39 ADRENOCORTICOSTEROIDS &

ADRENOCORTICAL ANTAGONISTS
AQSangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS Glucocorticoids

Adrenocorticosteroids
 Steroid hormones
 Released into circulation by the adrenal cortex
 Secretion is controlled by the release of ACTH
from the pituitary gland
 Secretion of aldosterone is under the influence
of angiotensin
1. Glucocorticoids
 Effects on intermediary metabolism, catabolism,
immune response, and inflammation
 Cortisol
2. Mineralocorticoids
 Salt-retaining activity by regulating Na+ and K+
reabsorption in the collecting tubules of the
kidney
 Aldosterone
3. Androgenic or estrogenic activity
 Dehydroepiandrosterone (DHEA)
 Major adrenal androgen
 Major endogenous precursors of estrogen in
women after menopause and in younger patients
whom ovarian function is deficient
ADRENOCORTICAL HORMONE
BIOSYNTHESIS
Cortisol
 Major natural occurring glucocorticoid
 Hydrocortisone, compound F
 Physiologic secretion
 Regulated by adrenocorticotropin
(ACTH)
 Circadian rhythm
 Varies during the day
 Peak occurs in the morning and
after meals
 Trough occurs about midnight
 Synthesized from cholesterol
 90% bound to corticosteroid-binding globulin
(CBG) in the plasma
 CBG is increased in pregnancy and with
estrogen administration and hyperthyroidism
 Low affinity to albumin
 Well absorbed from the GI tract
 Cleared by the liver
 1/3 is excreted in the urine and measured as 17-
hydroxysteroids
 Short duration of action compared with its
synthetic congeners, half-life of 60-90 minutes
 Diffuses poorly across normal skin
 Readily absorbed across inflamed skin and
mucous membranes
 Has a small but significant salt-retaining
(mineralocorticoid) effect
 Important cause of hypertension
 Cortisol-secreting adrenal tumor
 Pituitary ACTH-secreting tumor
(Cushing’s syndrome)

A. Mechanism of Action

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 Most of the effects are mediated by the widely
distributed glucocorticoid receptors
 Enter the cell and bind to cytosolic receptors that
transport the steroid into the nucleus
 Tissue specific responses to steroids are possible
 Different protein regulators present in
each tissue that control the interaction
between the hormone-receptor complex
Corticosteroids
Short-to medium-acting glucocorticoids
Hydrocortisone (cortisol)
Cortisone
Prednisone
Prednisolone
Methylprednisolone
Meprednisone
Intermediate-acting glucocorticoids
Triamcinolone
Paramethasone
Fluprednisolone
Long-acting glucocorticoids
Betamethasone
Dexamethasone
Mineralocorticoids
Fludcortisone
Deoxycorticosterone
and particular response elements
 Widespread effects because they
influence the function of most cells in
the body
 Steroid receptor complex alters gene expression
 Binds to glucocorticoid response
elements (GREs) or mineralocorticoid-
specific elements
 Form complexes and influences function
of other transcription factors
 Mediate anti-growth, anti-
inflammatory and
immunosuppressive effect of
glucocorticoids
B.Organ and Tissue Effects
1.Metabolic effects
 Stimulate gluconeogenesis, blood glucose rises
 Insulin secretion is stimulated
 Inhibits uptake of glucose by the muscle cells,
muscle protein is catabolized
 Stimulate hormone sensitive lipase
 Both lipolysis and lipogenesis are
stimulated
 Net increase of fat deposition in
certain areas
 Face (moon facies)
 Shoulders
 Back (buffalo hump)
 Fasting state
 Supply of glucose from gluconeogenesis
 Release of amino acids from muscle
catabolism
 Stimulation of lipolysis
 All contribute to maintenance of
adequate glucose supply to the
brain
2. Catabolic and antianabolic effects
 Muscle protein catabolism
 High concentrations can lead to lymphoid and
connective tissue, fat, and skin wasting/thinning
 Osteoporosis
 Growth is inhibited in children
3. Immunosuppressive effects
 Inhibit mechanisms involved in cell-mediated
immunologic functions
o Dependent on lymphocytes
 Actively lymphotoxic and are important in the
treatment of hematologic cancer
 Do not interfere with the development of normal
acquired immunity
 Delay rejection reactions in patients with organ
transplants
4. Anti-inflammatory effects
 Dramatic effect on the concentration distribution
and function of leukocytes
 Increase neutrophils
 Decrease lymphocytes, eosinophils,
basophils, and monocytes
 Migration of leukocytes is also
inhibited
 Suppressive effects on inflammatory cytokines
and chemokines and other mediators of
inflammation
 Biochemical mechanisms underlying the cellular
effects
 Induced synthesis of an inhibitor of
phospholipase A2
 Decrease mRNA for COX-2
 Decreases in IL-2 and IL-3, IL-12 and
gamma interferon
 Decreases in PGs, leukotrienes and
platelet activating factor (PAF)
5. Other Effects
 Required for normal renal excretion of water
loads
 Effects on the CNS

