CORTOCOSTEROIDS

- Dr. N.R. BISWAS -

ADRENOCORTICOIDADRENOCORTICOID HORMONESHORMONES

  Corticosteroid agonists  and antagonists Corticosteroid agonists  and antagonists AgonistsAgonists::

GlucocorticoidsGlucocorticoids: (prednisolone) : (prednisolone) MineralocorticoidsMineralocorticoids (fludrocortisone) (fludrocortisone)

  AntagonistsAntagonists::ReceptorReceptor antagonistantagonist: :

Glucocorticoid receptor antagonist::( mifepristone )Glucocorticoid receptor antagonist::( mifepristone )Mineralocorticoid receptor antagonist::(  spironolactone )Mineralocorticoid receptor antagonist::(  spironolactone )

SynthesisSynthesis inhibitorinhibitor: ketoconazole, aromatase inhibitors.. : ketoconazole, aromatase inhibitors..

HORMONES OF ADRENAL HORMONES OF ADRENAL CORTEXCORTEX

ZonaZona  GlomerulosaGlomerulosa:  Mineralocorticoids: :  Mineralocorticoids: ( aldosterone, desoxycorticosterone. )( aldosterone, desoxycorticosterone. )

  ZonaZona  FasciculataFasciculata:  Glucocorticoids: :  Glucocorticoids: ( cortisol, cortisone, corticosterone. )( cortisol, cortisone, corticosterone. )  ZonaZona  ReticularisReticularis:  Androgens:  :  Androgens:  ( testosterone, androstenedione)  ( testosterone, androstenedione)     

MECHANISMMECHANISM OFOF ACTIONACTION

    i. i. GenomicGenomic actionaction: :       Glucocorticoids  after entering the cell  bind to specific  Glucocorticoids  after entering the cell  bind to specific  receptors  in the cytoplasm (GRα  , GRβ). receptors  in the cytoplasm (GRα  , GRβ). The receptor  becomes activated and  steroid receptor  The receptor  becomes activated and  steroid receptor  complexes  form dimers and move  to nucleus and bind  tocomplexes  form dimers and move  to nucleus and bind  to glucocorticosteroid response elements ( GREs) in the DNA.glucocorticosteroid response elements ( GREs) in the DNA. The effect is either to The effect is either to repressrepress (prevent transcription e.g COX, (prevent transcription e.g COX, adhesion factors) or adhesion factors) or induceinduce (initiate transcription e.g. annexin- (initiate transcription e.g. annexin-1) particular genes1) particular genes. .

..ii. ii. NongenomicNongenomic actionaction: : through cell membrane receptors to cause changes within the cell through cell membrane receptors to cause changes within the cell (on intracellular calcium).(on intracellular calcium).

ACTIONS OF ACTIONS OF CORTICOSTEROIDSCORTICOSTEROIDS

  Divided  into: Divided  into: MineralocorticoidMineralocorticoid action action & &GlucocorticoidGlucocorticoid action action

A. A. MineralocorticoidMineralocorticoid actionaction::↑↑ Na+ reabsorption in DCT & Na+ reabsorption in DCT & ↑↑ excretion. in K+ and H+ excretion. in K+ and H+ InIn mineralocorticoidmineralocorticoid deficiencydeficiency::

Na+ is lost but not waterNa+ is lost but not water dilutional dilutional hyponatremiahyponatremia, & excess water enters , & excess water enters cells cells cellular hydration, decrease blood volume and raised hematocrit. cellular hydration, decrease blood volume and raised hematocrit. HyperkalemiaHyperkalemia and and acidosisacidosis occur. occur.

These distortions in fluid and electrolytes lead to These distortions in fluid and electrolytes lead to circulatorycirculatory collapsecollapse..

InIn excessiveexcessive mineralocorticoidmineralocorticoid activityactivity:: Fluid retention, hypertension, Fluid retention, hypertension, hypokalemia and alkalosis occurhypokalemia and alkalosis occur.  . 

