Professional Documents
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PL 413
ADRENAL STEROIDS
By
Dr. Mennatallah Gowayed
Intended learning outcomes (ILOs):
Adrenal Glands
• The adrenal glands (also known as suprarenal glands) are the
triangular-shaped endocrine glands that sit on top of the kidneys.
• Each adrenal gland is separated into two distinct structures, the adrenal
cortex and adrenal medulla. The adrenal cortex is formed of 3 zones:
1. zona glomerulosa = producing mineralocorticoids (aldosterone,
Deoxycorticosterone (DOC)). They cause sodium retention and potassium
wasting. When their level is increased, they produce edema and
hypertension.
2. zona fasciculata = producing glucocorticoids (cortisol, hydrocortisone).
They have a catabolic effect on carbohydrates, fats and proteins. They have
anti-inflammatory actions.
3. zona reticularis = producing sex
hormones, mainly androgens
(dehydroepiandrosterone (DHEA),
androstenedione, testosterone).
The adrenal medulla (for fight, flight &
fright reactions) mainly produces
Fig.1: Adrenal Glands.
epinephrine and norepinephrine.
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Synthesis & Pharmacokinetics:
• They are synthesized from their precursor “cholesterol” which is converted
to pregnenolone which by turn is transformed to adrenocortical steroids.
• Corticosteroids are well absorbed orally, bind to corticosteroid-binding
globulin (CBG or transcortin) and albumin, distributed all over the body
and passes the BBB.
• Not stored, rate of synthesis = rate of release
• In the liver, cortisol is reversibly converted to cortisone & conjugated with
glucuronic & sulfuric acid.
• They are metabolized in the liver into 17-ketosteroids which is excreted in
the urine. Determination of the level of 17-ketosteroids in a 24-hour
collective urine sample has a diagnostic value for any condition associated
with increased adrenal cortex hormones secretion, e.g., in hirsutism
(caused by increased testosterone secretion from the adrenal cortex)
Regulation of secretion:
1. Mineralocorticoids:
• Aldosterone is regulated by the
renin-angiotensin system (RAS)
and not by adrenocorticotrophic
hormone (ACTH),
2. Glucocorticoids:
• The release of cortisone is
regulated through the
hypothalamus-pituitary axis
(HPA): the hypothalamus
produces a corticotropin
releasing hormone (CRH) which
stimulates the anterior pituitary
Fig.2: Regulation of mineralocorticoids.
gland to release ACTH
(adrenocorticotrophic hormone) which by turn stimulates the adrenal
cortex to release cortisone. Cortisone causes a feedback inhibition of
ACTH & CRF release.
• This negative feedback may lead to atrophy of the adrenal gland upon long
term treatment with cortisone; therefore, cortisone must not be stopped
suddenly.
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• Cortisone release undergoes a
diurnal rhythm: i.e., the level in
blood is not constant all over the
day: Maximum level is at 8-10 AM
and minimum level is at midnight.
• This is very important in cortisone
therapy because it is better to
simulate natural release of
cortisone, therefore, cortisone is
given in the morning, also, if a blood
analysis for cortisone is requested, it
should be in the morning. Stress
also regulates the secretion
(hypoglycaemia, physical stress
etc.) Fig.3: Regulation of glucocorticoids.
Pharmacological actions:
I. Mineralocorticoids:
Stimulate sodium and water reabsorption from renal tubules. They also
stimulate potassium and protons excretion.
II. Glucocorticoids:
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1. Glucocorticoid Effects on Metabolism
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7. Growth & Cell
Inhibit cell division or DNA synthesis, delay the process of
division
healing and retard the growth of children
8. Bone
Inhibit intestinal absorption and enhance renal excretion of Ca2+
and indirectly results in loss of calcium from bones producing
osteoporosis.
9.Immunosuppression
• Suppresses all types of hypersensitivity and allergic
phenomenon
• At High dose: Interfere with all steps of immunological
response
• Reduction in the count of eosinophils and monocytes
increasing the susceptibility for infection.
• Transplant rejection
10. Anti-
• Anti-inflammatory effects are non-specific and covers all
inflammatory
components of inflammation
• Suppress the activation of T lymphocytes, monocytes &
macrophages (lymphotoxic)
• Decrease the recruitment of neutrophils, monocytes,
macrophage into affected area.