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  When given in large doses (especially
for long periods)
 Profound behavioral changes
 Insomnia, euphoria, depression
 Increase intracranial pressure
 Stimulate gastric acid secretion
 Development of peptic ulcer
 Suppressing local immune
response against H. pylori
 Promote fat redistribution with increase visceral,
facial, nuchal and supraclavicular fat
 Increase platelets and rbc
 Antagonize the effect of vitamin D on calcium
absorption
 Development of the fetal lung
 Structural and functional changes in the
lungs near term
 Production of pulmonary surface-active
material for air breathing (surfactant)
Synthetic glucocorticoids
A. Source
 Synthesized from cholic acid from cattle or
steroid sapogenins in plants
B. Disposition
 Rapidly and completely absorbed when given by
mouth
C. Pharmacodynamics
 Similar to cortisol
D. Mechanism of Action
 Identical to cortisol
 Reduced salt-retaining effect
 Better penetration of lipid barriers for topical
activity
Beclomethasone and budesonide
 Special glucocorticoids used in asthma and other
conditions
 Good surface activity on mucous membranes or
skin
 Readily penetrate the airway mucosa
 Very short half-lives after they enter the blood,
the systemic effects and toxicity are greatly
reduced
E. Clinical Uses
1. Adrenal disorders
 Addison’s disease
o Chronic adrenal cortical insufficiency
o Weakness, fatigue, weight loss,
hypotension, hyperpigmentation and
inability to maintain blood glucose level
in the fasting state
o Acute adrenal insufficiency associated
with life-threatening shock, infection, or
trauma
 Congenital adrenal hyperplasia (CAH)
 Synthesis of abnormal forms of
corticosteroid
 Genital abnormalities in the fetus
 Cushing’s syndrome
 Metabolic disorder caused by excess
secretion of adrenocorticoid steroids
 Most commonly due to increased
amounts of ACTH
 ACTH secreting pituitary adenoma
 Rounded plethoric face, truncal obesity,
muscle wasting, thinning, osteoporosis
 Aldosteronism
2. Nonadrenal disorders
 Many disorders respond to corticosteroid
therapy
 Anti-inflammatory or immunologic in nature
 Asthma
 Organ transplant rejection
 Collagen diseases
 Exophthalmos
 Hematopoietic cancers, neurologic disorders,
chemotherapy-induced vomiting, hypercalcemia,
and mountain sickness
 Betamethasone
 Glucocorticoid with a low degree of
protein binding to increase transfer
across the placenta
 Given to pregnant women in premature
labor (before 34 weeks)
 Hastens maturation of the fetal
lungs
 12 mg IM, additional dose of 12
mg 18-24 h later
 Degree of benefit differs considerably in
different disorders
 Not usually curative, pathologic process may
progress, manifestations are only suppressed
 Toxicity when given chronically limits their use
F. Toxicity
1. Iatrogenic Cushing’s syndrome
a. Due to excessive hormonal effects
2. Metabolic effects
a. Growth inhibition
b. Diabetes
c. Muscle wasting
d. Osteoporosis
3. Other effects
1. Peptic ulcer and its consequences
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 2. Salt and fluid retention due to
mineralocorticoid effect
3. Psychosis
4. Adrenal suppression
1. When administered for more than 2
weeks
2. From suppression of ACTH secretion
3. Suppression of the ability of the adrenal
cortex to produce corticosteroids
4. Most commonly due to iatrogenic effect
of prolonged exogenous glucocorticoid
treatment
G. Contraindications and Cautions
 Monitor for the development of
 Hyperglycemia glycosuria
 Hypokalemia peptic ulcer
 Osteoporosis hidden infection
 Sodium retention with edema and hypertension
 Methods for minimizing toxicities
 Dose should be kept as low as possible
 Alternate-day therapy
 Reduces pituitary suppression
after control is achieved
 Tapering the dose soon after achieving
therapeutic response
 Special dosage forms
 Local therapy
 Topical for skin
diseases
