- ACTH use
- probably not appropriate
as a therapeutic agent unless androgen
increase is desired
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- Corticosteroid dosage forms:
- ophthalmic -- eye disease
- intra-articular -- joint
disease
- hydrocortisone enemas--
ulcertive colitis
- aerosols (e.g.beclomethasone)
-- asthma
- nasal spray (beclomethasone,
triamcinolone, flunisolide) -- allergic
rhinitis
- ointments, creams --
dermatological applications
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- Mineralocorticoids (Aldosterone,
Desoxycorticosterone, Fludrocortisone)
- Most important
mineralocorticoid: aldosterone
- secondarily:
desoxycorticosterone (DOC)
- Most commonly prescribed
salt-retaining hormone: fludrocortisone
- Aldosterone:
- synthesized
in zona glomerulosa of the
adrenal cortex
- regulation
-- ACTH, angiotensin
- promotes
sodium reabsorption by distal
renal tubule (loosely coupled to
potassium and hydrogen on and
secretion)
- Excessive
aldosterone-- (secondary to tumor/overdosage):
- hypernatremia
- hypokalemia
- metabolic
alkalosis
- hypertension
- increased
plasma volume
- Mechanism
of Action:
- mineralocorticoid
binding to cytoplasmic
receptor (e.g.renal
collecting tubule
principal cells)
- subsequent
steps similar to those
described for
glucocorticoids
- Desoxycorticosterone (DOC)
- precursor
to aldosterone
- secretion
of DOC controlled by ACTH
- DOC
secretion enhanced in abnormal
conditions e.g.:
- adrenal
carcinoma
- congenital
adrenal hyperplasia (with
reduced P450c11or
P450c17)
- Fludrocortisone (Florinef)
- most
widely used mineralocorticoid
- glucocorticoid
and mineralocorticoid activity
- used in
management of adrenocortical
insufficiency
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- Adrenal
Androgens
- Large amounts of
dehydroepiandrosterone (DHEA) secreted;
smaller amounts of androstenedione and
testosterone secreted
- probably contribute to
normal maturation processes
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Antagonists of Adrenocortical Agents
- Synthesis Inhibitors and Glucocorticoid
Antagonists:
- Metyrapone:
- selective
inhibitor of steroid synthesis
(inhibiting 11-hydroxylation
which interferes with cortisol
and corticosterone synthesis)
- produces dizziness
and gastrointestinal disturbance
- not widely used
for Cushing's syndrome
- reduces cortisol
production to normal in some
patients with:
- adrenal
tumor
- ectopic
ACTH syndromes
- hyperplasia
- may be useful in
management of severe effects of
cortisol excess on a temporary
basis
- Major adverse
effects:
- salt and
water retention
- hirsuitism
- most commonly used
in adrenal function tests
- Aminoglutethimide:
- blocks
cholesterol to pregnenolone
conversion
- reduces
synthesis of all hormonally
active steroids
- used
together with dexamethasone
(Decadron) or hydrocortisone
(Cortef, Solu-Cortef) to
eliminate estrogen and androgen
production in patients with
breast carcinoma
- used with
ketoconazole (Nizoral) to reduce
steroid secretion impatience with
Cushing's syndrome (due to
adrenocortical cancer -- not
responding to mitotane)
- Ketoconazole: (Nizoral)
- antifungal
imidazole derivative: potent,
nonselective adrenal and gonadal
steroid synthesis inhibitor
- inhibition
of P450 enzymes induces a
compensatory increase in ACTH
production and increases in
progesterone, aldosterone and
suppression of plasma renin
activity
- occasionally
causes gynecomastia by increasing
estradiol/testosterone plasma
ratio
- use for
treating patients with Cushing's
disease
- Mifepristone (RU-486)
- synthetic, partial
agonist steroid
- binds to
glucocorticoid and progesterone
receptors
- treatment of
Cushing's syndrome (experimental)
- Mitotane--
toxicities resulted in drug withdrawal
from U.S. market
- interferes with
biosynthetic pathways in human
adrenal cortex
- Trilostane-- similar to
aminoglutethimide;3ß-17
hydroxysteroid dehydrogenase inhibitor
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- Mineralocorticoid Antagonists:
- Spironolactone: (Aldactone)
- used in
treating primary aldosteronism
- diagnostic
use
- management
of symptoms while patient awaits
adenoma surgical removal
- reating
hirsuitism in women
- Adverse effects:
- hyperkalemia
- menstrual
abnormalities
- gynecomastia
- sedation
- headache
- gastrointestinal
disturbances
- skin
rashes
- Drospirenone-- progestin;
antagonizes aldosterone effects
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