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Adrenocorticosteroids & Adrenocortical Antagonists (■…
Adrenocorticosteroids & Adrenocortical Antagonists
■ ADRENOCORTICOSTEROIDS
THE NATURALLY OCCURRING GLUCOCORTICOIDS; CORTISOL (HYDROCORTISONE)
Pharmacokinetics
FIGURE 39–2
(CBG), an α2 globulin by liver, binds
90
% of circulating; remainder
free
(5–10%) or loosely bound to
albumin
(5%);
half-life
of cortisol in circulation:
60–90 minutes
Only
1
% of cortisol excreted
unchanged in urine
as free cortisol;
20
% converted to
cortisone
by
11-hydroxysteroid dehydrogenase in kidney
and other tissues with mineralocorticoid receptors before reaching liver. Most cortisol metabolized in liver
Pharmacodynamics
A. Mechanism of Action
FIGURE 39–4
glucocorticoids bind mineralocorticoid receptors. mineralocorticoid effect of higher levels of cortisol is avoided in some tissues (eg, kidney, colon, salivary glands) by expression of 11β-hydroxysteroid dehydrogenase type 2, enzyme responsible for biotransformation to its 11-keto derivative (
cortisone), which has minimal action on aldosterone receptors
B. Physiologic Effects
permissive effects
: w/o which many normal functions become deficient. ex: response of vascular and bronchial smooth muscle to catecholamines diminished in absence of cortisol; lipolytic responses of fat cells to catecholamines, ACTH, and growth hormone are attenuated in absence of glucocorticoids.
C. Metabolic Effects
stimulate + required for gluconeogenesis and
glycogen synthesis
in fasting state--> incr serum glc-->
stimulate insulin release but inhibit uptake of glc by muscle
cells, while they
stimulate hormone-sensitive lipase
and thus lipolysis; incr insulin secretion stimulates lipogenesis and to a lesser degree inhibits lipolysis--> net
incr in fat deposition combined with incr release of FAs and glycerol
into circulation
D. Catabolic and Antianabolic Effects: stimulate RNA and pr
synth
in
liver
, they have
catabolic
and antianabolic effects in
lymphoid and connective tissue, muscle, peripheral fat, and skin
-->
decr muscle mass and weakness and thinning of skin
.
osteoporosis
in Cushing’s syndrome; In children, glucocorticoids reduce growth
E. Anti-Inflammatory and Immunosuppressive Effects
peripheral leukocytes extravasation + infiltration into affected tissue inhibited;
neutrophils
in circulation
incr
(bc incr influx into blood from bone marrow + decr migration from blood vessels) while
lymphocytes (T and B cells), monocytes, eosinophils, and basophils decr
(bc their movement from vascular bed to lymphoid tissue)
inhibit functions of tissue MQs + other APCs-->
less interleukin 12 and interferon-γ, important inducers of Th1 cell activity
, and cellular immunity
inhibiting phospholipase A2 + reduce expression of COX-2
vasoconstriction
when applied directly to
skin
, possibly by
suppressing mast cell degranulation
; also decr capillary permeability by
reducing amount of histamine
released by basophils and mast cells
complement
activation unaltered, but its
effects are inhibited
.
Ab
production
reduced
F. Other Effects
antagonize effect of vitamin D on calcium absorption.
development of
peptic ulcer
, possibly by suppressing local immune response against Helicobacter pylori
often produce behavioral disturbances in humans: initially insomnia and euphoria and subsequently depression
incr
number of
platelets
and
RBCs
structural and functional changes in lungs near term, including the production of pulmonary surface-active material required for air breathing (surfactant), stimulated
SYNTHETIC CORTICOSTEROIDS
TABLE 39–1
MINERALOCORTICOIDS
ALDOSTERONE
DEOXYCORTICOSTERONE
FLUDROCORTISONE
ADRENAL ANDROGENS
CLINICAL PHARMACOLOGY
B. Corticosteroids and Stimulation of Lung Maturation in the Fetus
C. Corticosteroids and Nonadrenal Disorders
TABLE 39–2
A. Diagnosis and Treatment of Disturbed Adrenal Function
Adrenocortical hypo- and hyperfunction
b. Cushing’s [syndrome]
c. Primary generalized glucocorticoid resistance
(Chrousos syndrome)
a.
CAH
cause
most common defect is a decr in or lack of P450c21
(
21α-hydroxylase
) activity--> adrenal becomes hyperplastic--> abnormally large amounts of precursors such as
17-hydroxyprogesterone
--> diverted to
androgen
pathway-->
virilization
+
ambiguous genitalia in female fetus
defect in
11-hydroxylation
--> large amounts of
deoxycorticosterone
(mineralocorticoid activity)-->
HTN w/ or w/o hypokalemic alkalosis
ensues.
17-hydroxylation defective
in adrenals and gonads-->
hypogonadism
also present. However, incr amounts of 11-deoxycorticosterone formed-->
HTN + hypokalemia
also observed
treatment:
hydrocortisone
d. Aldosteronism
Use of glucocorticoids for diagnostic purposes
Adrenocortical insufficiency
a. Chronic (Addison’s disease):
hydrocortisone
daily, incr during periods of stress. Although hydrocortisone has some mineralocorticoid activity, this must be supplemented by an appropriate amount of a
salt-retaining hormone
such as
fludrocortisone
b. Acute: large amounts of parenteral
hydrocortisone
■ ANTAGONISTS OF ADRENOCORTICAL AGENTS
SYNTHESIS INHIBITORS & GLUCOCORTICOID ANTAGONISTS
Trilostane
a 3β-17 hydroxysteroid dehydrogenase inhibitor (gonadal and adrenal)
Etomidate
for induction of general anesthesia and sedation
At subhypnotic doses of 0.1 mg/kg per hour inhibits adrenal steroidogenesis at the level of 11β-hydroxylase
Abiraterone
It blocks 17α-hydroxylase
treatment of
refractory prostate cancer
Ketoconazole
potent and rather nonselective inhibitor of adrenal and
gonadal steroid synthesis (inhibit 17 and 11 alpha hydroxylase)
Mifepristone
(RU-486)
a
glucocorticoid R antagonist
; a
progesterone antagonist
Cushing’s
Aminoglutethimide
blocks conversion of cholesterol to pregnenolone
used w/
dexamethasone or hydrocortisone
to reduce or
eliminate estrogen production in carcinoma of breast
used w/
metyrapone or ketoconazole
to
reduce steroid secretion in Cushing’s syndrome due to adrenocortical cancer
who do not respond to mitotane
Mitotane
nonselective cytotoxic action on the adrenal cortex
adrenal carcinoma
Metyrapone
only adrenal-inhibiting medication administered to
pregnant women with Cushing’s syndrome.
selective inhibitor of steroid 11-hydroxylation
MINERALOCORTICOID ANTAGONISTS
Eplerenone: somewhat more selective than spironolactone and has
no
reported effects on
androgen receptors
Drospirenone
Spironolactone
competes w/ dihydrotestosterone for androgen Rs in target tissues; reduces 17α-hydroxylase activity (lowering plasma levels of testosterone and androstenedione); dosages of 50–200 mg/d in treatment of
hirsutism
and acne