INSTRUCTOR:Scott T' Eblen Ph'D'

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Adrenal Steroids
INSTRUCTOR Scott T. Eblen Ph.D. Department of
Cell and Molecular Pharmacology eblen_at_musc.edu
Reading References Text Goodman and Gilman,
The Pharmacological Basis of Therapeutics, 11th
Edition, pp. 1587-1612.
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OBJECTIVES 1.Review the physiology of the
adrenocorticosteroids. 2.Review hyperfunction of
the adrenal cortex and the therapeutic
approaches to inhibit production of adrenal
steroids. 3.Review hypofunction of adrenal
cortex and the therapeutic approaches to
replacement therapy for the adrenal
steroids. 4.Describe a model of inflammation and
discuss the mechanism of action of the
glucocorticoids as antiinflammatory agents.
5.Describe the major side-effects of the
glucocorticoids.
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PROTOTYPE DRUGS Glucocorticoids Cortisol
(Cortex, Hydrocortisone) Prednisone
(Deltasone, Meticorten) Beclomethasone
Mineralocorticoid Fludrocortisone
(Florinef) Inhibitors of Steroid
Synthesis Metyrapone (Metopirone) Aminoglut
ethimide (Cytadren)
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• Introduction to endocrine pharmacology (adrenal
  steroids, sex hormones,)
• A. Clinical uses of endocrine drugs
• 1. Hormone replacement
• 2. Modulation of excess hormone production
• 3.Treatment of nonendocrine disease -
• e.g. asthma (glucocorticoids), hypertension
  (mineralocorticoid antagonists).

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B. Generalized scheme
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hypothalamic-pituitary portal vasculature
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CRH, corticotropin-releasing hormone TRH,
thyrotropin-releasing hormone GnRH,
gonadotropin-releasing hormone ACTH,
corticotropin TSH, thyrotropin LH, luteinizing
hormone FSH, follicle-stimulating hormone.
Peptide hormone- binds a GPCR (CRF1,2) in AP
39aa peptide hormone- binds a GPCR (MC2R)
Adrenal gland
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D. Examples of drugs used to affect endocrine
systems






Adrenal lecture
Sex hormone lecture
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• E. Serum binding proteins
• F. The nuclear receptor superfamily
• 1. Intracellular location
• 2. Transcription factors
• 3. Adrenal Cortex-
• a. Glucocorticoid
• b. Mineralocorticoid Aldosterone-electrolyte/wat
  er balance
• 4. Sex hormones
• a. Estrogen Receptor (alpha and beta)
• b. Progesterone Receptor (PR-A, PR-B)
• c. Androgen Receptor

