Pharmacology of corticosteroids
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Presentation for Medical undergraduates for teaching pharmacology. It deals with Physiology of steroid hormones and their action along with agents which are used therapeutically with their action, adverse effects and therapeutic uses.
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Pharmacology of corticosteroids
- 1. CORTICOSTEROIDS Dr Mayur Chaudhari Assistant Professor Department of Pharmacology Government Medical College, Surat
- 2. Steroids are fast catching up with antibiotics as the most abused class of drugs today 2
- 3. HISTORY 1855 – Thomas Addison 1856 – Charles-Edouard Brown-Sequard 1932 – Harvey Cushing 1936 – Edward Kendall & Tadeus Reichstein. 1949 – Phillip Hench 1954 – Aldosterone 1955 - ACTH 3
- 4. The adrenal produces various classes of hormones, each of which aid in dealing with the stress faced by animals and people almost daily. At least two of these groups – Glucocorticoids and Mineralocorticoids are necessary for life . Corticosteroids or corticoids refer to natural glucoand mineralo-corticoids and their synthetic analogues. 4
- 5. LEARNING OBJECTIVES Biosynthesis Actions Pharmacokinetics and Preparations Uses Dosage schedule and withdrawal ADRs and Contraindications Precautions during therapy Contraindications 5
- 6. ANATOMY 6
- 7. BIOSYNTHESIS OF ADRENAL HORMONES Mineralocorticoids Glucocorticoids Sex Hormones 11-OH Pregnenolone Dehydroepiandrosterone DHEA Cholesterol ACTH Pregnenolone 11 α OH 11 α OH 17,20 lyase 11-OH Progesterone 17,20 lyase Progesterone 11- Deoxy Corticosterone Androstenodione 11- Deoxy Cortisol Testosterone Cortisol Corticosterone AT II Dihydrotestosterone Aldosterone Estradiol 7
- 8. REGULATION Synthesized and Released under influence of ACTH and Pituitary. Regulated by CRH from hypothalamus and by feedback levels of blood concentrations 8
- 9. HPA AXIS 9
- 12. ACTIONS • Effect on Na+ Mineralocorticoid • Effect on K+ • Fluid Balance Glucocorticoid • Carbohydrate • Protein and Fat • Other Activities 12
- 13. MINERALOCORTICOID ACTIONS Enhanced absorption of Na+ from DT increased excretion of K+ and H+. Similar action on colon, sweat gland and salivary gland. 13
- 14. EXTREMES OF ALDOSTERONE Dilutional hypernatremia, Hyperkalamia, acidosis, massive loss of Na+ and decreased EFC volume Positive Na+ balance, expansion of ECF, Increased plasma Na, hypokalemia, alkalosis hypertension myocardial fibrosis 14
- 15. GLUCOCORTICOID ACTIONS CARBOHYDRATE METABOLISM Glycogen deposition in liver Gluconeogenesis Inhibit glucose utilization Hyperglycemia Insulin resistance, DM like state 15
- 16. PROTEIN METABOLISM Breakdown of protein Mobilize Amino Acid from peripheral tissues Muscle wasting, lympholysis, loss of osteoid from bone Thinning of skin Excess urea production – Negative nitrogen balance Increase uric acid excretion 16
- 17. FAT METABOLISM Permissive action due to Glucagon, Growth Hormone, Adrenaline and Thyroxine – Lipolysis. Increased breakdown of triglycerides. Redistribution of body fat – Moon face, Buffalo Hump, Fish Mouth. 17
- 18. CALCIUM METABOLISM Inhibition of intestinal absorption and promotion of excretion Loss of calcium from bone. Negative calcium balance Spongy bones – more sensitive. 18
- 19. WATER EXCRETION AND STOMACH Maintain normal GFR In adrenal insufficiency capacity is lost – water intoxication Gastric acid and pepsin secretion enhanced Aggravate peptic ulcer 19
