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

1050 Routes of Administration and Dosing
SECTION IV
INFLAMMATION, IMMUNOMODULATION, AND HEMATOPOIESIS
Inhaled Corticosteroids in Asthma. Inhaled corticosteroids are recommended
as first-line therapy for all patients with persistent asthma.
They should be started in any patient who needs to use a 2
agonist
inhaler for symptom control more than twice weekly. They are effective
in mild, moderate, and severe asthma and in children as well as
adults (Barnes et al., 1998b). Although it was recommended that ICS
be initiated at a relatively high dose and then the dose reduced once
control was achieved, there is no evidence that this is more effective
than starting with the maintenance dose. Dose-response studies for
ICS are relatively flat, with most of the benefit derived from doses
<400 g beclomethasone dipropionate or equivalent (Adams et al.,
2008). However, some patients (with relative corticosteroid resistance)
may benefit from higher doses (up to 2000 μg/day).
For most patients, ICS should be used twice daily, a regimen
that improves compliance once control of asthma has been achieved
(which may require four-times daily dosing initially or a course of
oral steroids if symptoms are severe). Administration once daily of
some steroids (e.g., budesonide, mometasone, and ciclesonide) is
effective when doses ≤400 g are needed. If a dose >800 μg daily via
pMDI is used, a spacer device should be employed to reduce the risk
of oropharyngeal side effects. ICS may be used in children in the
same way as in adults; at doses ≤400 μg/day there is no evidence of
significant growth suppression (Pedersen, 2001). The dose of ICS
should be the minimal dose that controls asthma; once control is
achieved, the dose should be slowly reduced (Hawkins et al., 2003).
Nebulized corticosteroids (e.g., budesonide) are useful in the treatment
of small children who are not able to use other inhaler devices.
Inhaled Corticosteroids in Chronic Obstructive Pulmonary
Disease. Patients with COPD occasionally respond to steroids, and
these patients are likely to have concomitant asthma. Corticosteroids
have no objective short-term benefit on airway function in patients
with true COPD, although these agents often produce subjective benefit
because of their euphoric effect. Corticosteroids do not appear to
have any significant anti-inflammatory effect in COPD; there
appears to be an active resistance mechanism, which may be
explained by impaired activity of HDAC2 as a result of oxidative
stress (Barnes, 2009). ICS have no effect on the progression of
COPD, even when given to patients with presymptomatic disease;
additionally, ICS have no effect on mortality (Calverley et al., 2007;
Yang et al., 2007). ICS reduce the number of exacerbations in
patients with severe COPD (FEV 1
<50% predicted) who have frequent
exacerbations and are recommended in these patients,
although there is debate about whether these effects are due to inappropriate
analysis of the data (Suissa et al., 2008). Oral corticosteroids
are used to treat acute exacerbations of COPD, but the effect
is very small (Niewoehner et al., 1999).
Patients with cystic fibrosis, which involves inflammation of
the airways, are also resistant to high doses of ICS.
Systemic Steroids. Intravenous steroids are indicated in acute
asthma if lung function is <30% predicted and in patients who show
no significant improvement with nebulized 2
agonist. Hydrocortisone
is the steroid of choice because it has the most rapid onset (5-6 hours
after administration), compared with 8 hours with prednisolone. The
required dose is uncertain; it is common to give hydrocortisone
4 mg/kg initially, followed by a maintenance dose of 3 mg/kg every
6 hours. Methylprednisolone is also available for intravenous use,
but there is no evidence that the high doses previously used (1 g) are
more effective. Intravenous therapy is usually given until a
satisfactory response is obtained, and then oral prednisolone may be
substituted. Oral prednisolone (40-60 mg) has a similar effect to
intravenous hydrocortisone and is easier to administer. A high dose
of inhaled fluticasone propionate (2000 g daily) is as effective as
a course of oral prednisolone in controlling acute exacerbations of
asthma in a family practice setting and in children in an emergency
department setting, although this route of delivery is more expensive
(Levy et al., 1996; Manjra et al., 2000).
Prednisolone and prednisone are the most commonly used
oral steroids. Clinical improvement with oral steroids may take
several days; the maximal beneficial effect is usually achieved with
30-40 mg prednisone daily, although a few patients may need 60-80 mg
daily to achieve control of symptoms. The usual maintenance dose
is ~10-15 mg/day. Short courses of oral steroids (30-40 mg prednisolone
daily for 1-2 weeks) are indicated for exacerbations of
asthma; the dose may be tapered over 1 week after the exacerbation
is resolved (the taper is not strictly necessary after a short course of
therapy, but patients find it reassuring). Oral steroids are usually
given as a single dose in the morning because this coincides with
the normal diurnal increase in plasma cortisol and produces less
adrenal suppression than if given in divided doses or at night.
Alternate-day treatment has the advantage of less adrenal suppression,
although in many patients control of asthma is not optimal on
this regimen.
Adverse Effects. Corticosteroids inhibit ACTH and cortisol secretion
by a negative feedback effect on the pituitary gland (Chapter 42).
Hypothalamic-pituitary-adrenal (HPA) axis suppression depends on
dose and usually only occurs with doses of prednisone >7.5-10 mg/day.
Significant suppression after short courses of corticosteroid therapy
is not usually a problem, but prolonged suppression may occur after
several months or years. Steroid doses after prolonged oral therapy
must be reduced slowly. Symptoms of “steroid withdrawal syndrome”
include lassitude, musculoskeletal pains, and, occasionally,
fever. HPA suppression with inhaled steroids is usually seen only
when the daily inhaled dose exceeds 2000 μg beclomethasone dipropionate
or its equivalent daily.
Side effects of long-term oral corticosteroid therapy include
fluid retention, increased appetite, weight gain, osteoporosis, capillary
fragility, hypertension, peptic ulceration, diabetes, cataracts, and
psychosis. Their frequency tends to increase with age. Very occasionally
adverse reactions (such as anaphylaxis) to intravenous
hydrocortisone have been described, particularly in aspirin-sensitive
asthmatic patients.
The incidence of systemic side effects after ICS is an important
consideration, particularly in children (Barnes et al., 1998b)
(Table 36–4). Initial studies suggested that adrenal suppression
occurred only with inhaled doses >1500-2000 μg/day. More sensitive
measurements of systemic effects include indices of bone metabolism,
such as serum osteocalcin and urinary pyridinium cross-links,
and in children, knemometry, which may be increased with inhaled
doses as low as 400 μg/day beclomethasone dipropionate in some
patients. The clinical relevance of these measurements is not yet
clear, however. Nevertheless, it is important to reduce the likelihood
of systemic effects by using the lowest dose of inhaled steroid