Corticosteroids

Department of Pharmacology
NEIGRIHMS, Shillong

Steroids
Steroids are fast catching up with antibiotics
as the most abused class of drugs today

High doses of corticosteroids and

other immunosuppressive agents may cause AIDS

Introduction
The adrenal produces various
classes of hormones, each of which
aid in dealing with the stress faced by
animals and people almost daily
At least two of these groups

Glucocorticoids and
Mineralocorticoids

Corticosteroids
are
necessary for or
lifecorticoids refer
to natural
gluco- and mineralo-corticoids and
their

Contents

History and Biosynthesis

Mechanism of action
Physiological and Pharmacological actions
Pharmacokinetics and preparations
Uses therapeutic and diagnostic
Dosage schedule and withdrawal
Adverse reactions and contraindications
Precautions during therapy
Contraindications

History
1855 Addison`s disease
1856 Adrenal glands essential for life
1930 Cortex > medulla
1932 Cushings syndrome
1952 Aldosterone

Anatomy

An inner medulla, is a

source of catecholamine
adrenaline and nor-adrenaline
Chromaffin cell is the principal
cell type
Medulla is richly innervated by
sympathetic fibres and is
considered as extension of
sympathetic nervous system
Medulla develops from
ectoderm (neural crest)

An outer cortex, which

secretes several classes of

steroid hormones including
Glucocorticoids and
Mineralocorticoids
Three different concentric
zones of cells that differ in
major steroid hormones they
secrete
Cortex develops from
mesoderm

Adrenal Cortex

The adrenal cortex is a factory of steroid hormones

10 30 different steroids are synthesized from this
tissue, but two classes are of importance

Steroid Class

Prototype

Mineralocorticoid Aldosterone (z. glomerulosa)

Glucocorticoid

Physiological effect
Na, K and water
homeostasis

Hydrocortisone or cortisol (z. fasciculata) Glucose and many

other homeostasis
Corticosterone

Adrenal cortex also produces sex steroids Androgens,

Dehydroepiandrosterone (DHEA) z. reticularis

Biosynthesis

Synthesized from cholesterol

through a series of enzymemediated transformations
ACTH stimulates adrenal
steroid synthesis
Aldosterone synthesis is not
stimulated by ACTH but by
angiotensin II, although ACTH
does stimulate synthesis of
aldosterone precursors
Circulating Potassium exerts a
permissive effect on
angiotensin II stimulation; high
potassium enhances and low
potassium diminishes

Steroid Biosynthesis - contd.

Basal Secretion
Group

Hormone

Daily

Glucocorticoids

Cortisol
Corticosterone

5 30 mg
2 5 mg

Mineralocorticoids

Aldosterone
11- deoxycorticosterone

5 150 mcg
Trace

DHEA
Progesterone
Oestradiol

15 30 mg
0.4 0.8 mg
Trace

Sex Hormones
Androgen
Progestogen
Oestrogen

Regulation of Synthesis
Synthesized

and
released under
influence of ACTH - Ant.
Pituitary (HPA axis)
Regulated by CRH
from hypothalamus
and by feedback
levels of blood
concentrations

Regulation of Synthesis - Others

1.

2.

Control by circadian
rhythm (Diurnal
rhythm) morning
rise
Stress:
hypoglycaemia,
physical stress etc.

Diurnal variation of Cortisol

Glucocorticoids - MOA

Not stored:

rate of synthesis = rate of release

Synthesize rhythmically and controlled by

irregular pulses of ACTH, influenced by light and
major pulses occur early in the morning and
after meals
Glucocorticoids act via their receptors located in
nucleus (GR)
GRs are widely distributed and located almost in
all cells of the body
They are made up of almost 800 amino acids

Glucocorticoids - MOA

GR receptors are located in the cytoplasm

One GR receptor has a DNA binding domain and a
ligand binding domain along with stabilizing proteins
(HSP 90 and HSP 70)
This receptor is incapable of activating transcription
Binding of free steroid molecule to GR forms an unstable
compound
Therefore HSP and other proteins get dissociated
The S+GR complex enters the nucleus and binds to
Glucocorticoids response element (GRE) on gene and
regulate transcription by RNA polymerase II and others
The resulting mRNA is transported to cytoplasm for
production of protein and bring about final response

