CorticosteroidsCorticosteroids

Department of PharmacologyDepartment of Pharmacology

NEIGRIHMS, ShillongNEIGRIHMS, Shillong

SteroidsSteroids

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

IntroductionIntroduction

• 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 Mineralocorticoidsare necessary for life • Corticosteroids or corticoids refer to natural gluco- and mineralo-corticoids and their synthetic analogues

ContentsContents

History and BiosynthesisHistory and Biosynthesis Mechanism of actionMechanism of action Physiological and Pharmacological actionsPhysiological and Pharmacological actions Pharmacokinetics and preparationsPharmacokinetics and preparations Uses – therapeutic and diagnosticUses – therapeutic and diagnostic Dosage schedule and withdrawalDosage schedule and withdrawal Adverse reactions and contraindicationsAdverse reactions and contraindications Precautions during therapyPrecautions during therapy ContraindicationsContraindications

HistoryHistory

1855 – Addison`s disease1855 – Addison`s disease

1856 – Adrenal glands essential for life1856 – Adrenal glands essential for life

1930 – Cortex > medulla1930 – Cortex > medulla

1932 – Cushing’s syndrome1932 – Cushing’s syndrome

1952 – Aldosterone1952 – Aldosterone

AnatomyAnatomy

An inner medulla,An inner medulla, is a is a source of catecholamine – source of catecholamine – adrenaline and nor-adrenalineadrenaline and nor-adrenaline

Chromaffin cell is the principal Chromaffin cell is the principal cell typecell 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 systemsympathetic 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 MineralocorticoidsMineralocorticoids

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 secretesecrete

Cortex develops from Cortex develops from mesodermmesoderm

Adrenal CortexAdrenal Cortex

The adrenal cortex is a factory of steroid hormonesThe 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 importancetissue, but two classes are of importance

Steroid ClassSteroid Class PrototypePrototype Physiological effectPhysiological effect

MineralocorticoidMineralocorticoid Aldosterone (z. glomerulosa)Aldosterone (z. glomerulosa) Na, K and water Na, K and water homeostasishomeostasis

GlucocorticoidGlucocorticoid Hydrocortisone or cortisol (z. fasciculata)Hydrocortisone or cortisol (z. fasciculata)

CorticosteroneCorticosterone

Glucose and many Glucose and many other homeostasisother homeostasis

Adrenal cortex also produces sex steroids – Androgens, Dehydroepiandrosterone (DHEA) – z. reticularis

BiosynthesisBiosynthesis Synthesized from cholesterol Synthesized from cholesterol

through a series of enzyme-through a series of enzyme-mediated transformationsmediated transformations

ACTH ACTH stimulates adrenal stimulates adrenal steroid synthesissteroid 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 precursorsaldosterone 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 diminishespotassium diminishes

Steroid Biosynthesis - contd.Steroid Biosynthesis - contd.

Basal SecretionBasal Secretion

GroupGroup HormoneHormone DailyDaily

GlucocorticoidsGlucocorticoids CortisolCortisol

CorticosteroneCorticosterone

5 – 30 mg5 – 30 mg

2 – 5 mg2 – 5 mg

MineralocorticoidsMineralocorticoids AldosteroneAldosterone

11- deoxycorticosterone11- deoxycorticosterone

5 – 150 mcg5 – 150 mcg

TraceTrace

Sex HormonesSex Hormones

AndrogenAndrogen

ProgestogenProgestogen

OestrogenOestrogen

DHEA DHEA

ProgesteroneProgesterone

OestradiolOestradiol

15 – 30 mg15 – 30 mg

0.4 – 0.8 mg0.4 – 0.8 mg

TraceTrace

Regulation of SynthesisRegulation of Synthesis

• Synthesized andreleased underinfluence of ACTH - Ant.Pituitary (HPA axis)

• Regulated by CRHfrom hypothalamusand by feedbacklevels of blood concentrations

1.1. Control by circadian Control by circadian rhythm (Diurnal rhythm (Diurnal rhythm) – morning rhythm) – morning riserise

