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Chapter 39 Adrenocorticosteroids

zona glomerulosa 15%


Secretes mineralocorticoids


Adrenal
gland
zona fasciculata 25%
Secretes glucocorticoids


cortex

zona reticularis 60%


Secretes adrenal androgens

Medulla secretes Epi& NE 1


Adrenal Gland

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Adrenocorticosteroids

Mineralocorticoids, Glucocorticoids ,inte- adrenal androgens&


have salt retaining mediate metabolism estrogens
capacity

aldosterone Cortisol dehydroepiandrosterone


desoxycorticosterone (Hydrocortisone)
Structure-activity relationships
1. Steroid nucleus is the common structure;
2. The keto group in C3, carbonyl group in
C20, and the double bond between C4 &
C5 are essential for both glucocorticoids
& mineralocorticoids
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21
20
17
hydrocortisone

aldosterone

3. There is an -hydroxyl group linked to


C17 in glucocorticoids but not in
mineralocorticoids.
4. In sex hormones, C20 & C21 are dehydroepiandrosterone
usually absent. 4
Adrenocrtical steroids include:
Glucocorticoids( cortisol, hydrocortisone) with
important effects in intermediary metabolism,
affecting carbohydrate,fat & protein metabolism.
They also affect body immunity & inflammation.
Mineralocorticoids (aldosterone) regulate water &
electrolyte balance(homeostasis) by altering K+ &
Mg+2 secretion & Na+ tubular reabsorption.
Androgenic & estrogenic steroids, testosterone,
dehydroepiandroeterone(DHEA)sulphate & estradiol
infleunce reproductive system as well as affecting
primary & secondary sex characteristics
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Androstenedione & androstendiol are weak
androgens or estrogen(by conversion)
Adrenal androgens are the main precursors of
estrogens in women after menopause or
younger patients with deficient ovarian function
The adrenals can synthesize estradiol & estrone
from testosterone & androstenedione
respectively

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Adrenocorticosteroids

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Physiological regulation & mechanism of glucocorticoids
secretion

_
(Hypothalamus-pituitary-adrenal gland axis)

Hypothalamus _
+ CRH CRH: corticotropin
_ releasing hormone;
Anterior pituitary
ACTH:
+ ACTH

plasma
adrenocorticotrophic

Adrenal cortex hormone

Cortisol(hydrocortisone)
secretion 8
Actions of mineralocorticoids & glucocrticoids
are not completely separate.
Some glucocorticoids have substantial salt
retaining effects & increase BP.
The adrenal gland is essential for life.

Deficiency in corticosteroids causes Addisons


disease, characterized by muscle weakness,
fatigue, low BP, depression, anorexia, weight
loss, hypoglycemia(due to glucocorticoid
insufficiency), hyperpigmentation of skin ( due
to excess ACTH) 9
Addisons disease may be due to autoimmune
defects or chronic inflammation such as
tuberculosis.
Excess glucocorticoids causes Cushings
syndrome
Excess aldosterone(called Cronns syndrome, or
primary hyperaldosteronism) causes
disturbances in Na+ and K+ balance.
Secondary hyperaldosteronism is due to
excessive rennin-angiotensin action that occurs
in liver cirrhosis, kidney disease or CHF 10
Pharmacokinetics:
Cortisol regulates many body functions including:
Intermediary metabolism, CVS function, growth, and
immunity.
Synthesis & secretion are regulated by CNS which is
very sensitive to negative feedback mechanism by
circulating cortisol or exogenous glucorticoids
Cortisol is synthesized from cholesterol
Secretion in normal adult without stress is10-20mg/d
Rate of secretion follows a circadian rhythm governed
by pulses of ACTH that peak in the early morning
hours and after meals
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Cortisol is transported bound to proteins (CBG)
CBG is increased in pregnancy, with estrogen
administration and in hyperthyroidism &
decreased by hypothyriodism, genetic defects &
protein deficiency states
T1/2 of cortisol is 60-90 min.
Excretion in urine as metabolites( cortisone,
dihydroxyketone etc)

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Fluctuation in plasma ACTH& glucorticoids
throughout the day in normal girl