• Decrease cytokine production & release, fibroblast
proliferation, fibrosis, collagenase enzyme activity
• Stabilize lysosomal membranes of neutrophils and
prevent the release of catabolic enzymes
• Stimulate the synthesis of “annexin-1” (“lipocortin”) which
inhibits phospholipase A2 and hence the synthesis of
eicosanoids including histamine, prostaglandins, leukotrienes
and prostacyclin (vasoconstriction and decrease capillary
permeability)
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Members of Corticosteroids with anti-inflammatory activity
The ideal selective anti-inflammatory corticosteroid should have no sodium &
water retention side effect (relative mineralocorticosteroid activity). Structural
changes to the basic cortisol molecule resulted in a number of compounds
with higher affinity for the receptor, are less activated, have little or no salt-
retaining properties, have greater potency and longer duration of action.
Classification:
I- According to the duration of action:
• Short acting (8-12 hours): Hydrocortisone, cortisone & Fludrocortisone.
• Intermediate (12-36 hours): Prednisolone, methyl prednisolone &
Triamcinolone
• Long acting (24-72 hours): Dexamethasone & Betamethasone
II- According to the potency (bioequivalence):
1. Cortisone (least potent) (25 mg)
2. Prednisolone, methyl prednisolone & Triamcinolone.
3. Hydrocortisone (Hydrocortisyl T, Solucortef inj. 20 mg)
4. Dexamethasone (Oradexon T, Decadron, Oradexon 0.75 mg) &
Betamethasone dipropionate & sodium phosphate (Diprofos)
III- According to the relative mineralocorticosteroid activity:
• Fludrocortisone acetate (Florinef T): it has an aldosterone-like activity
so it is used in Addison’s disease where both corticosteroids &
mineralocorticoids are needed as replacement therapy. It is given orally.
Treatment Regimen:
Glucocorticoids are given in a large initial dose until the condition is stabilized,
followed by a maintenance dose by reducing the dose gradually until reaching
the minimum effective dose with least side effects.
Corticosteroids should not be stopped abruptly to avoid Addison’s like
adrenal crisis. How?
Routes of administration
Parenteral (water soluble for emergency & water insoluble for prolonged use,
oral, topical and local (eye, ear and nasal drops, inhalation, enema, intra-
articular).
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Therapeutic uses
1. Replacement therapy in adrenal insufficiency (Addison’s disease) and in
congenital adrenal hyperplasia (CAH).
2. Inflammatory conditions: Ulcerative colitis, Rheumatoid arthritis, collagen
diseases as systemic lupus erythematosus (SLE) and connective tissue
diseases as arteritis nodosum.
3. Organ transplantation: This acute tissue rejection is treated by both
corticosteroids & immunosuppressants like cyclosporine or tacrolimus.
4. Allergic conditions:
i) Bronchial asthma: corticosteroids locally (inhalation), or orally.
ii) Status asthmaticus: emergency I.V. corticosteroids & theophylline.
iii) Allergic rhinitis: treated by sodium chromoglycate & corticosteroids.
iv) Allergic eye diseases & skin diseases
v) anaphylactic shocks: result from penicillin injection
5. Cancer: Because of their lymphotoxic effects, glucocorticoids are used in
the treatment of lymphocytic leukemias and lymphomas. They are also used
as a supportive treatment (together with 5HT3, Ondansetron) to prevent
nausea & vomiting associated with chemotherapy.
7. Nephrotic syndrome (escape of proteins in urine).
8. Liver, skin, infectious diseases, spinal cord injury and cerebral edema.
Side effects
During prolonged use of
corticosteroids, we should
take into consideration
other diseased conditions
together with the
administration of the
lowest possible dose by
the proper route. The side
effects are:
1. Iatrogenic (drug-
induced) Cushing’s
syndrome.
2. Infectious diseases due
to inhibition of immune
system leading to
reactivation of bacteria & Fig.5: Therapeutic effects and side effects of
fungi. corticosteroids.
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3. They are ulcerogenic causing ulcer formation & reactivation especially if
combined with NSAIDs.
4. Hyperglycemia, special care in diabetic patients.
5. Osteoporosis (long term use).
6. Cataract & increased intraoccular pressure when used in ophthalmic
preparations.
7. CNS disturbances producing psychosis (schizophrenia).
8. Fluid & electrolyte disturbances in the form of sodium and water retention
and loss of potassium.
Good luck!