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II. PHYSIOLOGY OF THE ADRENAL STEROIDS A.
Functions 1. Influence metabolism
(glucocorticoids) a. Carbohydrate and
protein metabolism i. Cellular uptake of
glucose- decreased ii. Protein
catabolism-increased Leads to hyperglycemia-
side effect of taking glucocorticoids. Stimulate
the liver to form glucose from amino acids
(gluconeogenesis) and glycerol and to store
glucose as liver glycogen. In periphery,
decrease glucose utilization, increase protein
breakdown Net result is increase in blood
glucose (hyperglycemia)
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b. Lipid metabolism increased lipolysis
altered distribution of body fat 2. Confer
resistance to stress 3. Regulation of immune
function- immunosuppression eg corticosteroids-tis
sue transplant to prevent rejection 4.
Modulation of the inflammatory response-antiinflam
matory 5. Electrolyte and water balance
(mineralocorticoids)-act on distal tubules and
collecting ducts of the kidney Na
retention K, H excretion also work in colon,
salivary glands, and sweat glands
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B. Synthetic Routes for Production of Adrenal
Steroids
rate limiting step
CYP11A1/desmolase
Sex Hormones ?
11-b-hydroxylase
Aldosterone
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C. Site of synthesis - adrenal cortex
Aldosterone-regulates Na, K, electrolytes
Cortisol-antiinflammatory, immunosuppression
Androgens
DHEA
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D. Glucocorticoid Synthesis and Release Are
Regulated by ACTH
CRH corticotropin releasing hormone ACTH
adrenocorticotropic hormone
Pro-inflammatory cytokines
TNF-? IL-1 IL-2 IL-6
Immune system
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Adrenal Hormones
Incr MC, GC activ, slower metab.
Required
Reduction required
Increases GC. activity
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E. Mechanism of Action of Adrenal
Steroids Steroid actions are mediated at target
tissues by intracellular receptor proteins that
directly regulate the transcription of sets of
target genes. Two receptor systems have been
identified, the glucocorticoid receptor (type II)
and the mineralocorticoid receptor (type
I). Steps in the mechanism of action 1. Steroid
binds to receptor protein in the cytoplasm 2.
Steroid-receptor complex is rapidly translocated
to the nucleus 3. Steroid-receptor complex binds
to DNA (GRE) 4. Direct regulation of
transcription of target genes 5. Resulting
change in protein synthesis
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Pharmacological studies have shown that the
steroid classes are not restricted to interacting
with a single receptor class the glucocorticoids
in particular can have substantial
mineralocorticoid activity. In support of these
studies, molecular cloning has shown that the
mineralocorticoid and glucocorticoid receptors
share a high degree of homology in their
DNA-binding domain and steroid-binding
domain. Plasma cortisol concentration is
100-fold higher than aldosterone concentration
11?-hydroxysteroid dehydrogenase Expressed in
aldosterone sensitive tissues- salivary gland,
colon, kidney Cortisol therapy can overwhelm the
system, causing Na retention
A major development for selective therapy has
been the chemical synthesis of synthetic
glucocorticoids which have relatively low
mineralocorticoid activity (e.g. prednisone).
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Glucocorticoid effect
Mineralocorticoid effect
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III. PHARMACOKINETICS A. Absorption
glucocorticoids are effective orally, topically,
and parenterally
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Also available as topical preparations
(dermatitis), aerosols (asthma), and
suppositories (ulcerative colitis) B. Transport
In plasma, 90 of cortisol is bound, mostly to
corticosteroid-binding globulin (CBG, aka
transcortin), but only 50 of aldosterone C.
Excretion in urine, as water soluble forms
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IV. HYPERFUNCTION OF THE ADRENAL
CORTEX Hypersecretion of mineralocorticoids by
the zona glomerulosa results in the syndrome of
primary hyperaldosteronism and hypersecretion of
glucocorticoids by the zona fasciculata results
in Cushings syndrome. A. Primary Aldosteronism
(usually due to a tumor) 1. Sustained
hypersecretion of aldosterone results in the
syndrome of primary aldosteronism. A major
symptom of this disorder is hypertension.
Hypervolemia and sodium retention are the likely
causes of the hypertension and are due to the
renal actions of aldosterone. 2. The
treatment for many forms of this disorder is
often surgical however, treatment for
bilateral hyperplasia is pharmacological with
the use of spironolactone (a competitive
aldosterone receptor antagonist). Spironolactone
reduces the hypervolemia and sodium retention
caused by the actions of aldosterone on the
kidney and ultimately reduces the blood pressure.
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• B. Hypercortisolism (Cushings Syndrome)
• The hypersecretion of cortisol can result from
  the excess production of ACTH (secondary -
  pituitary or ectopic derived) or from autonomous
  hypersecretion of cortisol by a tumor in the
  adrenal cortex (primary). The clinical
  manifestations include redistribution of fat
  (buffalo hump, moon face), muscle wasting,
  osteoporosis, and hypertension.

Buffalo Hump
Moon Face
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2. Treatment is often surgical or radiation
therapy however, pharmacological intervention of
cortisol action is possible with the
following a. Mitotane (O,P-DDD)
(LYSODREN) decreases circulating levels of
cortisol by a lytic action on the adrenal
fasciculata cells. Used for adrenal cancer
treatment, Cushings Syndrome. causes adrenal
atrophy b. Aminoglutethimide (CYTADREN)
inhibits the conversion of cholesterol to
pregnenolone, thereby inhibiting all steroid
synthesis- inhibits desmolase (CYP11A1). Also
inhibits aromatase
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c. Ketoconazole (NIZORAL) an antifungal agent.
inhibits steroid biosynthesis in higher doses.
Inhibits CYP17 (17a-hydroxylase). At even higher
doses, inhibits desmolase, blocking all
steroidogenesis. Most effective inhibitor of
steroidogenesis in Cushings disease d.
Metyraponedecreases circulating levels of
cortisol by inhibiting the 11-?-hydroxylase
reaction along the synthetic route to cortisol.
Also used as a diagnostic drug for testing
hypothalamic-pituitary ACTH function e.
Mifepristone glucocorticoid receptor
antagonist-not used as often-used when other
therapies fail
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IV. HYPOFUNCTION OF THE ADRENALS A. Adrenal
hypofunction exists in three major forms 1)
primary adrenal failure (Addisons disease), 2)
secondary hypoadrenalism (as a result of ACTH
deficiency), and 3) selective hypoaldosteronism B.
Adrenal insufficiency (primary and secondary)
coupled with hypoaldosteronism usually
presents with weight loss, fatigue, pigmentary
changes, hypotension, and muscle weakness. C.
Treatment of adrenal insufficiency consists of
glucocorticoid replacement (cortisol) and as
needed, mineralocorticoid replacement
(Fludrocortisone). The cortisol treatment
returns the metabolic disturbances towards
normal and the fludrocortisone returns the
electrolyte levels and blood pressure towards
normal.
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VI. Therapeutic principles- Antiinflammatory
A. Mineralocorticoid receptor blockers in CHF
and HT (spironolactone, eplerenone). B.
Glucocorticoid uses - except for replacement,
largely empirical when there is no known
disturbance of adrenal function.
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• C. Glucocorticoids as antiinflammatory drugs
• The development of an inflammatory reaction is
  dependent on
• a. Increased local blood flow and vascular
  permeability to allow for extravasation of fluid
  and cells (edema formation). These responses are
  mediated by vasoactive factors that include
  leukotrienes, prostaglandins, bradykinin, and
  histamine.
• b. The recruitment and migration of leukocytes
  to the area, which depends upon chemoattractant
  factors released during inflammation such as
  leukotrienes and interleukins.

