Corticosteroides Mdpm 408

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Corticosteroides Mdpm 408

  1. 1. CORTOCOSTEROIDS - Dr. N.R. BISWAS -
  2. 2. ADRENOCORTICOID HORMONES <ul><li>  </li></ul><ul><li>Corticosteroid agonists  and antagonists  </li></ul><ul><li>Agonists : </li></ul><ul><ul><li>Glucocorticoids : (prednisolone) </li></ul></ul><ul><ul><li>Mineralocorticoids (fludrocortisone) </li></ul></ul><ul><li>  Antagonists : </li></ul><ul><li>Receptor antagonist : </li></ul><ul><ul><ul><li>Glucocorticoid receptor antagonist::( mifepristone ) </li></ul></ul></ul><ul><ul><ul><li>Mineralocorticoid receptor antagonist::(  spironolactone ) </li></ul></ul></ul><ul><li>Synthesis inhibitor : ketoconazole, aromatase inhibitors.. </li></ul>
  3. 3. HORMONES OF ADRENAL CORTEX <ul><li>Zona   Glomerulosa :  Mineralocorticoids:  </li></ul><ul><li>( aldosterone, desoxycorticosterone. ) </li></ul><ul><li>  Zona   Fasciculata :  Glucocorticoids:  </li></ul><ul><li>( cortisol, cortisone, corticosterone. ) </li></ul><ul><li>  </li></ul><ul><li>Zona   Reticularis :  Androgens:   </li></ul><ul><li>( testosterone, androstenedione)  </li></ul><ul><li>  </li></ul>
  4. 4. MECHANISM OF ACTION <ul><li>   </li></ul><ul><li>i.  Genomic action : </li></ul><ul><li>    Glucocorticoids  after entering the cell  bind to specific  receptors  in the cytoplasm (GRα  , GRβ).  </li></ul><ul><li>The receptor  becomes activated and  steroid receptor  complexes  form dimers and move  to nucleus and bind  to glucocorticosteroid response elements ( GREs) in the DNA. </li></ul><ul><li>The effect is either to repress (prevent transcription e.g COX, adhesion factors) or induce (initiate transcription e.g. annexin-1) particular genes . </li></ul><ul><li>. ii.  Nongenomic action : </li></ul><ul><li>through cell membrane receptors to cause changes within the cell (on intracellular calcium). </li></ul>
  5. 5. ACTIONS OF CORTICOSTEROIDS <ul><li>  Divided  into:  Mineralocorticoid action & Glucocorticoid action </li></ul><ul><li>A.  Mineralocorticoid action : </li></ul><ul><li>↑ Na+ reabsorption in DCT & ↑ excretion. in K+ and H+ </li></ul><ul><li>In mineralocorticoid deficiency : </li></ul><ul><ul><li>Na+ is lost but not water  dilutional hyponatremia , & excess water enters cells  cellular hydration, decrease blood volume and raised hematocrit. Hyperkalemia and acidosis occur. </li></ul></ul><ul><ul><li>These distortions in fluid and electrolytes lead to circulatory collapse . </li></ul></ul><ul><li>In excessive mineralocorticoid activity : </li></ul><ul><ul><li>Fluid retention, hypertension, </li></ul></ul><ul><ul><li>hypokalemia and alkalosis occur .  </li></ul></ul><ul><li>  </li></ul><ul><li>  </li></ul>
  6. 6. GLUCOCORTICOID ACTIONS <ul><li>  </li></ul><ul><li>CARBOHYDRATE   metabolism : </li></ul><ul><li>Promote glycogen deposition in liver & gluconeogenesis. </li></ul><ul><li>↑ glucose release from liver and inhibit glucose utilisation- </li></ul><ul><li>produce hyperglycemia , resistance to insulin and/or diabetic like state. </li></ul><ul><li>PROTEIN   metabolism : </li></ul><ul><li>Break down of protein & mobilization of Amino Acid from peripheral tissues  muscle wasting, loss of osteoid from bone and thinning of skin . </li></ul><ul><li>These Amino Acid used up for neoglucogenesis , excess urea, negative nitrogen balance. They are thus catabolic . </li></ul><ul><li>FAT metabolism: </li></ul><ul><li>Promote lipolysis (stimulate lipase) due to other hormone like glucagon, GH, adrenaline, thyroxine. </li></ul><ul><li>Promote cAMP induced breakdown of triglycerides. </li></ul><ul><li>Redistribution of fat occurs ( from periphery to neck, face and supraclavicular area producing moon face, fish mouth and buffalo hump). </li></ul>
  7. 7. GLUCOCORTICOID ACTIONS <ul><li>Calcium metabolism : </li></ul><ul><li>Inhibition of Ca++absorption from intestine ( vit.D antagonism ) & ↑ its renal excretion. </li></ul><ul><li>Loss of Ca++ from bone ↑ resorption ( reduced function of osteoblast & ↑ function of osteoclast), & negative Ca++ balance. </li></ul><ul><li>Inhibit linear growth in children </li></ul>