2.2. Stress: Stress: hypoglycaemia, hypoglycaemia, physical stress etc.physical stress etc.

Regulation of Synthesis - OthersRegulation of Synthesis - Others

Diurnal variation of CortisolDiurnal variation of Cortisol

Glucocorticoids - MOAGlucocorticoids - MOA Not stored: Not stored:

rate of synthesis = rate of releaserate 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 mealsafter 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 bodyall cells of the body

They are made up of almost 800 amino acids They are made up of almost 800 amino acids

Glucocorticoids - MOAGlucocorticoids - MOA GR receptors are located in the cytoplasmGR 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 transcriptionThis 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

compoundcompound Therefore HSP and other proteins get dissociatedTherefore 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 othersregulate 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 responseproduction of protein and bring about final response

Glucocorticoids - MOAGlucocorticoids - MOA

ActionsActionsNumerous and widespread actions:Numerous and widespread actions: Carbohydrate, lipid and protein metabolismCarbohydrate, lipid and protein metabolism Fluid and electrolyte balanceFluid and electrolyte balance Normal functioning of CVS, immune system, kidneys, skeletal muscles and nervous systemNormal functioning of CVS, immune system, kidneys, skeletal muscles and nervous system Provides resistance to stress and noxious stimuli and environmental changesProvides resistance to stress and noxious stimuli and environmental changes Permits and facilitates the actions of other hormonesPermits and facilitates the actions of other hormones

Direct ActionsDirect Actions

Permissive ActionsPermissive Actions• Lipolytic effects• Effect on BP• Effect on bronchial muscles• (e.g.,sympathomimetic amine)

Actions of Corticosteroids - Actions of Corticosteroids - MineralocorticoidMineralocorticoid

Aldosterone is the prototype of mineralocorticoid effectsAldosterone 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 HIncrease excretion of K+ and H Similar effects occur in colon, sweat gland and salivary Similar effects occur in colon, sweat gland and salivary

glandgland Deficiency of mineralocorticoid action leads toDeficiency 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.

Glucocorticoid actions - Glucocorticoid actions - Carbohydrate & protein metabolismCarbohydrate & 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 – gluconeogenesisform 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 gluconeogenesisamino 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 utilizationfrom 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 productionup 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

Actions:Actions: Carbohydrate and protein metabolismCarbohydrate and protein metabolism

GluconeogenesisGluconeogenesis Peripheral actions Peripheral actions (mobilize AA & glucose and (mobilize AA & glucose and

glycogen)glycogen)

Hepatic actionsHepatic actions

Peripheral utilization of glucosePeripheral utilization of glucose

Glycogen deposition in liverGlycogen deposition in liver(activation of hepatic glycogen synthase)(activation of hepatic glycogen synthase)

Negative nitrogen balance & hyperglycaemia

Fat MetabolismFat Metabolism Redistribution of fats in different areas of the Redistribution of fats in different areas of the

bodybody 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 insulininsulin Deposition of fats in face, neck and shoulder – moon Deposition of fats in face, neck and shoulder – moon

face/buffalo humpface/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 depositionlipogenesis 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 depositionin face and neck predominant action – fat deposition

Actions of GlucocorticoidsActions of 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 adrenal insufficiency capacity to excrete water is lost – water intoxicationintoxication

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 - osteoporosisosteoporosis Skeletal muscle: Skeletal muscle:

Normal muscular activity needs Glucocorticoids at its optimum levelNormal muscular activity needs Glucocorticoids at its optimum level Excess level leads to muscular weakness and wastingExcess 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 hypokalaemiacirculation) and hypercorticism – due to hypokalaemia CNS:CNS:

Euphoria – in pharmacological dosesEuphoria – in pharmacological doses Addison's disease – apathy, depression and psychosisAddison's disease – apathy, depression and psychosis High doses – induce seizureHigh doses – induce seizure

Actions of GlucocorticoidsActions of Glucocorticoids CVS:CVS: Permissive role on pressor effect with Adr and angiotensinPermissive 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 adrenalineand poor response to adrenaline Cardiovascular collapse – along with mineralocorticoidsCardiovascular collapse – along with mineralocorticoids

