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Corticosteroids: Dr.R.Prameela, Assistant Professor of Pharmacology, GMC, Srikakulam
Corticosteroids: Dr.R.Prameela, Assistant Professor of Pharmacology, GMC, Srikakulam
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