 Ophthalmic forms
 Intra-articular injections
 Inhaled steroids
 Hydrocortisone enemas
o Aerosols for the treatment of
asthma and nasal sprays for
allergic rhinitis
 Beclomethasone
 Budesonide
 Flunisolide
 Mometasone
 Patients who have had long term
therapy
 To avoid adrenal
insufficiency
 Additional “stress doses” may
need to be given
 During serious illness
 Before major surgery
 Patients who are being
withdrawn after protracted use
 Doses tapered slowly,
over the course of
several months
 To allow recovery of
normal adrenal function
Mineralocorticoids
1. Aldosterone
 Major natural mineralocorticoid in humans
 Direct connection to hypertension
 Control of its secretion by angiotensin II
 Regulated by renin-angiotensin system
 Important in the regulation of blood volume and
BP
 Short half-life and little glucocorticoid activity
 Mechanism of action is the same as that of
glucocorticoid
 Promote sodium reabsorption from the DCT and
CCT
 Act by binding to mineralocorticoid receptor in
the cytoplasm of the target cell
 Increase expression of the Na+K+ATPase and
epithelial sodium channel
 Metabolism is similar to cortisol
2. Other Mineralocorticoids
Deoxycorticosterone
 Naturally occurring precursor of aldosterone
 Secretion under the control of ACTH
Fludrocortisone
 Both glucocorticoid and mineralocorticoid
activity
 Most widely used
 Oral with long duration of action
 Replacement therapy after adrenalectomy and in
other conditions in which mineralocorticoid is
needed
Corticosteroid Antagonists
1. Synthesis Inhibitors
 Used in the treatment of adrenal cancer
 When surgical therapy is impractical or
unsuccessful because of metastases
 Most important drugs
o Ketoconazole
o Aminoglutethimide
o Metyrapone
Aminoglutethimide
 Blocks the conversion of cholesterol to
pregnenolone
 Inhibits synthesis of all hormonally active
steroids
 Used in conjunction with other drugs
o Hydrocortisone or dexamethasone for
breast CA
o Tamoxifen
o Aromatase inhibitors
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 o Metyrapone or ketoconazole for steroid-  K+-sparing diuretic
producing adrenocortical cancer  Aldosterone antagonist
Ketoconazole  Slow onset of action
 Antifungal drug  Treatment of hypertension, aldosteronism,
 Nonselective inhibitor of CP450 enzymes hirsutism
necessary for the synthesis of all steroids Eplerenone
 Inhibitory effects seen only at high doses  Treatment of hypertension
 Adrenal carcinoma  More selective than spironolactone
 Hirsutism
 No effect on androgen receptor
 Breast and prostate cancer
 Hyperkalemia is mild
Metyrapone
Drospirenone
 Selective inhibitor of steroid 11-hydroxylation
 Inhibits the normal synthesis of cortisol and  Progestin in oral contraceptive
corticosterone  Antagonizes the effects of aldosterone
 Used in diagnostic test of adrenal and pituitary
function
 Lesser toxicity than mitotane
 Only drug that can be administered in pregnant
patients with Cushing's

Trilostane
 3 beta-17 hydroxysteroid dehydrogenase
inhibitor
 Interferes with synthesis of adrenal and gonadal
hormones
 Comparable with aminoglutethimide, no cross-
resistance
 Adverse effects in the GI
Abiraterone
 Orally active steroid prodrug
 Newest steroid synthesis inhibitor
 Blocks 17-alpha-hydroxylase and 17, 20-lyase
 Reduces cortisol and gonadal steroids

2. Glucocorticoid Receptor Antagonist

Mifepristone (RU-486)
 Inhibitor at glucocorticoid receptors as well as
progesterone receptors
 Pharmacologic antagonist at the steroid receptor
 20 half-life, strong binding to plasma proteins
 Treatment of Cushing’s syndrome
Mitotane
 Related to DDT insecticide
 Nonselective cytotoxic action on the adrenal
cortex
 Toxic effects are severe to require dose reduction
 Diarrhea, n/v, depression, somnolence, skin
rashes

3. Mineralocorticoid antagonists
 Compete with aldosterone for its receptor and
decrease its effect peripherally

Spirolonactone