Faculty of Pharmacy
Dept. of Pharmacology
Pharmacology-3 (L2)
Dr Waleed Barakat
02-10-2025
[Link]@[Link]
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Adrenal Hormones
I. OVERVIEW
The adrenal gland consists of:
- the medulla which secretes catecholamines, and
- the cortex which secretes two major classes of steroid hormones
from cholesterol:
-- the corticosteroids (glucocorticoids and mineralocorticoids),
-- the adrenal androgens.
The adrenal cortex has three zones:
- outer zona glomerulosa: produces mineralocorticoids (ex.
aldosterone) responsible for regulating salt and water metabolism,
- middle zona fasciculata: synthesizes glucocorticoids (ex. cortisol)
involved with metabolism and response to stress,
- inner zona reticularis: secretes adrenal androgens.
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Secretion by the two inner zones and,
to a lesser extent, the outer zone is
controlled by pituitary
adrenocorticotropic hormone (ACTH;
also called corticotropin),
which is released in response to
hypothalamic corticotropin-releasing
hormone (CRH).
Glucocorticoids serve as feedback
inhibitors of ACTH and CRH
secretion.
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II. CORTICOSTEROIDS
corticosteroids bind to specific intracellular
cytoplasmic receptors in target tissues:
- glucocorticoid receptors (widely distributed
throughout the body),
- mineralocorticoid receptors (mainly in
excretory organs as kidney, colon, salivary
glands, sweat glands)
- both receptor types are found in the brain.
After binding, the receptor–hormone
complex translocates into the nucleus, where
it modifies gene expression so effects of
corticosteroids take hours to days to occur.
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Corticosteroids Inhibitors of adrenocorticoid
Betanethasone biosynthesis or function
Cortisone Eplerenone
Dexamethasone Ketoconazole
Fludrocortisone Spironolactone
Hydrocortisone
Methylprednisolone
Prednisolone
Prednisone
Triamcinolone
Summary of adrenal corticosteroids.
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A. Glucocorticoids
Cortisol is the principal human glucocorticoid.
Normally, its production is diurnal, with a peak in early morning
followed by a decline and then a secondary, smaller peak in late
afternoon.
Stress and levels of the circulating steroid influence secretion.
Effects of glucocorticoids:
1. Promote normal intermediary metabolism:
- stimulate hepatic glucose production (gluconeogenesis)
2. Increase resistance to stress:
- provide the body with energy (glucose) to combat stress caused by
trauma, fright, infection, bleeding, or debilitating disease.
- glucocorticoid insufficiency may result in hypoglycemia (during
stressful periods or fasting)
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3. Alter blood cell levels in plasma:
- decrease in eosinophils, basophils, monocytes, and lymphocytes
by redistributing them from the circulation to lymphoid tissue.
- increase hemoglobin, erythrocytes, platelets, and
polymorphonuclear leukocytes.
4. Possess anti-inflammatory and immunosuppressive activities:
- reduce circulating lymphocytes,
- inhibit the ability of leukocytes and macrophages to respond to
mitogens and antigens,
- decrease the production and release of proinflammatory cytokines,
- enhance production of lipocortin (inhibitor of phospholipase A2, so
block release of arachidonic acid the precursor of prostaglandins and
leukotrienes), resulting in anti-inflammatory actions,
- stabilize mast cell/basophil membrane, so decrease histamine release.
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5. Affect other systems:
- provide negative feedback to reduce ACTH production and affect
the endocrine system by suppressing synthesis of glucocorticoids
and thyroid-stimulating hormone,
- adequate cortisol levels are essential for normal glomerular
filtration.
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B. Mineralocorticoids
Aldosterone is the primary physiologic mineralocorticoid.
- help to control fluid status and concentration of electrolytes,
especially sodium and potassium.
- acts on mineralocorticoid receptors in the distal tubules and
collecting ducts in the kidney, causing reabsorption of sodium,
bicarbonate, and water.
- decreases reabsorption of potassium, which, with H+, is lost in
urine,
- enhancement of sodium reabsorption in gastrointestinal mucosa
and in sweat and salivary glands,
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Elevated aldosterone levels may cause:
- alkalosis and hypokalemia,
- retention of sodium and water, and
- increased blood volume and blood pressure.
Hyperaldosteronism is treated with spironolactone, a potassium-
sparing diuretic that also acts as a mineralocorticoid (aldosterone)
receptor antagonist.