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Pharmacodynamics
A :Mechanism of action of corticosteroids:
The steroid (S) is transported in blood bound to plasma
globulin(CBG) but enters the cell as a free molecule.
The receptor (R) in cytoplasm is bound to a stabilizing protein
Hsp90.When it binds cortisol molecule, an unstable complex
is formed and the Hsp90 is released.
The steroid-receptor complex dimerize, enter the nucleus,
bind to a glucocorticoid response element (GRE) on the
regulatory region of the gene and regulates transcription by
RNA polymerase II and associated transcription factors.
The resulting mRNA is edited and exported to cytoplasm for
protein synthesis that brings about the response.
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Mechanism of action of glucocorticoids

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B. Physiological Effects 19/11/2015
They influence the function of most body cells.
They act directly in cells.
Many effects are dose related.
Some effects, called permissive effects need the
presence of glucocorticoids to occur, eg the response
of vascular and bronchial smooth muscle to
catecholamines is diminished in absence of cortisol.
Also the lipolytic effects of fat cells to
catecholamines, ACTH and GH are attenuated in
absence of glucocorticoids
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C. Metabolic Effects
Glucocorticoids have important dose related effects
on metabolism of carbohydrates, proteins and fats.
They stimulate and are required for gluconeogenesis
and glycogen synthesis in the fasting state
They increase serum glucose levels thus promote
insulin release and inhibit uptake of glucose by muscle
cells
They stimulate lipolysis by stimulating lipase
Increased insulin release stimulates lipogenesis and
inhibit lipoysis leading to a net effect of fat deposition
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Net effects of glucocorticoids on metabolism in
the fasting state is to:
-Increase glucose supply from gluconeogenesis
-Release of aminoacids from muscle catabolism
-Inhibition of peripheral glucose uptake
-Stimulation of lipolysis
All these actions maintain an adequate glucose
supply to the brain in the fasting state

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D. Catabolic & Antianaboloic Effects
Glucocorticoids stimulate protein synthesis in
liver, but have catabolic and antianabolic effects
in muscle, lymphoid tissue, peripheral fat & skin
Large concentrations of glucocorticoids or
prolonged use lead to decreased muscle mass,
weakness, thining of skin and poor wound
healing.
In bone these effects lead to osteoporosis as in
Cushings syndrome.
Reduce growth in children. 19
D. Anti-inflammatory &
immunosuprressive effects:
Reduce manifestation of inflammation by:
Decrease concentration and function of
leuckocytes
Decreased function and concentration of
inflammatory cytokines, chemokines and
other inflammatory mediators
They also inhibit functions of tissue
macrophages and other antigen- presenting
cells 20
Glucocorticoids also influence the inflammatory
response by reducing synthesis of PGs,LTs,and PAF
due to inhibition of phospholipase A2
They also reduce expression of COX-2 in
inflammatory cells thus reducing PGs synthesis.
Glucocorticoids cause vasoconistriction in skin due to
suppression of mast cells degranulation
They also reduce capillary permeability due to
reduction of insulin release by mast cells and basophils
The antiinflammatory and immunosupressant actions
of glucocorticoids are largely due to the actions
described above 21
Antiinflammatory effects of glucocorticoids
Glucocorticoids increase
the synthesis of
lipocortin-1, that has
inhibitory effect on
phospholipas A2 and
therefore inhibit the
production of lipid
mediators as well as
inhbit genes coding for
COX-2.

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Immunosuppressive action of glucocorticoids

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F. Other actions of glucocorticoids
Large amounts cause insomnia, euphoria then
depression
Increased intracranial pressure in large doses

Chronic doses suppress pitiutary release of


ACTH,GH,TSH, and LH
Large doses may cause peptic ulcer due to
suppression of local immune response against
H. pylori 15/11/2016

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They also promote fat redistribution in body with
increased visceral,facial, nuchal and supraclavicular fat,
they antagonize effect of vit D on calcium absorption
They have important effects on hematopoietic system
by increasing number of RBCs and platelets
Deficiency results in impaired renal function,increased
vaspressin secretion and diminished ability to excrete
water load
They are important in development of fetal lungs.
They are required for production of pulmonary
surface active materials(surfactants) required for air
breathing(permessive effects).
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G. Anti shock effect:
Mechanisms:
Decrease inflammatory factors release;
Increase body resistance to bacterial endotoxin;
Cause vasoconistriction & increase myocardial
contractibility
Decrease vascular sensitivity to some vasoconstrictors
Decrease myocardial depressant factor generation
because of stabilizing lysosome membrane.