Blood and lymphoid tissues:Blood and lymphoid tissues: Destruction of lymphoid tissue – modest in normal personsDestruction 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 RBCsIncrease in number of RBCs

Decreases the numbers of circulating lymphocytes, monocytes, Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increases Polymorphseosinophils and basophils but increases Polymorphs

Glucocorticoids – anti-inflammatory Glucocorticoids – anti-inflammatory and immunosuppressive effectsand 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, hypersensitivitystimuli, hypersensitivity

Underlying cause of disease is not correctedUnderlying cause of disease is not corrected Reduction in cardinal signs of inflammationReduction 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 activityleukocytes – 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 A2activation of phospholipase A2

Basis of exogenous use of most clinical usesBasis of exogenous use of most clinical uses

Glucorticoids - Multiple Mechanisms

Recruitment of Recruitment of WBC & WBC & monocytemonocyte - - macrophage into macrophage into affected area & elaboration of chemotactic substancesaffected area & elaboration of chemotactic substances

LipocortinLipocortin: decreased production of PG, LT and PAF: decreased production of PG, LT and PAF Negative regulation of COX 2: inducible PG Negative regulation of COX 2: inducible PG

productionproduction 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), TNFproduction of IL (1, 2, 3, 6), TNFαα, GM-CSF etc. – , GM-CSF etc. – fibroblast proliferation and T-lymphocyte function – fibroblast proliferation and T-lymphocyte function – interference with chemotaxis interference with chemotaxis

Contd.Contd.

In endothelial cells-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 interferedadhesion and localization of leucocytes interfered

Release of histamine from basophils is inhibitedRelease of histamine from basophils is inhibited Decreased production of Decreased production of collagenasecollagenase – prevention of – prevention of

tissue destructiontissue destruction Decreased functioning of Decreased functioning of osteoblasts osteoblasts and increased and increased

activity of activity of osteoclasticosteoclastic activity - activity - osteoporosisosteoporosis Decreased IgG productionDecreased IgG production Decreased generation of induced nitric oxideDecreased generation of induced nitric oxide

Phospholipids

Arachidonic acids

lipoxygenase Cycylooxygenase

LeukotrieneProstaglandins,ThromboxaneProstacyclins

Phospholipase A2

Lipocortin

Corticosteroids

PAF by lipocortin

Immunosuppressive & anti-allergic Immunosuppressive & anti-allergic actionsactions

Suppresses all types of hypersensitivity & Suppresses all types of hypersensitivity & allergic phenomenonallergic phenomenon

At High dose: Interfere with all steps of At High dose: Interfere with all steps of immunological responseimmunological 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.

Glucocorticoids – Anti-inflammatory Glucocorticoids – Anti-inflammatory and Immunosuppressive effectsand Immunosuppressive effects

Glucocorticoids - PharmacokineticsGlucocorticoids - Pharmacokinetics

Therapeutically given by various routes – orally, IM, IV, Therapeutically given by various routes – orally, IM, IV, topicallytopically

Hydrocortisone undergoes high first pass metabolismHydrocortisone undergoes high first pass metabolism Oral bioavailability of synthetic corticoids is highOral 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 compoundsactive compounds Metabolized in liver and excreted in urineMetabolized in liver and excreted in urine Exogenously administered hydrocortisone has t1/2 of 1.5 Exogenously administered hydrocortisone has t1/2 of 1.5

HrsHrs

Steroid PreparationsSteroid Preparations

An ideal GC should have no An ideal GC should have no mineralocorticoid activitymineralocorticoid 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 withcompounds with Minimal mineralocorticoid activityMinimal mineralocorticoid activity Greater potencyGreater potency Longer duration of actionLonger duration of action

Important agentsImportant agents Injectable:Injectable:

Betamethasone Dexamethasone Betamethasone Dexamethasone Prednisolone Methylprednisolone Prednisolone Methylprednisolone Hydrocortisone TriamcinoloneHydrocortisone Triamcinolone

