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

Adrenal Gland

Adrenocorticosteroids
Mineralocorticoids,
have salt retaining
capacity

Glucocorticoids ,inte- adrenal androgens&

mediate metabolism estrogens

aldosterone

Cortisol

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
3

dehydroepiandrosterone

C4 & C5 are essential for both

glucocorticoids & mineralocorticoids

21

hydrocortisone

aldosterone

3. There is an -hydroxyl group linked

to C17 in glucocorticoids but not in
mineralocorticoids.

20
17

4. In sex hormones, C20 & C21

are
us4ually absent.

dehydroepiandrosterone

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.
5

Androgenic & estrogenic steroids,

testosterone,

dehydroepiandroeterone(DHEA)sul
phate
&
estradiol
infleunce
reproductive system as well as affecting
primary
&
secondary
sex
characteristics

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

Adrenocorticosteroid
s

Physiological

regulation & mechanism of glucocorticoids

secretion
(Hypothalamus-pituitar

y-adrenal gland axis)

_
othalamus

_+ CRH
_

Hyp

Anterior pituitary
+ ACTH

pla

Adrenal cortex
Cortisol(hydrocortisone)

secretion

CRH: corticotropin

adrenocorticotrophic

releasing hormone; ACTH:

hormone

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

syndrom
e
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
oc curs in liver cirrhosis, kidney
disease or CHF
10

Pharmacokin
etics:
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
11

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
12

T1/2 of cortisol is 60-90

min.

Excretion in urine as metabolites(

cortisone,

dihydroxyketone
etc)

13

Fluctuation in plasma ACTH&

glucorticoids
throughout the day in normal girl

Pharmacodyna
mics

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.

Mechanism of action of
glucocorticoids

15

B.PhysiologicalEffects 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
16

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
17

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
18

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

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.

Anti-inflammatory
&
.
D
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
antigen20

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
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.

22

Immunosuppressive action of
glucocorticoids

23

F. Other actions of
glucocorticoids
Large amounts cause insomnia,
euphoria then

depressio
n
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
24

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).
25

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.
26

Pharmacological

effects

H. Hematic effects:

)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

)Lymphocytes in blood are decreased.

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.

Representative Glucocorticoids:
Natural:
hydrocortisone cortisone
Synthetic:
prednisone
prednisolone
methylprednisolone
triamcinolone

dexamethasone
betamethasone fluocilonone
beclometasone

30

Clinical use:
1. Replacement therapy(Adrenocortical insufficiency)
Addisons disease, anterior hypopituitarism , postsubtotal bilateral adrenalectomy .
2. Antiinflammatory effect Acute serious infectionsas
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
31

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

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

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 p

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

Adverse effects of
corticosteroids

37

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
38

2) Original disease relapse or aggravation

39

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 .

Pharmacokinetics

1. Absorption:

Oral or injectable
administration is easily
absorbed.
2. Transport: >90 % ofhydrocortisone 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.
40

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
prednisolon
e.
5.
kidney

41

Excretion:

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 10
20 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. 200300 mg, 1
g/d.
Shocks: hydrocortisone v.d. 1
g, 4-6 g/d.
43

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

(3) Metyrapone: inhibits cortisol

synthesis.
It inhibits steroid 11
hydroxylation.
In presence of normal pituitary,
there is a
compensatory increase in ACTH
release&
adrenal
11deoxycortisol
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

(5)

Abiratero
ne:
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)
Mifepristo
ne:

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

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

discontinue
d
Used in treatment of primary
aldosteronism.

Also used to diagnose primary

aldosternism

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

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

Thank
you

fo

r
listeni
ng
51