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

Coombs test) are treated with prednisone (1 mg/kg per day). In the
setting of severe hemolysis, higher doses may be used, with tapering
as the anemia improves. Small maintenance doses may be
required for several months in patients who respond.
Organ Transplantation. In organ transplantation, high doses of prednisone
(50-100 mg) are given at the time of transplant surgery, in
conjunction with other immunosuppressive agents, and most patients
are kept on a maintenance regimen that includes lower doses of glucocorticoids
(Chapter 35). For some solid organ transplants (e.g.,
pancreas), protocols that either withdraw corticosteroids early after
transplantation or that avoid them completely are becoming more
common (Meier-Kriesche et al., 2006).
Spinal Cord Injury. A meta-analysis of several randomized, controlled
trials (Bracken, 2002) demonstrated significant decreases
in neurological defects in patients with acute spinal cord injury
treated within 8 hours of injury with large doses of methylprednisolone
sodium succinate (30 mg/kg initially followed by an
infusion of 5.4 mg/kg per hour for 23 hours). One trial showed
further improvement with an additional 24 hours of treatment.
The ability of corticosteroids at these high doses to decrease neurological
injury may reflect inhibition of free radical–mediated
cellular injury, as occurs following ischemia and reperfusion.
Potential side effects include increased susceptibility to infection
and other wound complications.
Diagnostic Applications of Adrenocortical Steroids
In addition to its therapeutic uses, dexamethasone is used as a firstline
agent to diagnose hypercortisolism and to differentiate among
the different causes of Cushing’s syndrome (Arnaldi et al., 2003).
To determine if patients with clinical manifestations suggestive
of hypercortisolism have biochemical evidence of increased cortisol
biosynthesis, an overnight dexamethasone suppression test has
been devised. Patients are given 1 mg of dexamethasone orally at 11
P.M., and cortisol is measured at 8 A.M. the following morning.
Suppression of plasma cortisol to <1.8 μg/dL suggests strongly that
the patient does not have Cushing’s syndrome. Drugs such as barbiturates
that enhance dexamethasone metabolism or drugs (estrogens)
or conditions (pregnancy) that increase the concentrations of corticosteroid
binding globulin can interfere with suppression and compromise
the test. The formal dexamethasone suppression test is used
in the differential diagnosis of biochemically documented Cushing’s
syndrome. Following determination of baseline cortisol levels for 48
hours, dexamethasone (0.5 mg every 6 hours) is administered orally
for 48 hours. This dose markedly suppresses cortisol levels in normal
subjects, including those who have nonspecific elevations of
cortisol due to obesity or stress, but it does not suppress levels in
patients with Cushing’s syndrome. In the high-dose phase of the test,
dexamethasone is administered orally at 2 mg every 6 hours for
48 hours. Patients with pituitary-dependent Cushing’s syndrome
(i.e., Cushing’s disease) generally respond with decreased cortisol
levels. In contrast, patients with ectopic production of ACTH or with
adrenocortical tumors generally do not exhibit decreased cortisol
levels. Despite these generalities, dexamethasone may suppress cortisol
levels in some patients with ectopic ACTH production, particularly
with tumors such as bronchial carcinoids, and many experts
prefer to use inferior petrosal sinus sampling after CRH administration
to make this distinction.
INHIBITORS OF THE BIOSYNTHESIS
AND ACTION OF ADRENOCORTICAL
STEROIDS
Hypercortisolism with its attendant morbidity and mortality
is most frequently caused by corticotroph adenomas
that overproduce ACTH (Cushing’s disease) or by
adrenocortical tumors or bilateral hyperplasias that
overproduce cortisol (Cushing’s syndrome). Less frequently,
hypercortisolism may result from adrenocortical
carcinomas or ectopic ACTH- or CRH-producing
tumors. Although surgery is the treatment of choice, it
is not always effective, and adjuvant therapy with
inhibitors of steroidogenesis becomes necessary (Biller
et al., 2008). In these settings, ketoconazole,
metyrapone, etomidate, and mitotane are clinically useful.
Ketoconazole, etomidate, and mitotane are discussed
in more detail in other chapters. All of these
agents pose the common risk of precipitating acute
adrenal insufficiency; thus, they must be used in appropriate
doses, and the status of the patient’s HPA axis
must be carefully monitored. Agents that act as glucocorticoid
receptor antagonists (antiglucocorticoids) are
discussed later in this chapter; mineralocorticoid antagonists
are discussed in Chapter 25.
Ketoconazole. Ketoconazole (NIZORAL) is an antifungal agent, and
this remains its most important clinical role (Chapter 57). In doses
higher than those employed in antifungal therapy, it is an effective
inhibitor of adrenal and gonadal steroidogenesis, primarily because
of its inhibition of the activity of CYP17 (17α-hydroxylase). At even
higher doses, ketoconazole also inhibits CYP11A1, effectively
blocking steroidogenesis in all primary steroidogenic tissues.
Ketoconazole is the best tolerated and most effective inhibitor of
steroid hormone biosynthesis in patients with hypercortisolism. In
most cases, a dosage regimen of 600-800 mg/day (in two divided
doses) is required, and some patients may require up to 1200 mg/day
given in two to three doses. Side effects include hepatic dysfunction,
which ranges from asymptomatic elevations of transaminase levels
to severe hepatic injury. The potential of ketoconazole to interact
with CYP isoforms can lead to drug interactions of serious consequence
(Chapter 6). Further studies are needed to define the precise
role of ketoconazole in the medical management of patients with
excessive steroid hormonal production, and the FDA has not
approved this indication for ketoconazole use.
Metyrapone. Metyrapone (METOPIRONE) is a relatively selective inhibitor
of CYP11B1 (11β-hydroxylase), which converts 11-deoxycortisol
to cortisol in the terminal reaction of the glucocorticoid biosynthetic
pathway. Because of this inhibition, the biosynthesis of cortisol is
markedly impaired, and the levels of steroid precursors (e.g., 11-
deoxycortisol) are markedly increased. Although the biosynthesis of
aldosterone also is impaired, the elevated levels of 11-deoxycortisol
sustain mineralocorticoid-dependent functions. In a diagnostic test of
the entire HPA axis, metyrapone (30 mg/kg, maximum dose of 3 g)
is administered orally with a snack at midnight, and plasma cortisol
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CHAPTER 42
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX