Corticosteroids 2

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Corticosteroids 2

  1. 1. Corticosteroids (2 of 2)
  2. 2. Corticosteroids History Synthesis Pharmacological Actions Pharmacokinetics Preparations Therapeutic principles Dosage schedule & Steroid withdrawal Uses: – Therapeutic – Diagnostic Adverse reactions Contraindications Precautions during therapy Glucocorticoid antagonists
  3. 3. Pharmacokinetics • Absorption: all are rapidly & completely absorbed (Except DOCA) • Transport: • Transcortin 75% • Albumin 5% • Free form 20% • Metabolism: • by liver enzymes, conjugation & excretion by urine • partly excreted as 17-ketosteroids. • t1/2 of cortisol 1.5 hours
  4. 4. Preparations Glucocorticoids Short acting Intermediate acting Long acting Mineralocorticoids Inhalant steroids Topical steroids
  5. 5. Short Acting Preparations (t1/2 < 12 h) Drug Anti-inflam. Salt retaining Preapartions & dose Cortisol 1 1.0 • 5 mg tablet • 100 mg/vial (i.m., i.v) • Topical; enema Cortisone 0.8 0.8 • 5 mg tablet • 25 mg/vial (i.m) Intermediate Acting Preparations (t1/2 = 12 -36 h) Prednisone 4 0.8 - Prednisolone 5 0.3 • 5, 10 mg tablet • 20 mg/vial (i.m, intrarti) Methyl prednisolone 5 0 • 0.5, 1.0 gm inj. for i.m. or slow i.v. Triamcinolone 5 0 • 4 mg Tab., • 10, 40 mg/ml for i.m. & intrarticular inj.
  6. 6. Drug Anti- inflam. Salt retaining Preapartions & dose Long Acting Preparations (t1/2 > 36 h) Dexamethasone 25 0 0.5 mg tab. 4mg/ml inj (i.m., i.v.) Betamethasone 25 0 0.5, 1 mg tab. 4mg/ml inj (i.m., i.v.) Paramethasone 10 0 2- 20 mg/day (oral)
  7. 7. Mineralocorticoids - Preparations Drug Anti- inflammatory Salt retaining Preapartions & dose Fludrocortisone 10 150 100 mcg tab. DOCA 0 100 2.5 mg sublingual Aldosterone 0.3 3000 Not used clinically
  8. 8. Inhalant Steroids: Bronchial Asthma Beclomethasone dipropionate 50,100,200 mcg/md inhaler 100, 200, 400 mcg Rotacaps Fluticasone propionate 25, 50 mcg/md inhaler 25,50,125/md MDI 50, 100, 250 mcg Rotacaps Budesonide 100,200 mcg/md inhaler 0.25, 0.5 mg/ml respules
  9. 9. Drug Topical preparation Potency Beclomethasone dipropionate 0.025 % cream Potent Betamethasone benzoate & B. valerate 0.025 % cream, ointment 0.12 % cream, ointment Potent Clobetasol propionate 0.05 % cream Potent Halcinonide 0.1 cream Potent Triamcinolone actonide 0.1 % ointment Potent Fluocinolone actonide 0.025% ointment Moderate Mometasone 0.1 % cream, ointment Moderate Fluticasone 0.05 % cream Moderate Hydrocortisone acetate 2.5 % ointment Moderate Hydrocortisone acetate 0.1 – 1.0% ointment Mild Topical steroids
  10. 10. Topical Steroids Benefits due to anti-inflammatory, immunosuppressive, vasoconstrictor and anti-proliferative actions Good response Slow response Atopic eczema, Allergic contact dermatitis, Lichen simplex, Primary irritant dermatitis, Seborrheic dermatitis, Psoriasis of face, Varicose eczema Cystic acne Alopecia areata Discoid LE Hypertrophied scars Keloids Lichen planus Psoriasis of palm, sole, elbow & knee
  11. 11. Topical steroids are combined with antimicrobial agents for • Impetigo • Furunculosis • Secondary infected dermatoses • Napkin rash • Otitis externa • Intertriginous eruptions
  12. 12. Guidelines for topical steroids • Penetration differs at different sites: High: axilla, groin, face, scalp, scrotum Medium: limbs, trunk Low: palm, sole, elbow, knee • Occlusive dressing enhance absorption (10 fold) • Absorption is greater in infants & Children • Absorption depends on nature of lesion: High: atopic & exfoliative dermatitis Low: hyperkeratinized & plaque forming lesions • More than 3 applications a day is not needed • Choice of vehicle is important Lotions & creams: for exudative lesions Sprays & gels: for hairy regions Ointments: for chronic scaly lesions
  13. 13. Therapeutic principles  Dose selection by trial & error; Needs frequent evaluation  Single dose: No harm  Few days therapy unlikely to be harmful  Incidence of side effects related to duration of therapy  Use is only palliative (except replacement therapy)  Inter-current illness: Dose is doubled Abrupt cessation of prolonged high dose leads to adrenal insufficiency (contraindicated)
  14. 14. Goal of therapy: To relieve pain or distressing symptom (e.g., rheumatoid arthritis): start with low dose To treat life threatening condition (e.g., pemphigus): initial dose must be high Prevention of HPA axis suppression:  Single dose (morning)  Alternate dose therapy (short lived glucocorticoids)  Pulse therapy (higher glucocorticoid therapy) Dosage schedule
  15. 15. Longer the duration of therapy, slower the withdrawal • Less than 1 week: withdrawal in few steps – Rapid withdrawal: 50% reduction of dose every day – Slow withdrawal: 2.5 – 5 mg prednisolone reduced at an interval of 2-3 days • Longer period & high dose: – Halve the dose weekly until 25 mg prednisolone or equivalent is reached – Later reduce by about 1mg every 3-7 days. Steroid withdrawal HPA axis recovery may take months or up to 2 years
  16. 16. • Acute adrenal insufficiency • Primary adrenocortical insufficiency • Ad. Insufficiency second. to Ant. Pituitary • Congenital adrenal hyperplasia Therapeutic uses: Endocrine & Non-endocrine Endocrine Disorders • Isotonic saline • Glucose • Hydrocortisone inj. i.v. • Gradullay substitue with i.m or oral • Addison’s disease • Oral cortisol (20 +10 mg) • Fludrocortisone (0.1 or 0.2 mg daily, p.o.)
  17. 17. Congenital adrenal hyperplasia  Familial disorder  Signs of cortisol deficiency  Increased ACTH  Excessive androgens Deficiency of 21- β hydroxylase and 11 - β hydroxylase enzymes
  18. 18. Cholesterol Pregnenolone Progesterone Corticosterone 11-Desoxy- corticosterone 18-Hydroxy- corticosterone ALDOSTERONE 17-α- Hydroxy pregnenolone 11- Desoxy- cortisol 17- Hydroxy progesterone 21,β hydroxylase CORTISOL 11,β hydroxylase Dehydro-epi androsterone Andro- stenedione Oestrone Oestriol TESTOSTERONE OESTRADIOL
  19. 19. Non-endocrine diseases (1/7) 1. Arthritis • Not the drug of first choice • Prednisolone 5 or 7.5 mg • Intra-articular injection 2. Rheumatic carditis • Not responding to salicylates • Severely ill pts. • Prednisolone 40mg in divided doses • Salicylates given concurrently to prevent reactivation
  20. 20. Non-endocrine diseases (2/7) 3. Renal diseases (Nephrotic syndrome) • Prednisolone 60 mg in divided doses for 3 – 4 weeks • If remission occurs continue for 1 year • Do not modify the course of disease; Some may benefit 4. Collagen diseases • DLE, pemphigus vulgaris, polyarteritis nodosa • Defect in connective tissue proteins in joints, various organs and deeper layer of skin • Prednisolone 1mg/Kg start; gradually reduce the dose
  21. 21. Non-endocrine diseases (3/7) 5. Allergic diseases • Anaphylactic shock, blood transfusion reaction, hay fever • Prednisolone (short course) 6. Bronchial asthma • Not routinely used except in Status asthmaticus • Methyl prednisolone sodium i.v. given followed by oral prednisolone • Inhaled steroids (Minimal HPA axis suppression)
  22. 22. Non-endocrine diseases (4/7) 7. Ocular diseases Outer eye & anterior segment: local application Posterior segment: systemic use Caution: bacterial, viral & fungal conjunctivitis 8. Dermatological conditions • Pempigus: Life saving therapy is steroids • Eczema, dermatitis & psoriasis: respond well
  23. 23. Non-endocrine diseases (5/7) 9. Diseases of intestinal Tract • Ulcerative colitis: cortisol retention enema 10. Cerebral oedema • Questionable value in cerebral oedema following trauma, cerebrovascular oedema • Valuable in oedema associated with neoplasm and parasites 11. Malignancy • Part of multi drug regimens for acute lymphatic leukaemia (children), chronic lymphatic leukaemia (adult)
  24. 24. Non-endocrine diseases (6/7) 12. Liver diseases • Subacute hepatic necrosis & chronic active hepatitis: Improves survival rates • Alcoholic hepatitis: reserved for pts. with severe illness • Non-alcoholic cirrhosis: helpful if no ascites 13. Shock • Often helpful but no convincing evidence 14. Acute infectious diseases • Helpful due to its anti-stress & anti-toxic effects • Used in gram –ve septicemia, endotoxic shock, TB meningitis, miliary T.B., encephalitis • Appropriate anti-microbial agent is a MUST
  25. 25. • Organ transplantation • Bell’s palsy • Thrombocytopenia • Myasthenia gravis • Spinal cord injury • Sarcoidosis Non-endocrine diseases (7/7) - Miscellaneous
  26. 26. Diagnostic Uses • Cushing’s syndrome: • ACTH dependent (pituitary tumor, ectopic ACTH secreting tumors) • Non-ACTH dependent (obesity, tumor of adrenal cortex) • To locate the source of androgen production in hirusitism (Dexamethasone suppress androgen secretion from ad.cortex) (Dexamethsone suppression test is done)
  27. 27. Adverse reactions (1/2) • Metabolic toxicity: – Iatrogenic Cushing’s syndrome – Hyperglycaemia, glycosuria, diabetes – Myopathy (negative nitrogen balance) – Osteoporosis (vertebral compression fracture) – Retardation of growth (children) – Hypertension, oedema,CCF – Avascular necrosis of femur
  28. 28. Adverse reactions (2/2) • HPA axis suppression • Behavioral toxicity: Euphoria, psychomotor reactions, suicidal tendency • Ocular toxicity: steroid induced glaucoma, posterior subcapsular cataract. • Others: – Superinfections – Delayed wound healing – Steroid arthropathy – Peptic ulcer – Live vaccines are dangerous
  29. 29. Contraindications • Infections • Hypertension with CCF • Psychosis • Peptic ulcer • Diabetes mellitus • Osteoporosis • Glaucoma • Pregnancy : (prednisolone preferred)
  30. 30. Precautions during therapy Following examinations of the patient to be done before, during and after steroid therapy • Body weight • X-ray of spine • Blood glucose • Examination of the eye • B.P.
  31. 31. Glucocorticoids antagonists • Mitotane: structure similar to DDT, used in inoperable adrenal cancer • Metyrapone: inhibit 11 β-hydroxylase • Aminoglutethamide: inhibit conversion of cholesterol to pregnolone, medical adrenelectomy • Trilostane: inhibit conversion of pregnolone to progesterone; used in Cushing’s syndrome • Ketoconazole: anti-fungal, inhibit CYP450 enzymes, inhibit steroid synthesis in ad.cortex and testis; used in Cushing’s syndrome & Ca.prostate • Mifepristone: glucocorticoid receptor antagonist; anti-progesterone, used in Cushing’s syndrome
  32. 32. Cholesterol Pregnenolone Progesterone Corticosterone 11-Desoxy- corticosterone 18-Hydroxy- corticosterone ALDOSTERONE 17-α- Hydroxy pregnenolone 11- Desoxy- cortisol 17- Hydroxy progesterone 21,β hydroxylase CORTISOL 11,β hydroxylase Dehydro-epi androsterone Andro- stenedione Oestrone Oestriol TESTOSTERONE OESTRADIOL
  33. 33. Thanks for your patience

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