Page 725 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 39 Adrenocorticosteroids & Adrenocortical Antagonists 711

renal loss of potassium, which leads to hypokalemia, alkalosis, for cortisol or its metabolites (Liddle’s test); or dexamethasone is
and elevation of serum sodium concentrations. This syndrome given as a single dose of 8 mg at 11 pm, and the plasma cortisol
can also be produced in disorders of adrenal steroid biosynthesis is measured at 8 am the following day. In patients with Cushing’s
by excessive secretion of deoxycorticosterone, corticosterone, or disease, the suppressant effect of dexamethasone usually produces
18-hydroxycorticosterone—all compounds with inherent miner- a 50% reduction in hormone levels. In patients in whom suppres-
alocorticoid activity. sion does not occur, the ACTH level will be low in the presence of
In contrast to patients with secondary aldosteronism (see text that a cortisol-producing adrenal tumor and elevated in patients with
follows), these patients have low (suppressed) levels of plasma renin an ectopic ACTH-producing tumor.
activity and angiotensin II. When treated with fludrocortisone (0.2
mg twice daily orally for 3 days) or deoxycorticosterone acetate (20 B. Corticosteroids and Stimulation of Lung Maturation
mg/d intramuscularly for 3 days—but not available in the United in the Fetus
States), patients fail to retain sodium and the secretion of aldosterone Lung maturation in the fetus is regulated by the fetal secretion of
is not significantly reduced. When the disorder is mild, it may escape cortisol. Treatment of the mother with large doses of glucocorticoid
detection if serum potassium levels are used for screening. However, reduces the incidence of respiratory distress syndrome in infants
it may be detected by an increased ratio of plasma aldosterone to delivered prematurely. When delivery is anticipated before 34 weeks
renin. Patients generally improve when treated with spironolactone, of gestation, intramuscular betamethasone, 12 mg, followed by an
an aldosterone receptor-blocking agent, and the response to this agent additional dose of 12 mg 18–24 hours later, is commonly used. Beta-
is of diagnostic and therapeutic value.
methasone is chosen because maternal protein binding and placental
metabolism of this corticosteroid is less than that of cortisol, allowing
3. Use of glucocorticoids for diagnostic purposes—It is increased transfer across the placenta to the fetus. A study of more
sometimes necessary to suppress the production of ACTH to than 10,000 infants born at 23–25 weeks of gestation indicated that
identify the source of a particular hormone or to establish whether exposure to exogenous corticosteroids before birth reduced the death
its production is influenced by the secretion of ACTH. In these rate and evidence of neurodevelopmental impairment.
circumstances, it is advantageous to use a very potent substance
such as dexamethasone because the use of small quantities reduces
the possibility of confusion in the interpretation of hormone C. Corticosteroids and Nonadrenal Disorders
assays in blood or urine. For example, if complete suppression is The synthetic analogs of cortisol are useful in the treatment of
achieved by the use of 50 mg of cortisol, the urinary 17-hydroxy- a diverse group of diseases unrelated to any known disturbance
corticosteroids will be 15–18 mg/24 h, since one-third of the dose of adrenal function (Table 39–2). The usefulness of corticoste-
given will be recovered in urine as 17-hydroxycorticosteroid. If an roids in these disorders is a function of their ability to suppress
equivalent dose of 1.5 mg of dexamethasone is used, the urinary inflammatory and immune responses and to alter leukocyte
excretion will be only 0.5 mg/24 h and blood levels will be low. function, as previously described (see also Chapter 55). These
The dexamethasone suppression test is used for the diagnosis of agents are useful in disorders in which host response is the cause
Cushing’s syndrome and has also been used in the differential diag- of the major manifestations of the disease. In instances in which
nosis of depressive psychiatric states. As a screening test, 1 mg dexa- the inflammatory or immune response is important in control-
methasone is given orally at 11 pm, and a plasma sample is obtained ling the pathologic process, therapy with corticosteroids may be
the following morning. In normal individuals, the morning cortisol dangerous but justified to prevent irreparable damage from an
concentration is usually <3 mcg/dL, whereas in Cushing’s syndrome inflammatory response—if used in conjunction with specific
the level is usually >5 mcg/dL. The results are not reliable in the therapy for the disease process.
patient with depression, anxiety, concurrent illness, and other stress- Since corticosteroids are not usually curative, the pathologic
ful conditions or in the patient who is receiving a medication that process may progress while clinical manifestations are suppressed.
enhances the catabolism of dexamethasone in the liver. To distinguish Therefore, chronic therapy with these drugs should be undertaken
between hypercortisolism due to anxiety, depression, and alcoholism with great care and only when the seriousness of the disorder
(pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a warrants their use and when less hazardous measures have been
combined test is carried out, consisting of dexamethasone (0.5 mg exhausted.
orally every 6 hours for 2 days) followed by a standard corticotropin- In general, attempts should be made to bring the disease pro-
releasing hormone (CRH) test (1 mg/kg given as a bolus intravenous cess under control using medium- to intermediate-acting gluco-
infusion 2 hours after the last dose of dexamethasone). corticoids such as prednisone and prednisolone (Table 39–1), as
In patients in whom the diagnosis of Cushing’s syndrome has well as all ancillary measures possible to keep the dose low. Where
been established clinically and confirmed by a finding of elevated possible, alternate-day therapy should be used (see the following
free cortisol in the urine, suppression with large doses of dexa- text). Therapy should not be decreased or stopped abruptly. When
methasone will help to distinguish patients with Cushing’s disease prolonged therapy is anticipated, it is helpful to obtain chest
from those with steroid-producing tumors of the adrenal cortex x-rays and a tuberculin test, since glucocorticoid therapy can reac-
or with the ectopic ACTH syndrome. Dexamethasone is given in tivate dormant tuberculosis. The presence of diabetes, peptic ulcer,
a dosage of 0.5 mg orally every 6 hours for 2 days, followed by osteoporosis, and psychological disturbances should be taken into
2 mg orally every 6 hours for 2 days, and the urine is then assayed consideration, and cardiovascular function should be assessed.