Corticosteroids Pharmacology - drdhriti

Pharmacology ofPharmacology of
CorticosteroidsCorticosteroids
Dr. D. K. BrahmaDr. D. K. Brahma
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 Mineralocorticoids
are 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 sourceis a source
of catecholamine – adrenalineof catecholamine – adrenaline
and nor-adrenalineand nor-adrenaline
 Chromaffin cell is the principalChromaffin cell is the principal
cell typecell type
 Medulla is richly innervated byMedulla is richly innervated by
sympathetic fibres and issympathetic fibres and is
considered as extension ofconsidered as extension of
sympathetic nervous systemsympathetic nervous system
 Medulla develops fromMedulla develops from
ectoderm (neural crest)ectoderm (neural crest)
 An outer cortex,An outer cortex, whichwhich
secretes several classes ofsecretes several classes of
steroid hormones includingsteroid hormones including
GlucocorticoidsGlucocorticoids andand
MineralocorticoidsMineralocorticoids
 Three different concentricThree different concentric
zones of cells that differ inzones of cells that differ in
major steroid hormones theymajor steroid hormones they
secretesecrete
 Cortex develops fromCortex 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 this10 – 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 waterNa, K and water
homeostasishomeostasis
GlucocorticoidGlucocorticoid Hydrocortisone or cortisol (z. fasciculata)Hydrocortisone or cortisol (z. fasciculata)
CorticosteroneCorticosterone
Glucose and manyGlucose and many
other homeostasisother homeostasis
Adrenal cortex also produces sex steroids – Androgens,
Dehydroepiandrosterone (DHEA) – z. reticularis

BiosynthesisBiosynthesis
 Synthesized from cholesterolSynthesized from cholesterol
through a series of enzyme-through a series of enzyme-
mediated transformationsmediated transformations
 ACTHACTH stimulates adrenalstimulates adrenal
steroid synthesissteroid synthesis
 Aldosterone synthesis is notAldosterone synthesis is not
stimulated by ACTH but bystimulated by ACTH but by
angiotensin II, although ACTHangiotensin II, although ACTH
does stimulate synthesis ofdoes stimulate synthesis of
aldosterone precursorsaldosterone precursors
 Circulating Potassium exerts aCirculating Potassium exerts a
permissive effect onpermissive effect on
angiotensin II stimulation; highangiotensin II stimulation; high
potassium enhances and lowpotassium 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
DHEADHEA
ProgesteroneProgesterone
OestradiolOestradiol
15 – 30 mg15 – 30 mg
0.4 – 0.8 mg0.4 – 0.8 mg
TraceTrace

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

1.1. Control by circadianControl by circadian
rhythm (Diurnalrhythm (Diurnal
rhythm) – morningrhythm) – 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 bySynthesize rhythmically and controlled by
irregular pulses of ACTH, influenced by light andirregular pulses of ACTH, influenced by light and
major pulses occur early in the morning andmajor pulses occur early in the morning and
after mealsafter meals
 Glucocorticoids act via their receptors located inGlucocorticoids act via their receptors located in
nucleus (GR)nucleus (GR)
 GRs are widely distributed and located almost inGRs are widely distributed and located almost in
all cells of the bodyall cells of the body
 They are made up of almost 800 amino acidsThey are made up of almost 800 amino acids

 GR receptors are located in the cytoplasmGR receptors are located in the cytoplasm
 One GR receptor has a DNA binding domain and aOne GR receptor has a DNA binding domain and a
ligand binding domain along with stabilizing proteinsligand 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 unstableBinding 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 toThe S+GR complex enters the nucleus and binds to
Glucocorticoids response element (GRE) on gene andGlucocorticoids 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 forThe resulting mRNA is transported to cytoplasm for
production of protein and bring about final responseproduction of protein and bring about final response

ActionsActions
Numerous 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 salivarySimilar 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 volumemassive loss of Na+ and decreased EFC volume
(essential for survival)(essential for survival)
 Hyperaldosterinism:Hyperaldosterinism: Positive Na+ balance, expansion ofPositive Na+ balance, expansion of
ECF, increased plasma Na, hypokalaemia, alkalosis andECF, increased plasma Na, hypokalaemia, alkalosis and
progressive rise in BP – hypertension, myocardialprogressive rise in BP – hypertension, myocardial
fibrosis etc.fibrosis etc.

Glucocorticoid actions -Glucocorticoid actions -
Carbohydrate & protein metabolismCarbohydrate & protein metabolism
 Profound effect on carbohydrate and protein metabolismProfound 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 toPromotes 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 – formincrease 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 releaseDiabetes 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 usedNegative 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 skinMobilization of amino acids – muscles, thinning of bone and skin

Actions:Actions: Carbohydrate and protein metabolismCarbohydrate and protein metabolism
 GluconeogenesisGluconeogenesis

Peripheral actionsPeripheral 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 theRedistribution of fats in different areas of the
bodybody
 Due to permissive facilitation of effects of otherDue to permissive facilitation of effects of other
agents – GH, glucagons, Adr, thyroxine andagents – GH, glucagons, Adr, thyroxine and
insulininsulin

Deposition of fats in face, neck and shoulder – moonDeposition of fats in face, neck and shoulder – moon
face/buffalo humpface/buffalo hump

Glucocorticoids facilitated hormone sensitive lipolysisGlucocorticoids facilitated hormone sensitive lipolysis
action of GH and Adr. + Glucocorticoids mediatedaction of GH and Adr. + Glucocorticoids mediated
increased insulin = net result is insulin mediatedincreased insulin = net result is insulin mediated
lipogenesis and fat depositionlipogenesis and fat deposition

Peripheral adipocytes are less sensitive to insulin, butPeripheral 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 - inGlucocorticoids play important role in maintaining normal GFR - in
adrenal insufficiency capacity to excrete water is lost – water intoxicationadrenal insufficiency capacity to excrete water is lost – water intoxication
 Calcium Balance:Calcium Balance:

Decrease absorption of Ca++ in GIT and increased excretion – calciumDecrease 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 hypodynamicMuscular 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 contractilityMaintain tone of arterioles and myocardial contractility

Adrenal insufficiency leads to low cardiac output and arteriolar dilatationAdrenal 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 areIn presence of malignancy of lymphatic cells – lytic actions are
significant (apoptosis) – used in lymphomassignificant (apoptosis) – used in lymphomas (Basis of Use)(Basis of Use)

Minor effects on haemoglobin and RBCs – protect against haemolysis ofMinor 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-inflammatoryGlucocorticoids – 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 mediatedPathogens, 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 coversAnti-inflammatory effects are non—specific and covers
all components of inflammation:all components of inflammation:

Effects on concentration, distribution and functions of peripheralEffects on concentration, distribution and functions of peripheral
leukocytes – increased neutrophils & their activityleukocytes – increased neutrophils & their activity

In macrophages: reduction of arachidonic acid metabolitesIn 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 WBC & monocyte - macrophage intoRecruitment of WBC & monocyte - macrophage into
affected area & elaboration of chemotactic substancesaffected area & elaboration of chemotactic substances
 Lipocortin: decreased production of PG, LT and PAFLipocortin: decreased production of PG, LT and PAF
 Negative regulation of COX 2: inducible PGNegative regulation of COX 2: inducible PG
productionproduction
 Negative regulation of genes in cytokines ofNegative 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 chemotaxisinterference with chemotaxis

Contd.Contd.
 In endothelial cells-Endothelial leucocyte adhesionIn endothelial cells-Endothelial leucocyte adhesion
moleculemolecule (ELAM)(ELAM) and otherand other CAMCAM 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 ofDecreased production of collagenasecollagenase – prevention of– prevention of
tissue destructiontissue destruction
 Decreased functioning ofDecreased functioning of osteoblastsosteoblasts and increasedand increased
activity ofactivity 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
Leukotriene
Prostaglandins,
Thromboxane
Prostacyclins
Phospholipase A2
Lipocortin
Corticosteroids
PAF by lipocortin

Immunosuppressive & anti-allergicImmunosuppressive & anti-allergic
actionsactions
 Suppresses all types of hypersensitivity &Suppresses all types of hypersensitivity &
allergic phenomenonallergic phenomenon
 At High dose: Interfere with all steps ofAt High dose: Interfere with all steps of
immunological responseimmunological response
 Causes greater suppression of CMI (graftCauses greater suppression of CMI (graft
rejection & delayed hypersensitivity)rejection & delayed hypersensitivity)
 Transplant rejection: antigen expression fromTransplant rejection: antigen expression from
grafted tissues, delay revascularization,grafted tissues, delay revascularization,
sensitisation of T lymphocytes etc.sensitisation of T lymphocytes etc.

