Pharma lec 1 2nd term

Adrenal hormones
Most of organ function controlled by 2 systems:
1) Nervous system (hypothalamus controls action of hormones especially pituitary gland – master gland
– hormones)
2) Endocrine system (mainly from pituitary gland)
Pituitary gland consists of 3 lobes:
 Anterior lobe: secretes 5 hormones (ACTH – TSH – GH - Reproductive hormones - Prolactin)
 Middle lobe: not important in pharmacology (responsible for colour change)
 Posterior lobe: secretes 2 hormones (Antidiuretic hormone – oxytocin)
Hypothalamus secretes 2 different hormones
1- Releasing hormone: encourage hormones release
2- Release inhibitory hormone: inhibit hormones release
The adrenal gland consists of the cortex and the medulla. The latter secretes epinephrine, whereas the
cortex synthesizes and secretes two major classes of steroid hormones: the adrenocorticosteroids
(glucocorticoids and mineralocorticoids) and the adrenal androgens.
The adrenal cortex is divided into three zones that synthesize various steroids from cholesterol and then
secrete them.
 produces mineralocorticoids (for example, aldosterone), which are
responsible for regulating salt and water metabolism.
Outer zona glomerulosa  Production of aldosterone is regulated primarily by the renin-
angiotensin system
 synthesizes glucocorticoids (for example, cortisol), which are involved
The middle zona fasciculata
with normal metabolism and resistance to stress.
The inner zona reticularis  secretes adrenal androgens (for example, dehydroepiandrosterone).

Adrenocorticosteroids
 The adrenocorticoids bind to specific intracellular cytoplasmic receptors in target tissues.
 The glucocorticoid receptor is widely distributed throughout the body, whereas the mineralocorticoid
receptor is confined mainly to excretory organs, as the kidney, colon, and salivary and sweat glands.
 After dimerizing, the receptor-hormone complex translocates into the nucleus, where it attaches to
gene promoter elements, acting as a transcription factor to turn genes on or off, depending on the
tissue.

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A. Glucocorticoids
 Cortisol is the principal human glucocorticoid.
 Normally, its production is diurnal )‫(نهاري‬, with a peak early in the morning followed by a decline and
then a secondary, smaller peak in the late afternoon.
 Factors such as stress and levels of the circulating steroid influence secretion.
 The effects of cortisol are many and diverse:
 The glucocorticoids have wide spread effects because they influence the function of
most cells in the body. The major metabolic consequences of glucocorticoid
Physiologic secretion or administration are due to direct actions of these hormones in the cell.
Effects  Although many of the effects of glucocorticoids are dose-related and become
magnified when large amounts are administered for therapeutic purposes, there are
also other effects called -permissive effects- without which many normal functions
become deficient
 The glucocorticoids have important dose-related effects on carbohydrate, protein,
and fat metabolism.The same effects are responsible for some of the serious adverse
effects associated with their use in therapeutic doses.
 Glucocorticoids stimulate and are required for gluconeogenesis and glycogen
synthesis in the fasting state. They stimulate phosphoenolpyruvate carboxykinase,
glucose- 6-phosphatase, and glycogen synthase and the release of amino acids in the
course of muscle catabolism
Metabolic  Glucocorticoids increase serum glucose levels and thus stimulate insulin release and
Effects inhibit the uptake of glucose by muscle cells, while they stimulate hormone sensitive
lipase and thus lipolysis.
 The increased insulin secretion stimulates lipogenesis and to a lesser degree inhibits
lipolysis, leading to a net increase in fat deposition combined with increased release
of fatty acids and glycerol into the circulation.
 The net results of these actions are most apparent in the fasting state, when the
supply of glucose from gluconeogenesis, the release of amino acids from muscle
catabolism, the inhibition of peripheral glucose uptake, and the stimulation of
lipolysis all contribute to maintenance of an adequate glucose supply to the brain.
 Although glucocorticoids stimulate RNA and protein synthesis in the liver, they have
Catabolic and
catabolic and antianabolic effects in lymphoid and connective tissue, muscle,
Antianabolic
peripheral fat, and skin.
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Effects  Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and
weakness and thinning of the skin. (contraindicated in peptic ulcer)
 Catabolic and antianabolic effects on bone are the cause of osteoporosis in Cushing's
syndrome and impose a major limitation in the long-term therapeutic use of
glucocorticoids.
 In children, glucocorticoids reduce growth.
This effect may be partially prevented by administration of growth hormone in high doses.

