corticosteroidsclass-drdhriti-101009075439-phpapp02.pdf

corticosteroidsclass-drdhriti-101009075439-phpapp02.pdf

• 1.
  Pharmacology of Pharmacology of Corticosteroids Corticosteroids Dr.D. K. Brahma Dr. D. K. Brahma Department of Pharmacology Department of Pharmacology NEIGRIHMS, Shillong NEIGRIHMS, Shillong
• 2.
  Steroids Steroids Steroids are fastcatching up with antibiotics as the most abused class of drugs today High doses of corticosteroids and other immunosuppressive agents may cause AIDS
• 3.
  Introduction Introduction • The adrenalproduces 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 are necessary for life • Corticosteroids or corticoids refer to natural gluco- and mineralo-corticoids and their synthetic analogues
• 4.
  Contents Contents  History andBiosynthesis History and Biosynthesis  Mechanism of action Mechanism of action  Physiological and Pharmacological actions Physiological and Pharmacological actions  Pharmacokinetics and preparations Pharmacokinetics and preparations  Uses – therapeutic and diagnostic Uses – therapeutic and diagnostic  Dosage schedule and withdrawal Dosage schedule and withdrawal  Adverse reactions and contraindications Adverse reactions and contraindications  Precautions during therapy Precautions during therapy  Contraindications Contraindications
• 5.
  History History  1855 –Addison`s disease 1855 – Addison`s disease  1856 – Adrenal glands essential for life 1856 – Adrenal glands essential for life  1930 – Cortex > medulla 1930 – Cortex > medulla  1932 – Cushing’s syndrome 1932 – Cushing’s syndrome  1952 – Aldosterone 1952 – Aldosterone
• 6.
  Anatomy Anatomy  An innermedulla, An inner medulla, is a source is a source of catecholamine – adrenaline of catecholamine – adrenaline and nor-adrenaline and nor-adrenaline  Chromaffin cell is the principal Chromaffin cell is the principal cell type cell type  Medulla is richly innervated by Medulla is richly innervated by sympathetic fibres and is sympathetic fibres and is considered as extension of considered as extension of sympathetic nervous system sympathetic nervous system  Medulla develops from Medulla develops from ectoderm (neural crest) ectoderm (neural crest)  An outer cortex, An outer cortex, which which secretes several classes of secretes several classes of steroid hormones including steroid hormones including Glucocorticoids Glucocorticoids and and Mineralocorticoids Mineralocorticoids  Three different concentric Three different concentric zones of cells that differ in zones of cells that differ in major steroid hormones they major steroid hormones they secrete secrete  Cortex develops from Cortex develops from mesoderm mesoderm
• 7.
  Adrenal Cortex Adrenal Cortex The adrenal cortex is a factory of steroid hormones The adrenal cortex is a factory of steroid hormones  10 – 30 different steroids are synthesized from this 10 – 30 different steroids are synthesized from this tissue, but two classes are of importance tissue, but two classes are of importance Steroid Class Steroid Class Prototype Prototype Physiological effect Physiological effect Mineralocorticoid Mineralocorticoid Aldosterone (z. glomerulosa) Aldosterone (z. glomerulosa) Na, K and water Na, K and water homeostasis homeostasis Glucocorticoid Glucocorticoid Hydrocortisone or cortisol (z. fasciculata) Hydrocortisone or cortisol (z. fasciculata) Corticosterone Corticosterone Glucose and many Glucose and many other homeostasis other homeostasis Adrenal cortex also produces sex steroids – Androgens, Dehydroepiandrosterone (DHEA) – z. reticularis
• 8.
  Biosynthesis Biosynthesis  Synthesized fromcholesterol Synthesized from cholesterol through a series of enzyme- through a series of enzyme- mediated transformations mediated transformations  ACTH ACTH stimulates adrenal stimulates adrenal steroid synthesis steroid synthesis  Aldosterone synthesis is not Aldosterone synthesis is not stimulated by ACTH but by stimulated by ACTH but by angiotensin II, although ACTH angiotensin II, although ACTH does stimulate synthesis of does stimulate synthesis of aldosterone precursors aldosterone precursors  Circulating Potassium exerts a Circulating Potassium exerts a permissive effect on permissive effect on angiotensin II stimulation; high angiotensin II stimulation; high potassium enhances and low potassium enhances and low potassium diminishes potassium diminishes
• 9.
  Steroid Biosynthesis -contd. Steroid Biosynthesis - contd.
• 10.
  Basal Secretion Basal Secretion Group GroupHormone Hormone Daily Daily Glucocorticoids Glucocorticoids Cortisol Cortisol Corticosterone Corticosterone 5 – 30 mg 5 – 30 mg 2 – 5 mg 2 – 5 mg Mineralocorticoids Mineralocorticoids Aldosterone Aldosterone 11- deoxycorticosterone 11- deoxycorticosterone 5 – 150 mcg 5 – 150 mcg Trace Trace Sex Hormones Sex Hormones Androgen Androgen Progestogen Progestogen Oestrogen Oestrogen DHEA DHEA Progesterone Progesterone Oestradiol Oestradiol 15 – 30 mg 15 – 30 mg 0.4 – 0.8 mg 0.4 – 0.8 mg Trace Trace
• 11.
