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Corticosteroides Mdpm 408

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  • 1. CORTOCOSTEROIDS - Dr. N.R. BISWAS -
  • 2. ADRENOCORTICOID HORMONES
    •  
    • Corticosteroid agonists  and antagonists 
    • Agonists :
      • Glucocorticoids : (prednisolone)
      • Mineralocorticoids (fludrocortisone)
    •   Antagonists :
    • Receptor antagonist :
        • Glucocorticoid receptor antagonist::( mifepristone )
        • Mineralocorticoid receptor antagonist::(  spironolactone )
    • Synthesis inhibitor : ketoconazole, aromatase inhibitors..
  • 3. HORMONES OF ADRENAL CORTEX
    • Zona   Glomerulosa :  Mineralocorticoids: 
    • ( aldosterone, desoxycorticosterone. )
    •   Zona   Fasciculata :  Glucocorticoids: 
    • ( cortisol, cortisone, corticosterone. )
    •  
    • Zona   Reticularis :  Androgens:  
    • ( testosterone, androstenedione) 
    •  
  • 4. MECHANISM OF ACTION
    •   
    • i.  Genomic action :
    •     Glucocorticoids  after entering the cell  bind to specific  receptors  in the cytoplasm (GRα  , GRβ). 
    • The receptor  becomes activated and  steroid receptor  complexes  form dimers and move  to nucleus and bind  to glucocorticosteroid response elements ( GREs) in the DNA.
    • The effect is either to repress (prevent transcription e.g COX, adhesion factors) or induce (initiate transcription e.g. annexin-1) particular genes .
    • . ii.  Nongenomic action :
    • through cell membrane receptors to cause changes within the cell (on intracellular calcium).
  • 5. ACTIONS OF CORTICOSTEROIDS
    •   Divided  into:  Mineralocorticoid action & Glucocorticoid action
    • A.  Mineralocorticoid action :
    • ↑ Na+ reabsorption in DCT & ↑ excretion. in K+ and H+
    • In mineralocorticoid deficiency :
      • Na+ is lost but not water  dilutional hyponatremia , & excess water enters cells  cellular hydration, decrease blood volume and raised hematocrit. Hyperkalemia and acidosis occur.
      • These distortions in fluid and electrolytes lead to circulatory collapse .
    • In excessive mineralocorticoid activity :
      • Fluid retention, hypertension,
      • hypokalemia and alkalosis occur . 
    •  
    •  
  • 6. GLUCOCORTICOID ACTIONS
    •  
    • CARBOHYDRATE   metabolism :
    • Promote glycogen deposition in liver & gluconeogenesis.
    • ↑ glucose release from liver and inhibit glucose utilisation-
    • produce hyperglycemia , resistance to insulin and/or diabetic like state.
    • PROTEIN   metabolism :
    • Break down of protein & mobilization of Amino Acid from peripheral tissues  muscle wasting, loss of osteoid from bone and thinning of skin .
    • These Amino Acid used up for neoglucogenesis , excess urea, negative nitrogen balance. They are thus catabolic .
    • FAT metabolism:
    • Promote lipolysis (stimulate lipase) due to other hormone like glucagon, GH, adrenaline, thyroxine.
    • Promote cAMP induced breakdown of triglycerides.
    • Redistribution of fat occurs ( from periphery to neck, face and supraclavicular area producing moon face, fish mouth and buffalo hump).
  • 7. GLUCOCORTICOID ACTIONS
    • Calcium metabolism :
    • Inhibition of Ca++absorption from intestine ( vit.D antagonism ) & ↑ its renal excretion.
    • Loss of Ca++ from bone ↑ resorption ( reduced function of osteoblast & ↑ function of osteoclast), & negative Ca++ balance.
    • Inhibit linear growth in children
  • 8. Glucocorticoid  actions  
    • Skeletal   muscles :
      • Weakness occurs in both hypo and hypercorticism .
      • In hypocorticism : decrease work capacity & weakness are due to hypodynamic circulation.
      • In hypercorticism : weakness is due to hypokalemia (excess of mineralocorticoid), & muscle wasting and myopathy (excess of glucocorticoids).
    • Catabolic   and   antianabolic   effects :
      • Stimulate protein and RNA synthesis in liver, but have catabolic and antianabolic effect on lymphoid tissue, connective tissue, muscle, fat and skin  dec. muscle mass, thinning of skin and osteoporosis. In children- retardation of growth .
  • 9. Glucocorticoid   actions  
    • CNS :
      • Brain- euphoria, inc. motor activity, insomnia, anxiety or depression.
      • In Addison's disease- apathy, depression and psychosis .
      • High doses lower seizure threshold .
    • GIT :
      • Increased secretion of gastric acid and pepsin may aggravate peptic ulcer .
    • RBCs  and other blood cells:
      • Inc. in no. of RBCs and neutrophils and dec. in lymphocytes, eosinophils & basophils.
    • Involved  in Fetal lung development : :---
      • Destruction of lymphoid cells (T cells more than B cells) used in lymphomas. Hyperplasia of lymphoid tissue is seen in Addison’s disease.
    • Immunological  & allergic responses:
    • suppress all types of hypersensitization and allergic phenomena.