  

  

GLUCOCORTICOID ACTIONSGLUCOCORTICOID ACTIONS  CARBOHYDRATECARBOHYDRATE   metabolism   metabolism::Promote glycogen deposition in liver & Promote glycogen deposition in liver & gluconeogenesis. gluconeogenesis. ↑↑ glucose release from liver and inhibit glucose utilisation- glucose release from liver and inhibit glucose utilisation- produce produce hyperglycemiahyperglycemia, resistance to insulin and/or , resistance to insulin and/or diabetic like state.diabetic like state.

PROTEINPROTEIN  metabolism  metabolism::Break down of proteinBreak down of protein & mobilization of Amino Acid from peripheral tissues & mobilization of Amino Acid from peripheral tissues muscle wasting, loss of osteoid from bone and thinning of skinmuscle wasting, loss of osteoid from bone and thinning of skin. . These Amino Acid used up forThese Amino Acid used up for neoglucogenesis neoglucogenesis, excess urea, negative nitrogen , excess urea, negative nitrogen balance. They are thus balance. They are thus cataboliccatabolic. .

FATFAT metabolism: metabolism:Promote lipolysisPromote lipolysis (stimulate lipase) due to other hormone like glucagon, GH, (stimulate lipase) due to other hormone like glucagon, GH, adrenaline, thyroxine. adrenaline, thyroxine. Promote cAMP induced breakdown of triglycerides. Promote cAMP induced breakdown of triglycerides. Redistribution of fat occurs (Redistribution of fat occurs (from periphery to neck, face and supraclavicular area from periphery to neck, face and supraclavicular area producing moon face, fish mouth and buffalo hump). producing moon face, fish mouth and buffalo hump).

GLUCOCORTICOIDGLUCOCORTICOID ACTIONSACTIONS

CalciumCalcium metabolismmetabolism::

InhibitionInhibition of Ca++absorption from intestine of Ca++absorption from intestine ((vit.Dvit.D antagonismantagonism) & ) & ↑↑ its renal excretion. its renal excretion.

LossLoss ofof Ca++Ca++ from bone from bone ↑↑ resorption ( resorption (reduced reduced function of osteoblast & function of osteoblast & ↑↑ function of function of osteoclast),osteoclast), & negative & negative Ca++Ca++ balance. balance.

InhibitInhibit linear growth in children linear growth in children

Glucocorticoid  actionsGlucocorticoid  actions  

SkeletalSkeletal    musclesmuscles:: WeaknessWeakness occurs in both hypo and hypercorticism occurs in both hypo and hypercorticism. . In In hypocorticismhypocorticism: : decrease work capacity & weakness are due decrease work capacity & weakness are due

to to hypodynamic circulation.hypodynamic circulation. In In hypercorticismhypercorticism:: weakness is due to weakness is due to hypokalemia hypokalemia (excess of (excess of

mineralocorticoid), & mineralocorticoid), & muscle wasting and myopathymuscle wasting and myopathy (excess (excess of glucocorticoids). of glucocorticoids).

CatabolicCatabolic    andand  antianabolicantianabolic  effectseffects:: Stimulate protein and RNA synthesis in liver, but have Stimulate protein and RNA synthesis in liver, but have

catabolic and antianabolic effect on lymphoid tissue, catabolic and antianabolic effect on lymphoid tissue, connective tissue, muscle, fat and skinconnective tissue, muscle, fat and skindec. muscle mass, dec. muscle mass, thinning of skin and osteoporosis. In thinning of skin and osteoporosis. In children- retardation of children- retardation of growthgrowth. .

GlucocorticoidGlucocorticoid    actionsactions  CNSCNS::

Brain- Brain- euphoria,euphoria, inc. motor activity, insomnia, anxiety or depression. inc. motor activity, insomnia, anxiety or depression. In Addison's disease- apathy, depression and psychosisIn Addison's disease- apathy, depression and psychosis. . High doses High doses lower seizure thresholdlower seizure threshold. .

GITGIT:: Increased secretion of gastric acid and pepsin may Increased secretion of gastric acid and pepsin may aggravateaggravate pepticpeptic ulcerulcer. .