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C. Therapeutic uses of corticosteroids
1. Relief of inflammatory symptoms:
- inflammatory skin conditions (redness, swelling, heat, tenderness),
- symptom control in persistent asthma,
- exacerbations of asthma, rheumatoid arthritis, inflammatory bowel
disease, and other autoimmune disorders,
- osteoarthritis disease flare (intraarticular).
Corticosteroids are not curative in these disorders.
2. Treatment of asthma and allergies:
- drug, serum, and transfusion allergic reactions.
- allergic rhinitis and asthma: (ex. inhaled fluticasone which provide
long-term control of symptoms and minimize systemic effects,
reducing or eliminating the need for oral corticosteroids).
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3. Replacement therapy for primary adrenal insufficiency
(addison disease):
Addison disease:
- caused by dysfunction of the adrenal cortex (diagnosed by lack of
response to ACTH administration),
- patients may present with:
-- fatigue,
-- weight loss,
-- hypotension,
-- salt craving,
-- musculoskeletal or gastrointestinal complaints,
-- shock in severe cases.
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- this deficiency must be corrected by replacement therapy,
otherwise death would occur:
-- hydrocortisone (identical to natural cortisol): 2/3 of the daily
dosage is administered in the morning and 1/3 in the afternoon,
mimicking the normal diurnal variation in cortisol levels,
-- once-daily prednisone or dexamethasone are longer-acting
treatment alternatives,
- fludrocortisone (potent synthetic mineralocorticoid), may also be
necessary to correct mineralocorticoid deficiency.
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4. Replacement therapy for secondary or tertiary adrenal
insufficiency:
Hydrocortisone is used for treatment of secondary and tertiary
adrenal insufficiency caused by a defect in ACTH production by the
pituitary or in CRH production by the hypothalamus, respectively.
5. Diagnosis of cushing syndrome:
Cushing syndrome is caused by hypersecretion of glucocorticoids
(hypercortisolism) that results from:
- excessive release of ACTH by anterior pituitary (Cushing disease),
- an adrenal tumor, or
- an ectopic ACTH-producing tumor (secretion of ACTH by a
nonpituitary tumor as small cell lung cancer).
- exogenous chronic administration of high doses of glucocorticoid
medications (iatrogenic Cushing syndrome).
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Patients with Cushing syndrome may present with:
- central obesity,
- a round face (sometimes called moon facies),
- a fat pad at the back of the neck (buffalo hump),
- elevated blood pressure and
- glucose intolerance.
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Diagnosis of Cushing syndrome is established with:
- a late-night salivary cortisol level,
- measurement of 24-hour urine free cortisol, or
- the dexamethasone suppression test.
Under normal conditions cortisol is secreted intermittently, with
peak levels in the early morning around 7 to 8 am and a nadir late in
the evening around midnight.
Patients with Cushing syndrome do not have the typical evening
nadir in cortisol and demonstrate elevated salivary cortisol levels.
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With the dexamethasone suppression test (DST), a low dose of
dexamethasone is administered as a single dose in the late evening
(or as a series of eight doses over 2 days), and a serum cortisol level
is drawn at 8 am the following morning.
In patients without Cushing syndrome, administration of
dexamethasone suppresses CRH and ACTH secretion from the
hypothalamus and pituitary, respectively, resulting in a low serum
cortisol level.
In Cushing syndrome, the morning cortisol level is not suppressed.
The DST should not be used as a single diagnosis for Cushing syn.
Patients who are suspected to have Cushing syndrome based on the
results of the DST should have a confirmatory test using one of the
other testing methods.
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Treatment of Cushing syndrome:
- surgery to resect the pituitary, adrenal glands, or the ectopic
ACTH-producing tumor.
- in iatrogenic Cushing syndrome, the dose of glucocorticoid should
be reduced and tapered or alternative medications should be used to
manage the disorder that is being treated with glucocorticoids.
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6. Replacement therapy for congenital adrenal hyperplasia:
Congenital adrenal hyperplasia (CAH):
- a group of diseases resulting from an enzyme defect in the
synthesis of one or more of the adrenal steroid hormones,
- may lead to virilization in females due to overproduction of
adrenal androgens,
- treated with administration of sufficient corticosteroids to:
-- suppress release of CRH and ACTH,
-- normalize hormone levels, that
-- decreases production of adrenal androgens.
The choice of replacement hormone depends on the specific enzyme
defect.
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7. Acceleration of lung maturation:
Respiratory distress syndrome is:
- seen in premature infants due to their immature lungs,
- primarily caused by a deficiency of pulmonary surfactant.