  Regulation of Synthesis Regulationof Synthesis • Synthesized and released under influence of ACTH - Ant. Pituitary (HPA axis) • Regulated by CRH from hypothalamus and by feedback levels of blood concentrations
• 12.
  1. 1. Control bycircadian Control by circadian rhythm (Diurnal rhythm (Diurnal rhythm) – morning rhythm) – morning rise rise 2. 2. Stress: Stress: hypoglycaemia, hypoglycaemia, physical stress etc. physical stress etc. Regulation of Synthesis - Others Regulation of Synthesis - Others
• 13.
  Diurnal variation ofCortisol Diurnal variation of Cortisol
• 14.
  Glucocorticoids - MOA Glucocorticoids- MOA  Not stored: Not stored:  rate of synthesis = rate of release rate of synthesis = rate of release  Synthesize rhythmically and controlled by Synthesize rhythmically and controlled by irregular pulses of ACTH, influenced by light and irregular pulses of ACTH, influenced by light and major pulses occur early in the morning and major pulses occur early in the morning and after meals after meals  Glucocorticoids act via their receptors located in Glucocorticoids act via their receptors located in nucleus (GR) nucleus (GR)  GRs are widely distributed and located almost in GRs are widely distributed and located almost in all cells of the body all cells of the body  They are made up of almost 800 amino acids They are made up of almost 800 amino acids
• 15.
  Glucocorticoids - MOA Glucocorticoids- MOA  GR receptors are located in the cytoplasm GR receptors are located in the cytoplasm  One GR receptor has a DNA binding domain and a One GR receptor has a DNA binding domain and a ligand binding domain along with stabilizing proteins ligand binding domain along with stabilizing proteins (HSP 90 and HSP 70) (HSP 90 and HSP 70)  This receptor is incapable of activating transcription This receptor is incapable of activating transcription  Binding of free steroid molecule to GR forms an unstable Binding of free steroid molecule to GR forms an unstable compound compound  Therefore HSP and other proteins get dissociated Therefore HSP and other proteins get dissociated  The S+GR complex enters the nucleus and binds to The S+GR complex enters the nucleus and binds to Glucocorticoids response element (GRE) on gene and Glucocorticoids response element (GRE) on gene and regulate transcription by RNA polymerase II and others regulate transcription by RNA polymerase II and others  The resulting mRNA is transported to cytoplasm for The resulting mRNA is transported to cytoplasm for production of protein and bring about final response production of protein and bring about final response
• 16.
  Glucocorticoids - MOA Glucocorticoids- MOA
• 17.
  Actions Actions Numerous and widespreadactions: Numerous and widespread actions:  Carbohydrate, lipid and protein metabolism Carbohydrate, lipid and protein metabolism  Fluid and electrolyte balance Fluid and electrolyte balance  Normal functioning of CVS, immune system, kidneys, skeletal muscles and nervous system Normal functioning of CVS, immune system, kidneys, skeletal muscles and nervous system  Provides resistance to stress and noxious stimuli and environmental changes Provides resistance to stress and noxious stimuli and environmental changes  Permits and facilitates the actions of other hormones Permits and facilitates the actions of other hormones  Direct Actions Direct Actions  Permissive Actions Permissive Actions • Lipolytic effects • Effect on BP • Effect on bronchial muscles • (e.g.,sympathomimetic amine)
• 18.
  Actions of Corticosteroids- Actions of Corticosteroids - Mineralocorticoid Mineralocorticoid  Aldosterone is the prototype of mineralocorticoid effects Aldosterone is the prototype of mineralocorticoid effects  Acts on the distal tubule to enhance absorption of Na+ Acts on the distal tubule to enhance absorption of Na+  Increase excretion of K+ and H Increase excretion of K+ and H  Similar effects occur in colon, sweat gland and salivary Similar effects occur in colon, sweat gland and salivary gland gland  Deficiency of mineralocorticoid action leads to Deficiency of mineralocorticoid action leads to – – dilutional hyponatraemia, hyperkalamia, acidosis, dilutional hyponatraemia, hyperkalamia, acidosis, massive loss of Na+ and decreased EFC volume massive loss of Na+ and decreased EFC volume (essential for survival) (essential for survival)  Hyperaldosterinism: Hyperaldosterinism: Positive Na+ balance, expansion of Positive Na+ balance, expansion of ECF, increased plasma Na, hypokalaemia, alkalosis and ECF, increased plasma Na, hypokalaemia, alkalosis and progressive rise in BP – hypertension, myocardial progressive rise in BP – hypertension, myocardial fibrosis etc. fibrosis etc.
• 19.