  8. 8. Glucocorticoid  actions   <ul><li>Skeletal   muscles : </li></ul><ul><ul><li>Weakness occurs in both hypo and hypercorticism . </li></ul></ul><ul><ul><li>In hypocorticism : decrease work capacity & weakness are due to hypodynamic circulation. </li></ul></ul><ul><ul><li>In hypercorticism : weakness is due to hypokalemia (excess of mineralocorticoid), & muscle wasting and myopathy (excess of glucocorticoids). </li></ul></ul><ul><li>Catabolic   and   antianabolic   effects : </li></ul><ul><ul><li>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 . </li></ul></ul>
  9. 9. Glucocorticoid   actions   <ul><li>CNS : </li></ul><ul><ul><li>Brain- euphoria, inc. motor activity, insomnia, anxiety or depression. </li></ul></ul><ul><ul><li>In Addison's disease- apathy, depression and psychosis . </li></ul></ul><ul><ul><li>High doses lower seizure threshold . </li></ul></ul><ul><li>GIT : </li></ul><ul><ul><li>Increased secretion of gastric acid and pepsin may aggravate peptic ulcer . </li></ul></ul><ul><li>RBCs  and other blood cells: </li></ul><ul><ul><li>Inc. in no. of RBCs and neutrophils and dec. in lymphocytes, eosinophils & basophils. </li></ul></ul><ul><li>Involved  in Fetal lung development : :--- </li></ul><ul><ul><li>Destruction of lymphoid cells (T cells more than B cells) used in lymphomas. Hyperplasia of lymphoid tissue is seen in Addison’s disease. </li></ul></ul><ul><li>Immunological  & allergic responses: </li></ul><ul><li>suppress all types of hypersensitization and allergic phenomena. </li></ul><ul><li>Produce greater suppression of CMI in which T cells are involved - as in delayed hypersensitivity, graft rejection- autoimmune disease. </li></ul>
  10. 10. Glucocorticoid   actions   <ul><li>Inflammatory   responses:-- </li></ul><ul><li>Nonspecific suppression of all components, stages and cardinal signs of inflammation . </li></ul><ul><li>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 . </li></ul><ul><li>Action  on inflammatory cells. </li></ul><ul><li>Decrease migration & reduced activity of neutrophils & macrophages . </li></ul><ul><li>Decrease action of T helper cells , </li></ul>
  11. 11. Glucocorticoid   actions   <ul><li>Action   on   inflammatory   mediators :----- </li></ul><ul><li>Induction of annexin I ( lipocortin) which inhibits phospholipase A2  inhibiting production of eicosanoids & PAF; </li></ul><ul><li>Dec. expression of COX2- dec. production of prostanoids . </li></ul><ul><li>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. </li></ul><ul><li>Dec. in conc. of complement components in plasma. </li></ul><ul><li>Dec. generation of induced NO </li></ul><ul><li>Dec. release of histamine from basophils. </li></ul><ul><li>Dec. IgG production. </li></ul>
  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.
  13. 14. CORTICOSTEROIDS <ul><li>To control inflammatory and immunological diseases </li></ul><ul><li>Effects nonspecific </li></ul><ul><li>Probable actions – </li></ul><ul><li>a) Stabilization of lysosomal membrane </li></ul><ul><li>b) Retardation of macrophage movement </li></ul><ul><li>c) Prevention of Kinin release </li></ul><ul><li>d) Inhibition of lymphocytes and neutrophil function </li></ul><ul><li>e) Inhibition of prostaglandin synthesis </li></ul><ul><li>f) Decrease of antibody production </li></ul>
  14. 15. HYDROCORTISONE ACETATE <ul><li>Naturally occurring Glucocorticoids. </li></ul><ul><li>Glucocorticoids have important dose-related effects on Carbohydrate,Protein & Fat metabolism. </li></ul><ul><li>They have Anti-inflammatory & Immunosuppresive Effects </li></ul><ul><li>Large doses of Glucocorticoids have been associated with the development of peptic ulcer,possibly by suppressing the local immune response against H.pylori. </li></ul><ul><li>Adverse Effects : Prolong use may cause glaucoma, cataract exacerbation of acute infection, osteoporosis in Cushing’s syndrome. </li></ul>