 Glucocorticoids dramatically reduce the manifestations of inflammation. This is due

to their profound effects on the concentration, distribution, and function of
peripheral leukocytes and to their suppressive effects on the inflammatory cytokines
and chemokines and on other mediators of inflammation.
 Inflammation, regardless of its cause, is characterized by the extravasation and
Anti- infiltration of leukocytes into the affected tissue
Inflammatory  Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-
and presenting cells.
Immuno-  The ability of these cells to respond to antigens and mitogens is reduced.
suppressive
 The effect on macrophages is particularly marked and limits their ability to
Effects
phagocytose and kill microorganisms and to produce tumor necrosis factor-α,
interleukin-1, metalloproteinases, and plasminogen activator
 Glucocorticoids cause vasoconstriction when applied directly to the skin, possibly by
suppressing mast cell degranulation.
 They also decrease capillary permeability by reducing the amount of histamine
released by basophils and mast cells.
 Glucocorticoids have important effects on the nervous system. Adrenal insufficiency
causes marked slowing of the alpha rhythm of the electroencephalogram and is
associated with depression.
 Increased amounts of glucocorticoids often produce behavioural disturbances in
humans: initially msomnia and euphoria and subsequently depression.
 Large doses of glucocorticoids may increase intracranial pressure (pseudotumor
cerebri).
 Glucocorticoids given chronically suppress the pituitary release of ACTH, growth
hormone, thyroid- stimulating hormone, and luteinizing hormone
Other Effects
 Large doses of glucocorticoids have been associated with the development of peptic
ulcer, possibly by suppressing the local immune response against Helicobacter pylori.
 They also promote fat redistribution in the body, with increase of visceral, facial,
nuchal, and supraclavicular fat, and they appear to antagonize the effect of vitamin D
on calcium absorption.
 They increase the number of platelets and red blood cells.
 Cortisol deficiency results in impaired renal function (particularly glomerular
filtration)
 Glucocorticoids have important effects on the development of the fetal lungs.
Indeed, the structural and functional changes in the lungs near term, including the
production of pulmonary surface-active material required for air breathing
(surfactant), are stimulated by glucocorticoids.

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Therapeutic uses of the adrenal corticosteroids
1. Several semisynthetic derivatives of the glucocorticoids have been developed that vary in
their anti-inflammatory potency, degree to which they cause sodium retention, and duration
of action
2. Replacement therapy for primary adrenocortical insufficiency (Addison's disease): This disease is
caused by adrenal cortex dysfunction (as diagnosed by the lack of patient response to corticotropin
‫ ر‬. Hydrocortisone, which is identical to
administration) ‫مشوح بالتفصيل يف اخر صفحه لو حابب تزود معلومات‬
natural cortisol, is given to correct the deficiency
3. Replacement therapy for secondary or tertiary adrenocortical insufficiency: These deficiencies are
caused by a defect either in CRH production by the hypothalamus or in corticotropin production by
the pituitary.
4. The adrenal cortex responds to corticotropin (ACTH) administration by synthesizing and releasing the
adrenal corticosteroids.
Applications of Glucocorticoids
1. Replacement therapy for congenital adrenal hyperplasia:
- This is a group of diseases resulting from an enzyme defect in the synthesis of one or more of the
adrenal steroid hormones.
- This condition may lead to virilization in females due to overproduction of adrenal androgens.
- Treatment of this condition requires administration of sufficient corticosteroids to normalize the
patient's hormone levels by suppressing release of CRH and ACTH. This decreases production of
adrenal androgens.
2. Relief of inflammatory symptoms:
- Glucocorticoids dramatically reduce the manifestations of inflammations (for example, rheumatoid
and osteoarthritic inflammations, as well as inflammatory conditions of the skin), including the
redness, swelling. heat, and tenderness that are commonly present at the inflammatory site.
- The effect of glucocorticoids on the inflammatory process is the result of a number of actions,
including the redistribution of leukocytes to other body compartments, thereby lowering their
blood concentration.
3. Treatment of allergies
- Glucocorticoids are beneficial in the treatment of the symptoms of bronchial asthma, allergic
rhinitis, and drug, serum and transfusion allergic reactions.
- These drugs are not, however, curative.
4. Acceleration of lung maturation
- Respiratory distress syndrome is a problem in premature infants.
- Fetal cortisol is a regulator of lung maturation.
- Consequently, a dose of beclomethasone is administered intramuscularly to the mother 48 hours
prior to birth, followed by a second dose 24 hours before delivery.