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Pharmacological effects
H. Hematic effects:
1)Stimulation of hematopoiesis in bone marrow
Leading to increased RBCs,increased haemoglobin,
increased platelets and increased fibrinogen (in
high dose).
Neutrophils increases in number, but decreases in
function
2) Lymphocytes in blood are decreased.
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Pharmacological effects

J. Gastrointestinal effects:
Increased gastric acid, increased pepsin
leading to peptic ulceration.
K. Central nervous exciting effects:
Euphoria, excitation, insomnia;
Anoia induced occasionally;
High dose induces convulsion in chidren.

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Representative Glucocorticoids:

Natural:
hydrocortisone cortisone
Synthetic:
prednisone prednisolone
methylprednisolone triamcinolone
dexamethasone betamethasone
fluocilonone beclometasone
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Clinical use:
1. Replacement therapy(Adrenocortical insufficiency)
Addisons disease, anterior hypopituitarism , post-
subtotal bilateral adrenalectomy .
2.Antiinflammatory effect Acute serious infections as
adjuvants in:
Bacterial infection: fulminant dysentery, bacterial
meningitis, toxic pneumonia, heavy typhoid, acute miliary
tuberculosis, scarlatina, septicemia
Viral infection: heavy infectious hepatitis, epidemic
parotitis, measles, encephalitis
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Clinical uses cont.:
3. Sequalae of some inflammation: conglutination or scar
pyogenic meningitis, encephalitis, pericarditis, rheumatic heart
disease, traumatic arthritis, testitis, iritis, keratitis, burn.
4. Autoimmunity diseases & allergic diseases
1) Autoimmunity diseases
rheumatic fever, rheumatic myocarditis, rheumatic arthritis
rheumatoid arthritis, systemic lupus erythematosus , polyarteritis
nodosa, dermatomyositis, nephrotic syndrome, etc.
2) Organ transplantation rejection
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Clinical use:
4. Autoimmunity diseases & allergic diseases
3) Allergic diseases
urticaria, pollenosis, serum sickness, angioneurotic
edema, allergic rhinitis, asthma, etc.
5. Shocks
1) Septic shock: early, short, large dose.
2) Anaphylactic shock: the support drugs
3) Cardiogenic shock
4) Hypovolemic shock: transfusion first
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Clinical use
6. Hematic diseases
acute lymphoblastic leukemia, aplastic anemia,
granulocytopenia, thrombocytopenia, allergic purpura
syndrome
7. Local use on skin
contact dermatitis, eczema, anus tickle, psoriasis,
neurodermatitis
Hydrocortisone, prednisolone & fluocilonone prefered

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Adverse Effects:
1. Complications during chronic uses
1) Cushings syndromes
body obesity, rounded face, increased fat around the
neck, thinning arms & legs, acne, hirsutism, edema,
hypokalemia, hypertension, diabetes.
2) Inducement or aggravation of infections
3) Complications of digestive system
inducement or aggravation of peptic ulcer
pancreatitis, sebaceous hepatitis appeared occasionally
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Adverse effects of corticosteroids

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2.Adverse Reactions
1. Complications during chronic uses
4) Complications of cardiovascular system
hypertension, atherosclerosis.
5) Osteoporosis, sweeny and wound healing delay
6) Other complications
anoia, teratogenesis

2. Withdraw
1) Iatrogenic adrenal insufficiency
2) Original disease relapse or aggravation
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Contraindications:
Patients with:
peptic ulcer, heart disease, heavy hypertension with
heart failure, infectious disease such as varicella,
tuberculosis, and psychoses, epilepsy, osteoporosis,
diabetes, or glaucoma
Carefully used or forbidden!
In summary, decision & caution both needed for
the use of glucocorticoids; evaluate advantages &
disadvantages of using glucocorticoids before use .
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Pharmacokinetics
1. Absorption: Oral or injectable
administration is easily absorbed.
2. Transport: >90 % of hydrocortisone is
reversibly bound to protein if its total
concentration in plasma < 25g %; 2 plasma
proteins: cortisosteroid-binding globulin
(CBG) & albumin.
3. Distribution: The concentration in liver is
high.
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4. Metabolism: Activity losing for all &
activation for some are performed in liver
=O in C11 replaced by OH in liver are
essential for getting activities. e.g.
cortisonehydrocortisone; prednisone
prednisolone.
5. Excretion: kidney

