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

Studies with other forms of renal disease, such as membranous
and membranoproliferative glomerulonephritis and focal sclerosis,
have provided conflicting data on the role of glucocorticoids.
In clinical practice, patients with these disorders often are given a
therapeutic trial of glucocorticoids with careful monitoring of laboratory
indices of response. In the case of membranous glomerulonephritis,
many nephrologists recommend a trial of alternate-day
glucocorticoids for 8-10 weeks (e.g., prednisone, 120 mg every other
day), followed by a 1- to 2-month period of tapering.
Allergic Disease. The onset of action of glucocorticoids in allergic
diseases is delayed, and patients with severe allergic reactions such
as anaphylaxis require immediate therapy with epinephrine. The
manifestations of allergic diseases of limited duration—such as hay
fever, serum sickness, urticaria, contact dermatitis, drug reactions,
bee stings, and angioneurotic edema—can be suppressed by adequate
doses of glucocorticoids given as supplements to the primary
therapy. In severe disease, intravenous glucocorticoids (methylprednisolone,
125 mg intravenously every 6 hours, or equivalent) are
appropriate. In less severe disease, antihistamines are the drugs of
first choice. In allergic rhinitis, intranasal steroids are now viewed as
the drug of choice by many experts.
Bronchial Asthma and Other Pulmonary Conditions. Corticosteroids
frequently are used in bronchial asthma (Chapter 36). Although they
sometimes are employed in chronic obstructive pulmonary disease
(COPD), particularly when there is some evidence of reversible
obstructive disease, data supporting the efficacy of corticosteroids
are much less convincing than for bronchial asthma. The increased
use of corticosteroids in asthma reflects an increased appreciation
of the role of inflammation in the immunopathogenesis of this disorder.
In severe asthma attacks requiring hospitalization, treatment
with high-dose parenteral glucocorticoids is essential. Symptomatic
relief sometimes is very rapid; however, the onset of a maintained
response may take up to 6-12 hours. Intravenous administration of
60-120 mg methylprednisolone (or equivalent) every 6 hours is used
initially, followed by daily oral doses of prednisone (30-60 mg) as the
acute attack resolves. The dose then is tapered gradually, with withdrawal
planned for 10 days to 2 weeks after initiation of steroid therapy.
In general, patients subsequently can be managed on their prior
medical regimen.
Less severe acute exacerbations of asthma (as well as acute
flares of COPD) often are treated with brief courses of oral glucocorticoids.
In adult patients, 30-60 mg prednisone is administered daily
for 5 days; an additional week of therapy at lower doses also may be
required. Upon resolution of the acute exacerbation, the glucocorticoids
generally can be rapidly tapered without significant deleterious
effects. Any suppression of adrenal function usually dissipates within
1-2 weeks. In the treatment of severe chronic bronchial asthma (or,
less frequently, COPD) that is not controlled by other measures, the
long-term administration of glucocorticoids may be necessary. As
with other long-term uses of these agents, the lowest effective dose
is used, and care must be exercised when withdrawal is attempted.
Given the risks of long-term treatment with glucocorticoids, it is
especially important to document objective evidence of a response
(e.g., an improvement in pulmonary function tests). In addition, these
risks dictate that long-term glucocorticoid therapy be reserved for
those patients who have failed to respond to adequate regimens of
other medications (Chapter 36).
In many patients, inhaled steroids (see Table 42–4) can either
reduce the need for oral corticosteroids or replace them entirely.
Many physicians prefer inhaled glucocorticoids over previously recommended
oral theophylline in the treatment of children with moderately
severe asthma, in part because of the behavioral toxicity
associated with chronic theophylline administration. The oral
bioavailability of inhaled corticosteroids varies considerably; however,
when used as recommended, inhaled glucocorticoids are effective
in reducing bronchial hyperreactivity and are less likely to
suppress adrenal function than are the oral glucocorticoids.
Dysphonia or oropharyngeal candidiasis may develop, but the incidence
of such side effects can be reduced substantially by maneuvers
that reduce drug deposition in the oral cavity, such as spacers and
mouth rinsing or by using corticosteroids with low oral bioavailability.
For example, ciclesonide (ALVESCO, OMNARIS) and beclomethasone
dipropionate (BECONASE AQ, QVAR), are inactive compounds that are
activated on site by lung esterases; therefore they are less likely to
adversely affect the oral cavity (Derendorf et al., 2006). The status
of glucocorticoids in asthma therapy is discussed in Chapter 36.
Antenatal glucocorticoids are used frequently in the setting of
premature labor, decreasing the incidence of respiratory distress syndrome,
intraventricular hemorrhage, and death in infants delivered prematurely.
Betamethasone (12 mg intramuscularly every 24 hours for
two doses) or dexamethasone (6 mg intramuscularly every 12 hours for
four doses) is administered to women with definitive signs of premature
labor between 26 and 34 weeks of gestation (Roberts and Dalziel,
2006). Due to evidence of decreased birthweight and adrenal suppression
in infants whose mothers were given repeated courses of glucocorticoids,
only a single course of glucocorticoids should be administered.
Infectious Diseases. Although the use of immunosuppressive glucocorticoids
in infectious diseases may seem paradoxical, there are a
limited number of settings in which they are indicated in the therapy
of specific infectious pathogens. One dramatic example of such beneficial
effects is seen in AIDS patients with Pneumocystis carinii
pneumonia and moderate to severe hypoxia; addition of glucocorticoids
to the antibiotic regimen increases oxygenation and lowers the
incidence of respiratory failure and mortality. Similarly, glucocorticoids
clearly decrease the incidence of long-term neurological
impairment associated with Haemophilus influenzae type b meningitis
in infants and children ≥2 months of age.
A long-standing controversy in medicine is the use of glucocorticoids
in septic shock (Sprung et al., 2008). Supraphysiological
doses of glucocorticoids had been used routinely as adjunctive therapy
in subjects with septic shock associated with gram-negative bacteremia
until it was recognized that glucocorticoid therapy in
supraphysiologic doses actually increased mortality. Subsequent
studies then examined the benefit of somewhat lower doses of glucocorticoids
(e.g., 100 mg hydrocortisone every 8 hours) administered
to patients early in the course of their disease. In one
multicenter randomized placebo-controlled trial, beneficial effects
of hydrocortisone plus fludrocortisone were seen only in subjects
with adrenal insufficiency as determined by the rapid cosyntropin
stimulation test. Although a second large study using hydrocortisone
alone failed to demonstrate a beneficial effect regardless of adrenal
status, current guidelines suggest that hydrocortisone be used in adult
patients with septic shock whose blood pressure fails to respond
adequately to fluids and vasopressors (Dellinger et al., 2008).
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CHAPTER 42
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX