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Adrenocorticosteroids & Adrenocortical
antagonists
Introduction
• The adrenal cortex synthesizes three classes of
steroids: the glucocorticoids, mineralocorticoids
and the androgens
• Glucocorticoids, those having important effects
on intermediary metabolism and immune
function, mineralocorticoids, those having
principally salt-retaining activity and those
steroids having androgenic or estrogenic activity
Introduction
• In humans, cortisol (hydrocortisone) is the
glucocorticoid
and
aldosterone
is
the
mineralocorticoid
main
main
• Quantitatively, dehydroepiandrosterone (DHEA) is the
major adrenal androgen (20 mg) secreted daily
• Adrenal androgens constitute the major endogenous
precursors of estrogen in women after menopause and in
younger patients in whom ovarian function is deficient or
absent
Introduction
• The adrenal gland synthesizes steroids from cholesterol,
which is derived from plasma lipoproteins
• Some of the reactions in the biosynthetic pathway can be
inhibited by drug
• Ex: Metyrapone prevents the β-hydroxylation at C11, and
thus the formation of hydrocortisone and corticosterone
From: Adrenocorticosteroids & Adrenocortical Antagonists
Basic & Clinical Pharmacology, 13e, 2015
Legend:
Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is
the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes
and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure.
When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Reproduced, with
permission, from Ganong WF: Review of Medical Physiology, 22nd ed. McGraw-Hill, 2005. Copyright © The McGraw-Hill
Companies,
Inc.) 2/15/2015
Date of download:
Copyright © 2015 McGraw-Hill Education. All rights reserved.
Introduction
• Both natural and synthetic corticosteroids are used for the
diagnosis and treatment of a variety of inflammatory and
immunological disorders
• Secretion of the adrenocortical steroids is controlled by the
pituitary release of corticotropin (ACTH)
• Secretion of the salt retaining hormone aldosterone is primarily
under the influence of angiotensin
• Inhibitors of the synthesis or antagonists of the action of
adrenocortical steroids are important in the treatment of
several conditions
The role of the HPA in the regulation
of glucorticoid hormone synthesis and release
Stress
+
+
Hypothalamus
+
CRH
-
Anterior pituitary
gland
-
ACTH
+
Adrenal cortex
Cortisol
Circardian & pulsatile
rhythms
Regulation of adrenocortical hormone Secretion
• Three characteristic modes of regulation of the HPA axis:
a) Diurnal rhythm in basal steroidogenesis
b) Marked increases in steroidogenesis in response to
stress (e.g injury, hemorrhage, severe infection, major
surgery, hypoglycemia, cold, pain, and fear)
c) Negative feedback regulation by adrenal corticosteroids
Glucocorticoids
• Principal human glucocorticoid is cortisol
• In the normal adult, in the absence of stress, 10–20 mg of
cortisol is secreted daily
• It exerts a wide range of physiologic effects, including
regulation of intermediary metabolism, CV function,
growth, and immunity
• Rate of secretion follows circadian rhythm governed by
irregular pulses of ACTH that peak in the early morning
hours and after meals
From: Adrenocorticosteroids & Adrenocortical Antagonists
Basic & Clinical Pharmacology, 13e, 2015
Legend:
Circadian variation in plasma cortisol throughout the 24-hour day (upper panel). The sensitivity of tissues to glucocorticoids is also
circadian but inverse to that of cortisol, with low sensitivity in the late morning and high sensitivity in the evening and early night
(lower panel). The sensitivity of tissues to glucocorticoids is inversely related to that of glucocorticoid receptor (GR) acetylation by
the transcription factor CLOCK; the acetylated receptor has decreased transcriptional activity. (Adapted, with permission, from
Nader N, Chrousos GP, Kino T: Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab
2010;21:277.
Copyright
Elsevier.) Copyright © 2015 McGraw-Hill Education. All rights reserved.
Date of download:
2/15/2015
Pharmacokinetic
• In plasma, 90% of cortisol is bound to CBG
• ~5–10% is free or loosely bound to albumin (large capacity
but low affinity)
• CBG is increased in pregnancy and with estrogen
administration and in hyperthyroidism
• Synthetic corticosteroids (dexamethasone) largely bound to
albumin rather than CBG
• T1/2 of cortisol in the circulation ~60–90 minutes
• Only 1% of free cortisol is excreted unchanged in the urine;
most is metabolized in the liver
Synthetic glucocorticoids
• Alterations in the glucocorticoid molecule influence its
protein-binding affinity, side chain stability, rate of
elimination, and metabolic products
• Chemical modifications to the cortisol molecule have
generated derivatives with greater separations of
glucocorticoid and mineralocorticoid activity
• The relative anti-inflammatory potency of each of the
synthetic analogues is compared with cortisol and is roughly
correlated with its biological half-life
Synthetic glucocorticoids
• All of the other undesirable side effects of
supraphysiological concentrations of hydrocortisone
have been observed with the synthetic analogues
• Available in a wide range of preparations: orally, IV,
IM, intra-articularly, topically, or as an aerosol for
inhalation
Activity1
Equivalent Oral
Salt-Retaining Dose (mg)
Forms Available
1
20
Oral, injectable, topical
0.8
0.3
0.3
25
5
5
Oral
Oral
Oral, injectable
0.25
4
Oral, injectable
0
4
Oral, injectable
7
0
0
0
4
2
1.5
Oral, injectable, topical
Oral, injectable
Oral
10
10
0
0
0.6
0.75
Oral, injectable, topical
Oral, injectable, topical
2
Oral
Agent
AntiTopical
Inflammatory
Short- to medium-acting glucocorticoids
Hydrocortisone
1
1
(cortisol)
Cortisone
0.8
0
Prednisone
4
0
Prednisolone
5
4
5
Methylprednisolone
Meprednisone2 5
Intermediate-acting glucocorticoids
Triamcinolone
5
Paramethasone2 10
Fluprednisolone2 15
Long-acting glucocorticoids
Betamethasone 25–40
Dexamethasone 30
Mineralocorticoids
Fludrocortisone 10
5
0
250
Desoxycorticosteron 0
e acetate2
0
20
53
Injectable, pellets
Metabolic effects
• GCs have important dose-related effects on CHO, protein,
and fat metabolism
• Glucocorticoids stimulate and are required for
gluconeogenesis and glycogen synthesis in the fasting state
• Stimulate the release of amino acids in the course of muscle
catabolism
• Glucocorticoids increase serum glucose levels and inhibit
the uptake of glucose by muscle cells resulting in increased
blood glucose levels
Metabolic effects
• They stimulate hormone sensitive lipase and thus lipolysis
• The increased insulin secretion stimulates stimulates lipogenesis
and to a lesser degree inhibits lipolysis
• Net effect is to increase in fat deposition combined with
increased release of FA and glycerol into the circulation
• These results are most apparent in the fasting state where
maintains adequate glucose supply to the brain
Anti-inflammatory & Immunosuppressive Effects
•
Glucocorticoids dramatically reduce the manifestations
of inflammation
•
They inhibit both the early and the late manifestations
of inflammation
•
They reverse virtually all types of inflammatory
reaction, whether caused by invading pathogens, by
chemical or physical stimuli, or by inappropriate
deployed immune responses (hypersensitivity or
autoimmune disease)
Catabolic and Antianabolic Effects
•
Glucocorticoids have catabolic and antianabolic
effects in lymphoid and connective tissue, muscle,
peripheral fat, and skin
•
Supraphysiologic amounts of glucocorticoids lead to
decreased muscle mass and weakness and thinning
of the skin
•
Catabolic and antianabolic effects on bone are the
cause of osteoporosis in Cushing's syndrome
•
In children, glucocorticoids reduce growth
Other physiologic effect
• CNS effects: Indirect and direct effects on mood,
behaviour, and brain excitability (adrenal insufficiency is
associated with depression). Large doses of glucocorticoids
may increase intracranial pressure (pseudotumor cerebri).
• GIT: Large doses of glucocorticoids have been associated
with the development of peptic ulcer
• GC tend to produce a negative calcium balance: decrease
Ca2+ absorption in the GIT and increase its excretion by
the kidney
• Chronically suppress the pituitary release of ACTH, GH,
TSH, and LH
Other physiologic effect
• Development of the fetal lungs: stimulates the
production of surfactant required for air breathing
during development of fetal lungs
Clinical Pharmacology
1.
Replacement therapy in adrenocortical insufficiency
•
Adrenal insufficiency can result from:
a) Structural or functional lesions of the adrenal cortex
(primary adrenal insufficiency or Addison's disease)
b) Structural or functional lesions of the anterior pituitary or
hypothalamus OR exogenous corticosteroid use
(secondary adrenal insufficiency)
Clinical Pharmacology
a.
Chronic adrenocortical insufficiency (Addison's disease):
• Characterized by weakness, fatigue, weight loss,
hypotension, hyperpigmentation, and inability to maintain
blood glucose during fasting
• About 20–30 mg of hydrocortisone must be given daily,
with increased amounts during periods of stress
• Synthetic glucocorticoids that are long-acting and devoid
of salt-retaining activity should not be administered to
these patients
Clinical Pharmacology
a.
Chronic adrenocortical insufficiency (Addison's disease):
• Although hydrocortisone has some mineralocorticoid
activity, this must be supplemented by an appropriate
amount of a salt-retaining hormone such as
fludrocortisone
• In an effort to mimic the normal diurnal rhythm of
cortisol secretion, glucocorticoids are generally in two
divided doses; two-thirds in the morning and one-third in
the afternoon
Clinical Pharmacology
b. Acute adrenocortical insufficiency (adrenal crisis)
• Life-threatening disease characterized by GI symptoms
(nausea, vomiting, and abdominal pain), dehydration,
hyponatremia, hyperkalemia, weakness, lethargy, and
hypotension
• The most common cause is abrupt withdrawal of
exogenous glucocorticoids in patients receiving chronic
treatment
• When acute adrenocortical insufficiency is suspected,
treatment must be instituted immediately with parenteral
hydrocortisone
Clinical Pharmacology
2. Congenital Adrenal Hyperplasia (CAH)
• In 90% of patients results from mutations in CYP21 (21βhydroxylase) leading to virilization
• The goals of therapy are to normalize the patient hormone
level by suppressing the release of CRH and ACTH
(decrease production of adrenal androgens)
• Patients require replacement therapy with hydrocortisone,
and those with salt wasting also require mineralocorticoid
replacement (fludrocortisone acetate)
P450scc
Clinical Pharmacology
3. Acceleration of Lung Maturation
•
Reduces the incidence of respiratory distress syndrome in
premature infants
•
When delivery is anticipated before 34 weeks of gestation,
intramuscular betamethasone, 12 mg, followed by an
additional dose of 12 mg 18–24 hours later
Clinical Pharmacology
5. Non-endocrine Diseases
•
The synthetic analogues of cortisol are useful in the
treatment of a diverse group of diseases unrelated to
any known disturbance of adrenal function
•
The usefulness of corticosteroids in these disorders is a
function of their ability to suppress inflammatory and
immune responses and to alter leukocyte function
Therapeutic Indications for the Use of Glucocorticoids in Nonadrenal
Disorders
Disorder
Allergic reactions
Examples
Angioneurotic edema, asthma, bee stings, contact dermatitis, drug reactions, allergic rhinitis,
serum sickness, urticaria
Collagen-vascular disorders Giant cell arteritis, lupus erythematosus, mixed connective tissue syndromes, polymyositis,
polymyalgia rheumatica, rheumatoid arthritis, temporal arteritis
Eye diseases
Acute uveitis, allergic conjunctivitis, choroiditis, optic neuritis
Gastrointestinal diseases
Inflammatory bowel disease, nontropical sprue, subacute hepatic necrosis
Hematologic disorders
Acquired hemolytic anemia, acute allergic purpura, leukemia, autoimmune hemolytic anemia,
idiopathic thrombocytopenic purpura, multiple myeloma
Systemic inflammation
Acute respiratory distress syndrome (sustained therapy with moderate dosage accelerates
recovery and decreases mortality)
Infections
Acute respiratory distress syndrome, sepsis
Inflammatory conditions of Arthritis, bursitis, tenosynovitis
bones and joints
Neurologic disorders
Cerebral edema (large doses of dexamethasone are given to patients following brain surgery to
minimize cerebral edema in the postoperative period), multiple sclerosis
Organ transplants
Prevention and treatment of rejection (immunosuppression)
Pulmonary diseases
Aspiration pneumonia, bronchial asthma, prevention of infant respiratory distress syndrome,
sarcoidosis
Nephrotic syndrome
Renal disorders
Skin diseases
Thyroid diseases
Miscellaneous
Atopic dermatitis, dermatoses, lichen simplex chronicus (localized neurodermatitis), mycosis
fungoides, pemphigus, seborrheic dermatitis, xerosis
Malignant exophthalmos, subacute thyroiditis
Hypercalcemia, mountain sickness
Dosage
• In determining the dosage of adrenocortical
steroids many factors need to be considered:
1)
2)
3)
4)
Glucocorticoid: mineralocorticoid activity
Duration of therapy
Seriousness of the disease
Amount of drug likely to be required to obtain
the desired effect
5) Type of preparation
6) Time of day when the steroid is administered
Route of administration of glucocorticoids
Route of
administration
Agent
Oral
All can be administered orally
IM
Cortisone, desoxycorticosterone, triamicnolone
IV, IM
Aerosol
Intra-nasal
Topical
Dexamethasone, hydrocortisone, methylprednisolone,
prednisolone
Beclomethasone, flunisolide, triamcinolone
Beclomethasone dipropionate, triamcinolone
acetonide, budesonide, flunisolide
Beclomethasone, dexamethasone, hydrocortisone,
triamcinolone
ADEs
• Two categories of toxic effects result from the
therapeutic use of corticosteroids:
a) Those resulting from continued use at supraphysiological doses
b) Those resulting from withdrawal of steroid
therapy
ADE
• Iatrogenic Cushing’s syndrome
• Rounding, puffiness, fat deposition, and plethora (moon
facies)
• Fat redistribution from the extremities to the trunk, the back
of the neck, and the supraclavicular fossae
• Increase growth of fine hair over thigh, trunk & face
• Acne
• Insomnia & increase appetite
• Wound healing impairement
• Myopathy and muscle wasting
• Thinning of the skin, with striae and bruising
• Hyperglycemia; and eventually diabetes
• Osteoprosis
• Aseptic necrosis of the hip
ADEs
•
Immune Responses: glucocorticoid use is associated with an
increased susceptibility to infection and a risk for
reactivation of latent TB
• Fluid and Electrolyte Handling: hypokalemic alkalosis and
hypertension .Use synthetic non-salt-retaining steroids, Na+
restriction, & potassium supplements
• CNS:
– Hypomania or acute psychosis may occur, particularly in
patients receiving very large doses of corticosteroids
– Long-term therapy with intermediate- and long-acting
steroids is associated with depression and the
development
ADEs
•
•
Ocular: Increased intraocular pressure is common, and
glaucoma may be induced.