  15. 16. SYNTHETIC GLUCOCORTICOIDS <ul><li>1) Short acting – </li></ul><ul><li>Examples –cortisone, prednisolone, Methylprednisolone </li></ul><ul><li>2) Intermediate acting — </li></ul><ul><li>Ex.—Triamcinolone, paramethasone, Fluprednisolone </li></ul><ul><li>3) Long acting — </li></ul><ul><li>Ex.—Betamthasone, Dexamethasone </li></ul><ul><li>MINERALOCORTICOIDS –Ex.Fludrocortisone, Aldosterone. </li></ul>
  16. 17. ADVERSE EFFECTS of prolonged use of glucocorticoids <ul><li>1) Metabolic Effects : —Weight gain, hyperglycemia, aseptic necrosis of the hip bone. </li></ul><ul><li>2) Other Complications :—Peptic ulcer, depression, hypomania or acute psychosis, hypertension, heart failure. </li></ul><ul><li>3) Adrenal suppression </li></ul>
  17. 18. CONTRAINDICATIONS of Corticosteroids <ul><li>They must be used with great cautions in patients with--- </li></ul><ul><li>1) Peptic ulcer </li></ul><ul><li>2) Heart disease or hypertension with heart failure </li></ul><ul><li>3) Infections like varicella & Tuberculosis </li></ul><ul><li>4) Psychosis </li></ul><ul><li>5) Diabetes , osteoporosis or glaucoma </li></ul>
  18. 19. <ul><li>Epidermal and dermal atrophy </li></ul><ul><li>(thinning of the skin, striae, telangiectases ,superficial fissures and purpura) </li></ul><ul><li>Acne, folliculitis, </li></ul><ul><li>Hypertrichosis </li></ul><ul><li>Hypopigmentation </li></ul><ul><li>Allergic contact dermatitis (uncommon) </li></ul><ul><li>Masking or aggravation of dermatophytoses, impetigo or scabies </li></ul>Adverse skin reactions to topical glucocorticoids
  19. 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
  20. 21. THERAPEUTIC USES of glucocoricoids <ul><li>1.SUBSTITUTION THERAPY — </li></ul><ul><li>A) Chronic adrenal insufficiency </li></ul><ul><li>B) Acute adrenal insufficiency </li></ul><ul><li>C) Septic shock </li></ul>
  21. 22. USES ( Contd .) <ul><li>2) PHARMACOLOGICAL THERAPY — </li></ul><ul><li>A) Pulse therapy : –in acute rejection of renal graft. </li></ul><ul><li>B) Intensive short term therapy :–in status asthmaticus. </li></ul><ul><li>C) Cerebral edema </li></ul><ul><li>D) Prolonged , high dose suppressive therapy :---in acute lymphatic leukemia </li></ul>
  22. 23. USES ( Contd .) <ul><li>E) Low-dose , chronic palliative therapy : ----in Rheumatoid arthritis </li></ul><ul><li>F ) Chronic suppression of ACTH secretion : ---in congenital ,virilizing adrenocortical hyperplasia. </li></ul><ul><li>G) Neonatal Respiratory Syndrome </li></ul><ul><li>H) Topical application : –in dermatological, ocular & external ear conditions. </li></ul><ul><li>I) Intra-articular & Intratendinous use : —in painful osteoarthritis & fascial nodules. </li></ul>
  23. 24. <ul><li>Hydrocortisone hemisuccinate by IV </li></ul><ul><li>infusion, 100 mg every 4-6 hours </li></ul><ul><li>Dextrose in normal saline in adequate </li></ul><ul><li>amounts </li></ul><ul><li>Vasopressor drugs to maintain blood </li></ul><ul><li>pressure; and </li></ul><ul><li>Antibiotics </li></ul>Principles of treatment of acute adrenal insufficiency
  24. 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 <ul><li>Check periodically for: weight gain, edema, hyperglycemia, hypertension, infection, GI bleeding, hypokalemia, ocular changes </li></ul><ul><li>Monitor growth in children </li></ul><ul><li>Instruct the patient not to stop the drug abruptly (severe infection, major surgery) </li></ul><ul><li>Prescribe oral calcium and vitamin D supplements; alendronate; antacids; H 2 receptor blockers </li></ul>
  25. 26. MINERALOCORTICOIDS <ul><li>Examples— </li></ul><ul><li>1) Aldosterone </li></ul><ul><li>2) Deoxycorticosterone </li></ul><ul><li>3) Fludrocortisone (Synthetic ) </li></ul><ul><li>Pharmacological action- --They promote the reabsorption of sodium from the distal convoluted and cortical collecting renal tubules. </li></ul>
  26. 27. Therapeutic Uses of Mineralocortcoids <ul><li>1) Addison’s disease </li></ul><ul><li>2) Salt losing congenital adrenal hyperplasia </li></ul><ul><li>3) Hyporeninemic hypoaldosteronism </li></ul><ul><li>ADVERSE EFFECTS of Mineralocorticoids------------- </li></ul><ul><li>Weight gain, edema, hypertension & hypokalemia. </li></ul>

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