- 20. CARDIOVASCULAR SYSTEM Permissive role on pressor effect with Adr and angiotensin Maintain tone of arterioles and myocardial contractility Adrenal insufficiency leads to low cardiac output and arteriolar dilatation and poor response to adrenaline Cardiovascular collapse – along with mineralocorticoids 20
- 21. SKELETAL MUSCLES Hypocorticism: Decreased work capacity, weakness Hypercorticism: Excess Mineralocorticoid .Hypokalemia – Weakness. Excess glucocorticoid : Muscle wasting, weakness and myopathy 21
- 22. CENTRAL NERVOUS SYSTEM Mild euphoria, increased motor activity Insomnia, hypomania or depression Apathy, depression and psychosis in Addison’s disease. Maintenance of perceptions and excitability of neurons Lowers seizure threshold 22
- 23. LYMPHOID TISSUE Destruction of lymphoid tissue – modest in normal persons In presence of malignancy of lymphatic cells – lytic actions are significant (apoptosis) – used in lymphomas (Basis of Use) Minor effects on haemoglobin and RBCs – protect against haemolysis of RBCs – Increase in number of RBCs Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increases Polymorphs 23
- 24. INFLAMMATION Prevent migration of leucocytes Prevent chemotaxis and lysosomal enzyme synthesis Diminish production of PGs, LTs, PAF and histamine release Stabilize lysosomal membrane preventing spillage of lysosomal enzymes 24
- 25. INFLAMMATION Suppress inflammatory response to all noxious stimuli at all stages Cardinal signs of inflammation inhibited Root cause remain intact Favor spread of infection Interfere with healing and scar formation Silent perforation 25
- 26. IMMUNOLOGICAL ACTION Inhibit function of macrophages, Reduce ability to respond to antigen Inhibit activation of cytotoxic T lymphocytes, cause lysis of T Lymphocytes Effects of complement are inhibited Prevent Homograft rejection 26
- 27. IMMUNOLOGICAL ACTION Impair immunological competence Suppress all types of hypersensitization and allergy. Suppression of CMI – delayed hypersensitivity, graft rejection Inhibit release of IL1 from macrophages, IL2 formation Suppression of natural killer cell 27
- 28. MISCELLANEOUS Uricosuric action Nonspecific antipyretic Structural and functional maturation of fetal lung 28
- 29. PHARMACOKINETICS Therapeutically given by various routes – orally, IM, IV, topically Hydrocortisone undergoes high first pass metabolism Oral bioavailability of synthetic corticoids is high Both, endogenous and therapeutically administered GC are bound to Corticosteroid Binding Globulin (CBG) 29
- 30. PHARMACOKINETICS Synthetic steroids have to undergo reduction in liver to active compounds Metabolized in liver and excreted in urine Exogenously administered hydrocortisone has t1/2 of 1.5 Hrs 30
- 31. HYDROCORTISONE Rapid but short acting with significant Mineralocorticoid activity Used for replacement therapy, shock, Status asthmaticus and adrenal insufficiency Topically and as enema for ulcerative colitis 31
- 32. PREDNISOLONE More potent than hydrocortisone, more GC activity Intermediate duration of action Less HPA axis suppression Used for allergic, inflammation autoimmune diseases, malignancy 32
- 33. METHYLPREDNISOLONE More potent and more selective Retention enema in ulcerative colitis Pulse therapy in non responsive RA Renal transplant, pemphigus Minimal suppression of HPA axis. 33
- 34. TRIAMCINOLONE Potent and selective glucocorticoid Used as intraarticular injection DEXAMETHASONE Potent and highly selective, long acting Marked HPA suppression Inflammatory and allergic condition Shock, cerebral edema. 34