Growth retardation: particularly medium-,
intermediate-, and long-acting glucocorticoids
ADEs
• Withdrawal of Therapy
•
Characterized by flare-up of the underlying disease for
which steroids were prescribed and acute adrenal
insufficiency, results from overly rapid withdrawal of
corticosteroids after prolonged therapy has suppressed the
HPA axis
•
A characteristic glucocorticoid withdrawal syndrome
consists of fever, myalgia, arthralgia, malaise, and N, V,
which may be difficult to differentiate from some of the
underlying diseases for which steroid therapy was
instituted
Contraindications & Cautions
• CONTRAINDICATIONS:
•
•
•
•
Peptic ulcer
Hypertension
Infections
Psychoses
•
•
•
•
Diabetes
Heart failure
Osteoporosis
Glaucoma
• CAUTIONS:
• Monitor for developing hyperglycemia, hypokalemia,
hypernatremia
• In case of withdrawal supply with adequate fluids and maintain
electrolyte balance
Mineralocorticoids
• The most important mineralocorticoid in humans is
aldosterone
• Fludrocortisone, a synthetic corticosteroid, is the most
common prescribed salt-retaining hormone
• The quantities of aldosterone produced by the adrenal
cortex and its plasma concentrations are insufficient to
participate in any significant feedback control of ACTH
secretion
• ACTH produces a moderate stimulation of its release
Renin-Angiotensin System
 renal blood flow &/or  Na+
++ Juxtaglomerular apparatus of kidneys
Renin
Angiotensinogen
Angiotensin I
ACE
Angiotensin III
Angiotensin II
(powerful vasoconstrictor)
(powerful vasoconstrictor)
Adrenal
cortex
Aldosterone
Corticosterone
Physiologic & Pharmacologic Effects
• Aldosterone and other steroids with mineralocorticoid
properties promote the reabsorption of Na+ from the distal
part of the distal convoluted tubule and from the cortical
collecting renal tubules, loosely coupled to the excretion of
K+ and H+
• Excessive levels of aldosterone (tumors or overdosage with
synthetic mineralocorticoids) lead to hypokalemia,
metabolic alkalosis, increased plasma volume, and
hypertension
Mineralocorticoid Deficiency
• Leads to hypotension and vascular collapse, Na+ wasting and
contraction of the extracellular fluid volume, hyperkalemia,
and acidosis
• Oral fludrocortisone is used
adrenocortical
insufficiency
mineralocorticoid deficiency
in
the treatment of
associated
with
• Has both mineralo- & glucocorticoid and activity but the
doses used are to small to exert anti-inflammatory and
antigrowth effects
Antagonists of Adrenocortical
agents
Synthesis Inhibitors
a) Aminoglutethimide
•
Blocks the conversion of cholesterol to pregnenolone and
causes a reduction in the synthesis of all hormonally active
steroids
•
Aminoglutethimide can be used in conjunction with
metyrapone or ketoconazole to reduce steroid secretion in
patients with Cushing’s syndrome due to adrenocortical
cancer who do not respond to mitotane
1. Synthesis Inhibitors
b) Metyrapone
•
Interferes with corticosteroid synthesis by blocking the
final step (11-hydroxylation) in glucocorticoid synthesis,
leading to an increase in 11-deoxycortisol and the potent
mineralocorticoid 11-deoxycorticosterone
•
It can be used in diagnostic tests of adrenal function and
can be used to treat pregnant women with Cushing’s
syndrome
•
ADEs: water retention, hirsutism, transient dizziness, & GIT
disturbances
1. Synthesis Inhibitors
e) Abiraterone
• It blocks 17α-hydroxylase (P450c17) and 17,20-lyase, and
predictably reduces synthesis of cortisol in the adrenal and
gonadal steroids in the gonads
• A compensatory increase occurs in ACTH and aldosterone
synthesis, but this can be prevented by concomitant
administration of dexamethasone
• Abiraterone is approved for the treatment of refractory
prostate cancer
2. Recptor antagonists
a) Mifepristone (RU 486)
• At high doses, it is a potent glucocorticoid antagonist as
well as an antiprogestin
• Its use can only be recommended for inoperable patients
with ectopic ACTH secretion or adrenal carcinoma who
have failed to respond to other options tone
2. Recptor antagonists
b) Spironolactone
• Competes aldosterone for the MR and thus inhibits sodium
reabsorption in the kidney
• It also compete with DHT for the androgen receptor and
inhibits 17α-hydroxylase activity
• It is effective against hyperaldosteronism. It is also useful in
the treatment of hirsutism in women, probably due to
interference at the androgen receptor of the hair follicle
• ADEs:
hyperkalemia,
gynecomastia,
menstrual
irregularities, and skin rask
2. Recptor antagonists
c) Eplerenone is a aldosterone antagonist approved for the
treatment of HTN. It specifically avoids the gynecomastia
associated with spironolactone
d) Drospirenone is a progestin in an oral contraceptive
(Yasmin®), also antagonizes the effects of aldosterone