  Glucocorticoid actions - Glucocorticoidactions - Carbohydrate & protein metabolism Carbohydrate & protein metabolism  Profound effect on carbohydrate and protein metabolism Profound effect on carbohydrate and protein metabolism – aimed at protecting glucose dependent tissues (brain – aimed at protecting glucose dependent tissues (brain and heart) and heart)  Promotes glycogen deposition in liver and stimulate it to Promotes glycogen deposition in liver and stimulate it to form glucose from amino acids – gluconeogenesis form glucose from amino acids – gluconeogenesis  In peripheral tissues decreases utilization of glucose, In peripheral tissues decreases utilization of glucose, increase protein breakdown and activate lipolysis – form increase protein breakdown and activate lipolysis – form amino acids and glycerol for gluconeogenesis amino acids and glycerol for gluconeogenesis  All these results in - All these results in -  Diabetes like stat resistant to insulin – increased glucose release Diabetes like stat resistant to insulin – increased glucose release from liver + decreased peripheral glucose utilization from liver + decreased peripheral glucose utilization  Negative Nitrogen balance (catabolic effect) – amino acid used Negative Nitrogen balance (catabolic effect) – amino acid used up in gluconeogenesis – increased urea production up in gluconeogenesis – increased urea production  Mobilization of amino acids – muscles, thinning of bone and skin Mobilization of amino acids – muscles, thinning of bone and skin
• 20.
  Actions: Actions: Carbohydrate andprotein metabolism Carbohydrate and protein metabolism  Gluconeogenesis Gluconeogenesis  Peripheral actions Peripheral actions (mobilize AA & glucose and (mobilize AA & glucose and glycogen) glycogen)  Hepatic actions Hepatic actions  Peripheral utilization of glucose Peripheral utilization of glucose  Glycogen deposition in liver Glycogen deposition in liver (activation of hepatic glycogen synthase) (activation of hepatic glycogen synthase) Negative nitrogen balance & hyperglycaemia
• 21.
  Fat Metabolism Fat Metabolism Redistribution of fats in different areas of the Redistribution of fats in different areas of the body body  Due to permissive facilitation of effects of other Due to permissive facilitation of effects of other agents – GH, glucagons, Adr, thyroxine and agents – GH, glucagons, Adr, thyroxine and insulin insulin  Deposition of fats in face, neck and shoulder – moon Deposition of fats in face, neck and shoulder – moon face/buffalo hump face/buffalo hump  Glucocorticoids facilitated hormone sensitive lipolysis Glucocorticoids facilitated hormone sensitive lipolysis action of GH and Adr. + Glucocorticoids mediated action of GH and Adr. + Glucocorticoids mediated increased insulin = net result is insulin mediated increased insulin = net result is insulin mediated lipogenesis and fat deposition lipogenesis and fat deposition  Peripheral adipocytes are less sensitive to insulin, but Peripheral adipocytes are less sensitive to insulin, but in face and neck predominant action – fat deposition in face and neck predominant action – fat deposition
• 22.
  Actions of Glucocorticoids Actionsof Glucocorticoids  Water excretion: Water excretion:  Glucocorticoids play important role in maintaining normal GFR - in Glucocorticoids play important role in maintaining normal GFR - in adrenal insufficiency capacity to excrete water is lost – water intoxication adrenal insufficiency capacity to excrete water is lost – water intoxication  Calcium Balance: Calcium Balance:  Decrease absorption of Ca++ in GIT and increased excretion – calcium Decrease absorption of Ca++ in GIT and increased excretion – calcium depletion - depletion - osteoporosis osteoporosis  Skeletal muscle: Skeletal muscle:  Normal muscular activity needs Glucocorticoids at its optimum level Normal muscular activity needs Glucocorticoids at its optimum level  Excess level leads to muscular weakness and wasting Excess level leads to muscular weakness and wasting  Muscular weakness occurs in both Hypocorticism (due to hypodynamic Muscular weakness occurs in both Hypocorticism (due to hypodynamic circulation) and hypercorticism – due to hypokalaemia circulation) and hypercorticism – due to hypokalaemia  CNS: CNS:  Euphoria – in pharmacological doses Euphoria – in pharmacological doses  Addison's disease – apathy, depression and psychosis Addison's disease – apathy, depression and psychosis  High doses – induce seizure High doses – induce seizure
• 23.
  Actions of Glucocorticoids Actionsof Glucocorticoids  CVS: CVS: Permissive role on pressor effect with Adr and angiotensin Permissive role on pressor effect with Adr and angiotensin  Maintain tone of arterioles and myocardial contractility Maintain tone of arterioles and myocardial contractility  Adrenal insufficiency leads to low cardiac output and arteriolar dilatation Adrenal insufficiency leads to low cardiac output and arteriolar dilatation and poor response to adrenaline and poor response to adrenaline  Cardiovascular collapse – along with mineralocorticoids Cardiovascular collapse – along with mineralocorticoids  Blood and lymphoid tissues: Blood and lymphoid tissues:  Destruction of lymphoid tissue – modest in normal persons Destruction of lymphoid tissue – modest in normal persons  In presence of malignancy of lymphatic cells – lytic actions are In presence of malignancy of lymphatic cells – lytic actions are significant (apoptosis) – used in lymphomas significant (apoptosis) – used in lymphomas (Basis of Use) (Basis of Use)  Minor effects on haemoglobin and RBCs – protect against haemolysis of Minor effects on haemoglobin and RBCs – protect against haemolysis of RBCs – RBCs – Increase in number of RBCs Increase in number of RBCs  Decreases the numbers of circulating lymphocytes, monocytes, Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increases Polymorphs eosinophils and basophils but increases Polymorphs
• 24.