RBCs  and other blood cells:RBCs  and other blood cells: Inc. in no. of RBCs and neutrophils and dec. in lymphocytes, eosinophils & basophils.Inc. in no. of RBCs and neutrophils and dec. in lymphocytes, eosinophils & basophils.

Involved  in Fetal lung developmentInvolved  in Fetal lung development: :---: :--- Destruction of lymphoid cellsDestruction of lymphoid cells (T cells more than B cells) used in lymphomas. Hyperplasia (T cells more than B cells) used in lymphomas. Hyperplasia

of lymphoid tissue is seen in Addison’s disease. of lymphoid tissue is seen in Addison’s disease.

Immunological  & allergic responses:Immunological  & allergic responses:

suppress all types of hypersensitization and allergic phenomena.suppress all types of hypersensitization and allergic phenomena. Produce greater suppression of CMI in which T cells are involved - as in Produce greater suppression of CMI in which T cells are involved - as in delayed hypersensitivity, graft rejection- autoimmune disease.delayed hypersensitivity, graft rejection- autoimmune disease.

GlucocorticoidGlucocorticoid    actionsactions  

InflammatoryInflammatory    responses:--responses:--

Nonspecific suppression of all components, stages and Nonspecific suppression of all components, stages and cardinal signs of inflammationcardinal signs of inflammation. . Produce vasoconstriction, reduce capillary permeability, local Produce vasoconstriction, reduce capillary permeability, local exudation, cellular infiltration, phagocytic activity& late responses exudation, cellular infiltration, phagocytic activity& late responses like capillary proliferation, collagen deposition, fibroblastic activity, & like capillary proliferation, collagen deposition, fibroblastic activity, & scar formation- scar formation- actionaction isis directdirect andand locallocal..

Action  on inflammatory cells.Action  on inflammatory cells.

Decrease migration & reduced activity of neutrophils & Decrease migration & reduced activity of neutrophils & macrophagesmacrophages. .

Decrease action of T helper cellsDecrease action of T helper cells, ,

GlucocorticoidGlucocorticoid    actionsactions  ActionAction    onon  inflammatoryinflammatory  mediatorsmediators:-----:-----

Induction of annexin IInduction of annexin I ( lipocortin) which ( lipocortin) which inhibits phospholipase A2 inhibits phospholipase A2 inhibitinginhibiting production of eicosanoids & PAF;production of eicosanoids & PAF; Dec. expression of COX2- dec. production of Dec. expression of COX2- dec. production of prostanoidsprostanoids. .

Dec. production of Dec. production of cytokinescytokines -IL1 -IL1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF γ and cell , IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF γ and cell adhesion factors- through inhibition of transcription of the relevant genes. adhesion factors- through inhibition of transcription of the relevant genes.

Dec. in conc. of Dec. in conc. of complementcomplement components in plasma. components in plasma.

Dec. generation of induced Dec. generation of induced NONO

Dec. release of Dec. release of histaminehistamine from basophils. from basophils.

Dec. Dec. IgGIgG production. production.

Relative potencies and equivalent doses of corticosteroids

__________________________________________________________________________________________________________________________ RELATIVE ANTI- RELATIVE APPROXIMATE

INFLAMMATORY Na+- DURATION OF

EQUIVALENT COMPOUND POTENCY RETAINING ACTION* DOSE † POTENCY (mg) __________________________________________________________________________________________________________________________Cortisol (Hydrocortisone) 1 1 S 20Tetrahydrocortisol 0 0 - -Prednisone(∆1-Cortisone) 4 0.8 I 5Prednisolone(∆1-Cortisol) 4 0.8 I 56-Methylprednisolone 5 0.5 I 4Fludrocortisone(9-Fluorocortisol) 10 125 S -11-Desoxycortisol) 0 0 - -Cortisone(11-Dehydrocortisol) 0.8 0.8 S 25Corticosterone 0.35 15 S -Triamcinolone(9-Fluoro-16-hydroxyprednisolone) 5 0 I 4Paramethasone(6-Fluoro-16-methylprednisolone) 10 0 L 2Betamethasone(9-Fluro-16-methylprednisolone) 25 0 L 0.75Dexamethasone(9-Fluoro-16-methylprednisolone) 25 0 L 0.75_________________________________________________________________________________________________________________________

*S=Short, or 8 to 12 hour biological half-life; I=intermediate, or 12 to 36 hour biological half-life; L=long, or 36 to 72 hour biological half-life. † These dose relationships apply only to oral or intravenous administration; relative potencies may differ greatly when injected intramuscularly or into joint spaces.