‫انا بكتبلك محاضه تذاكر فيها العمر كله‬

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Pharmacokinetics
Absorption and fate
- Synthetic glucocorticoid preparations with unique pharmacokinetic
characteristics are used therapeutically.
- Those that are administered orally are readily absorbed from the
gastrointestinal tract.
Selected compounds can also be administered intravenously,
intramuscularly, intra-articularly (for example, into arthritic joints),
topically, or as an aerosol for inhalation.
Metabolism
- Greater than 90 percent of the absorbed glucocorticoids are bound
to plasma proteins most to corticosteroid- binding globulin, and the
remainder to albumin.
- Corticosteroids are metabolized by the liver microsomal oxidizing
enzymes.
Elimination ): ‫الصوره واالمثله مهمه‬
- The metabolites are conjugated to glucuronic acid or sulfate, and the products are excreted by the
kidney
Dosage:
In determining the dosage of adrenocortical steroids, many factors need to be considered, including:
1. glucocorticoid versus mineralocorticoid activity
2. duration of action
3. type of preparation
4. Time of day when the steroid is administered.
Toxicity (IMP)
- The benefits obtained from glucocorticoids vary considerably. Use of these drugs must be carefully
weighed in each patient against their widespread effects on every part of the organism.
- The major undesirable effects of glucocorticoids are the result of their hormonal actions, which lead to
‫ ر‬. When
the clinical picture of iatrogenic Cushing's syndrome ‫مشوح بالتفصيل يف اخر صفحه لو حابب تزود معلومات‬
glucocorticoids are used for short periods (< 2 weeks), it is unusual to see serious adverse effects even
with moderately large doses.
- However, insomnia, behavioral changes (primarily hypomania), and acute peptic ulcers are
occasionally observed even after only a few days of treatment.
Complications
A. Metabolic Effects
- Most patients who are given daily doses of 100 mg of hydrocortisone or more (or the equivalent
amount of synthetic steroid) for longer than 2 weeks undergo a series of changes that
have been termed iatrogenic Cushing's syndrome.
- The rate of development is a function of the dosage and the genetic background of the patient. In the
face, rounding, puffiness, fat deposition, and plethora usually appear (moon faces).
- Similarly, fat tends to be redistributed from the extremities to the trunk, the back of the neck, and the
supraclavicular fossae. There is an increased growth of fine hair over the face, thighs and trunk
B. Other Complications
- Other serious adverse effects of glucocorticoids include peptic ulcers and their consequences.

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- The clinical findings associated with certain disorders, particularly bacterial and mycotic infections,
may be masked by the corticosteroids, and patients must be carefully monitored to avoid serious
mishap when large doses are used.
- Severe myopathy is more frequent in patients treated with long-acting glucocorticoids.
- The administration of such compounds has been associated with nausea, dizziness, and weight loss in
some patient.
C. Adrenal Suppression
- When corticosteroids are administered for more than 2 weeks, adrenal suppression may occur.
- If treatment extends over weeks to months, the patient should be given appropriate supplementary
therapy at times of minor stress (two-fold dosage increases for 24- 48 hours) or severe stress (up to
ten-fold dosage increases for 48-72 hours) such as accidental trauma or major surgery.
Contraindications & Cautions
A. Special Precautions
Patients receiving glucocorticoids must be monitored carefully for the development of hyperglycemia,
glycosuria, sodium retention with edema or hypertension, hypokalemia, peptic ulcer, osteoporosis,
and hidden infections. The dosage should be kept as low as possible, and intermittent administration
(eg, alternate-day) should be used when satisfactory therapeutic results can be obtained on this
schedule.
B. Contraindications
Glucocorticoids must be used with great caution in patients with peptic ulcer, heart disease or
hypertension with heart failure, certain infectious illnesses such as varicella and tuberculosis, psychoses,
diabetes, osteoporosis, or glaucoma.
Withdrawal
Withdrawal from these drugs can be a serious problem, because if the patient has experienced HPA
suppression, abrupt removal of the corticosteroids causes an acute adrenal insufficiency syndrome that
can be lethal.
This, coupled with the possibility of psychologic dependence on the drug and the fact that withdrawal
might cause an exacerbation of the disease, means the dose must be tapered according to the
individual, possibly through trial and error. The patient must be monitored carefully.
Inhibitors of adrenocorticoid biosynthesis
Several substances have proven to be useful as inhibitors of the synthesis of adrenal steroids:
metyrapone, aminoglutethimide, ketoconazole, trilostane, spironolactone, and eplerenone.
Mifepristone  competes with glucocorticoids for the receptor.
 is used for tests of adrenal function and can be used for the treatment of pregnant
women with Cushing's syndrome.
Metyrapone interferes with corticosteroid synthesis by blocking the final step (11-
hydroxylation) in glucocorticoid synthesis, leading to an increase in 11 -
deoxycortisol as well as adrenal androgens and the potent mineralocorticoid 11-
Metyrapone deoxycorticosterone.
 The adverse effects include
- salt and water retention
- hirsutism ) ‫( ظهور علمات الذكوره عل الناث‬
- transient dizziness
- gastrointestinal disturbances.
Amino-  This drug acts by inhibiting the conversion of cholesterol to pregnenolone.

