Adrenocorticosteroids

Dr. Asma Khan

Associate Professor
Dept. of Pharmacology
Adrenocorticosteroids
⚫Mineralocoticoids :- Aldosterone
⚫Glucocorticoids :- Cortisol
Hydrocortisone
Corticosterone
⚫Sex hormones
Adrenal gland
Zona
 Hypothalamus

_ Corticotrophin releasing hormone _

-- --
--
Anterior pituitary

ACTH
Shor
Lon t
Feedback
g
Feedbac
-- Adrenal cortex inhibitio
k n
inhibitio
n --
Glucocorticoid Mineralocorticoid
Biosynthesis of Corticosteroids
 21
18

17
11
19

1 9
10

O
H
Cholesterol
Classification of synthetic glucocorticoid

Short to medium acting glucocorticoids:

1. Hydrocortisone (Cortisol)
2. Cortisone
3. Prednisone
4. Prednisolone
5. Methylprednisolone
6. Meprednisone
Intermediate acting Glucocorticoids:
1. Triamcinolone
2. Paramethasone
3. Fluprednisolone
Long acting Glucocoticoids:
4. Betamethasone
5. Dexamethasone
 R+ Hsp90
Hsp9 (Unstable
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S S
Steroid-receptor
R+ R+ Dimer
S S (activated)
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S R+ GR
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Response

Protein

Transcriptio
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Physiological & Pharmacological effects of
Glucocorticoid
A. Physiological effects : the glucocorticoids have
wide spread effects because they influence the
function of most cells of the body.

Permissive effect: many normal reactions that take

place at a significant rate only in the presence of
corticosteroid, e.g. The response of vascular and
bronchial smooth muscle to catecholamine is
diminished in absence of cortisol and restored by
physiologic amount of glucocorticoid.
Cont…
Absence of glucocorticoid – catecholamine, ACTH,
GH have minor effects of lipolysis.
Administration of glucocortiod – potentiate the
effect of lipolysis.
B) Metabolic effects : (dose related )
1) CHO metabolism :
⚫ Stimulate gluconeogenesis in fasted and
diabetes
⚫ Peripheral utilization of glucose is ↓ ed ->
insulin antagonism.
⚫ ↑plasma glucose conc.
Cont…
⚫ Liver - ↑ glycogen deposition by stimulating
glycogen synthase.
Result :
⚫ Hyperglycemia & glycosuria result.
⚫ Latent diabetes become overt.
2) Protein metabolism :
⚫ ↑ed mobilization of AA from skeletal muscle.
⚫ ↑ed nitrogen excretion in the urine
⚫ Negative nitrogen balance with muscle wasting.
Cont…
Result:
⚫Osteoporosis (reduction of bone protein matrix)
⚫Slow growth in children
⚫Skin atrophy.
⚫↑ ed capillary fragility causes bruising & striae.
⚫Healing of PU or wound is delayed.
Cont…
3) Fat Metabolism : -
⚫Promote fat mobilization.
⚫Fat redistributed from periphery to face –moon
face, back of the neck – buffalo hump and at
supra-clvicular region.
C) Catabolic and anti-anabolic effects :
⚫ Glucocorticoids have catabolic and antianabolic
effects in lymphoid and connective tissues,
muscle, peripheral fat and skin.
⚫ Supraphysiologic amounts if glucocorticoids lead
to decreased muscle mass, muscle weakness, and
thinning of skin.
⚫ Osteoporosis occurs in Cushing syndrome and
long term glucocorticoid therapy.
⚫ In children, it reduces growth.
D) : Anti inflammatory and
immunosuppressive effects
⚫ Glucocorticoid dramatically reduce the
manifestation of inflammation
⚫This is due to -
⮚ their effects on the concentration, distribution and
function of peripheral leucocytes
⮚ their suppressive effects on the inflammatory
cytokines, chemokines and on other mediators of
inflammation
What happen in inflammation?
In Inflammation, there is :-
a) extravasation and infiltration of leucocytes to the
affected tissue.
b) interaction of white cell adhesion molecule of
endothelial cells.
⚫Endothelial leukocyte adhesion molecule – 1,
⚫ICAM – 1
.
What Glucocorticoids do in inflammation ?