  Glucocorticoids – anti-inflammatory Glucocorticoids– anti-inflammatory and immunosuppressive effects and immunosuppressive effects  Suppress inflammatory response to all noxious stimuli: Suppress inflammatory response to all noxious stimuli: Pathogens, chemical,physical and immune mediated Pathogens, chemical,physical and immune mediated stimuli, hypersensitivity stimuli, hypersensitivity  Underlying cause of disease is not corrected Underlying cause of disease is not corrected  Reduction in cardinal signs of inflammation Reduction in cardinal signs of inflammation  Anti-inflammatory effects are non—specific and covers Anti-inflammatory effects are non—specific and covers all components of inflammation: all components of inflammation:  Effects on concentration, distribution and functions of peripheral Effects on concentration, distribution and functions of peripheral leukocytes – increased neutrophils & their activity leukocytes – increased neutrophils & their activity  In macrophages: reduction of arachidonic acid metabolites In macrophages: reduction of arachidonic acid metabolites (mediators) like PG, LT and PAF synthesis that results from (mediators) like PG, LT and PAF synthesis that results from activation of phospholipase A2 activation of phospholipase A2 Basis of exogenous use of most clinical uses Basis of exogenous use of most clinical uses
• 25.
  Glucorticoids - Multiple Mechanisms Recruitment of WBC & monocyte - macrophage into Recruitment of WBC & monocyte - macrophage into affected area & elaboration of chemotactic substances affected area & elaboration of chemotactic substances  Lipocortin: decreased production of PG, LT and PAF Lipocortin: decreased production of PG, LT and PAF  Negative regulation of COX 2: inducible PG Negative regulation of COX 2: inducible PG production production  Negative regulation of genes in cytokines of Negative regulation of genes in cytokines of macrophages, endothelial cells and lymphocytes: macrophages, endothelial cells and lymphocytes: production of IL (1, 2, 3, 6), TNF production of IL (1, 2, 3, 6), TNFα α, GM-CSF etc. – , GM-CSF etc. – fibroblast proliferation and T-lymphocyte function – fibroblast proliferation and T-lymphocyte function – interference with chemotaxis interference with chemotaxis
• 26.
  Contd. Contd.  In endothelialcells-Endothelial leucocyte adhesion In endothelial cells-Endothelial leucocyte adhesion molecule molecule (ELAM) (ELAM) and other and other CAM CAM are inhibited – are inhibited – adhesion and localization of leucocytes interfered adhesion and localization of leucocytes interfered  Release of histamine from basophils is inhibited Release of histamine from basophils is inhibited  Decreased production of Decreased production of collagenase collagenase – prevention of – prevention of tissue destruction tissue destruction  Decreased functioning of Decreased functioning of osteoblasts osteoblasts and increased and increased activity of activity of osteoclastic osteoclastic activity - activity - osteoporosis osteoporosis  Decreased IgG production Decreased IgG production  Decreased generation of induced nitric oxide Decreased generation of induced nitric oxide
• 27.
  Phospholipids Arachidonic acids lipoxygenase Cycylooxygenase Leukotriene Prostaglandins, Thromboxane Prostacyclins PhospholipaseA2 Lipocortin Corticosteroids PAF by lipocortin
• 28.
  Immunosuppressive & anti-allergic Immunosuppressive& anti-allergic actions actions  Suppresses all types of hypersensitivity & Suppresses all types of hypersensitivity & allergic phenomenon allergic phenomenon  At High dose: Interfere with all steps of At High dose: Interfere with all steps of immunological response immunological response  Causes greater suppression of CMI (graft Causes greater suppression of CMI (graft rejection & delayed hypersensitivity) rejection & delayed hypersensitivity)  Transplant rejection: antigen expression from Transplant rejection: antigen expression from grafted tissues, delay revascularization, grafted tissues, delay revascularization, sensitisation of T lymphocytes etc. sensitisation of T lymphocytes etc.
• 29.
  Glucocorticoids – Anti-inflammatory Glucocorticoids– Anti-inflammatory and Immunosuppressive effects and Immunosuppressive effects
• 30.
