ADRENOCORTICOSTEROIDS

& ADRENOCORTICAL
ANTAGONISTS
Sukit Roongapinun, MD
Department of Pharmacology
Chiang Mai University

www.esnips.com/user/drsukit
 ADRENOCORTICOSTEROIDS
 Glucocorticoids: cortisol
 Mineralocorticoid: aldosterone
 adrenal androgen: DHEA
adrenocortical hormone
biosynthesis
 CORTISOL
(HYDROCORTISONE)
 peak in the early morning
hours and after meals

 Don’t forget a negative feedback

ACTH --- Cortisol
MECHANISM OF ACTION
• Bind to intracellular receptor
• heat shock proteins (Hsp)
• Dissociate from Hsp before
translocating into the nucleus

coactivators
coactivators
corepressors
corepressors

glucocorticoid forms complexes

receptor with transcription
elements factors, such as
AP1 and NF-kB
(GRE)

Between 10% and 20% of expressed genes in a

cell are regulated by glucocorticoids.
 genes for the human
glucocorticoid receptor
• hGR alpha - is the FUNCTIONAL one!

• hGR beta - inhibit hGR alpha

 PHYSIOLOGIC EFFECTS
glucocorticoids
• CHO: gluconeogenesis and glycogen synthesis
– increase serum glucose levels
– stimulate insulin release --> lipogenesis --> fat deposition & more FA to release.
• Catabolic effect - decreased muscle mass, osteoporosis
• Anti-inflammatory effect & Immunosuppressive effect
– Neutrophil increased in blood pool
– Lymphocyte, monocyte, eosinophils : decreased
– inhibit the functions of macrophages and other antigen-presenting cells.
– Inh phospholipase A2 --> reduction in prostaglandin
– Downregulate cyclooxygenase-2
– vasoconstriction & low capillary permeability
– Decrease Antibody production
• insomnia and euphoria and subsequently depression. pseudotumor cerebri
• development of peptic ulcer
• fat redistribution
• antagonize the effect of vitamin D
• increase the number of platelets and red blood cells.
• development of the fetal lungs (surfactant)
 SYNTHETIC
CORTICOSTEROIDS

Equivalent Oral
Salt-Retaining
Inflammatory

Dose (mg)
Anti-
Hydrocortisone (cortisol) 1 1 20
Cortisone 0.8 0.8 25
Prednisone 4 0.3 5
Prednisolone 5 0.3 5
Methylprednisolone 5 0 4
 SYNTHETIC
CORTICOSTEROIDS 2

Equivalent Oral
Salt-Retaining
Inflammatory

Dose (mg)
Anti-
Triamcinolone 5 0 4
Betamethasone 25–40 0 0.6
Dexamethasone 30 0 0.75
 Indication of use & related
diseases
• Adrenocortical insufficiency
• Addison's disease : autoimmune destruction of adrenal gland
• Congenital adrenal hyperplasia: some enzyme deficiency  no
glucocorticoid & mineralocorticoid available
• Cushing's disease: ACTH-secreting pituitary adenoma (Rx by
surgery)
• Aldosteronism from adrenal adenoma (rx by spironolactone)
• Dexamethasone suppression test
• Stimulation of lung maturation in the fetus (Lung maturation in
the fetus is regulated by the fetal secretion of cortisol.)
Dexamethasone suppression test

• dexamethasone, 1 mg, is given orally at 11

PM, and a plasma sample is obtained the

• following morning. In normal individuals, the

morning cortisol concentration is usually less
than 3 mcg/dL

• Cushing's syndrome : the level is usually

greater than 5 mcg/dL.
Indications of corticosteroids
(cont.)
Indications of corticosteroids
(cont.)
 Cautions
• Before long-term use (> 2 weeks),
• : obtain chest x-rays and a tuberculin te
st, since glucocorticoid therapy can reac
tivate dormant disease.
• diabetes, peptic ulcer, osteoporosis, an
d psychologic disturbances
 Toxicity
• In the face, rounding, puffiness, fat
deposition, and plethora usually appear
(moon facies).
• Similarly, fat tends to be redistributed from
the extremities to the trunk, the back of the
neck, and the supraclavicular fossae.
TRUNCAL OBESITY
• There is an increased growth of fine hair over
the face, thighs and trunk.
 Toxicity 2
• acne insomnia and increased appetite
• breakdown of protein
– muscle wasting;
– thinning of the skin, with striae and bruising
• hyperglycemia;
• Wound healing is also impaired
• Systemic bacterial and mycotic infections,
• cataracts.
• hydrocortisone has mineralocorticoid effects
 ADRENAL SUPPRESSION
• If more than 2 weeks of use
• If stop immediately, adrenal gland sleeps so long will
not easily wake up.
• What to do?
– should be tapered slowly.
– minor stress (twofold dose increases for 24–48 hours)
– severe stress (up to tenfold dose increases for 48–72 hours)

• In the suppression, cortisol levels may not return to n

ormal for 6–9 months.
 Other hormones by adrenal
glands
• MINERALOCORTICOIDS
– ALDOSTERONE, DEOXYCORTICOSTERONE
– FLUDROCORTISONE synthetic

• ADRENAL ANDROGENS
– DHEA
– This is not a major androgen for puberty
 ANTAGONISTS OF ADRENOC
ORTICAL AGENTS
• Metyrapone is a selective inhibitor of 11-hydroxylation, so, cortisol and
corticosterone synthesis.
• Aminoglutethimide blocks the conversion of cholesterol to pregnenolo
ne FOR BREAST CANCER (no more hormone)
• Ketoconazole inhibits the cholesterol side chain cleavage, P450c17, C
17,20-lyase, 3 -hydroxysteroid dehydrogenase, and P450c11 enzymes
required for steroid hormone synthesis.
• Mifepristone (RU 486) exert antiglucocorticoid activity by preventing
the dissociation of Hsp
• Trilostane is a 3 -17 hydroxysteroid dehydrogenase inhibitor (compara
ble to aminoglutethimide.)

• MINERALOCORTICOID ANTAGONISTS
– Spironolactone, Eplerenone, Drospirenone,
•
adrenocortical hormone
biosynthesis