Pharmacology 2

Adrenal
 Hormones
Rufayda Manassrah
2024-2025
Introduction
⮚ The adrenal gland: cortex and medulla.
⮚ The medulla → catecholamines
⮚ The cortex → two types of corticosteroids (glucocorticoids
and mineralocorticoids) + adrenal androgens
Introduction
The adrenal cortex has three zones, each zone
synthesizes different type of steroid hormone from
cholesterol.
– Outer zona glomerulosa → mineralocorticoids (aldosterone)
→ regulate salt+water metabolism (Regulated by the
renin–angiotensin system).
– Middle zona fasciculata → glucocorticoids (cortisol) →
involved with metabolism +
response to stress.
– Inner zona reticularis → adrenal androgens.

⮚ Secretions controlled by pituitary

adrenocorticotropic hormone
response to
(ACTH/corticotropin), which released in
hypothalamic corticotropin
releasing hormone (CRH). ⮚
Glucocorticoids serve as feedback inhibitors of ACTH
and CRH secretion
Hypothalamo-pituitary-adrenal axis

GFR
ACT

Introduction
Biosynthesis of corticosteroids
 Corticosteroids
The corticosteroids bind to specific intracellular
cytoplasmic receptors in target tissues.
– Glucocorticoid receptors widely distributed in the body
– Mineralocorticoid receptors mainly at excretory organs
(kidney, colon, salivary glands, sweat glands).
– Both types of receptors are found in the brain.

• Receptor–hormone complex activate or inhibit

proteins synthesis into nucleus.
• Other glucocorticoid effects are immediate, e.g.,
interaction with catecholamines to mediate relaxation
of bronchia.
Corticosteroids
• After dimerizing, receptor
hormone complex recruits
coactivator or corepressor
proteins into nucleus→ attaches
to gene promoter elements→ acts
 as transcription factor to turn
genes on (coactivators) or off
(corepressors), depending on the
tissue.
• This mechanism requires time to
produce an effect.
Glucocorticoids
• Cortisol (principal human glucocorticoid). • Its
production is diurnal,
• Peak early in the morning followed by decline
then secondary, smaller peak in late afternoon.
 Cortisol-Diurnal Normal
• Factors such as stress + level of circulating steroid
influence secretion.
The effects of cortisol
The effects of cortisol are many and diverse.
In general, all glucocorticoids:
1. Promote normal intermediary metabolism
2. Increase resistance to stress
3. Alter blood cell levels in plasma
4. Have anti-inflammatory action
5. Affect other systems
The effects of cortisol
The effects of cortisol
• Promote normal intermediary metabolism: –
 ↑gluconeogenesis →↑amino acid uptake by the liver
and kidney + ↑activity of gluconeogenic enzymes. –
stimulate protein catabolism (except in liver) + lipolysis,
so providing building blocks and energy needed for
glucose synthesis.

• Glucocorticoid insufficiency result in

hypoglycemia (e.g., during stressful periods or
fasting)
The effects of cortisol
2. Increase resistance to stress:
By raising plasma glucose levels, provide body
with energy to combat stress caused by: –
trauma,
– fright,
– infection,
– bleeding,
– debilitating disease.
The effects of cortisol
3. Alter blood cell levels in plasma: • ↓
eosinophils, basophils, monocytes,
lymphocytes by redistributing them from the
circulation to lymphoid tissue.
(anti-immunological)

• ↑ hemoglobin, erythrocytes, platelets,

polymorphonuclear leukocytes.
The effects of cortisol
4. Have anti-inflammatory action:
The most important therapeutic properties are potent
anti-inflammatory and immunosuppressive activities.
The effects of cortisol
4. Have anti-inflammatory action:
The most important therapeutic properties are potent anti

inflammatory and immunosuppressive activities. •

↓circulating lymphocytes
• inhibit ability of leukocytes and macrophages to respond
to mitogens and antigens.
• ↓production and release of proinflammatory cytokines. •
inhibit phospholipase A2 , blocks release of arachidonic
acid (precursor of prostaglandins (PG) and leukotrienes
(LT)) from membrane-bound phospholipid.
– The decreased production of PG and LT → anti-inflammatory
action.
– PG and LT influence the inflammatory response by stabilizing
mast cell and basophil membranes, resulting in ↓ histamine
release.
The effects of cortisol

5. Affect other systems:

• High levels of glucocorticoids
serve
as feedback inhibitors of ACTH +
endocrine system by suppressing
synthesis of glucocorticoids and TSH.
 • Adequate cortisol levels essential for normal
glomerular filtration (kidney function), salt and water
retention.