Oral:Oral:Betamethasone FludricortisoneBetamethasone FludricortisonePrednisolone PrednisonePrednisolone PrednisoneMethylprednisoloneMethylprednisolone

Topical:Topical:Betamethasone ClobetasolBetamethasone ClobetasolFlucinolone MometasoneFlucinolone Mometasone

Inhalation:Inhalation:Beclomethasone BudesonideBeclomethasone BudesonideFlunisolodeFlunisolode

Chemical StructuresChemical StructuresPharmaceutical steroids are usually obtained from “cholic acid” (obtained from cattle) or sapogenins found in plants of Liliacaceae

Cyclopentanoperhydrophenanthrene skeleton

Rings are labeled as A, B, C and D.

Natural steroids have two methyls

Numbering of each position essentially follows a uniform pattern except for the methyls.

Relative ActivityRelative Activity

CompoundCompound Duration Duration GCGC MCMC Equivalent Equivalent dose (mg)dose (mg)

HydrocortisoneHydrocortisone SASA 11 11 2020

PrednisolonePrednisolone IAIA 44 0.80.8 55

MethylMethyl

PrednisolonePrednisolone

IAIA 55 0.50.5 44

TriamcinoloneTriamcinolone IAIA 55 00 44

DexamethasoneDexamethasone LALA 2525 00 0.750.75

BetmethasoneBetmethasone LALA 2525 00 0.750.75

AldosteroneAldosterone MCMC 0.30.3 500 - 3000500 - 3000 NUNU

Desoxycortisone Desoxycortisone acetate (DOCA)acetate (DOCA)

MCMC 00 100100 2.5 (S. 2.5 (S. lingual)lingual)

Corticosteroids - Clinical Corticosteroids - Clinical PharmacologyPharmacology

Therapeutic usesTherapeutic uses A number of diverse disease states respond to A number of diverse disease states respond to

GCsGCs 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 diseaseAddison`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 diseaseinflammatory 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 effectsfor their immunosuppressive effects

Replacement TherapyReplacement Therapy

Adrenal insufficiency – acute/chronicAdrenal insufficiency – acute/chronic Abrupt withdrawal of steroid therapyAbrupt withdrawal of steroid therapy Chronic infections – TuberculosisChronic infections – Tuberculosis Autoimmune adrenal diseaseAutoimmune adrenal disease Surgery, Hemorrhage and AIDSSurgery, Hemorrhage and AIDS

Congenital adrenal hyperplasiaCongenital 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 productionincreased androgen production

CAH

Replacement TherapyReplacement Therapy Acute adrenal insufficiencyAcute adrenal insufficiency

IV replacement of sodium chloride and fluidIV 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 secretionevery 8 Hrs – maximal daily rate of secretion

(alternatively, dexamethasone can be used)(alternatively, dexamethasone can be used) Chronic adrenal insufficiencyChronic adrenal insufficiency

HydrocortisoneHydrocortisone Prednisolone or dexamethasone – long actingPrednisolone or dexamethasone – long acting Fludrocortisone for mineralocorticoid effectsFludrocortisone for mineralocorticoid effects

Congenital adrenal hyperplasiaCongenital adrenal hyperplasia Hydrocortisone 0.6 mg/kg in divided doses – to Hydrocortisone 0.6 mg/kg in divided doses – to

maintain feedback suppressionmaintain feedback suppression

Anti-inflammatory UsesAnti-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 casessevere 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

CHFCHF Gout – NSAID failed cases and colchicine failed Gout – NSAID failed cases and colchicine failed

cases – intra-articular injectioncases – intra-articular injection Vasculitic disorders: Polyarteritis nodosaVasculitic disorders: Polyarteritis nodosa

Intra-articular SteroidsIntra-articular Steroids

Can be used in inflammatoryNon-inflammatory diseases• Knee joint• Shoulder joint• Tennis elbow• Carpal tunnel syndrome

Autoimmune diseasesAutoimmune diseases

Autoimmune haemolytic anaemiaAutoimmune haemolytic anaemia Idiopathic thrombocytopenic purpuraIdiopathic thrombocytopenic purpura Active chronic hepatitis, alcoholic hepatitisActive 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

