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

1234 and 11-deoxycortisol are measured at 8 A.M. the next morning.
A plasma cortisol <8 μg/dL validates adequate inhibition of
CYP11B1; in this setting, an 11-deoxycortisol level <7 μg/dL is
highly suggestive of impaired hypothalamic-pituitary-adrenal function.
An abnormal response does not identify the site of the defect;
hypothalamic CRH release, ACTH production, or adrenal biosynthetic
capacity could be impaired. Some authorities avoid overnight
metyrapone testing in outpatients thought to have a reasonable probability
of impaired HPA function because there is some risk of precipitating
acute adrenal insufficiency. Others believe that the ability
to assess the entire HPA axis with a relatively easy test justifies the
use of metyrapone testing in outpatients.
Metyrapone also is used to diagnose patients with Cushing’s
syndrome who respond equivocally to the formal dexamethasone suppression
test. Those with pituitary-dependent Cushing’s syndrome
exhibit a normal response, whereas those patients with ectopic secretion
of ACTH exhibit no changes in ACTH or 11-deoxycortisol levels.
Therapeutically, metyrapone has been used to treat the hypercorticism
resulting from either adrenal neoplasms or tumors producing
ACTH ectopically. Maximal suppression of steroidogenesis
requires doses of 4 g/day. More frequently, metyrapone is used as
adjunctive therapy in patients who have received pituitary irradiation
or in combination with other agents that inhibit steroidogenesis.
In this setting, a dose of 500-750 mg three or four times daily is
employed. The use of metyrapone in the treatment of Cushing’s syndrome
secondary to pituitary hypersecretion of ACTH is more controversial.
Chronic administration of metyrapone can cause
hirsutism, which results from increased synthesis of adrenal androgens
upstream from the enzymatic block, and hypertension, which
results from elevated levels of 11-deoxycortisol. Other side effects
include nausea, headache, sedation, and rash.
Etomidate. Etomidate (AMIDATE), a substituted imidazole used primarily
as an anaesthetic agent and sedative, inhibits cortisol secretion
at subhypnotic doses primarily by inhibiting CYP11B1 activity. It
is administered intravenously and has been used off-label to treat
hypercortisolism when rapid control is required in a patient who cannot
take medication by the oral route. An international consensus
panel recommends that etomidate be administered as a bolus of
0.03 mg/kg intravenously, followed by an infusion of 0.1 mg/kg per
hour to a maximum of 0.3 mg/kg per hour (Biller et al., 2008).
Mitotane. Mitotane (o,p’-DDD; LYSODREN) is an adrenocorticolytic
agent used to treat inoperable adrenocortical carcinoma. Its cytolytic
action is due to its metabolic conversion to a reactive acyl chloride
by adrenal mitochondrial CYPs and subsequent reactivity with cellular
proteins. In a few centers, it has been used for long-term control
of hypercortisolism. Doses range from 0.5-3 g administered
three times daily. Its onset of action takes weeks to months, and GI
disturbances and ataxia are its major toxicities.
SECTION V
HORMONES AND HORMONE ANTAGONISTS
Aminoglutethimide. Aminoglutethimide (α-ethyl-p-aminophenylglutarimide;
CYTADREN) primarily inhibits CYP11A1, which catalyzes
the initial and rate-limiting step in the biosynthesis of all physiological
steroids and also inhibits CYP11B1 and CYP19 (aromatase). As a result,
the production of all classes of steroid hormones is impaired. Although
used at one time to treat hypercortisolism and advanced cancer of the
breast and prostate, aminoglutethimide recently has been withdrawn
from the market by the manufacturer and is no longer available.
Trilostane. Trilostane (4α,5α,17β)-4-5-epoxy-3,17-dihydroxyandrost-
2-ene-2-carbonitrile), a competitive inhibitor of the type II 3βhydroxysteroid
dehydrogenase (Figure 42–3), also interferes with
the synthesis of both adrenal and gonadal hormones, but it is more
effective in dogs than in humans. For this reason, trilostane is not
used in humans but still has a place in veterinary medicine.
ANTIGLUCOCORTICOIDS
The progesterone receptor antagonist mifepristone (MIFEPREX; RU-486;
11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-
dien-3-one) has received considerable attention because of its use as
an antiprogestogen that can terminate early pregnancy (Chapter 66).
At higher doses, mifepristone also inhibits the GR, blocking feedback
regulation of the HPA axis and secondarily increasing endogenous
ACTH and cortisol levels. Because of its ability to inhibit
glucocorticoid action, mifepristone also has been studied as a potential
therapeutic agent in a small number of patients with hypercortisolism
(Johanssen and Allolio, 2007). Currently, its use for this
purpose is considered investigational and is restricted to patients with
inoperable causes of cortisol excess that have not responded to other
agents.
CLINICAL SUMMARY
Glucocorticoids are administered in multiple formulations
(e.g., oral, parenteral, and topical) for disorders that
share an inflammatory or immunological basis. Except in
patients receiving replacement therapy for adrenal insufficiency,
glucocorticoids are neither specific nor curative,
but rather are palliative because of their anti-inflammatory
and immunosuppressive actions. 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. After therapy is initiated, the minimal dose
needed 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) is unlikely to cause harm in the absence of specific
contraindications. As the duration of glucocorticoid
therapy increases beyond 1 week, adverse effects
increase in a time- and dose-related manner. Abrupt cessation
of glucocorticoids after prolonged therapy is associated
with the risk of adrenal insufficiency due to
suppression of the HPA axis, and it may be fatal.
BIBLIOGRAPHY
Allolio B, Arlt W. DHEA treatment: Myth or reality? Trends
Endocrinol Metab, 2002, 341:288–294.
Arnaldi G, Angeli A, Atkinson AB, et al. Diagnosis and complications
of Cushing’s syndrome: A consensus statement. J Clin
Endocrinol Metab, 2003, 88:5593–5602.