PHARMACOLOGY

ADRENO- CORTICOSTEROIDS

Assist. Prof. Dr. Kamal Al- Yassiry

The adrenal gland consists of the cortex and the medulla. The medulla secretes epinephrine.
The adrenal cortex is divided into three zones that synthesize various steroids from
cholesterol and then secrete them.
1. The outer zona glomerulosa produces mineralocorticoids (for
example, aldosterone which regulated primarily by the renin-angiotensin
system and elevated K+ level), which are responsible for regulating salt and
water metabolism.
2. The middle zona fasciculata synthesizes glucocorticoids (for example,
cortisol), which are involved with normal metabolism and resistance to
stress.
3. The inner zona reticularis secretes adrenal androgens (for example,
dehydroepiandrosterone DHEA).
•The adrenocorticoids bind to specific intracellular
cytoplasmic receptors (superfamily of nuclear receptors,
which includes steroid, sterol (vitamin D), thyroid, and
retinoic acid) in target tissues.
• The glucocorticoid receptor is widely distributed
throughout the body, whereas the mineralocorticoid
receptor is confined mainly to excretory organs, such as
the kidney, colon, and salivary and sweat glands.
•This mechanism requires time to produce an effect but other glucocorticoid
effects, such as their interaction with catecholamines to mediate relaxation of
bronchial musculature or lipolysis, have effects that are immediate.
 Glucocorticoids
•Cortisol (also called hydrocortisone, compound F) is the
naturally occurring glucocorticoid.
•Its production is diurnal, with a peak early in the morning
followed by a decline and then a secondary, smaller peak in
the late afternoon.
•Stress and levels of the circulating steroid affect its secretion.
It synthesized from cholesterol. In the normal adult, in the
absence of stress, 10–20 mg of cortisol is secreted daily.
 The effects of cortisol:
1- Metabolic effects:
a.Glucocorticoids favor gluconeogenesis.
b.They stimulate protein catabolism (except in the liver) and lipolysis
(augmenting the action of growth hormone on adipocytes, causing an
increase in the activity of hormone-sensitive lipase) in certain parts of
the body and lipogenesis in others causing central obesity.
2- Increase resistance to stress:
By raising plasma glucose levels for energy and it can cause a modest
rise in blood pressure, apparently by enhancing the vasoconstrictor
action of adrenergic stimuli.
3- Effects on blood cells:
c. Decrease in eosinophils, basophils, monocytes, and lymphocytes.
d. Increase the blood levels of hemoglobin, erythrocytes, platelets, and
polymorphonuclear leukocytes
4- Anti-inflammatory action:
Inhibitionof phospholipase A2, effects on blood cell and
interference with mast cell degranulation results in decreased
histamine and capillary permeability.
5- Endocrine effect:
Feedback inhibition of corticotropin production by elevated
glucocorticoids causes inhibition of further synthesis of both
glucocorticoid and thyroid-stimulating hormones.
6- Others:
a.Adequate cortisol levels are essential for normal glomerular
filtration.
b.High doses of glucocorticoids stimulate gastric acid and pepsin
production and may exacerbate ulcers.
c.Influence mental status.
d.Chronic glucocorticoid therapy can cause severe bone loss and
myopathy.
 Mineralocorticoids
•Mineralocorticoids help to control the body’s water volume and
concentration of electrolytes, especially sodium and potassium by:
1.Aldosterone acts on kidney tubules and collecting ducts (also
occurs in gastrointestinal mucosa, sweat and salivary glands)
causing a re-absorption of sodium, bicarbonate, and water.
2.Decreases reabsorption of potassium, which, with H+, is then lost
in the urine.
3.Deoxycorticosterone (DOC), which also serves as a precursor of
aldosterone differs from that of aldosterone in that the secretion
of DOC is primarily under the control of ACTH.
4.Fludrocortisone is a potent steroid with both glucocorticoid and
mineralocorticoid activity
 Pharmacokinetics
1.Those that are administered orally are readily absorbed from the
gastrointestinal tract. Many of them can also be administered
intravenously, intramuscularly, intra-articularly, locally and topical
applications (creams, intranasal, inhalations, enemas).
2.More than 90 percent of the absorbed glucocorticoids are bound to
plasma protein (globulin-CBG).
3.CBG is increased in pregnancy, estrogen administration and in
hyperthyroidism. It is decreased by hypothyroidism, genetic defects
in synthesis, and protein deficiency states.
4.They are metabolized by the liver.
5.The only glucocorticoid that has no effect on the fetus in pregnancy
is prednisone.
 Therapeutic uses of the adrenal corticosteroids
1- Replacement therapy for primary adrenocortical
insufficiency (Addison disease):
Hydrocortisone is given in divided dose. Fludrocortisone
may also be necessary to raise the mineralocorticoid activity
to normal levels.
2- Replacement therapy for secondary or tertiary
adrenocortical insufficiency:
The defect either in CRH production by the hypothalamus or
in corticotropin production by the pituitary.
Hydrocortisone is used.
3- Diagnosis of Cushing syndrome:
The dexamethasone suppression test is used to diagnose
and differentiate the cause of Cushing syndrome in which
dexamethasone suppresses cortisol release in individuals with
pituitary-dependent Cushing syndrome, but it does not suppress
glucocorticoid release from adrenal tumors.
4- Replacement therapy for congenital adrenal hyperplasia.
5- Relief of inflammatory symptoms.
6-Treatment of allergies:
7- Acceleration of lung maturation in fetal respiratory distress
syndrome (dexamethasone is used).
 Adverse effects
The risk for adverse effects depended both on dose and duration of
therapy:
Osteoporosis is the most common adverse effect due to the ability
of glucocorticoids to suppress intestinal Ca2+ absorption, inhibit
bone formation, and decrease sex hormone synthesis.
Cushing-like syndrome, redistribution of body fat with trunkal
obesity, puffy face, increased body hair growth, acne, insomnia, and
increased appetite.
Cataracts
Hyperglycemia and Hypokalemia.
 Withdrawal

•Abrupt removal of the corticosteroids causes an

acute adrenal insufficiency syndrome that can be
lethal.
•This risk, coupled with the possibility of
psychological dependence on the drug and the fact
that withdrawal might cause an exacerbation of the
disease, means the dose must be tapered.
Inhibitors of adrenocorticoid biosynthesis or
function:
1. Ketoconazole: inhibits all gonadal and adrenal steroid
hormone synthesis and is used in the treatment of
patients with Cushing syndrome.
2. Spironolactone: It is effective against hyper-
aldosteronism and hirsutism in women.
3. Eplerenone: specifically binds to the mineralocorticoid
receptor
4. Aminoglutethimide: blocks the conversion of
cholesterol to pregnenolone.
5. Metyrapone: is a relatively selective inhibitor of steroid 11-
hydroxylation, interfering with cortisol and corticosterone
synthesis. It used for the treatment of Cushing's syndrome.
Metyrapone is the only adrenal-inhibiting medication that can be
administered to pregnant women with Cushing's syndrome.
6.Mitotane: has a nonselective cytotoxic action on the adrenal
cortex. adrenal carcinoma show a reduction in tumor mass in
30% of patients
7.Mifepristone: it has a pharmacologic antagonist at the steroid
receptor. It is given orally to several patients with Cushing's
syndrome due to ectopic ACTH production or adrenal carcinoma