Renal diseases Renal diseases

Nephrotic syndrome in childrenNephrotic syndrome in children Renal disease secondary to SLERenal disease secondary to SLE Renal sarcoidosisRenal sarcoidosis Glomerulonephritis – membranous typeGlomerulonephritis – 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

Organ TransplantOrgan Transplant

Combined with other immunosuppressants Combined with other immunosuppressants – cyclosporin, azathioprine– cyclosporin, azathioprine

For prolonged use:For prolonged use: Prednisolone or methylprednisolone are Prednisolone or methylprednisolone are

usedused Intermediate duration of actionIntermediate duration of action Can be easily tapered Can be easily tapered Can be converted to an alternate regimeCan be converted to an alternate regime

Allergic DisordersAllergic 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 choiceserum 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 supplementscorticosteroids as supplements

Intranasal administration in allergic rhinitis - Intranasal administration in allergic rhinitis - budesonide and flunisolidebudesonide and flunisolide

Bronchial AsthmaBronchial 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 corticosteroidsuse of corticosteroids

In severe asthma attacksIn severe asthma attacks IV hydrocortisone MethylprednisoloneIV hydrocortisone Methylprednisolone Oral prednisoloneOral prednisolone

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

Infectious DiseasesInfectious Diseases

Indicated only in severe infective diseases Indicated only in severe infective diseases to tide over crisis or prebent complictionsto tide over crisis or prebent complictions AIDS and pneumocystis carinii pneumoniaAIDS and pneumocystis carinii pneumonia In haemophilus influenza meningitis to reduce In haemophilus influenza meningitis to reduce

neurological complicationsneurological complications Tubercular meningitisTubercular meningitis Lepra reactionLepra reaction ScepticaemiaScepticaemia

Lepra reaction

Ocular DiseasesOcular Diseases

Important drug therapy for suppressing Important drug therapy for suppressing inflammation in eye and preservation of sightinflammation 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 chamberSystemic steroids for the posterior chamber Dexamethasone topical 0.1%Dexamethasone topical 0.1% Prednisolone oralPrednisolone oral Contraindicated in viral, fulminant bacterial Contraindicated in viral, fulminant bacterial

infections, fungal infections and injuriesinfections, fungal infections and injuries

Skin DiseasesSkin Diseases

The largest application of steroid therapyThe largest application of steroid therapy Topical forms are widely used in many Topical forms are widely used in many

eczematous skin diseaseseczematous 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 vulgarisPemphigus vulgaris Exfoliative dermatitisExfoliative dermatitis Stevens-Johnson syndromeStevens-Johnson syndrome

Pemphigus vulgaris

GITGIT

Inflammatory conditions of intestine like Inflammatory conditions of intestine like Ulcerative colitisUlcerative colitis Crohn`s diseaseCrohn`s disease Coeliac diseaseCoeliac 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 peritonitisperforation and peritonitis

MalignancyMalignancy

Essential for combined chemotherapy of Essential for combined chemotherapy of Acute lymphatic leukemiaAcute lymphatic leukemia Hodgkin's and other lymphomasHodgkin's and other lymphomas Hormone responsive breast carcinomaHormone 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 hypercalcaemiacontrolling secondary hypercalcaemia

Hodgkin`s lymphoma

Cerebral OedemaCerebral 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 neurocysticercosisBell`s palsy and neurocysticercosis

(Oral Prednisolone is the preferred drug)(Oral Prednisolone is the preferred drug)

Other UsesOther Uses

Antiemetic – with ondansetronAntiemetic – with ondansetron Acute mountain sicknessAcute mountain sickness Aspiration pneumonia, pulmonary oedema Aspiration pneumonia, pulmonary oedema

from drowningfrom drowning Hyperthyroidism – thyroid stormHyperthyroidism – thyroid storm

Adverse EffectsAdverse Effects

Two types:Two types: From abrupt withdrawalFrom abrupt withdrawal Chronic therapeutic use of high doseChronic therapeutic use of high dose