• The effects of corticosteroids on other systems

mostly associated with adverse effects.
The effects of cortisol
• 5. Affect other systems:
• CNS effect: initial euphoria followed by
 depression
• Effect on eyes: ↑IOP
• Effect on bones: ↓ bone matrix and ↑ Ca+2
excretion
• Effect on growth and development: growth
retardation
Spironolactone

• Mineralocorticoids help to control fluid status and

concentration of electrolytes (sodium + potassium) •
Aldosterone acts on distal tubules and collecting
ducts in the kidney, ↑ reabsorption of Na+,
bicarbonate, and water.
• Aldosterone ↓reabsorption of K+ →↑excretion in
the urine.
Mineralocorticoids
• ↑reabsorption of Na+ also occurs in gastrointestinal
mucosa, sweat, salivary glands.

• Elevated aldosterone levels cause alkalosis and

hypokalemia, retention of sodium and water,
increased blood volume and blood pressure. •
Hyperaldosteronism is treated with spironolactone
 • Target cells for aldosterone contain mineralocorticoid
receptors that interact with the hormone in a manner
analogous to that of glucocorticoid receptors
Therapeutic uses of corticosteroids
• Semisynthetic derivatives of corticosteroids.
• They vary in anti-inflammatory potency, mineralocorticoid
activity, and duration of action.
• Used in:
1. replacement therapy: adrenocortical insufficiency (Addison
disease), hydrocortisone
2. treatment of severe allergic reactions: e.g. urticaria, asthma
3. rheumatoid arthritis,
4. inflammatory disorders: e.g. neuritis, dermatitis
5. Autoimmune diseases: e.g. vasculitis, ulcerative colitis 6. Organ
transplantation: as immunosuppressive to prevent graft rejection
7. Shock and hypotension: hydrocortisone
8. Cerebral edema: dexamethasone
9. some cancers: e.g. lymphoma, leukemias, multiple myeloma
10. Stimulation of fetus lung maturation: dexamethasone or beta
Therapeutic uses of

corticosteroids Natural cortisol

 Synthetic t1/2=1-1.5hr

Therapeutic uses of corticosteroids

1. Replacement therapy for primary adrenocortical
insufficiency (Addison disease):
• Addison disease caused by adrenal cortex dysfunction
(diagnosed by the lack of response to ACTH administration). •
Hydrocortisone (identical to natural cortisol), given to correct
the deficiency.
• Failure to treat results in death.
• The dosage of hydrocortisone is
divided so that two-thirds in the
morning and one-third in the
 afternoon.
• Adding fludrocortisone (potent
synthetic mineralocorticoid with some
glucocorticoid activity) also necessary
to supplement mineralocorticoid
deficiency.
Therapeutic uses of corticosteroids
2. Replacement therapy for secondary or
tertiary adrenocortical insufficiency: • These
disorders are caused by a defect in CRH
production by the hypothalamus or in ACTH
production by the pituitary.
 • Under these conditions, the synthesis of
mineralocorticoids in the adrenal cortex is less
impaired than that of glucocorticoids. •
Hydrocortisone is used for treatment
Therapeutic uses of corticosteroids
3. Diagnosis of Cushing syndrome:
• Cushing syndrome caused by hypersecretion of
glucocorticoids (hypercortisolism), results from excessive
release of ACTH by anterior pituitary or an adrenal tumor.
• Chronic treatment with high doses of glucocorticoids is a
frequent cause of iatrogenic Cushing syndrome
• Cortisol levels (urine, plasma,
saliva) and the dexamethasone
suppression test are used to
diagnose Cushing syndrome.
• The synthetic glucocorticoid
dexamethasone suppresses
cortisol release in normal
individuals, but not those with
Cushing syndrome.
Therapeutic uses of
corticosteroids
4. Replacement therapy for congenital adrenal
hyperplasia (CAH): • CAH is a group of diseases resulting
from an enzyme defect in the synthesis of one or more of
the adrenal steroid hormones. • CAH may lead to
virilization in females due to overproduction of adrenal
androgens.
• Treatment is administration of sufficient corticosteroids
to normalize hormone levels by suppressing release of
 CRH and ACTH. • This decreases production of adrenal
androgens.
• The choice of replacement hormone depends on the
specific enzyme defect.
Therapeutic uses of corticosteroids
5. Relief of inflammatory symptoms:
Reduce the manifestations of inflammation associated with:
• Rheumatoid arthritis
• Inflammatory skin conditions (redness, swelling, heat,
tenderness that present at the site of inflammation). •
Symptom control in persistent asthma
• Management of asthma exacerbations
• Active inflammatory bowel disease.
• In non-inflammatory disorders
(e.g., osteoarthritis) intra
articular corticosteroids used
for
treatment of disease flare.
• Corticosteroids are not curative.
Therapeutic uses of corticosteroids
6. Treatment of allergies:
Corticosteroids are beneficial in the
treatment of:
• Allergic rhinitis,
• Drug, serum, transfusion allergic reactions.