1) The conc. of neutrophils ↑ ed due to ↑ ed influx

into the blood from bone marrow and ↓ed rate
of removal from the circulation

(This is ‘receptor mediated non-genomic’ action of

Glucocorticoid –which phosphorylate a protein
annexin-1 in cytosol, having potent inhibitory effect
on leukocyte trafficking and other biological
actions. It happens within seconds)
Cont…
2) ↓ es the activity of Macrophage
3) ↓ ed number of circulating lymphocytes,
eosinophils, monocytes & basophils – due to
their movement from the vascular bed to
lymphoid tissue.
4) In areas of acute inflammation 🡪 ↓ ed influx and
activity of leucocytes.
5) In areas of chronic inflammation 🡪 ↓ed activity
of mononuclear cells, ↓ ed proliferation of
blood vessels 🡪 less fibrosis
Cont…
6) It induce lipocortin that inhibit PLA2 🡪
reducing PG, leukotriene and platelet
activating factor (PAF) synthesis. It
reduces the expression of cyclooxygenase-
2.
7) They decrease capillary permeability by ↓
ing histamine release from basophils and
mast cells.
8) Stabilize lysosomal membrane – reducing
the conc. of proteolytic enzyme at the site
of inflammation.
9) Inhibit phagocytosis and killing of micro-
-organism by macrophage.
Effects of glucocorticoids on components
of immune response :
In Immune response-
1) Macrophage produce TNF – α, IL -1, IL -6
metalloproteinase and plasminogen activator.
2) Lymphocytes produce Interleukins TNF – α,
GM-CSF, interferon –γ
Cont…
Glucocorticoids 🡪
⚫ It inhibits the functions of Macrophages and
other antigen presenting cells. Their ability to
respond to antigen and mitogens are reduced.
⚫ ↓es action of T – helper cells and reduced clonal
proliferation of T cells.
Cont…
⚫In lymphoid tissue -- ↓ es clonal expression
of T & B lymphocyte & ↓ ed action of
cytokines – including many Interleukins,
TNF, GM-CSF.
⚫Antibody production can be reduced by
large dose of steroids.

Anti-inflammatory and immunosuppressive

effects of glucocorticods are widely useful
therapeutically
E) Other effects :

Nervous system:
⚫Excess glucocorticoid produce initially insomnia
and euphoria and subsequently depression.
⚫May ↑ intracranial pressure (Pseudotomor
cerebri).
⚫Pituitary -> chronic use suppress pituitary release
of ACTH,GH,TSH and LH.
Other effects
⚫Large doses are associated with Peptic ulcer.
⚫Fat redistribution with ↑ of visceral, facial,
nuchal and supraclavicular fat.
⚫In absence of physiologic amount of cortisol –
⮚ renal function (particularly GFR) is impaired
⮚ vasopressin secretion is augmented
⮚ inability to excrete a water load normally.
Other effects
⚫They antagonize Vit – D, and calcium absorption
⚫Glucocorticoids have important effects on fetal
lung – both structural and functional maturation
near term, including induction of production of
Surfactant.
Adverse effects:
1. Iatrogenic Cushing syndrome.
2. Avascular necrosis if bone (femoral
head) – due to restriction of blood
flow through bone capillaries.
3. Diabetes mellitus.
4. Growth in children is impaired.
5. Peptic ulcer
6. Hypertension
Cont…
7. Depression and Psychoses, insomnia is common
8. Eye -> posterior subcapsular lens cataract,
glaucoma.
9. Increased risk of infections e.g. – previously
dormant TB become active, herpes of the eye
become severe, fungal diseases develop.
10. Osteoporosis, muscle wasting, delayed wound
healing.
11. Hypothalamic / Pituitary / adrenal suppression
Cont…
12. In pregnancy:- intrauterine growth retardation,
risk gestational DM, pregnancy induced HTN
13. Delayed wound healing
14. Fragile skin, proximal myopathy
Indications of glucocorticoid therapy :