Glucocorticoids – Anti-inflammatoryGlucocorticoids – 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 GCBoth, 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 toSynthetic 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 1.5Exogenously administered hydrocortisone has t1/2 of 1.5
HrsHrs

Steroid PreparationsSteroid Preparations
 An ideal GC should have noAn ideal GC should have no
mineralocorticoid activitymineralocorticoid activity
 Structural changes to the basic cortisolStructural changes to the basic cortisol
molecule resulted in a number ofmolecule 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 DexamethasoneBetamethasone Dexamethasone
Prednisolone MethylprednisolonePrednisolone Methylprednisolone
Hydrocortisone TriamcinoloneHydrocortisone Triamcinolone
 Oral:Oral:
Betamethasone FludricortisoneBetamethasone Fludricortisone
Prednisolone PrednisonePrednisolone Prednisone
MethylprednisoloneMethylprednisolone
 Topical:Topical:
Betamethasone ClobetasolBetamethasone Clobetasol
Flucinolone MometasoneFlucinolone Mometasone
 Inhalation:Inhalation:
Beclomethasone BudesonideBeclomethasone Budesonide
FlunisolodeFlunisolode

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

Cyclopentanoperhydrop
henanthrene skeleton
Rings are labeled as A,
B, C and D.
Natural steroids have
two methyls
Numbering of each position
essentially follows a uniform
pattern except for the
methyls.

Relative ActivityRelative Activity
CompoundCompound DurationDuration GCGC MCMC EquivalentEquivalent
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
DesoxycortisoneDesoxycortisone
acetate (DOCA)acetate (DOCA)
MCMC 00 100100 2.5 (S.2.5 (S.
lingual)lingual)

Corticosteroids - ClinicalCorticosteroids - Clinical
PharmacologyPharmacology

Therapeutic usesTherapeutic uses
 A number of diverse disease states respond toA number of diverse disease states respond to
GCsGCs
 Physiologic doses of Corticosteroids are usedPhysiologic doses of Corticosteroids are used
for replacement therapy in primary andfor replacement therapy in primary and
secondary adrenal insufficiency such assecondary 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 andinflammatory effects in arthritis, asthma and
inflammatory bowel diseaseinflammatory bowel disease
 In organ transplant patients and those withIn organ transplant patients and those with
autoimmune disorders corticosteroids are usedautoimmune 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 mgIV 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 – toHydrocortisone 0.6 mg/kg in divided doses – to
maintain feedback suppressionmaintain feedback suppression

Anti-inflammatory UsesAnti-inflammatory Uses
 For suppression of inflammatory components inFor suppression of inflammatory components in
––

Rheumatoid arthritis – as adjuvant with NSAIDs inRheumatoid arthritis – as adjuvant with NSAIDs in
severe casessevere cases

Osteoarthritis – NSAIDs, intra-articular injectionOsteoarthritis – NSAIDs, intra-articular injection

Rheumatic fever – severe cases with carditis andRheumatic fever – severe cases with carditis and
CHFCHF

Gout – NSAID failed cases and colchicine failedGout – 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 inflammatory
Non-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 withdrawalremission followed by gradual withdrawal
or low dose maintenance)or low dose maintenance)
ITP

Renal diseasesRenal 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 tolarge doses followed by tapering to
maintenance dose)maintenance dose)
SLE

Organ TransplantOrgan Transplant
 Combined with otherCombined with other
immunosuppressants – cyclosporin,immunosuppressants – cyclosporin,
azathioprineazathioprine
 For prolonged use:For prolonged use:
 Prednisolone or methylprednisolone arePrednisolone or methylprednisolone are
usedused

Intermediate duration of actionIntermediate duration of action

Can be easily taperedCan 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 hrsExhibit a delayed response in allergies (1-2 hrs
even in IV injection)even in IV injection)
 In anaphylaxis, angioneurotic oedema andIn 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 byAllergic 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 andThe increased recognition of the immunological and
inflammatory nature of Bronchial asthma has led to theinflammatory 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 diseasesIndicated 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 reduceIn haemophilus influenza meningitis to reduce
neurological complicationsneurological complications

Tubercular meningitisTubercular meningitis

Lepra reactionLepra reaction

ScepticaemiaScepticaemia
Lepra reaction

Ocular DiseasesOcular Diseases
 Important drug therapy for suppressingImportant drug therapy for suppressing
inflammation in eye and preservation of sightinflammation in eye and preservation of sight
 Topical instillations are used for conditions of theTopical 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 bacterialContraindicated 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 manyTopical forms are widely used in many
eczematous skin diseaseseczematous skin diseases
 Systemic therapy are also required andSystemic therapy are also required and
may be life saving inmay be life saving in

