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

Cushing’s disease) and an ectopic source of ACTH. After two baseline
blood samples are obtained 15 minutes apart, CRH (1μg/kg) is
administered intravenously over a 30- to 60-second interval, and
peripheral blood samples are obtained at 15, 30, and 60 minutes for
ACTH measurement. It is important that the blood samples be handled
as recommended for the ACTH assay. At the recommended
dose, CRH generally is well tolerated, although flushing may occur,
particularly if the dose is administered as a bolus. Patients with
Cushing’s disease respond to CRH with either a normal or an exaggerated
increase in ACTH, whereas ACTH levels generally do not
increase in patients with ectopic sources of ACTH. This test is not
perfect: ACTH levels are induced by CRH in occasional patients
with ectopic ACTH, and ~5-10% of patients with Cushing’s disease
fail to respond.
To improve the diagnostic accuracy of the CRH stimulation
test, many authorities advocate sampling of blood from the inferior
petrosal sinuses and the peripheral circulation after peripheral
administration of CRH. In this test, an inferior petrosal/peripheral
ratio of >2.5 supports a pituitary source of ACTH. When performed
by a skilled neuroradiologist, this procedure increases diagnostic
accuracy with a tolerable risk of complications from the catheterization
procedure (Arnaldi et al., 2003).
Absorption and Fate. ACTH is readily absorbed from parenteral sites.
The hormone rapidly disappears from the circulation after intravenous
administration; in humans, the t 1/2
in plasma is ~15 minutes,
primarily due to rapid enzymatic hydrolysis.
Toxicity of ACTH. Aside from rare hypersensitivity reactions, the toxicity
of ACTH is primarily attributable to the increased secretion of
corticosteroids. Cosyntropin generally is less antigenic than native
ACTH; thus, cosyntropin is the preferred agent for clinical use.
ADRENOCORTICAL STEROIDS
The adrenal cortex synthesizes two classes of steroids:
the corticosteroids (glucocorticoids and mineralocorticoids),
which have 21 carbon atoms, and the androgens,
which have 19 carbons (Figure 41–3). The actions of corticosteroids
historically were described as glucocorticoid
(reflecting their carbohydrate metabolism–regulating
activity) and mineralocorticoid (reflecting their electrolyte
balance–regulating activity). In humans, cortisol
(hydrocortisone) is the main glucocorticoid and aldosterone
is the main mineralocorticoid. Table 42–1 shows
typical rates of secretion of cortisol and aldosterone, as
well as their normal circulating concentrations.
Although the adrenal cortex is an important source of androgen
precursors in women, patients with adrenal insufficiency can be
restored to normal life expectancy by replacement therapy with glucocorticoids
and mineralocorticoids. Adrenal androgens are not
essential for survival. The levels of dehydroepiandrosterone (DHEA)
and its sulfated derivative DHEA-S peak in the third decade of life
and decline progressively thereafter. Moreover, patients with a number
of chronic diseases have very low DHEA levels, leading some to
propose that DHEA treatment might at least partly alleviate the loss
Table 42–1
Normal Daily Production Rates and Circulating
Levels of the Predominant Corticosteroids
CORTISOL ALDOSTERONE
Rate of secretion 10 mg/day 0.125 mg/day
under optimal
conditions
Concentration in
peripheral
plasma:
8 A.M. 16 μg/100 mL 0.01 μg/100 mL
4 A.M. 4 μg/100 mL 0.01 μg/100 mL
of libido, the decline in cognitive function, the decreased sense of
well-being, and other adverse physiological consequences of aging.
Whereas some studies have shown that addition of DHEA to the
standard replacement regimen in women with adrenal insufficiency
improved subjective well-being and sexuality, others have failed to
show any benefit of DHEA replacement in either men or women
(Chang et al., 2008). Nevertheless, DHEA is widely used as an overthe-counter
nutritional supplement for its alleged health benefits,
despite the absence of definitive data.
Physiological Functions and
Pharmacological Effects
Physiological Actions. Corticosteroids have numerous
and widespread effects, which include alterations in
carbohydrate, protein, and lipid metabolism; maintenance
of fluid and electrolyte balance; and preservation
of normal function of the cardiovascular system, the
immune system, the kidney, skeletal muscle, the
endocrine system, and the nervous system. In addition,
corticosteroids endow the organism with the capacity
to resist such stressful circumstances as noxious stimuli
and environmental changes. In the absence of the
adrenal cortex, survival is made possible only by
maintaining an optimal environment, including adequate
and regular feeding, ingestion of relatively large
amounts of sodium chloride, and maintenance of an
appropriate environmental temperature; stresses such
as infection, trauma, and extremes in temperature in this
setting can be life threatening.
Traditionally, the effects of administered corticosteroids have
been viewed as physiological (reflecting actions of corticosteroids at
doses corresponding to normal daily production levels) or pharmacological
(representing effects seen only at doses exceeding the normal
daily production of corticosteroids). More recent concepts
suggest that the anti-inflammatory and immunosuppressive actions
1215
CHAPTER 42
ACTH, ADRENAL STEROIDS, AND PHARMACOLOGY OF THE ADRENAL CORTEX