WithdrawalWithdrawal Flare up of underlying diseaseFlare up of underlying disease Suppression of HPA axis and acute adrenal Suppression of HPA axis and acute adrenal

insufficiencyinsufficiency Increased ICT and papilloedemaIncreased ICT and papilloedema

Adverse EffectsAdverse Effects

Cushing`s habitus

Other Important Adverse EffectsOther Important Adverse Effects Fluid and Electrolyte Disturbance – Na and water Fluid and Electrolyte Disturbance – Na and water

retentionretention Precipitation of Diabetes mellitus – hyperglycemiaPrecipitation of Diabetes mellitus – hyperglycemia Increased susceptibility to infections – immune response Increased susceptibility to infections – immune response

suppressionsuppression Peptic ulceration – bleeding & perforationPeptic ulceration – bleeding & perforation Osteoporosis – flat spongy bonesOsteoporosis – flat spongy bones Osteonecrosis – avascular necrosis of head of femur, Osteonecrosis – avascular necrosis of head of femur,

humorous etc.humorous etc. Myopathy – weakness of musclesMyopathy – weakness of muscles Cataract – posterior sub capsularCataract – posterior sub capsular Glaucoma – prolonged topical therapyGlaucoma – prolonged topical therapy Growth retardation – in children Growth retardation – in children

ContraindicationsContraindications Say no to any drug formulation combined with Say no to any drug formulation combined with

steroidssteroids Remember that STEROIDS are life saving drugsRemember 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 ulcerPeptic ulcer Hypertension and Diabetes mellitusHypertension and Diabetes mellitus Viral and fungal infectionsViral and fungal infections Tuberculosis and other diseasesTuberculosis and other diseases OsteoporosisOsteoporosis Epilepsy and psychosisEpilepsy and psychosis CHF and renal failureCHF and renal failure

Choosing a Steroid Choosing a Steroid

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

are usedare used Minimal dose to achieve the desired Minimal dose to achieve the desired

effects is choseneffects is chosen Topical or local therapy is preferred Topical or local therapy is preferred

whenever possiblewhenever possible

Choosing a Steroid – contd.Choosing a Steroid – contd.

• Once daily dosing is usually Once daily dosing is usually preferred for oral glucocorticoidspreferred for oral glucocorticoids• Large steroid doses are Large steroid doses are administered in divided doses to administered in divided doses to reduce local GIT effectsreduce 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 AM6-10 AM• Alternate day therapy allows the Alternate day therapy allows the HPA axis to recover on off daysHPA axis to recover on off days

Single doseSteroid

Withdrawal of Steroid TherapyWithdrawal 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 dailyprednisolone 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 taperingacting agent for further tapering

Intermediate acting corticosteroids allow for more flexible Intermediate acting corticosteroids allow for more flexible dosing scheduledosing schedule

Have potent glucocorticoid effectsHave potent glucocorticoid effects Causes lesser suppression of HPA axisCauses lesser suppression of HPA axis Causes less GIT irritationCauses less GIT irritation Preferred for oral therapyPreferred 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 formslife of 12-36 Hrs, are available in a number of dosage forms

Adrenocorticosteroid InhibitorsAdrenocorticosteroid Inhibitors Metyrapone:Metyrapone: 11 beta-hydroxylase11 beta-hydroxylase enzyme inhibitor – enzyme inhibitor –

used in Cushing`s syndrome and test of pituitary used in Cushing`s syndrome and test of pituitary efficiencyefficiency

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 femalesyndrome and also in hirsutism in female

Must Know!Must Know!

Biosynthesis and Regulation of Biosynthesis and Regulation of CorticosteroidsCorticosteroids

Mechanism of action of CorticosteroidsMechanism of action of Corticosteroids Name of commonly used GlucocorticoidsName of commonly used Glucocorticoids Anti-inflammatory and immunosuppressive Anti-inflammatory and immunosuppressive

actions of Glucocorticoidsactions of Glucocorticoids Important Adverse effects of Important Adverse effects of

CorticosteroidsCorticosteroids Therapeutic uses of CorticosteroidsTherapeutic uses of Corticosteroids

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