Basic and Clinical Pharmacology  90% bound to corticosteroid-binding

C39 ADRENOCORTICOSTEROIDS & globulin (CBG) in the plasma

ADRENOCORTICAL ANTAGONISTS  CBG is increased in pregnancy and with
Adrenocorticosteroids estrogen administration and
hyperthyroidism
 Steroid hormones
 Low affinity to albumin
 Released into circulation by the adrenal cortex
 Well absorbed from the GI tract
 Secretion is controlled by the release of ACTH
from the pituitary gland  Cleared by the liver
 Secretion of aldosterone is under the influence of  1/3 is excreted in the urine and measured
angiotensin as 17-hydroxysteroids
 Glucocorticoids  Short duration of action compared with its
synthetic congeners, half-life of 60-90
 Effects on intermediary metabolism,
minutes
catabolism, immune response, and
inflammation  Diffuses poorly across normal skin
 Cortisol  Readily absorbed across inflamed skin
and mucous membranes
 Mineralocorticoids
 Has a small but significant salt-retaining
 Salt-retaining activity by regulating Na and K
+ +

(mineralocorticoid) effect
reabsorption in the collecting tubules of the
kidney  Important cause of hypertension
 Aldosterone  Cortisol-secreting adrenal tumor
 Androgenic or estrogenic activity  Pituitary ACTH-secreting tumor
(Cushing’s syndrome)
 Dehydroepiandrosterone (DHEA)
 Major adrenal androgen
 Mechanism of Action
 Major endogenous precursors of estrogen in
women after menopause and in younger  Most of the effects are mediated by
patients whom ovarian function is deficient 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 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
 Glucocorticoids  Mediate anti-growth, anti-
 Cortisol inflammatory and
 Major natural occurring glucocorticoid immunosuppressive effect of
 Hydrocortisone, compound F glucocorticoids
 Physiologic secretion  Organ and Tissue Effects
 Regulated by adrenocorticotropin  Metabolic effects
(ACTH)  Stimulate gluconeogenesis,
 Circadian rhythm blood glucose rises
 Varies during the day  Insulin secretion is
 Peak occurs in the morning and after stimulated
meals  Inhibits uptake of
 Trough occurs about midnight glucose by the muscle
 Synthesized from cholesterol
 cells, muscle protein is
catabolized
 Stimulate hormone sensitive
lipase
 Both lipolysis
lipogenesis
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
maintenance
adequate glucose
supply to the brain
 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
 Immunosuppressive effects
 Inhibit mechanisms involved in cell-
mediated immunologic functions
 Dependent on lymphocytes
 Actively lymphotoxic and
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
 Anti-inflammatory effects
 Dramatic effect on the concentration
distribution and function
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)
and  Other effects
are  Required for normal renal
excretion of water loads
 Effects on the CNS
 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
to  Antagonize the effect of vitamin D on
of 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)
are
of
 Synthetic glucocorticoids
 Source
 Synthesized from cholic acid from cattle
or steroid sapogenins in plants
 Disposition
 Rapidly and completely absorbed when
given by mouth
 Pharmacodynamics
 Similar to cortisol
 Mechanism of Action
 Identical to cortisol
 Reduced salt-retaining effect
  Better penetration of lipid barriers for  Glucocorticoid with a low degree of
topical activity protein binding to increase transfer
 Beclomethasone and budesonide across the placenta
 Special glucocorticoids used in asthma and  Given to pregnant women in premature
other conditions labor (before 34 weeks)
 Good surface activity on mucous membranes  Hastens maturation of the fetal lungs
or skin  12 mg IM, additional dose of 12 mg 18-
 Readily penetrate the airway mucosa 24 h later
 Very short half-lives after they enter the  Degree of benefit differs considerably in
blood, the systemic effects and toxicity are different disorders
greatly reduced  Not usually curative, pathologic process may