Fetal cortisol is a regulator of lung maturation so, a regimen of
betamethasone or dexamethasone administered intramuscularly to a
mother at risk for preterm delivery can accelerate lung maturation in
the fetus and prevent respiratory distress syndrome.
Ideally the regimen should be initiated at least 48 hours prior to
delivery.
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Pharmacologic effects and duration of action of some commonly
used natural and synthetic corticosteroids.
Activities are all relative to that of hydrocortisone, which is considered to be 1.
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D. Pharmacokinetics
1. Absorption and fate:
Corticosteroids are readily absorbed after oral
administration.
Selected compounds may be administered
intravenously, intramuscularly, intraarticularly,
topically, or via inhalation or intranasal delivery.
All topical and inhaled glucocorticoids are
absorbed to some extent and, therefore, have the
potential to suppress the hypothalamic–
pituitary–adrenal (HPA) axis.
After absorption, glucocorticoids are greater
than 90% bound to plasma proteins, mostly
corticosteroid-binding globulin or albumin.
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Corticosteroids are metabolized by the liver microsomal oxidizing
enzymes. The metabolites are conjugated to glucuronic acid or
sulfate and excreted by the kidney.
The half-life of corticosteroids may increase substantially in hepatic
dysfunction.
Prednisone is preferred in pregnancy because it minimizes steroid
effects on the fetus. It is a prodrug that is not converted to the active
compound, prednisolone, in the fetal liver.
Any prednisolone formed in the mother is biotransformed to
prednisone by placental enzymes.
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2. Dosage:
Factors that should be considered in determining the dosage of
corticosteroids include:
- glucocorticoid versus mineralocorticoid activity,
- duration of action,
- type of preparation, and
- time of day when the drug is administered.
When large doses of corticosteroids are required for more than 2
weeks, suppression of the HPA axis occurs.
Alternate-day administration of corticosteroids may prevent this
adverse effect by allowing the HPA axis to recover/function on days
the hormone is not administered.
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E. Adverse effects
Common adverse effects of long-term corticosteroid therapy are
often dose related;
- osteoporosis due to the ability of glucocorticoids to:
-- suppress intestinal Ca2+ absorption,
-- inhibit bone formation, and
-- decrease sex hormone synthesis.
Glucocorticoid-induced osteoporosis may be treated with:
--- calcium and vitamin D supplements,
--- bisphosphonates
- increased appetite (not necessarily an adverse effect and may be
one of the reasons for the use of prednisone in cancer
chemotherapy).
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- Cushing-like syndrome (redistribution of body fat, puffy face,
hirsutism, and increased appetite),
- cataracts,
- hyperglycemia and diabetes (dose adjustment needed in diabetic
patients),
- topical therapy can cause skin atrophy, ecchymosis, purple striae,
- inhaled therapy is associated with oral candidiasis, hoarseness, and
throat irritation.
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F. Discontinuation
Sudden discontinuation of these drugs can cause serious
consequences if the patient has suppression of the HPA axis:
- cause acute adrenal insufficiency (adrenal crisis) that
-- can be fatal,
-- may manifest with:
--- nausea, vomiting,
--- fever,
--- dehydration,
--- hypotension,
--- shock,
--- hypoglycemia and
--- hyperkalemia.
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Therefore:
- the dose must be tapered slowly according to individual tolerance,
- the patient must be monitored carefully
To avoid:
- the risk of adrenal insufficiency,
- the possibility that withdrawal of the corticosteroid could
exacerbate the disease being treated with this agent.
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G. Inhibitors of adrenocorticoid biosynthesis or function
1. Ketoconazole:
- antifungal agent that strongly inhibits all gonadal and adrenal
steroid hormone synthesis,
- used in the treatment of patients with Cushing syndrome when
surgical management is not an option.
2. Eplerenone:
- acts as a selective aldosterone antagonist on the mineralocorticoid
receptor (has a much lower affinity for the androgen receptor, and
this lessens the potential for gynecomastia and irregular menstrual
bleeding associated with spironolactone).
- approved for the treatment of:
-- hypertension
-- heart failure.
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3. Spironolactone:
- antihypertensive drug that competes for the mineralocorticoid
receptor and, thus,
- inhibits sodium reabsorption in the kidney,
- also antagonizes aldosterone and testosterone synthesis.
- effective for the management of:
-- hyperaldosteronism,
-- resistant hypertension,
-- hepatic cirrhosis,
-- hirsutism in women, probably due to antiandrogen activity on
the hair follicle.
Adverse effects include:
- hyperkalemia, - gynecomastia,
- menstrual irregularities, and - skin rashes.
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Thank You
Good Luck
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