  Glucocorticoids - Pharmacokinetics Glucocorticoids- Pharmacokinetics  Therapeutically given by various routes – orally, IM, IV, Therapeutically given by various routes – orally, IM, IV, topically topically  Hydrocortisone undergoes high first pass metabolism Hydrocortisone undergoes high first pass metabolism  Oral bioavailability of synthetic corticoids is high Oral bioavailability of synthetic corticoids is high  Both, endogenous and therapeutically administered GC Both, endogenous and therapeutically administered GC are bound to Corticosteroid Binding Globulin (CBG) are bound to Corticosteroid Binding Globulin (CBG)  Synthetic steroids have to undergo reduction in liver to Synthetic steroids have to undergo reduction in liver to active compounds active compounds  Metabolized in liver and excreted in urine Metabolized in liver and excreted in urine  Exogenously administered hydrocortisone has t1/2 of 1.5 Exogenously administered hydrocortisone has t1/2 of 1.5 Hrs Hrs
• 31.
  Steroid Preparations Steroid Preparations An ideal GC should have no An ideal GC should have no mineralocorticoid activity mineralocorticoid activity  Structural changes to the basic cortisol Structural changes to the basic cortisol molecule resulted in a number of molecule resulted in a number of compounds with compounds with  Minimal mineralocorticoid activity Minimal mineralocorticoid activity  Greater potency Greater potency  Longer duration of action Longer duration of action
• 32.
  Important agents Important agents Injectable: Injectable: Betamethasone Dexamethasone Betamethasone Dexamethasone Prednisolone Methylprednisolone Prednisolone Methylprednisolone Hydrocortisone Triamcinolone Hydrocortisone Triamcinolone  Oral: Oral: Betamethasone Fludricortisone Betamethasone Fludricortisone Prednisolone Prednisone Prednisolone Prednisone Methylprednisolone Methylprednisolone  Topical: Topical: Betamethasone Clobetasol Betamethasone Clobetasol Flucinolone Mometasone Flucinolone Mometasone  Inhalation: Inhalation: Beclomethasone Budesonide Beclomethasone Budesonide Flunisolode Flunisolode
• 33.
  Chemical Structures Chemical Structures Pharmaceuticalsteroids are usually obtained from “cholic acid” (obtained from cattle) or sapogenins found in plants of Liliacaceae
• 34.
  Cyclopentanoperhydrop henanthrene skeleton Rings arelabeled as A, B, C and D. Natural steroids have two methyls Numbering of each position essentially follows a uniform pattern except for the methyls.
• 35.
  Relative Activity Relative Activity Compound CompoundDuration Duration GC GC MC MC Equivalent Equivalent dose (mg) dose (mg) Hydrocortisone Hydrocortisone SA SA 1 1 1 1 20 20 Prednisolone Prednisolone IA IA 4 4 0.8 0.8 5 5 Methyl Methyl Prednisolone Prednisolone IA IA 5 5 0.5 0.5 4 4 Triamcinolone Triamcinolone IA IA 5 5 0 0 4 4 Dexamethasone Dexamethasone LA LA 25 25 0 0 0.75 0.75 Betmethasone Betmethasone LA LA 25 25 0 0 0.75 0.75 Aldosterone Aldosterone MC MC 0.3 0.3 500 - 3000 500 - 3000 NU NU Desoxycortisone Desoxycortisone acetate (DOCA) acetate (DOCA) MC MC 0 0 100 100 2.5 (S. 2.5 (S. lingual) lingual)
• 36.
  Corticosteroids - Clinical Corticosteroids- Clinical Pharmacology Pharmacology
• 37.
  Therapeutic uses Therapeutic uses A number of diverse disease states respond to A number of diverse disease states respond to GCs GCs  Physiologic doses of Corticosteroids are used Physiologic doses of Corticosteroids are used for replacement therapy in primary and for replacement therapy in primary and secondary adrenal insufficiency such as secondary adrenal insufficiency such as Addison`s disease Addison`s disease  Supraphysiologic doses are used for their anti- Supraphysiologic doses are used for their anti- inflammatory effects in arthritis, asthma and inflammatory effects in arthritis, asthma and inflammatory bowel disease inflammatory bowel disease  In organ transplant patients and those with In organ transplant patients and those with autoimmune disorders corticosteroids are used autoimmune disorders corticosteroids are used for their immunosuppressive effects for their immunosuppressive effects
• 38.
  Replacement Therapy Replacement Therapy Adrenal insufficiency – acute/chronic Adrenal insufficiency – acute/chronic  Abrupt withdrawal of steroid therapy Abrupt withdrawal of steroid therapy  Chronic infections – Tuberculosis Chronic infections – Tuberculosis  Autoimmune adrenal disease Autoimmune adrenal disease  Surgery, Hemorrhage and AIDS Surgery, Hemorrhage and AIDS  Congenital adrenal hyperplasia Congenital adrenal hyperplasia  Congenital disorder due to deficiency of 21- Congenital disorder due to deficiency of 21- hydroxylse enzyme – no cortisol but ACTH – hydroxylse enzyme – no cortisol but ACTH – increased androgen production increased androgen production CAH
• 39.