- 35. FLUDROCORTISONE Potent mineralocorticoid having some GC activity Replacement therapy in Addison’s disease Congenital adrenal hyperplasia Idiopathic hypotension 35
- 36. THERAPEUTIC USES Physiologic doses of Corticosteroids are used for replacement therapy Supraphysiologic doses are used for their antiinflammatory effects immunosuppressive effects In organ transplant patients and those with autoimmune disorders 36
- 37. REPLACEMENT THERAPY Adrenal insufficiency – acute/chronic Abrupt withdrawal of steroid therapy Chronic infections – Tuberculosis Autoimmune adrenal disease Surgery, Hemorrhage and AIDS Congenital adrenal hyperplasia Congenital disorder due to deficiency of 21-hydroxylse enzyme – no cortisol but ACTH – increased androgen production 37
- 38. REPLACEMENT THERAPY ACUTE ADRENAL INSUFFICIENCY IV Hydrocortisone/ Dexamethasone bolus f/b infusion Monitor CVP Short term infusion of dopamine CHRONIC ADRENAL INSUFFICIENCY Hydrocortisone orally If needed ad fludrocortisone 38
- 39. REPLACEMENT THERAPY CONGENITAL ADRENAL HYPERPLASIA Hydrocortisone 0.6 mg/kg in divided doses Fludrocortisone 10-20 µg/kg if salt wasting persist 39
- 40. MUST KNOW Biosynthesis and Regulation of Corticosteroids Mechanism of action of Corticosteroids Name of commonly used Glucocorticoids Anti-inflammatory and immunosuppressive actions of Glucocorticoids 40
- 42. CORTICOSTEROIDS Dr Mayur Chaudhari Assistant Professor Department of Pharmacology Government Medical College, Surat
- 43. OBJECTIVES Pharmacotherapy Adverse Effects Contraindications 43
- 44. GENERAL PRINCIPLES Single dose is not harmful Short Courses Long term use – Hazardous Initial Dose – According to severity No abrupt withdrawal Local Therapy 44
- 46. ARTHRITIDES Rheumatoid Arthritis Osteoarthritis Rheumatic fever Gout 46
- 47. COLLAGEN DISEASES Systemic Lupus Erythematous Nephrotic Syndrome Glomerulonephritis 47
- 48. SEVERE ALLERGIC REACTIONS Anaphylaxis Angioneurotic edema Urticaria Serum Sickness Allergic conjunctivitis Allergic Rhinitis 48
- 49. AUTOIMMUNE DISEASES Hemolytic anemia Idiopathic thrombocytopenic purpura Active chronic hepatitis 49
- 50. BRONCHIAL ASTHMA Status asthmaticus Acute asthma exacerbation Severe chronic asthma 50
- 51. LUNG DISEASES Aspiration pneumonia Pulmonary edema Lung maturation in fetus 51
- 52. INFECTION Severe tuberculosis Lepra reaction Bacterial meningitis Pneumocystis carinii pneumonia 52
- 53. EYE DISEASES Allergic conjunctivitis Iritis Iridocyclitis Keratitis 53
- 54. SKIN DISEASES Eczema Pemphigus vulgaris Exfoliative dermatitis Steven Johnson Syndrome 54
- 55. INTESTINAL DISEASES Ulcerative colitis Crohn’s Disease Coeliac Disease 55
- 56. CEREBRAL OEDEMA NEUROCYSTICERCOSIS MALIGNANCIES ORGAN TRANSPLANT SKIN ALLOGRAFT 56
- 57. SEPTIC SHOCK THYROID STORM PITUITARY ADRENAL AXIS FUNCTION 57
- 59. MINERALOCORTICOID Na+ and water retention Edema Hypokalemic alkalosis Progressive rise in BP 59
- 60. GLUCOCORTICOID Cushing’s habitus Fragile skin, Purple Striae Hyperglycemia Muscular Weakness Delayed healing 60
- 61. Susceptibility to infection Peptic Ulceration Osteoporosis Posterior Sub capsular cataract Glaucoma Growth Retardation Foetal abnormality 61
- 62. Psychiatric Disturbances HPA Axis Suppression 62
- 63. CONTRAINDICATIONS Peptic ulcer Diabetes mellitus Hypertension Viral and fungal infections Tuberculosis 63
- 64. CONTRAINDICATIONS Osteoporosis Herpes simplex keratitis Psychosis Epilepsy Congestive heart failure Renal Failure 64
- 65. SUMMARY Guidelines for use of glucocorticoids Pharmacotherapy Adverse effects Contraindications 65