1. Corticosteroids (1 of 2)

2. Steroids the Sleaziest of Drugs Steroids are fast catching up with antibiotics as the most abused class of drugs in doctor's black bag. High doses of corticosteroids and other immunosuppressive agents cause AIDS Mohammed Ali Al-Bayati Ph.D

4. Corticosteroids History Synthesis Pharmacological Actions Pharmacokinetics Preparations Therapeutic principles Dosage schedule & Steroid withdrawal Uses: –Therapeutic –Diagnostic Adverse reactions Contraindications Precautions during therapy Glucocorticoid antagonists

5. History 1855 – Addison's diseaseAddison's disease 1856 – Adrenal glands essential for life 1930 – Cortex > medulla 1932 – Cushing’s syndrome 1949 – Hench et al (Steroids in rheumatoid arthritis) 1952 – Aldosterone

8. Basal secretions GroupHormoneDaily secretions Glucocorticoids Cortisol Corticosterone 5 – 30 mg 2 – 5 mg Mineralocorticoids Aldosterone 11 - deoxycorticosterone 5 – 150 mcg Trace Sex Hormones Androgen Progestogen Oestrogen DHEA Progesterone Oestradiol 15 – 30 mg 0.4 – 0.8 mg Trace From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

10. 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 TESTOSTERONEOESTRADIOL ACTH

11. Pharmacological Actions Direct Actions Permissive Actions Lipolytic effects Effect on BP Effect on bronchial muscles (e.g.,sympathomimetic amine)

12. Pharmacological Actions 1.Carbohydrate 2.Protein 3.Lipid 4.Electrolyte & water 5.CVS 6.Sk. Muscle 7.CNS 8.Stomach 9. Blood 10. Anti-inflammatory 11. Immunosuppressant 12. Respiratory system 13. Growth & Cell Division 14. Calcium metabolism

13. Actions: Carbohydrate and protein metabolism Gluconeogenesis –Peripheral actions (mobilize AA & glucose and glycogen) –Hepatic actions Peripheral utilization of glucose Glycogen deposition in liver (activation of hepatic glycogen synthase) Negative nitrogen balance & hyperglycaemia

14. Redistribution of Fat Buffalo hump Moon face Promote adipokinetic agents activity (glucagon, growth hormone, adrenaline, thyroxine) Actions: Lipid metabolism

15. Aldosterone is more important Act on D.T. & C.D. of kidney – Na + reabsorption – Urinary excretion of K + and H + Addison’s disease ?? Actions: Electrolyte and water balance Na+ loss Shrinkage of ECF Cellular hydration Hypodynamic state of CVS Circulatory collapse, renal failure, death

16. Restrict capillary permeability Maintain tone of arterioles Myocardial contractility Actions: Cardiovascular system Mineralocorticoid induced hypertension ?? Na+ sensitize blood vessels to the action of catecholamines & angiotensin

17. Addison's disease: weakness & fatique is due to Prolonged use: Actions: Skeletal Muscles Needed for maintaining the normal function of Sk. muscle inadequacy of circulatory system Steroid myopathy

18. Direct: –Mood –Behaviour –Brain excitability Indirect: –maintain glucose, circulation and electrolyte balance Actions: CNS ICP (pseudotumor cerebri) - Rarepseudotumor cerebri

19. Pseudotumor cerebri (Intracranial hypertension) Glucocorticoids Mineralocorticoids Amiodarone Vitamin A Oral contraceptives Tetracyclines From Harrison. 15 th edition, volume 1, page 435

20. Aggravate peptic ulcer. May be due to – Acid & pepsin secretion – immune response to H.Pylori Actions: Stomach

21. RBC: Hb & RBC content ( erythrophagocytosis ) WBC: Lymphocytes, eosinophils, monocytes, basophils Polymorphonucleocytes Actions: Blood

22. Recruitment of WBC & monocyte- macrophage into affected area & elaboration of chemotactic substancesWBC & monocyte- Lipocortin ELAM1 & ICAM-1 in endothelial cells TNF from phagocytic cells IL1 from monocyte-macrophage Formation of Plasminogen Activator Action of MIF & fibroblastic activity Expression of cyclooxygenase II Actions: Anti-inflammatory

23. Phospholipids Arachidonic acids lipoxygenase Cycylooxygenase Leukotriene Prostaglandins, Thromboxane Prostacyclins Phospholipase A2 Lipocortin Corticosteroids Return PAF by lipocortin

24. Anti-inflammatory actions of corticosteroids Corticosteroid inhibitory effect Return

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

27. Inhibit cell division or synthesis of DNA Delay the process of healing Retard the growth of children Actions: Growth & Cell division

28. Intestinal absorption Renal excretion Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs etc) Actions: Calcium metabolism

29. Not bronchodilators Most potent and most effective anti-inflammatory Effects not seen immediately (delay 6 or more hrs) Inhaled corticosteroids are used for long term control Actions: Respiratory system Return

30. Preparations DrugAnti-inflam.Salt retainingTopical Cortisol 11.01 Cortisone 0.8 0 Prednisone 40.80 Prednisolone 50.34 Methylpredni- solone 505 Intermediate acting Triamcinolone 505 Paramethasone 100- Fluprednisolone 1507

31. Preparations DrugAnti-inflam.Salt retainingTopical Long acting Betamethasone 25-40010 Dexamethasone 30010 Mineralocorticoids Fludrocortisone 1025010 DOCA 0200

32. To be Continued in the next Class ……

33. Synthesis StimuliPartPrincipal product Angiotensin IIZona glomerulosa ACTHZona fasiculata & reticularis Sympathetic nervous system Medulla Aldosterone Cortisol Adrenal androgens Adrenaline & Nor-adrenaline