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glutethimide  As a result, the synthesis of all hormonally active steroids is reduced.
 Aminoglutethimide has been used therapeutically in the treatment of breast
cancer to reduce or eliminate androgen and estrogen production. In these cases,
it is used in conjunction with dexamethasone.
 is an antifungal agent that strongly inhibits all gonadal and adrenal steroid
Ketoconazole hormone synthesis. It is used in the treatment of patients with Cushing's
syndrome.
 reversibly inhibits 3β-hydroxysteroid dehydrogenase and, thus, affects
Trilostane aldosterone, cortisol, and gonadal hormone synthesis.
 Its side effects are gastrointestinal.
 At high doses, mifepristone is a potent glucocorticoid antagonist as well as an
antiprogestin.
 It forms a complex with the glucocorticoid receptor, but the rapid dissociation of
Mifepristone
the drug from the receptor leads to a faulty translocation into the nucleus.
 Its use is presently limited to the treatment of inoperable patients with ectopic
ACTH syndrome
 This antihypertensive drug competes for the mineralocorticoid receptor and, thus,
inhibits sodium reabsorption in the kidney.
 It can also antagonize aldosterone and testosterone synthesis. It is effective
against hyperaldosteronism.
 Spironolactone is also useful in the treatment of hirsutism in women, probably
Spironolactone due to interference at the androgen receptor of the hair follicle.
 Adverse effects include:
- hyperkalemia
- gynecomastia
- menstrual irregularities
- skin rashes.
 specifically binds to the mineralocorticoid receptor, where it acts as an
aldosterone antagonist.
Eplerenone
 This specificity avoids the side effect of gynecomastia that is associated with the
use of spironolactone. It is approved as an antihypertensive.
Adverse effect ‫ كـ‬gynecomastia ‫ بس مبيعملش‬Spironolactone ‫زي الـ‬
B. Mineralocorticoids
 Mineralocorticoids help to control the body's water volume and concentration of electrolytes,
especially sodium and potassium.
 Aldosterone acts on kidney tubules and collecting ducts, causing a reabsorption of sodium,
bicarbonate, and water.
 Conversely, aldosterone decreases reabsorption of potassium, which, with H+, is then lost in the
urine.
 Enhancement of sodium reabsorption by aldosterone also Occurs in gastrointestinal mucosa and in
sweat and salivary glands
 Elevated aldosterone levels may cause alkalosis and hypokalemia, whereas retetion of sodium
and water leads to an increase in blood volume and blood pressure.
 Hyperaldosteronism is treated with spironolactone.