CORTICOSTEROIDS

To control inflammatory and immunological diseases

Effects nonspecific

Probable actions –

a) Stabilization of lysosomal membrane b) Retardation of macrophage movement

c) Prevention of Kinin release d) Inhibition of lymphocytes and neutrophil function e) Inhibition of prostaglandin synthesis f) Decrease of antibody production

HYDROCORTISONE ACETATE

Naturally occurring Glucocorticoids.

Glucocorticoids have important dose-related effects on Carbohydrate,Protein & Fat metabolism.

They have Anti-inflammatory & Immunosuppresive Effects

Large doses of Glucocorticoids have been associated with the development of peptic ulcer,possibly by suppressing the local immune response against H.pylori.

Adverse Effects : Prolong use may cause glaucoma, cataract exacerbation of acute infection, osteoporosis in Cushing’s syndrome.

SYNTHETIC GLUCOCORTICOIDSSYNTHETIC GLUCOCORTICOIDS

1) 1) ShortShort actingacting – –Examples –cortisone, prednisolone, MethylprednisoloneExamples –cortisone, prednisolone, Methylprednisolone

2) 2) IntermediateIntermediate actingacting——Ex.—Triamcinolone, paramethasone, FluprednisoloneEx.—Triamcinolone, paramethasone, Fluprednisolone

3) 3) LongLong actingacting——Ex.—Betamthasone, DexamethasoneEx.—Betamthasone, Dexamethasone

MINERALOCORTICOIDSMINERALOCORTICOIDS –Ex.Fludrocortisone, –Ex.Fludrocortisone, Aldosterone. Aldosterone.

ADVERSE EFFECTS of prolonged ADVERSE EFFECTS of prolonged use of glucocorticoidsuse of glucocorticoids

1) 1) MetabolicMetabolic EffectsEffects : —Weight gain, : —Weight gain, hyperglycemia, aseptic necrosis of the hip hyperglycemia, aseptic necrosis of the hip bone.bone.

2) 2) OtherOther ComplicationsComplications :—Peptic ulcer, :—Peptic ulcer, depression, hypomania or acute depression, hypomania or acute psychosis, hypertension, heart failure.psychosis, hypertension, heart failure.

3) 3) AdrenalAdrenal suppressionsuppression

CONTRAINDICATIONSCONTRAINDICATIONS ofof CorticosteroidsCorticosteroids

They must be used with great cautions in They must be used with great cautions in patients with---patients with---

1) Peptic ulcer1) Peptic ulcer

2) Heart disease or hypertension with 2) Heart disease or hypertension with heart failureheart failure

3) 3) InfectionsInfections likelike varicellavaricella & & TuberculosisTuberculosis

4) Psychosis4) Psychosis

5) 5) DiabetesDiabetes, osteoporosis or , osteoporosis or glaucomaglaucoma

Epidermal and dermal atrophy (thinning of the skin, striae, telangiectases ,superficial fissures and purpura)

Acne, folliculitis,

Hypertrichosis

Hypopigmentation

Allergic contact dermatitis (uncommon)

Masking or aggravation of dermatophytoses, impetigo or scabies

Glucocorticoid dosage is decreased: Antibiotics (erythromycin, trioleandomycin), cyclosporin, isoniazid and ketoconazole reduce the metabolic clearance of glucocorticoids. Estrogens increase the levels of corticosteroid binding protein and thus reduce the free fraction; they also reduce the clearance.

Cholestyramine decreases the intestinal absorption. Antiepileptic drugs(barbiturates, phenytoin, carbamazemine), rifampicin,, aminoglutethimide increase the metabolism by inducing hepatic microsomal enzymes.

Antianxiety and antipsychotic drugs: Recurrent or poor control of CNS symptoms due to inherent glucocorticoid effects.