progress, manifestations are only
 CLINICAL USES suppressed
Adrenal disorders  Toxicity when given chronically limits their
 Addison’s disease use
 Partial or complete loss of adrenocortical
function, including loss of glucocorticoid  Toxicity
and mineralocorticoid function  Iatrogenic Cushing’s syndrome
 Adrenal suppression  Due to excessive hormonal effects
 Suppression of the ability of the adrenal  Metabolic effects
cortex to produce corticosteroids  Growth inhibition
 Most commonly due to iatrogenic effect  Diabetes
of prolonged exogenous glucocorticoid  Muscle wasting
treatment  Osteoporosis
 Chronic adrenal cortical insufficiency  Other effects
 Weakness, fatigue, weight loss,  Peptic ulcer and its
hypotension, hyperpigmentation and consequences
inability to maintain blood glucose level in  Salt and fluid retention due
the fasting state to mineralocorticoid effect
 Acute adrenal insufficiency associated  Psychosis
with life-threatening shock, infection, or  Adrenal suppression
trauma  When administered
 Congenital adrenal hyperplasia (CAH) for more than 2
 Synthesis of abnormal forms of weeks
corticosteroid  From suppression of
 Genital abnormalities in the fetus ACTH secretion
 Cushing’s syndrome  Contraindications and Cautions
 Metabolic disorder caused by excess  Monitor for the development of
secretion of adrenocorticoid steroids  Hyperglycemia glycosuria
 Most commonly due to increased  Hypokalemia peptic ulcer
amounts of ACTH  Osteoporosis hidden infection
 ACTH secreting pituitary adenoma  Sodium retention with edema and
 Rounded plethoric face, truncal obesity, hypertension
muscle wasting, thinning, osteoporosis  Methods for minimizing toxicities
 Aldosteronism  Dose should be kept as low as
Nonadrenal disorders possible
 Many disorders respond to corticosteroid  Alternate-day therapy
therapy  Reduces pituitary suppression after
 Anti-inflammatory or immunologic in control is achieved
nature  Tapering the dose soon after
 Asthma achieving therapeutic response
 Organ transplant rejection  Special dosage forms
 Collagen diseases  Local therapy
 Exophthalmos  Topical for skin diseases
 Hematopoietic cancers, neurologic  Ophthalmic forms
disorders, chemotherapy-induced  Intra-articular injections
vomiting, hypercalcemia, and mountain
 Inhaled steroids
sickness
 Hydrocortisone enemas
 Aerosols for the treatment of asthma and
 Betamethasone
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
 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
 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
 Synthesis Inhibitors
 Used in the treatment of adrenal cancer
 When surgical therapy is impractical or
unsuccessful because of metastases
 Most important drugs
 Ketoconazole
 Aminoglutethimide
 Metyrapone
Aminoglutethimide
 Blocks the conversion of cholesterol to
pregnenolone
 Inhibits synthesis of all hormonally active
steroids
 Used in conjunction with other drugs
 Hydrocortisone or dexamethasone
for breast CA
 Tamoxifen
 Aromatase inhibitors
 Metyrapone or ketoconazole for
steroid-producing adrenocortical
cancer
Ketoconazole
 Antifungal drug
 Nonselective inhibitor of CP450 enzymes
necessary for the synthesis of all steroids
 Inhibitory effects seen only at high doses
 Adrenal carcinoma
 Hirsutism
 Breast and prostate cancer
Metyrapone
 Selective inhibitor of steroid 11-
hydroxylation
 Inhibits the normal synthesis of cortisol
and corticosterone
 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
 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

 Mineralocorticoid antagonists
 Compete with aldosterone for its receptor
and decrease its effect peripherally

Spironolactone
 K+-sparing diuretic
 Aldosterone antagonist
 Slow onset of action
 Treatment of hypertension, aldosteronism

Eplerenone
 Treatment of hypertension
 More selective than spironolactone
 No effect on androgen receptor
 Hyperkalemia is mild

Drospirenone
 Progestin in oral contraceptive
 Antagonizes the effects of aldosterone