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 Target cells for aldosterone action contain mineralocorticoid receptors that interact with
the hormones in a manner analogous to that of the glucocorticoid receptor
Physiologic& Pharmacologic Effects
 Aldosterone and other steroids with mineralocorticoid properties promote the reabsorption of
sodium from the distal part of the distal convoluted tubule and from the cortical collecting renal
tubules, loosely coupled to the excretion of potassium and hydrogen ion.
 Sodium reabsorption in the sweat and salivary glands, gastrointestinal mucosa, and across cell
membranes in general is also increased.
 Excessive levels of aldoste rone produced by tumors or overdosage with synthetic mineralocorticoids
lead to hypokalemia, metabolic alkalosis, increased plasma volume, and hypertension.
 Mineralocorticoids act by binding to the mineralocorticoid receptor in the cytoplasm of target cells,
especially principal cells of the distal convoluted and collecting tubules of the kidney.
 The drug-receptor compiex activates a series of events similar to those described above for the
glucocorticoids.
 It is of interest that this receptor has the same affinity for cortisol, which is present in much higher
concentrations in the extracellular fluid
 The specificity for mineralocorticoids in the kidney appears to be conferred, at least in part, by the
presence of the enzyme 11-hydroxysteroid dehydrogenase type 2, which converts cortisol to
cortisone. The latter has low affinity for the receptor and is inactive as a mineralocorticoid or
glucocorticoid.
 The major effect of activation of the aldosterone receptor is increased expression of Na+,K+ ATPase
and the epithelial sodium channel (ENaC)
Metabolism
 Aldosterone is secreted at the rate of 100-200 mcg/d in normal individuals with a moderate dietary
salt intake. The plasma level in men (resting supine) is about 0.007 mcg/dL. The half-life of
aldosterone injected in tracer quantities is 15-20 minutes, and it does not appear to be firmly bound
to serum proteigs
 The metabolism of aldosterone is similar to that of cortisol about 50 mcg/24 h appearing in the urine
as conjugated tetrahydroaldosterone.
Approximately 5-15 mcg/24 h is excreted free or as the 3- oxo glucuronide.
Deoxycorticosterone (DOC)
- DOC, which also serves as a precursor of aldosterone, is normally secreted in amounts of about 200
mcg/d.
- Its half-life when injected into the human circulation is about 70 minutes.
- The control of its secretion differs from that of aldosterone in that the secretion of DOC is primarily
under the control of ACTH
- Although the response to ACTH is enhanced by dietary sodium restriction, a low-salt diet does not
increase DOC secretion.
Fludrocortisone
- This compound, a potent steroid with both glucocorticoid and mineralocorticoid activity, is the most
widely used mineralocorticoid.
- Oral doses of 0.1 mg two to seven times weekly have potent salt retaining activity and are used in the
treatment of adrenocortical insufficiency associated with mineralocorticoid deficiency.
- These dosages are too small to have important anti- inflammatory or antigrowth effects.

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Addison’s Disease )‫(زياده‬

 Adrenocortical Insufficiency: Hypofunction of adrenal cortex. So which hormones will be decreased?

ALL OF THEM (so the treatment is hormones replacement).
 Types of adrenocortical insufficiency:
PRIMARY (ADDISON’S DISEASE) SECONDARY
All hormones will be decreased: from all 3 cortical Only glucocorticoids will be decreased
layers .
autoimmune , idiopathic, infection (TB) , inadequate pituitary ACTH secretion.
iatrogenic
ACTH normal or high ACTH is low
Hyperpigmentation No pigmentation
High K and low Na Normal K and normal Na or low
Metabolic Acidosis No metabolic Acidosis
ETIOLOGY OF ADDISON'S
 Idiopathic atrophy → autoimmune condition where antibodies attack against own adrenal cortex,
and 90% of tissue destroyed.
 TB/fungal infections (histoplasmosis)
 Iatrogenic causes → adrenalectomy, chemotherapy, anticoagulant tx
SIGNS & SYMPTOMS:
 Fluid & electrolyte imbalances:  Changes in skin pigmentation : ↓cortisol -
- Hypotension . ↑ACTH - ↑MSH
- Hyponatremia .  Muscular weakness.
- Hyperkalemia (serum is high but urine is low).  Androgens are low causing: pubic hair loss and
- Hypoglycemia . decreased
 Salt craving.  sexual drive for women. (men are not affected)
 Fatigue, weight loss, anorexia ; due to low  Mental disturbances: anxiety, irritability, etc.
cortisol.
Cushing’s Syndrome )‫(زياده‬
 TOO MUCH CORTISOL! Increases secretion of cortisol from adrenal cortex, or it can be from another
source (endogenous or exogenous).
 4 times more frequent in females, and usually occurs at 35-50 years of age.
ETIOLOGY
 Primary (20%): Tumor of the adrenal cortex
 Secondary (80%): Tumor of the anterior pituitary gland
 Ectopic: ACTH secreting tumor
 Iatrogenic: Therapeutic steroid administration
SIGNS & SYMPTOMS:
Cushing’s original description was a “tomato head, potato body, and four matches as legs.”

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