Glucocorticoid dosage is increased:

Glucocorticoid dosage needs adjustment:

Anticholinesterases: May precipitate myasthenic crisis

Anticoagulants: Effectiveness of anticoagulants decreases

Antihypertensives: Their effectiveness decreases

Oral hypoglycemics: Their effectiveness decreases

Sympathomimetics: Their effectiveness increases

Salicylates: Their clearance is increased

THERAPEUTICTHERAPEUTIC USESUSES ofof glucocoricoidsglucocoricoids

1.SUBSTITUTION1.SUBSTITUTION THERAPYTHERAPY——

A) Chronic adrenal insufficiencyA) Chronic adrenal insufficiency

B) Acute adrenal insufficiencyB) Acute adrenal insufficiency

C) Septic shockC) Septic shock

USESUSES ( (ContdContd.).)

2) 2) PHARMACOLOGICALPHARMACOLOGICAL THERAPYTHERAPY——A) A) PulsePulse therapytherapy : –in acute rejection of renal : –in acute rejection of renal graft.graft.

B) B) IntensiveIntensive shortshort termterm therapytherapy :–in status :–in status asthmaticus.asthmaticus.

C) Cerebral edemaC) Cerebral edema

D) D) ProlongedProlonged , , highhigh dosedose suppressivesuppressive therapytherapy :---in acute lymphatic leukemia :---in acute lymphatic leukemia

USESUSES ( (ContdContd.).)

E) E) Low-doseLow-dose, , chronicchronic palliativepalliative therapytherapy: ----in : ----in Rheumatoid arthritisRheumatoid arthritis

F ) F ) ChronicChronic suppressionsuppression ofof ACTHACTH secretionsecretion: ---in : ---in congenital ,virilizing adrenocortical hyperplasia.congenital ,virilizing adrenocortical hyperplasia.

G) Neonatal Respiratory SyndromeG) Neonatal Respiratory Syndrome

H) H) TopicalTopical applicationapplication: –in dermatological, ocular & : –in dermatological, ocular & external ear conditions.external ear conditions.

I) I) Intra-articularIntra-articular & &IntratendinousIntratendinous useuse: —in painful : —in painful osteoarthritis & fascial nodules.osteoarthritis & fascial nodules.

Hydrocortisone hemisuccinate by IV infusion, 100 mg every 4-6 hours

Dextrose in normal saline in adequate amounts

Vasopressor drugs to maintain blood pressure; and

Antibiotics

Enquire about and check for: peptic ulcer, diabetes mellitus, tuberculosis, any other infection (especially one not amenable to chemotherapy).

Prescribe the drug with food

Diet low in calories and sodium, and high in potassium Check periodically for: weight gain, edema, hyperglycemia, hypertension,

infection, GI bleeding, hypokalemia, ocular changes Monitor growth in children Instruct the patient not to stop the drug abruptly (severe infection, major surgery)

Prescribe oral calcium and vitamin D supplements; alendronate; antacids; H2

receptor blockers

MINERALOCORTICOIDSMINERALOCORTICOIDS

Examples—Examples—1) Aldosterone1) Aldosterone2) Deoxycorticosterone2) Deoxycorticosterone3) Fludrocortisone (Synthetic )3) Fludrocortisone (Synthetic )

PharmacologicalPharmacological action-action---They promote --They promote the reabsorption of sodium from the distal the reabsorption of sodium from the distal convoluted and cortical collecting renal convoluted and cortical collecting renal tubules. tubules.

Therapeutic Uses of Therapeutic Uses of MineralocortcoidsMineralocortcoids

1) Addison’s disease1) Addison’s disease2) Salt losing congenital adrenal 2) Salt losing congenital adrenal hyperplasiahyperplasia3) Hyporeninemic hypoaldosteronism3) Hyporeninemic hypoaldosteronism

ADVERSE EFFECTS of ADVERSE EFFECTS of Mineralocorticoids-------------Mineralocorticoids-------------Weight gain, edema, hypertension & Weight gain, edema, hypertension & hypokalemia. hypokalemia.