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• Glucocorticoid treatment suppresses inflammation
  in part by blocking the synthesis of these
  inflammatory mediators.
• Ligand-receptor complex is a transcription factor
  that directly suppresses transcription of these
  inflammatory mediators (e.g. COX-2).
• Ligand-receptor complex also interacts with other
  transcription factors (e.g. NF-?B and AP-1) to
  oppose their proinflammatory activities.
• D. Glucocorticoids as immunosuppressive drugs
  Similarly, glucocorticoids inhibit the synthesis
  of immunoregulatory molecules such as
  interleukins and other cytokines.

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• E. Side effects of long term usage
• 1. Hyperglycemia-can be managed with diet and/or
  insulin
• 2. Fluid and electrolyte disturbances-
  hypertension, edema
• 3. Increased susceptibility to infection
• 4. Myopathy can be severe, recovery may be
  slow or incomplete
• 5. Osteoporosis Ca2 uptake, all ages, related
  to dosage and duration, ribs/vertebrae, Ca2,
  vitamin D therapy 30-50 of chronic
• 6. Osteonecrosis mainly femoral head, joint
  pain/stiffness, progressive
• 7. Cataracts especially children, may not
  resolve with cessation
• 8. Behavioral disturbances nervousness,
  insomnia
• 9. Iatrogenic adrenal insufficiency prolonged
  suppression of the hypothalamic-pituitary axis

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Corticosteroid Withdrawal Should Be Gradual
Most frequent side effect- flare-up or the
underlying disease Sudden cessation leads to
acute adrenal insufficiency, due to the prolonged
suppression of the HPA axis Need
weeks/months/year to have full recovery of the
HPA axis Normal withdrawal symptoms- fever,
muscle and joint pain, and malaise
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F. Therapeutic considerations 1.
Contraindications peptic ulcer, osteoporosis,
hypertension, infection, psychosis 2. Alternate
day therapy- decreases the prolonged
suppression 3. Relief of symptoms
glucocorticoids do not cure 4. Especially
useful for a. Diseases that occur in episodes
(e.g. rheumatoid arthritis) b. Topical
applications
G. Future selective modulators
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H. In practice (Goodman and Gilman) 1. For any
disease, in any patient, the appropriate dose to
achieve a given therapeutic effect must be
determined by trial and error and be reevaluated
from time to time as the stage and the activity
of the disease change. 2. A single dose of
corticosteroid, even a large one, is virtually
without harmful effects. 3. A few days of
corticorticosteroid therapy, in the absence of
specific contraindications, is unlikely to
produce harmful results except at the most
extreme dosages. 4. As corticosteroid therapy is
prolonged over periods of weeks or months, and to
the extent that the dose exceeds the equivalent
of substitution therapy, the incidence of
disabling and potentially lethal effects
increases. 5. Except in adrenal insufficiency,
the administration of corticosteroids is neither
specific nor curative therapy, but only
palliative by virtue of their antiinflammatory
and immunosuppressive effects. 6. Abrupt
cessation of prolonged, high-dose corticosteroid
therapy is associated with a significant risk of
adrenal insufficiency of sufficient severity to
be threatening to life.