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Dosage & schedule
Low dosage for replacement therapy
Addisons disease, anterior hypopituitarism ,
post subtotal bilateral adrenalectomy
cortisone 12.525 mg/d, or hydrocortisone
1020 mg/d.
Universal dosage for long term therapy in:
inflammations, rheumatoid arthritis,
lymphoma, lymphoblastic leukemia.
Started with prednisone 1020 mg, tds;
gradually decreased to the maintenance dose
after obtained the initial effect. 42
High dosage for implosive therapy
Serious infections: hydrocortisone i.v.d.
200-300 mg, 1 g/d.
Shocks: hydrocortisone v.d. 1 g, 4-6 g/d.

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Antagonists of Adrenocortical Agents:
Synthesis inhibitors and glucocorticiod
antagonists:
(1)Aminoglutethemide blocks the conversion
of cholesterol to pregnenolone thus reduces
production of steroids
It is used in conjunction with dexamethasone or
hydrocortisone to reduce or eliminate estrogen
production in breast carcinoma
(2) ketoconazole is an antifungal that inhibits
synthesis of adrenal and gonadal steroids
It is used to treat Cushings syndrome 44
(3)Metyrapone: inhibits cortisol synthesis.
It inhibits steroid 11 hydroxylation.

In presence of normal pituitary, there is a


compensatory increase in ACTH release&
adrenal 11-deoxycortisol secretion.Thus
metyrapone is used to diagnose& assess anterior
pituitary function
Can be given to pregnants with Cushings syndrome
(4)Trilostane: is a 3-17 hydroxysteroid
dehydrogenase inhibitor .It interferes with adrenal&
gonadal hormones synthesis
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(5) Abiraterone:
It blocks 17 hydroxylase and 17,20 lyase and thus
reduces synthesis of adrenal and gonadal steroids
It is tested for treatment of refractory prostate
cancer
(6) Mifepristone:
Is an antagonist at steroid receptor

It has strong antiprogestin and antiglucocorticoid


receptor activity
Is used in treatment of Cushings syndrome

(7) Mitotane: has cytotoxic effect on adrenal


cortex. Reduces adrenal tumors 46
Mineralocorticoids Antagonists
Agents that inhibit aldosterone synthesis
include:
Agents that interfere with aldosterone action on
its receptor site such as spironolactone. Have a
slow onset of action but
but effects last for 2-3 days after drug is
discontinued
Used in treatment of primary aldosteronism.

Also used to diagnose primary aldosternism


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Is also an androgen antagonist & can be
used to treat hirsutism in women
Is also used as a diuretic

Eplerinone is a selective receptor


antagonist without androgenic effects.
Is used in hypertension.

Drospirenone is a progestin that


antagonizes the effects of aldosterone

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Objectives for Adrenocorticosteroids
Diseases and clinical manifestations to consider:
Primary and secondary adrenocorical
insufficiency: (Addisons disease)
-weakness, fatigue,weight loss, inability to maintain
blood glucose levels during fasting(due to
glucorticoids insuffiency), hyperpigmentation of skin
(due to excess ACTH).
Adrenocortical Hyperactivity(congenital adrenal
hyperplasia)
-adrenocortical hypertrophy(due to hyperstimulation by
ACTH),virilization(due to excessive androgen
production) 49
Cushings syndrome:
-muscle atrophy,thinning of skin, redistribution of fat
to face and trunk,poor wound healing (due to
excessive glucocorticoid activity)
Primary Aldosteronism(Conns syndrome)

-hypertension,polyuria,muscle weakness and


tetany(due to excessive mineralocorticoid activity)
Drugs to consider:

-synthetic glucocorticoids: cortisol,cortisone,


dexamethasone, triamcinolone, betamethasone.
Synthetic mineralocorticoids: fludrocortisone.

Aldosterone antagonists: spironolactone. .50


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