Glucocorticoids - MOA

Actions
Numerous and widespread actions:

Carbohydrate, lipid and protein metabolism

Fluid and electrolyte balance
Normal functioning of CVS, immune system, kidneys, skeletal muscles and nervous system
Provides resistance to stress and noxious stimuli and environmental changes
Permits and facilitates the actions of other hormones

Direct Actions

Permissive Actions

Lipolytic effects
Effect on BP
Effect on bronchial muscles
(e.g.,sympathomimetic amine)

Actions of Corticosteroids Mineralocorticoid

Aldosterone is the prototype of mineralocorticoid effects

Acts on the distal tubule to enhance absorption of Na+
Increase excretion of K+ and H
Similar effects occur in colon, sweat gland and salivary
gland
Deficiency of mineralocorticoid action leads to
dilutional hyponatraemia, hyperkalamia, acidosis,
massive loss of Na+ and decreased EFC volume
(essential for survival)
Hyperaldosterinism: Positive Na+ balance, expansion of
ECF, increased plasma Na, hypokalaemia, alkalosis and
progressive rise in BP hypertension, myocardial
fibrosis etc.

Glucocorticoid actions Carbohydrate & protein metabolism

Profound effect on carbohydrate and protein metabolism

aimed at protecting glucose dependent tissues (brain
and heart)
Promotes glycogen deposition in liver and stimulate it to
form glucose from amino acids gluconeogenesis
In peripheral tissues decreases utilization of glucose,
increase protein breakdown and activate lipolysis form
amino acids and glycerol for gluconeogenesis
All these results in

Diabetes like stat resistant to insulin increased glucose release

from liver + decreased peripheral glucose utilization
Negative Nitrogen balance (catabolic effect) amino acid used
up in gluconeogenesis increased urea production
Mobilization of amino acids muscles, thinning of bone and skin

Actions: Carbohydrate and protein metabolism

Negative nitrogen balance & hyperglycaemia

Gluconeogenesis

Peripheral actions (mobilize AA &

Hepatic actions

glucose and glycogen)

Peripheral utilization of glucose

Glycogen deposition in liver

(activation of hepatic glycogen synthase)

Fat Metabolism

Redistribution of fats in different areas of the

body
Due to permissive facilitation of effects of other
agents GH, glucagons, Adr, thyroxine and
insulin

Deposition of fats in face, neck and shoulder moon

face/buffalo hump
Glucocorticoids facilitated hormone sensitive lipolysis
action of GH and Adr. + Glucocorticoids mediated
increased insulin = net result is insulin mediated
lipogenesis and fat deposition
Peripheral adipocytes are less sensitive to insulin, but
in face and neck predominant action fat deposition

Actions of Glucocorticoids

Water excretion:

Calcium Balance:

Decrease absorption of Ca++ in GIT and increased excretion calcium

depletion - osteoporosis

Skeletal muscle:

Glucocorticoids play important role in maintaining normal GFR - in

adrenal insufficiency capacity to excrete water is lost water intoxication

Normal muscular activity needs Glucocorticoids at its optimum level

Excess level leads to muscular weakness and wasting
Muscular weakness occurs in both Hypocorticism (due to hypodynamic
circulation) and hypercorticism due to hypokalaemia

CNS:

Euphoria in pharmacological doses

Addison's disease apathy, depression and psychosis
High doses induce seizure

Actions of Glucocorticoids

CVS: Permissive role on pressor effect with Adr and angiotensin

Maintain tone of arterioles and myocardial contractility

Adrenal insufficiency leads to low cardiac output and arteriolar dilatation
and poor response to adrenaline
Cardiovascular collapse along with mineralocorticoids

Blood and lymphoid tissues:

Destruction of lymphoid tissue modest in normal persons

In presence of malignancy of lymphatic cells lytic actions are
significant (apoptosis) used in lymphomas (Basis of Use)
Minor effects on haemoglobin and RBCs protect against haemolysis of
RBCs Increase in number of RBCs
Decreases the numbers of circulating lymphocytes, monocytes,
eosinophils and basophils but increases Polymorphs

Glucocorticoids anti-inflammatory
and immunosuppressive effects

Suppress inflammatory response to all noxious stimuli:

Pathogens, chemical,physical and immune mediated
stimuli, hypersensitivity
Underlying cause of disease is not corrected
Reduction in cardinal signs of inflammation
Anti-inflammatory effects are nonspecific and covers
all components of inflammation:

Effects on concentration, distribution and functions of peripheral

leukocytes increased neutrophils & their activity
In macrophages: reduction of arachidonic acid metabolites
(mediators) like PG, LT and PAF synthesis that results from
activation of phospholipase A2

Basis of exogenous use of most clinical uses

Glucorticoids - Multiple
Mechanisms

Recruitment of WBC & monocyte - macrophage into

affected area & elaboration of chemotactic substances
Lipocortin: decreased production of PG, LT and PAF
Negative regulation of COX 2: inducible PG
production
Negative regulation of genes in cytokines of
macrophages, endothelial cells and lymphocytes:
production of IL (1, 2, 3, 6), TNF, GM-CSF etc.
fibroblast proliferation and T-lymphocyte function
interference with chemotaxis

Contd.

In endothelial cells-Endothelial leucocyte adhesion

molecule (ELAM) and other CAM are inhibited
adhesion and localization of leucocytes interfered
Release of histamine from basophils is inhibited
Decreased production of collagenase prevention of
tissue destruction
Decreased functioning of osteoblasts and increased
activity of osteoclastic activity - osteoporosis
Decreased IgG production
Decreased generation of induced nitric oxide

Corticosteroids
Lipocortin
Phospholipids
Phospholipase A2
Arachidonic acids

Cycylooxygenase

lipoxygenase

Leukotriene
PAF by lipocortin

Prostaglandins,
Thromboxane
Prostacyclins

Immunosuppressive & anti-allergic

actions

Suppresses all types of hypersensitivity &

allergic phenomenon
At High dose: Interfere with all steps of
immunological response
Causes greater suppression of CMI (graft
rejection & delayed hypersensitivity)
Transplant rejection: antigen expression from
grafted tissues, delay revascularization,
sensitisation of T lymphocytes etc.

Glucocorticoids Anti-inflammatory
and Immunosuppressive effects

Glucocorticoids - Pharmacokinetics

Therapeutically given by various routes orally, IM, IV,

topically
Hydrocortisone undergoes high first pass metabolism
Oral bioavailability of synthetic corticoids is high
Both, endogenous and therapeutically administered GC
are bound to Corticosteroid Binding Globulin (CBG)
Synthetic steroids have to undergo reduction in liver to
active compounds
Metabolized in liver and excreted in urine
Exogenously administered hydrocortisone has t1/2 of 1.5
Hrs

Steroid Preparations
An ideal GC should have no

mineralocorticoid activity
Structural changes to the basic cortisol
molecule resulted in a number of
compounds with

Minimal mineralocorticoid activity

Greater potency
Longer duration of action

Important agents

Injectable:
Betamethasone
Prednisolone
Hydrocortisone

Oral:
Betamethasone
Prednisolone
Methylprednisolone

Fludricortisone
Prednisone

Topical:
Betamethasone
Flucinolone

Dexamethasone
Methylprednisolone
Triamcinolone

Clobetasol
Mometasone

Inhalation:
Beclomethasone
Flunisolode

Budesonide

Chemical Structures
Pharmaceutical steroids are usually obtained from
cholic acid (obtained from cattle) or sapogenins found
in plants of Liliacaceae

Cyclopentanoperhydrop
henanthrene skeleton

Rings are labeled as A,

B, C and D.

Numbering of each position

essentially follows a uniform
pattern except for the
methyls.

Natural steroids have

two methyls

Relative Activity
Compound

Duration

GC

MC

Equivalent
dose (mg)

Hydrocortisone

SA

20

Prednisolone

IA

0.8

Methyl
Prednisolone

IA

0.5

Triamcinolone

IA

Dexamethasone

LA

25

0.75

Betmethasone

LA

25

0.75

Aldosterone

MC

0.3

500 - 3000

NU

Desoxycortisone
acetate (DOCA)

MC

100

2.5 (S.
lingual)

Corticosteroids - Clinical
Pharmacology

Therapeutic uses

A number of diverse disease states respond to

GCs
Physiologic doses of Corticosteroids are used for
replacement therapy in primary and secondary
adrenal insufficiency such as Addison`s disease
Supraphysiologic doses are used for their antiinflammatory effects in arthritis, asthma and
inflammatory bowel disease
In organ transplant patients and those with
autoimmune disorders corticosteroids are used
for their immunosuppressive effects

Replacement Therapy
Adrenal insufficiency acute/chronic

Abrupt withdrawal of steroid therapy

Chronic infections Tuberculosis
Autoimmune adrenal disease
Surgery, Hemorrhage and AIDS

Congenital adrenal hyperplasia

Congenital disorder due to deficiency of 21hydroxylse enzyme no cortisol but ACTH

increased androgen production

CAH

Replacement Therapy

Acute adrenal insufficiency

IV replacement of sodium chloride and fluid

IV hydrocortisone 100 mg stat followed by100 mg
every 8 Hrs maximal daily rate of secretion

(alternatively, dexamethasone can be used)

Chronic adrenal insufficiency

Hydrocortisone
Prednisolone or dexamethasone long acting
Fludrocortisone for mineralocorticoid effects

Congenital adrenal hyperplasia

Hydrocortisone 0.6 mg/kg in divided doses to

maintain feedback suppression

Anti-inflammatory Uses

For suppression of inflammatory components in

Rheumatoid arthritis as adjuvant with NSAIDs in

severe cases
Osteoarthritis NSAIDs, intra-articular injection
Rheumatic fever severe cases with carditis and
CHF
Gout NSAID failed cases and colchicine failed
cases intra-articular injection
Vasculitic disorders: Polyarteritis nodosa

Intra-articular Steroids
Can be used in inflammatory
Non-inflammatory diseases
Knee joint
Shoulder joint
Tennis elbow
Carpal tunnel syndrome

Autoimmune diseases
ITP

Autoimmune haemolytic anaemia

Idiopathic thrombocytopenic purpura
Active chronic hepatitis, alcoholic hepatitis

(Prednisolone 1-2 mg/kg/day given till

remission followed by gradual withdrawal
or low dose maintenance)

Renal diseases
SLE

Nephrotic syndrome in children

Renal disease secondary to SLE
Renal sarcoidosis
Glomerulonephritis membranous type

(Life saving importance usually given in

large doses followed by tapering to
maintenance dose)

Organ Transplant
Combined with other immunosuppressants

cyclosporin, azathioprine
For prolonged use:
Prednisolone or methylprednisolone are
used

Intermediate duration of action

Can be easily tapered
Can be converted to an alternate regime

Allergic Disorders

Exhibit a delayed response in allergies (1-2 hrs

even in IV injection)
In anaphylaxis, angioneurotic oedema and
serum sickness etc. adrenaline is the choice
Seasonal allergies, bee sting, drug allergies

Allergic reactions can be suppressed by

corticosteroids as supplements

Intranasal administration in allergic rhinitis budesonide and flunisolide

Bronchial Asthma

The increased recognition of the immunological and

inflammatory nature of Bronchial asthma has led to the
use of corticosteroids
In severe asthma attacks
IV hydrocortisone
Oral prednisolone

Methylprednisolone

Acute attacks:
*Inhaled beclmethasone, budesonide, flunisolide
alone or combined with beta-2 agonists/ipratropium
*Oral steroids

Infectious Diseases
Indicated only in severe infective diseases

to tide over crisis or prebent complictions

AIDS and pneumocystis carinii pneumonia

In haemophilus influenza meningitis to reduce
neurological complications
Tubercular meningitis
Lepra reaction
Scepticaemia
Lepra reaction

Ocular Diseases

Important drug therapy for suppressing

inflammation in eye and preservation of sight
Topical instillations are used for conditions of the
anterior chamber allergic conjunctivitis, iritis,
iridocyclitis and keratitis etc.
Systemic steroids for the posterior chamber
Dexamethasone topical 0.1%
Prednisolone oral
Contraindicated in viral, fulminant bacterial
infections, fungal infections and injuries

Skin Diseases
Pemphigus
vulgaris

The largest application of steroid therapy

Topical forms are widely used in many

eczematous skin diseases

Systemic therapy are also required and
may be life saving in

Pemphigus vulgaris
Exfoliative dermatitis
Stevens-Johnson syndrome

GIT

Inflammatory conditions of intestine like

Ulcerative colitis
Crohn`s disease
Coeliac disease
(oral therapy or retention enema with hydrocortisone)

May mask the major complications like

perforation and peritonitis

Malignancy
Hodgkin`s
lymphoma

Essential for combined chemotherapy of

Acute lymphatic leukemia

Hodgkin's and other lymphomas
Hormone responsive breast carcinoma

Symptomatic relief in other advance

malignancies by improving appetite and

controlling secondary hypercalcaemia

Cerebral Oedema
Cerebral oedema due to tumors

(neoplasms)
Traumatic and poststroke oedema (?)
(Dexamethasone or betamethasone is
preferred because no Na+ retaining
activity)
Other CNS conditions - spinal chord injury,
Bell`s palsy and neurocysticercosis
(Oral Prednisolone is the preferred drug)

Other Uses

Antiemetic with ondansetron

Acute mountain sickness
Aspiration pneumonia, pulmonary oedema

from drowning
Hyperthyroidism thyroid storm

Adverse Effects
Two types:

From abrupt withdrawal

Chronic therapeutic use of high dose

Withdrawal

Flare up of underlying disease

Suppression of HPA axis and acute adrenal
insufficiency
Increased ICT and papilloedema

Adverse Effects

Cushing`s habitus

Other Important Adverse Effects

Fluid and Electrolyte Disturbance Na and water retention

Precipitation of Diabetes mellitus hyperglycemia
Increased susceptibility to infections immune response
suppression
Peptic ulceration bleeding & perforation
Osteoporosis flat spongy bones
Osteonecrosis avascular necrosis of head of femur,
humorous etc.
Myopathy weakness of muscles
Cataract posterior sub capsular
Glaucoma prolonged topical therapy
Growth retardation in children

Contraindications

Say no to any drug formulation combined with

steroids
Remember that STEROIDS are life saving drugs
Note the following conditions where u have to be
extremely cautious:

Peptic ulcer
Hypertension and Diabetes mellitus
Viral and fungal infections
Tuberculosis and other diseases
Osteoporosis
Epilepsy and psychosis
CHF and renal failure

Choosing a Steroid
Benefit/risk ratio is a major consideration
Drugs with primary glucocorticoid activity

are used
Minimal dose to achieve the desired
effects is chosen
Topical or local therapy is preferred
whenever possible

Choosing a Steroid contd.

Once daily dosing is usually
preferred for oral glucocorticoids
Large steroid doses are
administered in divided doses to
reduce local GIT effects
In order to mimic the normal diurnal
cycle and reduce the risk of
adrenal suppression, GCs should
be given in the morning between
6-10 AM
Alternate day therapy allows the
HPA axis to recover on off days

Single
dose
Steroid

Withdrawal of Steroid Therapy

Taper the dose to reduce GC dose by 2.5-5 mg of

prednisolone equivalent daily
Once the GC dose is reduced to 5 mg of prednisolone
equivalent, the patient may be switched to a shorter
acting agent for further tapering
Intermediate acting corticosteroids allow for more flexible
dosing schedule

Have potent glucocorticoid effects

Causes lesser suppression of HPA axis
Causes less GIT irritation
Preferred for oral therapy
Prednisolone, methylprednisolone and triacinolone have a half
life of 12-36 Hrs, are available in a number of dosage forms

Adrenocorticosteroid Inhibitors

Metyrapone: 11 beta-hydroxylase enzyme inhibitor used

in Cushing`s syndrome and test of pituitary efficiency

Aminoglutethemide: Stops conversion of cholesterol to

pregnelone (Medical adrenalectomy) Breast cancers

Mifepristone: Progesterone antagonist

Spironolactone: Aldosterone antagonist

Ketoconazole: Inhibits synthesis of all hormones in testes

and adrenal cortex used in Cushing`s syndrome and
also in hirsutism in female

Must Know!
Biosynthesis and Regulation of

Corticosteroids
Mechanism of action of Corticosteroids
Name of commonly used Glucocorticoids
Anti-inflammatory and immunosuppressive
actions of Glucocorticoids
Important Adverse effects of Corticosteroids
Therapeutic uses of Corticosteroids

Thank You