corticosteroids

Dr.R.Prameela ,
Assistant professor of Pharmacology,
GMC,Srikakulam.
contents
Introduction
Biosynthesis
Actions
Pharmacokinetics
Chemistry and relative activity
Distinctive features
Uses
Adverse effects
Contraindications
Conclusion
Introduction
Hormones secreted by adrenal glands
Adrenals ---- cortex ----glucocorticoids
mineralocorticoids
sex steroids
medulla ----adrenaline
noradrenaline
Biosynthesis
Regulation of corticosteroid production
Basal secretion
The normal rate of secretion of the two principal
corticoids in man is
Hydrocortisone – 10-20 mg daily
Aldosterone - 0.125 mg daily
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 - their presence facilitates other
hormones to exert that action
• 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
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
 Water excretion:
Glucocorticoids play important role in maintaining
normal GFR - in adrenal insufficiency capacity to
excrete water is lost – water intoxication
Calcium Balance:
Decrease absorption of Ca++ in GIT and increased
excretion – calcium depletion - osteoporosis
Skeletal muscle:
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 non—specific 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), TNFα, GM-CSF etc. – fibroblast proliferation and T-
lymphocyte function – interference with chemotaxis
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
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 - 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
Mechanism of action
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
Chemical Structures
Distinctive features
Hydrocortisone
Acts rapidly , short duration of action
Both glucocorticoid and mineralocorticoid activity
Used for
 replacement therapy - 20mg morning and 10mg
afternoon orally
 Shock,status asthmaticus,acute adrenal insufficiency -
100mg IV bolus and 100mg 8th hrly IV infusion
 Topically and as suspension for enema in ulcerative
colitis
Prednisolone
4times more potent than hydrocortisone
More selective glucocorticoid
Fluid retention occurs with high doses
Intermediate duration of action
Used for
 Allergic
 Inflammatory
 Autoimmune disease
 Malignancies
Dose : 5-60 mg/day oral
10-40 mgIM or intraarticular
 Also topically
Methyl prednisolone
Slightly more potent and more selective than
prednisolone
Used in
 Ulcerative colitis
 Nonresponsive active rheumatoid arthritis
 Renal transplant
 Pemphigus etc.,
Triamcinolone
Slightly more potent than prednisolone but highly
selective glucocorticoid
Dose :4-32mg/day oral
5-40mg IM,intraarticular
also topically
Dexamethasone
Verypotent
Highly selective glucocorticoid
Long acting,causes marked pituitary adrenal suppresion
Used for
 Inflammatory and allergic conditions – 0.5-5mg/day
oral
 Shock,cerebral oedema etc., - 4-20mg/day IVinfusion/IM
 Can also be used topically
Betamethasone
Similar to dexamethasone
Deflazocort
Glucocorticoid potency is less thanprednisolone but
lacks mineralocorticoid activity
Recommende for paediatric use- less growth
retardation
Dose : 60-120mg/dayinitially,6-18mg/dayfor
maintenance,
children : 0.25 -1.5 mg/kg daily or on alternate days
Desoxycorticosterone acetate (DOCA)
Only mineralocorticoid activity
Occasionally used for replacement therapy in
Addison’s disease
2-5mg sublingual
10-20mg IM once or twice weekly
Fludrocortisone
Potent mineralocorticoid having some glucocorticoid
activity
Orally active
Used for
 replacement therapy in Addison’s disease – 50-
200mcgdaily
 Congenital adrenal hyperplasia - – 50-200mcg/day
 Idiopathic postural hypotension – 100-200mcg/day
Aldosterone
Most potent mineralocorticoid
Not used clinically because of low oral bioavailability
uses
Replacement therapy
Acute adrenal insufficiency
Chronic adrenal insufficiency
Congenital adrenal hyperplasia
Pharmacotherapy
General principles
 Single dose – not harmful
 Short courses even in high dose not harmful
 Longterm use –potentially hazardous
 Initial dose depends on severity of disease
 No abrupt withdrawl after 2-3 weeks therapy
 Stress ,infection,trauma surgery – increase the dose
 Local therapy wherever possible
Arthritides
 Rheumatoid arthritis
 Osteoarthritis
 Rheumatic fever
 Gout
Collagen diseases
Severe allergic reactions
Autoimmune diseases
Bronchial asthma
Other lung diseases – aspiration pneumonia,pulmonary
oedema from drowning
Given in late pregnancy – accelerate lung maturation
and surfactant production
Infective diseases
Eye diseases
Skin diseases
Intestinal diseases
Neurological conditions
Malignancies
Organ transplantation and skin allograft
Septic shock
Thyroid storm
To test pituitary adrenal axis function
Adverse effects
Extension of the pharmacological action – prolonged
therapy
Mineralocorticoid : - sodium and water retention ,
oedema , hypokalaemic alkalosis and progressive rise
in BP
Glucocorticoid :
 Cushing’s habitus
Contraindications

Peptic ulcer
Diabetes mellitus
Hypertension
Viral and fungal infections
Tuberculosis
Osteoporosis
Herpes simplex keratitis
Psychosis
Epilepsy
CHF
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
Thank you