⮚ In the treatment of allergic rhinitis and

asthma:
Fluticasone and others are applied topically
to the respiratory tract through inhalation
from a metered dose dispenser.
This minimizes systemic effects and allows
the patient to reduce or eliminate the use of
oral corticosteroids.
Therapeutic uses of corticosteroids
7. Acceleration of lung maturation:
• Respiratory distress syndrome (problem in
premature infants).
• Fetal cortisol is a regulator of lung maturation.

• Regimen of betamethasone or dexamethasone

administered IM to the mother within the 48
hours proceeding premature delivery can
accelerate lung maturation in the fetus.
 Pharmacokinetics of Corticosteroids
Absorption and fate:
• Readily absorbed after oral administration. • Selected
compounds can also be administered: IV, IM,
intra-articularly (e.g., into arthritic joints), topically, or
via inhalation or intranasal delivery
• All topical and inhaled glucocorticoids are absorbed to
some extent, so have the potential to cause
hypothalamic–pituitary–adrenal (HPA) axis
suppression.
• Greater than 90% of absorbed glucocorticoids are
bound to plasma proteins, mostly corticosteroid

binding globulin (90%) or albumin.

Pharmacokinetics of Corticosteroids
• Metabolized by the liver.
• The metabolites are conjugated to glucuronic acid
or sulfate
• 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.
Dosage of Corticosteroids
Many factors should be considered in determining
the dosage of corticosteroids, including:
✔Glucocorticoid versus mineralocorticoid activity,
✔Duration of action,
 ✔Type of preparation,
✔Time of day when the drug is administered.

• If large doses of the hormone are required for

more than 2 weeks, suppression of the HPA axis
occurs.
– Alternate-day administration of the corticosteroid
prevent this adverse effect by allowing the HPA axis to
recover/function on days the hormone is not taken.
Common side effects of long-term
corticosteroid therapy
 Adverse effects of Corticosteroids

• Adverse effects are

often dose related.
– For example, in patients
with rheumatoid
arthritis, the daily dose
of prednisone was the
strongest predictor of
occurrence of adverse
effects
 Adverse effects of Corticosteroids
• Osteoporosis is the most common adverse effect: – They
suppress intestinal Ca2+ absorption, inhibit bone formation,
decrease sex hormone synthesis.
– Patients should take calcium and vitamin D supplements. –
Bisphosphonates also useful in treatment of glucocorticoid-induced
osteoporosis.
• Increased appetite (not necessarily an adverse effect):
– it is one of the reasons for the use of prednisone in cancer
chemotherapy.
• The classic Cushing-like syndrome (redistribution of body fat,
puffy face, hirsutism, and increased appetite) is observed in
excess corticosteroid replacement.
• Cataracts also occur with long-term corticosteroid therapy.
• Hyperglycemia may develop and lead to diabetes mellitus.
Diabetic patients should monitor blood glucose and adjust
medications accordingly if taking corticosteroids.
• Topical therapy cause skin atrophy, ecchymosis, purple striae.
Discontinuation of Corticosteroids
• Sudden discontinuation cause serious problem if the
patient has suppression of the HPA axis.
• In this case, abrupt removal of corticosteroids causes
acute adrenal insufficiency that can be fatal. • The risk
coupled with the possibility that withdrawal might
cause an exacerbation of the disease. • Dose must be
tapered slowly according to individual tolerance. The
patient must be monitored carefully.
Inhibitors of adrenocorticoid
biosynthesis or function
Several substances useful as inhibitors of synthesis
or function of adrenal steroids: ketoconazole,
spironolactone, eplerenone.

1. Ketoconazole: antifungal agent, strongly inhibits

all gonadal and adrenal steroid hormone synthesis.
It is used in the treatment of patients with Cushing
syndrome.
Inhibitors of adrenocorticoid
biosynthesis or function

2. Spironolactone:
• Antihypertensive drug competes for the mineralocorticoid
receptor, inhibits sodium reabsorption in the kidney. • Effective
for hyperaldosteronism: Antagonize aldosterone and
testosterone synthesis.
• Used along with other standard therapies for the treatment of
 heart failure with reduced ejection fraction.
• Treatment of hirsutism in women: interfere at the androgen
receptor of the hair follicle.
• Adverse effects: hyperkalemia, gynecomastia, menstrual
irregularities, skin rashes.
Inhibitors of
adrenocorticoid
biosynthesis or function
3. Eplerenone:
• Specifically binds to the mineralocorticoid
receptor (aldosterone antagonist).
• This specificity avoids the side effect of
gynecomastia that is associated with the use
of spironolactone.
• Approved for the treatment of hypertension
and for heart failure with reduced ejection
fraction.