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

Cataracts. Cataracts are a well-established complication of glucocorticoid
therapy and related to dosage and duration of therapy.
Children appear to be particularly at risk. Cessation of therapy may
not lead to complete resolution of opacities, and the cataracts may
progress despite reduction or cessation of therapy. Patients on
long-term glucocorticoid therapy at doses of prednisone of
≥10-15 mg/day should receive periodic slit-lamp examinations to
detect glucocorticoid-induced posterior subcapsular cataracts.
Osteoporosis. Osteoporosis, a frequent serious complication of glucocorticoid
therapy, occurs in patients of all ages and is related to dosage
and duration of therapy (Woolf, 2007). A reasonable estimate is that
30-50% of all patients who receive chronic glucocorticoid therapy
ultimately will develop osteoporotic fractures. Glucocorticoids preferentially
affect trabecular bone and the cortical rim of the vertebral
bodies; the ribs and vertebrae are the most frequent sites of fracture.
Glucocorticoids decrease bone density by multiple mechanisms,
including inhibition of gonadal steroid hormones, diminished gastrointestinal
absorption of Ca 2+ , and inhibition of bone formation due
to suppressive effects on osteoblasts and stimulation of resorption by
osteoclasts via changes in the production of osteoprotegerin and
RANK ligand. In addition, glucocorticoid inhibition of intestinal Ca 2+
uptake may lead to secondary increases in parathyroid hormone,
thereby increasing bone resorption.
The considerable morbidity of glucocorticoid-related osteoporosis
has led to efforts to identify patients at risk for fractures and
to prevent or reverse bone loss in patients requiring chronic glucocorticoid
therapy. The initiation of glucocorticoid therapy—that is,
≥5 mg/day prednisone (or its equivalent) for ≥3 months—is considered
an indication for bone densitometry to detect abnormalities in
trabecular bone. Because bone loss associated with glucocorticoids
predominantly occurs within the first 6 months of therapy,
densitometric evaluation, preferably with techniques such as dualenergy
x-ray absorptiometry of the lumbar spine and hip, along with
prophylactic measures should be initiated with therapy or shortly
thereafter. Most authorities advocate maintaining a Ca 2+ intake of
1500 mg/day by diet plus Ca 2+ supplementation and vitamin D intake
of 800 IU/day, assuming that these measures do not increase urinary
calcium excretion above the normal range. Although gonadal hormone
replacement therapy has been widely used in specific groups
of patients receiving chronic glucocorticoid therapy, this is the subject
of considerable debate based on recently published results from
randomized placebo-controlled trials (Chapter 40). Recombinant
parathyroid hormone 1-34 (teriparatide, FORTEO) also has received
considerable attention as a potential therapy of glucocorticoidinduced
osteoporosis.
The most important advance to date in the prevention of
glucocorticoid-related osteoporosis is the successful use of bisphosphonates,
which have been shown to decrease the decline in bone
density and the incidence of fractures in patients receiving glucocorticoid
therapy. Additional discussion of these issues is found in
Chapters 40 and 44.
Osteonecrosis. Osteonecrosis (also known as avascular or aseptic
necrosis) is a relatively common complication of glucocorticoid therapy.
The femoral head is affected most frequently, but this process
also may affect the humeral head and distal femur. Joint pain and
stiffness usually are the earliest symptoms, and this diagnosis should
be considered in patients receiving glucocorticoids who abruptly
develop hip, shoulder, or knee pain. Although the risk increases with
the duration and dose of glucocorticoid therapy, osteonecrosis also
can occur when high doses of glucocorticoids are given for short
periods of time. Osteonecrosis generally progresses, and most
affected patients ultimately require joint replacement.
Regulation of Growth and Development. Growth retardation in children
can result from administration of relatively small doses of glucocorticoids.
Although the precise mechanism is unknown, there are
reports that collagen synthesis and linear growth in these children
can be restored by treatment with growth hormone; further studies
are needed to define the role of concurrent treatment with growth
hormone in this setting. Further studies also are needed to explore the
possible effects of exposure to corticosteroids in utero. In experimental
animals, antenatal exposure to glucocorticoids is clearly
linked to cleft palate and altered neuronal development, ultimately
resulting in complex behavioral abnormalities. Thus, although the
actions of glucocorticoids to promote cellular differentiation play
important physiological roles in human development in late gestation
and in the neonatal period (e.g., production of pulmonary surfactant
and induction of hepatic gluconeogenic enzymes), the possibility
remains that antenatal steroids can lead to subtle abnormalities in
fetal development.
Therapeutic Uses
With the exception of replacement therapy in deficiency
states, the use of glucocorticoids largely is empirical.
Based on extensive clinical experience, a number of
therapeutic principles can be proposed. Given the number
and severity of potential side effects, the decision to
institute therapy with glucocorticoids always requires
a careful consideration of the relative risks and benefits
in each patient. For any disease and in any patient,
the appropriate dose to achieve a given therapeutic
effect must be determined by trial and error and must be
reevaluated periodically as the activity of the underlying
disease changes or as complications of therapy
arise. A single dose of glucocorticoid, even a large one,
is virtually without harmful effects, and a short course
of therapy (up to 1 week), in the absence of specific contraindications,
is unlikely to be harmful. As the duration
of glucocorticoid therapy is increased beyond 1 week,
there are time- and dose-related increases in the incidence
of disabling and potentially lethal effects. Except
in patients receiving replacement therapy, glucocorticoids
are neither specific nor curative; rather, they are
palliative by virtue of their anti-inflammatory and
immunosuppressive actions. Finally, abrupt cessation
of glucocorticoids after prolonged therapy is associated
with the risk of adrenal insufficiency, which may be
fatal.
These principles have several implications for
clinical practice. When glucocorticoids are to be given
over long periods, the dose must be determined by trial
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CHAPTER 42
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX