of ICS and in children. Ciclesonide is
another choice; it is a prodrug that is converted to the
active metabolite by esterases in the lung, giving it a
low oral bioavailability and a high therapeutic index
(Manning et al., 2008).
When doses of inhaled steroid exceed 800 μg
beclomethasone dipropionate or equivalent daily, a
large volume spacer is recommended to reduce oropharyngeal
deposition and systemic absorption in the case
of beclomethasone dipropionate. All currently available
ICS are absorbed from the lung into the systemic circulation,
so that some systemic absorption is inevitable.
However, the amount of drug absorbed does not appear
to have clinical effects in doses of <800 g beclomethasone
dipropionate equivalent. Although there are
potency differences among corticosteroids, there are
relatively few comparative studies, partly because dose
comparison of corticosteroids is difficult due to their
long time course of action and the relative flatness of
their dose-response curves. Triamcinolone and flunisolide
appear to be the least potent, with beclomethasone
dipropionate and budesonide approximately of
equal potency; fluticasone propionate is approximately
twice as potent as beclomethasone dipropionate.
Future Developments. Early treatment with ICS in both
adults and children may give a greater improvement in
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CHAPTER 36
PULMONARY PHARMACOLOGY