A) Diagnosis and treatment of disturbed adrenal

function :
1. Adreno-cortical insufficiency:
a)Chronic (Addison’s disease)
b)Acute adrenal insufficiency
2. Adrenocortical hypofunction
Cont…
3. Adrenocortical hyper-function:
a) Congenital adrenal hyperplasia – At high risk,
Dexamethasone administration to the mother
protect the fetus from genital abnormalities.
b) Cushing syndrome : during and after surgery of
the tumor producing ACTH or cortisol,
irradiation of pituitary tumor or resection of
one or both adrenals.
4. Diagnostic purpose – dexamethasone
suppression test.
Cont…
B) Stimulation of lung maturation in the fetus –
Betamethasone is the drug of choice, because of
its plasma protein binding and less placental
metabolism
C) Non-adrenal disorders – The synthetic analogs
of cortisol are useful in the treatment of a diverse
group of disease unrelated to any known
disturbances of adrenal functions.
Some therapeutic indications for use of
glucocorticoids in non-adrenal disorders :

1) Allergic reactions – Angeoneurotic oedema,

asthma, bee stings, contact dermatitis, drug
reactions, allergic rhinitis, serum sickness,
urticaria.
2) Collagen vascular disorders – Giant cell arteritis,
Lupus erythemetosus, Mixed connective tissue
syndrome, Polymyocitis, Polymyalgia
rheumatica, Rheumatoid arthritis, Temporal
arteritis.
Cont…
3) Eye disease – acute uveitis , allergic
conjunctivitis, choroiditis, optic neuritis.
4) Gastrointestinal diseases – IBS, nontropical
sprue, sub acute hepatic necrosis
5) Hematologic disorders – Acquired Hemolytic
anemia, acute allergic purpura, ITP, Multiple
Myeloma, leukemia.
6) Systemic inflammations – Acute respiratory
distress syndrome
7) Infections - Acute respiratory distress
syndrome, sepsis, TB.
Cont…
8) Inflammatory conditions of bones and joints:
arthritis, bursitis, tenosynuvitis.
9) Neurologic disorders – Cerebral oedema,
multiple sclerosis.
10) Organ transplants – prevention and treatment
of rejection.
11) Pulmonary disease – aspiration pneumonia,
Bronchial asthma, prevention of infant
respiratory distress syndrome, sarcoidosis.
12) Renal disorders – Nephrotic syndrome.
Cont…
13) Skin disease – Atopic dermatitis, dermatoses,
lichen simplex chronicus, mycosis fungoides,
Pemphigus, seborrhic dermatitis, Xerosis.
14) Thyroid disease - Malignant exophthalmos,
subacute thyroiditis.
15) Miscellaneous – Hypocalcaemia, mountain
sickness.
Cont…
15. Neoplastic diseases :-
⚫In combination of cytotoxic drugs in the Rx of
Hodgkin's disease, acute lymphocytic leukemia.
⚫To reduce cerebral edema in pts with primary or
metastatic brain tumor. Dexamethasone is the
drug of choice.
⚫As a component of antiemetic treatment in
conjunction with chemotherapy.
16. Immunological indications :
Graft versus host defense :-
Following organ or bone marrow transplantation –
⚫ Glucocorticoid reduce antigen release from graft
tissue
⚫ Delay revascularization
⚫ Interfere the sensitization of antibody forming
cells
Delayed hypersensitivity reactions :-
⚫ Inhibition of the production & effect of IL-2
⚫ Block the effect of migration inhibitory factor and
Macrophage IF
Patient check-up before & during
corticosteroid therapy
⚫Pulse, BP (weekly)
⚫ Blood sugar (monthly)
⚫Chest X-ray (to exclude latent TB)
⚫ECG
⚫Other bone X-ray (Osteoporosis)
⚫Endoscopy (PUD)
Therapy
⚫More than 2weeks therapy – hypothalamo-
hypophysial axis of cortisol regulation become
suppressed
⚫Withdrawal should be gradual – in tapering dose
over long time
⚫Short course - < 1 week – don’t require gradual
withdrawal
Cont…
⚫ Dosage should be kept as low as possible
⚫ Intermittent administration (alternate day)
⚫ In pts maintained on relatively low dose
corticosteroid may require supplement therapy at
times of stress – e.g. surgical procedure,
intercurrent illness or accidents
Monitoring

Patients receiving Glucocorticoids must be

monitored carefully for –
⚫ Hyperglycemia
⚫ Glycosuria
⚫ Sodium retention with oedema
⚫ Hypertension
⚫ Hypokalemia
⚫ Peptic ulcer
⚫ Osteoporosis
⚫ Hidden infections
Cautions & relative contraindications :

Glucocorticoids must be used with great caution in

pts with –
⚫Peptic ulcer
⚫Heart disease
⚫Hypertension with heart failure
⚫Certain infectious, such as – varicella,TB, fungus
⚫Psychoses, epilepsy
⚫ Diabetes mellitus
⚫Osteoporosis
⚫Glaucoma
⚫Renal failure
Special dosage forms:

⚫ Topical preparations for skin disease

⚫ Ophthalmic preparations for eye disease
⚫ Intra-articular injections for joint disease
⚫ Inhaled steroids for asthma
⚫ Hydrocortisone enemas for ulcerative colitis
Steroids used in asthma as aerosol->
Beclomethasone dipropionate, Budesonide,
Fluticasone, Flunisolide, Momentasone furoate.
⚫Steroids used in allergic rhinitis as spray ->
Beclomethasone dipropionate, Triamcinolone
acetonide, Budesonide, Flunisolide,
Momentasone furoate.
⚫Steroid use in skin disease ->
hydrocortisone, methylprednisolon,
betamethasone, dexamethasone, triamcinolone,
clobetasol
Inhibitors of steroid synthesis :

⚫Aminoglutethimide
⚫Ketoconazole
⚫Metyrapone
⚫Trilostane
⚫Abiraterone
⚫Mitotane
Glucocorticoid receptor antagonist:
Mifepristone (RU-486)
Mineralocortocoids
⚫Aldosterone (natural)
⚫Synthetic – Deoxycorticosterone (DOC),
Fludrocortisones
Mineralocorticoid antagonist:
1. Aldosterone synthesis inhibitors
2. Aldosterone receptor blockers->
⚫Spirenolactone
⚫Eplerenone
⚫Drospirenone
Factors regulating Aldosterone secretion :-
⚫ ed K+ conc. In ECF
⚫ ed Na+ conc. In ECF
⚫ACTH
⚫ ed ECF volume -> ed renin secretion ->
Angiotensinogen Angiotensin I
ACE+
Angiotensin II
+

secretion of Aldosterone.
+
Regulation of Cortisol secretion :-
⚫ACTH
⚫Neuro-hormonal mechanism – different types of stress
(emotion, fear, anxiety, trauma, infection, intense heat or
cold ) cell bodies of CRH secreting neurons
release of CRH stimulates + anterior pituitary to
secret ACTH Zona+ fasciculata to secret Cortisol.
⚫Negative feedback mechanism :- +
Cortisol both Hypothalamus and Pituitary
Metabolites relieve stress 🡪 withdrawal of excitatory
stimulations to hypothalamus.
_
Synthetic corticosteroids:-

Alteration in the glucocorticoid molecule influence its

affinity for glucocorticoid and mineralocorticoid
receptor as well as protein binding affinity, side chain
stability, rate of elimination and metabolic products.
Fluorination at position 9 or 6 has resulted in highly
potent compounds. This and also unsaturation of Δ1-2
bond of A ring and methylation at 2 or 16 position
prolong half life by more than 50%
 CH2O
H
C=
18 O -------
O or 17 OH
OH 16 ----OH or
19 F CH3
1 9
2
3
O

Structure in blue is
Desoxycorticosterone