Pemphigus vulgarisPemphigus vulgaris

Exfoliative dermatitisExfoliative dermatitis

Stevens-Johnson syndromeStevens-Johnson syndrome
Pemphigus
vulgaris

GITGIT
 Inflammatory conditions of intestine likeInflammatory 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 likeMay mask the major complications like
perforation and peritonitisperforation and peritonitis

MalignancyMalignancy
 Essential for combined chemotherapy ofEssential 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 advanceSymptomatic relief in other advance
malignancies by improving appetite andmalignancies by improving appetite and
controlling secondary hypercalcaemiacontrolling secondary hypercalcaemia
Hodgkin`s
lymphoma

Cerebral OedemaCerebral Oedema
 Cerebral oedema due to tumorsCerebral 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+ retainingpreferred 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 oedemaAspiration 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 adrenalSuppression 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 waterFluid and Electrolyte Disturbance – Na and water
retentionretention
 Precipitation of Diabetes mellitus – hyperglycemiaPrecipitation of Diabetes mellitus – hyperglycemia
 Increased susceptibility to infections – immune responseIncreased 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 childrenGrowth retardation – in children

ContraindicationsContraindications
 Say no to any drug formulation combined withSay 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 beNote 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 SteroidChoosing a Steroid
 Benefit/risk ratio is a major considerationBenefit/risk ratio is a major consideration
 Drugs with primary glucocorticoid activityDrugs with primary glucocorticoid activity
are usedare used
 Minimal dose to achieve the desiredMinimal dose to achieve the desired
effects is choseneffects is chosen
 Topical or local therapy is preferredTopical or local therapy is preferred
whenever possiblewhenever possible

Choosing a Steroid – contd.Choosing a Steroid – contd.
• Once daily dosing is usuallyOnce daily dosing is usually
preferred for oral glucocorticoidspreferred for oral glucocorticoids
• Large steroid doses areLarge steroid doses are
administered in divided doses toadministered in divided doses to
reduce local GIT effectsreduce local GIT effects
• In order to mimic the normal diurnalIn order to mimic the normal diurnal
cycle and reduce the risk ofcycle and reduce the risk of
adrenal suppression, GCs shouldadrenal suppression, GCs should
be given in the morning betweenbe given in the morning between
6-10 AM6-10 AM
• Alternate day therapy allows theAlternate day therapy allows the
HPA axis to recover on off daysHPA axis to recover on off days
Single
dose
Steroid

Withdrawal of Steroid TherapyWithdrawal of Steroid Therapy
 Taper the dose to reduce GC dose by 2.5-5 mg ofTaper 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 prednisoloneOnce the GC dose is reduced to 5 mg of prednisolone
equivalent, the patient may be switched to a shorterequivalent, the patient may be switched to a shorter
acting agent for further taperingacting agent for further tapering
 Intermediate acting corticosteroids allow for more flexibleIntermediate 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 halfPrednisolone, 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 pituitaryused in Cushing`s syndrome and test of pituitary
efficiencyefficiency
 Aminoglutethemide:Aminoglutethemide: Stops conversion of cholesterol toStops conversion of cholesterol to
pregnelonepregnelone (Medical adrenalectomy)(Medical adrenalectomy) – Breast cancers– Breast cancers
 Mifepristone:Mifepristone: Progesterone antagonistProgesterone antagonist
 Spironolactone:Spironolactone: Aldosterone antagonistAldosterone antagonist
 Ketoconazole:Ketoconazole: Inhibits synthesis of all hormones inInhibits synthesis of all hormones in
testes and adrenal cortex – used in Cushing`stestes 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 ofBiosynthesis and Regulation of
 Mechanism of action of CorticosteroidsMechanism of action of Corticosteroids
 Name of commonly used GlucocorticoidsName of commonly used Glucocorticoids
 Anti-inflammatory andAnti-inflammatory and
immunosuppressive actions ofimmunosuppressive actions of
GlucocorticoidsGlucocorticoids
 Important Adverse effects ofImportant Adverse effects of
 Therapeutic uses of CorticosteroidsTherapeutic uses of Corticosteroids

Corticosteroids Pharmacology - drdhriti

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