    • Produce greater suppression of CMI in which T cells are involved - as in delayed hypersensitivity, graft rejection- autoimmune disease.
  • 10. Glucocorticoid   actions  
    • Inflammatory   responses:--
    • Nonspecific suppression of all components, stages and cardinal signs of inflammation .
    • Produce vasoconstriction, reduce capillary permeability, local exudation, cellular infiltration, phagocytic activity& late responses like capillary proliferation, collagen deposition, fibroblastic activity, & scar formation- action is direct and local .
    • Action  on inflammatory cells.
    • Decrease migration & reduced activity of neutrophils & macrophages .
    • Decrease action of T helper cells ,
  • 11. Glucocorticoid   actions  
    • Action   on   inflammatory   mediators :-----
    • Induction of annexin I ( lipocortin) which inhibits phospholipase A2  inhibiting production of eicosanoids & PAF;
    • Dec. expression of COX2- dec. production of prostanoids .
    • Dec. production of cytokines -IL1 , 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.
    • Dec. in conc. of complement components in plasma.
    • Dec. generation of induced NO
    • Dec. release of histamine from basophils.
    • Dec. IgG production.
  • 12.  
  • 13. 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 20 Tetrahydrocortisol 0 0 - - Prednisone (∆ 1 -Cortisone) 4 0.8 I 5 Prednisolone (∆ 1 -Cortisol) 4 0.8 I 5 6  -Methylprednisolone 5 0.5 I 4 Fludrocortisone (9  -Fluorocortisol) 10 125 S - 11-Desoxycortisol) 0 0 - - Cortisone (11-Dehydrocortisol) 0.8 0.8 S 25 Corticosterone 0.35 15 S - Triamcinolone (9  -Fluoro-16  -hydroxyprednisolone) 5 0 I 4 Paramethasone (6  -Fluoro-16  -methylprednisolone) 10 0 L 2 Betamethasone (9  -Fluro-16  -methylprednisolone) 25 0 L 0.75 Dexamethasone (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.
  • 14. 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
  • 15. 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.
  • 16. SYNTHETIC GLUCOCORTICOIDS
    • 1) Short acting –
    • Examples –cortisone, prednisolone, Methylprednisolone
    • 2) Intermediate acting —
    • Ex.—Triamcinolone, paramethasone, Fluprednisolone
    • 3) Long acting —
    • Ex.—Betamthasone, Dexamethasone
    • MINERALOCORTICOIDS –Ex.Fludrocortisone, Aldosterone.
  • 17. ADVERSE EFFECTS of prolonged use of glucocorticoids
    • 1) Metabolic Effects : —Weight gain, hyperglycemia, aseptic necrosis of the hip bone.
    • 2) Other Complications :—Peptic ulcer, depression, hypomania or acute psychosis, hypertension, heart failure.
    • 3) Adrenal suppression
  • 18. CONTRAINDICATIONS of Corticosteroids
    • They must be used with great cautions in patients with---
    • 1) Peptic ulcer
    • 2) Heart disease or hypertension with heart failure
    • 3) Infections like varicella & Tuberculosis
    • 4) Psychosis
    • 5) Diabetes , osteoporosis or glaucoma
  • 19.
    • 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
    Adverse skin reactions to topical glucocorticoids
  • 20. Drug interactions of glucocorticoids  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
  • 21. THERAPEUTIC USES of glucocoricoids
    • 1.SUBSTITUTION THERAPY —
    • A) Chronic adrenal insufficiency
    • B) Acute adrenal insufficiency
    • C) Septic shock
  • 22. USES ( Contd .)
    • 2) PHARMACOLOGICAL THERAPY —
    • A) Pulse therapy : –in acute rejection of renal graft.
    • B) Intensive short term therapy :–in status asthmaticus.
    • C) Cerebral edema
    • D) Prolonged , high dose suppressive therapy :---in acute lymphatic leukemia
  • 23. USES ( Contd .)
    • E) Low-dose , chronic palliative therapy : ----in Rheumatoid arthritis
    • F ) Chronic suppression of ACTH secretion : ---in congenital ,virilizing adrenocortical hyperplasia.
    • G) Neonatal Respiratory Syndrome
    • H) Topical application : –in dermatological, ocular & external ear conditions.
    • I) Intra-articular & Intratendinous use : —in painful osteoarthritis & fascial nodules.
  • 24.
    • 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
    Principles of treatment of acute adrenal insufficiency
  • 25. Precautions during glucocorticoid therapy Before starting therapy  Enquire about and check for: peptic ulcer, diabetes mellitus, tuberculosis, any other infection (especially one not amenable to chemotherapy). During therapy  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; H 2 receptor blockers
  • 26. MINERALOCORTICOIDS
    • Examples—
    • 1) Aldosterone
    • 2) Deoxycorticosterone
    • 3) Fludrocortisone (Synthetic )
    • Pharmacological action- --They promote the reabsorption of sodium from the distal convoluted and cortical collecting renal tubules.
  • 27. Therapeutic Uses of Mineralocortcoids
    • 1) Addison’s disease
    • 2) Salt losing congenital adrenal hyperplasia
    • 3) Hyporeninemic hypoaldosteronism
    • ADVERSE EFFECTS of Mineralocorticoids-------------
    • Weight gain, edema, hypertension & hypokalemia.

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