  Replacement Therapy Replacement Therapy Acute adrenal insufficiency Acute adrenal insufficiency  IV replacement of sodium chloride and fluid IV replacement of sodium chloride and fluid  IV hydrocortisone 100 mg stat followed by100 mg IV hydrocortisone 100 mg stat followed by100 mg every 8 Hrs – maximal daily rate of secretion every 8 Hrs – maximal daily rate of secretion (alternatively, dexamethasone can be used) (alternatively, dexamethasone can be used)  Chronic adrenal insufficiency Chronic adrenal insufficiency  Hydrocortisone Hydrocortisone  Prednisolone or dexamethasone – long acting Prednisolone or dexamethasone – long acting  Fludrocortisone for mineralocorticoid effects Fludrocortisone for mineralocorticoid effects  Congenital adrenal hyperplasia Congenital adrenal hyperplasia  Hydrocortisone 0.6 mg/kg in divided doses – to Hydrocortisone 0.6 mg/kg in divided doses – to maintain feedback suppression maintain feedback suppression
• 40.
  Anti-inflammatory Uses Anti-inflammatory Uses For suppression of inflammatory components in For suppression of inflammatory components in – –  Rheumatoid arthritis – as adjuvant with NSAIDs in Rheumatoid arthritis – as adjuvant with NSAIDs in severe cases severe cases  Osteoarthritis – NSAIDs, intra-articular injection Osteoarthritis – NSAIDs, intra-articular injection  Rheumatic fever – severe cases with carditis and Rheumatic fever – severe cases with carditis and CHF CHF  Gout – NSAID failed cases and colchicine failed Gout – NSAID failed cases and colchicine failed cases – intra-articular injection cases – intra-articular injection  Vasculitic disorders: Polyarteritis nodosa Vasculitic disorders: Polyarteritis nodosa
• 41.
  Intra-articular Steroids Intra-articular Steroids Canbe used in inflammatory Non-inflammatory diseases • Knee joint • Shoulder joint • Tennis elbow • Carpal tunnel syndrome
• 42.
  Autoimmune diseases Autoimmune diseases Autoimmune haemolytic anaemia Autoimmune haemolytic anaemia  Idiopathic thrombocytopenic purpura Idiopathic thrombocytopenic purpura  Active chronic hepatitis, alcoholic hepatitis Active chronic hepatitis, alcoholic hepatitis (Prednisolone 1-2 mg/kg/day given till (Prednisolone 1-2 mg/kg/day given till remission followed by gradual withdrawal remission followed by gradual withdrawal or low dose maintenance) or low dose maintenance) ITP
• 43.
  Renal diseases Renal diseases Nephrotic syndrome in children Nephrotic syndrome in children  Renal disease secondary to SLE Renal disease secondary to SLE  Renal sarcoidosis Renal sarcoidosis  Glomerulonephritis – membranous type Glomerulonephritis – membranous type (Life saving importance – usually given in (Life saving importance – usually given in large doses followed by tapering to large doses followed by tapering to maintenance dose) maintenance dose) SLE
• 44.
  Organ Transplant Organ Transplant Combined with other Combined with other immunosuppressants – cyclosporin, immunosuppressants – cyclosporin, azathioprine azathioprine  For prolonged use: For prolonged use:  Prednisolone or methylprednisolone are Prednisolone or methylprednisolone are used used  Intermediate duration of action Intermediate duration of action  Can be easily tapered Can be easily tapered  Can be converted to an alternate regime Can be converted to an alternate regime
• 45.
  Allergic Disorders Allergic Disorders Exhibit a delayed response in allergies (1-2 hrs Exhibit a delayed response in allergies (1-2 hrs even in IV injection) even in IV injection)  In anaphylaxis, angioneurotic oedema and In anaphylaxis, angioneurotic oedema and serum sickness etc. – adrenaline is the choice serum sickness etc. – adrenaline is the choice  Seasonal allergies, bee sting, drug allergies – Seasonal allergies, bee sting, drug allergies –  Allergic reactions can be suppressed by Allergic reactions can be suppressed by corticosteroids as supplements corticosteroids as supplements  Intranasal administration in allergic rhinitis - Intranasal administration in allergic rhinitis - budesonide and flunisolide budesonide and flunisolide
• 46.
  Bronchial Asthma Bronchial Asthma The increased recognition of the immunological and The increased recognition of the immunological and inflammatory nature of Bronchial asthma has led to the inflammatory nature of Bronchial asthma has led to the use of corticosteroids use of corticosteroids  In severe asthma attacks In severe asthma attacks IV hydrocortisone Methylprednisolone IV hydrocortisone Methylprednisolone Oral prednisolone Oral prednisolone  Acute attacks: Acute attacks: *Inhaled beclmethasone, budesonide, flunisolide *Inhaled beclmethasone, budesonide, flunisolide alone or combined with beta-2 agonists/ipratropium alone or combined with beta-2 agonists/ipratropium *Oral steroids *Oral steroids
• 47.
  Infectious Diseases Infectious Diseases Indicated only in severe infective diseases Indicated only in severe infective diseases to tide over crisis or prebent complictions to tide over crisis or prebent complictions  AIDS and pneumocystis carinii pneumonia AIDS and pneumocystis carinii pneumonia  In haemophilus influenza meningitis to reduce In haemophilus influenza meningitis to reduce neurological complications neurological complications  Tubercular meningitis Tubercular meningitis  Lepra reaction Lepra reaction  Scepticaemia Scepticaemia Lepra reaction
• 48.
  Ocular Diseases Ocular Diseases Important drug therapy for suppressing Important drug therapy for suppressing inflammation in eye and preservation of sight inflammation in eye and preservation of sight  Topical instillations are used for conditions of the Topical instillations are used for conditions of the anterior chamber – allergic conjunctivitis, iritis, anterior chamber – allergic conjunctivitis, iritis, iridocyclitis and keratitis etc. iridocyclitis and keratitis etc.  Systemic steroids for the posterior chamber Systemic steroids for the posterior chamber  Dexamethasone topical 0.1% Dexamethasone topical 0.1%  Prednisolone oral Prednisolone oral  Contraindicated in viral, fulminant bacterial Contraindicated in viral, fulminant bacterial infections, fungal infections and injuries infections, fungal infections and injuries
• 49.
  Skin Diseases Skin Diseases The largest application of steroid therapy The largest application of steroid therapy  Topical forms are widely used in many Topical forms are widely used in many eczematous skin diseases eczematous skin diseases  Systemic therapy are also required and Systemic therapy are also required and may be life saving in may be life saving in  Pemphigus vulgaris Pemphigus vulgaris  Exfoliative dermatitis Exfoliative dermatitis  Stevens-Johnson syndrome Stevens-Johnson syndrome Pemphigus vulgaris
• 50.
  GIT GIT  Inflammatory conditionsof intestine like Inflammatory conditions of intestine like  Ulcerative colitis Ulcerative colitis  Crohn`s disease Crohn`s disease  Coeliac disease Coeliac disease (oral therapy or retention enema with hydrocortisone) (oral therapy or retention enema with hydrocortisone)  May mask the major complications like May mask the major complications like perforation and peritonitis perforation and peritonitis
• 51.
  Malignancy Malignancy  Essential forcombined chemotherapy of Essential for combined chemotherapy of  Acute lymphatic leukemia Acute lymphatic leukemia  Hodgkin's and other lymphomas Hodgkin's and other lymphomas  Hormone responsive breast carcinoma Hormone responsive breast carcinoma  Symptomatic relief in other advance Symptomatic relief in other advance malignancies by improving appetite and malignancies by improving appetite and controlling secondary hypercalcaemia controlling secondary hypercalcaemia Hodgkin`s lymphoma
• 52.
  Cerebral Oedema Cerebral Oedema Cerebral oedema due to tumors Cerebral oedema due to tumors (neoplasms) (neoplasms)  Traumatic and poststroke oedema (?) Traumatic and poststroke oedema (?) (Dexamethasone or betamethasone is (Dexamethasone or betamethasone is preferred because no Na+ retaining preferred because no Na+ retaining activity) activity)  Other CNS conditions - spinal chord injury, Other CNS conditions - spinal chord injury, Bell`s palsy and neurocysticercosis Bell`s palsy and neurocysticercosis  (Oral Prednisolone is the preferred drug) (Oral Prednisolone is the preferred drug)
• 53.
  Other Uses Other Uses Antiemetic – with ondansetron Antiemetic – with ondansetron  Acute mountain sickness Acute mountain sickness  Aspiration pneumonia, pulmonary oedema Aspiration pneumonia, pulmonary oedema from drowning from drowning  Hyperthyroidism – thyroid storm Hyperthyroidism – thyroid storm
• 54.
  Adverse Effects Adverse Effects Two types: Two types:  From abrupt withdrawal From abrupt withdrawal  Chronic therapeutic use of high dose Chronic therapeutic use of high dose  Withdrawal Withdrawal  Flare up of underlying disease Flare up of underlying disease  Suppression of HPA axis and acute adrenal Suppression of HPA axis and acute adrenal insufficiency insufficiency  Increased ICT and papilloedema Increased ICT and papilloedema
• 55.
  Adverse Effects Adverse Effects Cushing`shabitus
• 56.
  Other Important AdverseEffects Other Important Adverse Effects  Fluid and Electrolyte Disturbance – Na and water Fluid and Electrolyte Disturbance – Na and water retention retention  Precipitation of Diabetes mellitus – hyperglycemia Precipitation of Diabetes mellitus – hyperglycemia  Increased susceptibility to infections – immune response Increased susceptibility to infections – immune response suppression suppression  Peptic ulceration – bleeding & perforation Peptic ulceration – bleeding & perforation  Osteoporosis – flat spongy bones Osteoporosis – flat spongy bones  Osteonecrosis – avascular necrosis of head of femur, Osteonecrosis – avascular necrosis of head of femur, humorous etc. humorous etc.  Myopathy – weakness of muscles Myopathy – weakness of muscles  Cataract – posterior sub capsular Cataract – posterior sub capsular  Glaucoma – prolonged topical therapy Glaucoma – prolonged topical therapy  Growth retardation – in children Growth retardation – in children
• 57.
  Contraindications Contraindications  Say noto any drug formulation combined with Say no to any drug formulation combined with steroids steroids  Remember that STEROIDS are life saving drugs Remember that STEROIDS are life saving drugs  Note the following conditions where u have to be Note the following conditions where u have to be extremely cautious: extremely cautious:  Peptic ulcer Peptic ulcer  Hypertension and Diabetes mellitus Hypertension and Diabetes mellitus  Viral and fungal infections Viral and fungal infections  Tuberculosis and other diseases Tuberculosis and other diseases  Osteoporosis Osteoporosis  Epilepsy and psychosis Epilepsy and psychosis  CHF and renal failure CHF and renal failure
• 58.
  Choosing a Steroid Choosinga Steroid  Benefit/risk ratio is a major consideration Benefit/risk ratio is a major consideration  Drugs with primary glucocorticoid activity Drugs with primary glucocorticoid activity are used are used  Minimal dose to achieve the desired Minimal dose to achieve the desired effects is chosen effects is chosen  Topical or local therapy is preferred Topical or local therapy is preferred whenever possible whenever possible
• 59.
  Choosing a Steroid– contd. Choosing a Steroid – contd. • Once daily dosing is usually Once daily dosing is usually preferred for oral glucocorticoids preferred for oral glucocorticoids • Large steroid doses are Large steroid doses are administered in divided doses to administered in divided doses to reduce local GIT effects reduce local GIT effects • In order to mimic the normal diurnal In order to mimic the normal diurnal cycle and reduce the risk of cycle and reduce the risk of adrenal suppression, GCs should adrenal suppression, GCs should be given in the morning between be given in the morning between 6-10 AM 6-10 AM • Alternate day therapy allows the Alternate day therapy allows the HPA axis to recover on off days HPA axis to recover on off days Single dose Steroid
• 60.
  Withdrawal of SteroidTherapy Withdrawal of Steroid Therapy  Taper the dose to reduce GC dose by 2.5-5 mg of Taper the dose to reduce GC dose by 2.5-5 mg of prednisolone equivalent daily prednisolone equivalent daily  Once the GC dose is reduced to 5 mg of prednisolone Once the GC dose is reduced to 5 mg of prednisolone equivalent, the patient may be switched to a shorter equivalent, the patient may be switched to a shorter acting agent for further tapering acting agent for further tapering  Intermediate acting corticosteroids allow for more flexible Intermediate acting corticosteroids allow for more flexible dosing schedule dosing schedule  Have potent glucocorticoid effects Have potent glucocorticoid effects  Causes lesser suppression of HPA axis Causes lesser suppression of HPA axis  Causes less GIT irritation Causes less GIT irritation  Preferred for oral therapy Preferred for oral therapy  Prednisolone, methylprednisolone and triacinolone have a half Prednisolone, methylprednisolone and triacinolone have a half life of 12-36 Hrs, are available in a number of dosage forms life of 12-36 Hrs, are available in a number of dosage forms
• 61.
  Adrenocorticosteroid Inhibitors Adrenocorticosteroid Inhibitors Metyrapone: Metyrapone: 11 beta-hydroxylase 11 beta-hydroxylase enzyme inhibitor – enzyme inhibitor – used in Cushing`s syndrome and test of pituitary used in Cushing`s syndrome and test of pituitary efficiency efficiency  Aminoglutethemide: Aminoglutethemide: Stops conversion of cholesterol to Stops conversion of cholesterol to pregnelone pregnelone (Medical adrenalectomy) (Medical adrenalectomy) – Breast cancers – Breast cancers  Mifepristone: Mifepristone: Progesterone antagonist Progesterone antagonist  Spironolactone: Spironolactone: Aldosterone antagonist Aldosterone antagonist  Ketoconazole: Ketoconazole: Inhibits synthesis of all hormones in Inhibits synthesis of all hormones in testes and adrenal cortex – used in Cushing`s testes and adrenal cortex – used in Cushing`s syndrome and also in hirsutism in female syndrome and also in hirsutism in female
• 62.
  Must Know! Must Know! Biosynthesis and Regulation of Biosynthesis and Regulation of Corticosteroids Corticosteroids  Mechanism of action of Corticosteroids Mechanism of action of Corticosteroids  Name of commonly used Glucocorticoids Name of commonly used Glucocorticoids  Anti-inflammatory and Anti-inflammatory and immunosuppressive actions of immunosuppressive actions of Glucocorticoids Glucocorticoids  Important Adverse effects of Important Adverse effects of Corticosteroids Corticosteroids  Therapeutic uses of Corticosteroids Therapeutic uses of Corticosteroids
• 63.
  Thank You Thank You