Molecular & Cellular Pharmacology & Mechanism of Action of Corticosteroids.pptx

Regulation, Mode of action, pharmacokinetics, therapeutic agents, replacements therapy of glucocorticoids & mineralocorticoids.

1. Molecular & Cellular Pharmacology & Mechanism of Action of Corticosteroids By Samiksha Tukaram Hamane. M Pharm (Sem II)

2. Content Introduction Anatomy Biosynthesis of adrenal hormone Basal secretion Regulation & synthesis Glucocorticoids – MOA Action of mineralocorticoids Pharmacokinetics of glucocorticoids Therapeutic agent Replacement therapy Adverse effect Contraindication

3. Introduction Corticosteroids are hormone produced in cortex of adrenal gland. At least two of these groups – Glucocorticoids and Mineralocorticoids are necessary for life . Corticosteroids or corticoids refer to natural glucocorticoids and mineralo-corticoids and their synthetic analogues. Corticoids are 21 carbon compound chain with steroid nucleus.

4. Anatomy An inner medulla, is a source is a source of catecholamine – adrenaline and nor-adrenaline develops from ectoderm (neural crest) An outer cortex, which secretes several classes of steroid hormones including steroid hormones including Glucocorticoids and Mineralocorticoids Three different concentric zones of cells that differ in major steroid hormones they secrete. Zona glomerulosa – mineralocorticoids Zona fasciculata – glucocorticoids Zona reticularis – androgen precursors Cortex develops from mesoderm

5. Adrenal Cortex The adrenal cortex is a factory of steroid hormones 10-30 different steroids are synthesized from this tissue, but two classes are of importance Mineralocorticoids – aldosterone (z. glomerulosa) – sodium, potassium and water homeostasis Glucocorticoids – hydrocortisone or cortisol and corticosteroids – glucose and many other homeostasis.

6. Biosynthesis of Adrenal Hormone

7. Basal secretion Group Hormone Daily Glucocorticoids Cortisol 5-30mg Corticosterone 2-5mg Mineralocorticoids Aldosterone 5-150mcg 11- deoxycorticosterone trace

8. Regulation & Synthesis Synthesized and released under influence of ACTH and Pituitary. Regulated by CRH from hypothalamus and by feedback levels of blood concentrations

9. Glucocorticoids MOA They are nuclear receptors but present in inactivate form & found in cytoplasm. There are 3 domain binding sites 1. Glucocorticoid binding domain 2. DNA binding domain 3. Transcription binding domain

10. Action of Mineralocorticoids Aldosterone is the prototype of mineralocorticoid effects Acts on the distal tubule to enhance absorption of Na+ Increase excretion of K+ and H Similar effects occur in colon, sweat gland and salivary gland Deficiency of mineralocorticoid action leads to – Dilutional hyponatremia Hyperkalemia Acidosis Massive loss of Na+ and decreased EFC volume (essential for survival)

11. Hyperaldosteronism: Positive Na+ balance expansion of ECF increased plasma Na Hypokalaemia Alkalosis progressive rise in BP – hypertension myocardial fibrosis

12. Glucocorticoid Actions - Carbohydrate & protein metabolism Profound effect on carbohydrate and protein metabolism aimed at protecting glucose dependent tissues (brain and heart) Promotes glycogen deposition in liver and stimulate it to form glucose from amino acids – gluconeogenesis In peripheral tissues decreases utilization of glucose, increase protein breakdown and activate lipolysis - form amino acids and glycerol for gluconeogenesis A All these results in – Diabetes like stat resistant to insulin - increased glucose release from liver + decreased peripheral glucose utilization Negative Nitrogen balance (catabolic effect) - amino acid used up in gluconeogenesis - increased urea production

13. Fat metabolism Redistribution of fats in different areas of the body Due to permissive facilitation of effects of other agents - GH, glucagons, ADR, thyroxine and insulin Deposition of fats in face, neck and shoulder - moon face/buffalo hump Glucocorticoids facilitated hormone sensitive lipolysis action of GH and ADR + Glucocorticoids mediated increased insulin = net result is insulin mediated lipogenesis and fat deposition Peripheral adipocytes are less sensitive to insulin, but in face and neck predominant action - fat deposition

14. Actions of Glucocorticoids Water excretion: Glucocorticoids play important role in maintaining normal GFR - in adrenal insufficiency capacity to excrete water is lost - water intoxication Calcium Balance: Decrease absorption of Ca++ in GIT and increased excretion - calcium depletion – osteoporosis Skeletal muscle: Normal muscular activity needs Glucocorticoids at its optimum level. Excess level leads to muscular weakness and wasting Muscular weakness occurs in both Hypocorticism (due to hypodynamic circulation) and hypercorticism - due to hypokalaemia

15. Actions of Glucocorticoids CVS: 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 Blood and lymphoid tissues: Destruction of lymphoid tissue - modest in normal persons In presence of malignancy of lymphatic cells - lytic actions are significant (apoptosis) - used in lymphomas Minor effects on hemoglobin and RBCs - protect against hemolysis of RBCs - Increase in number of RBCs Decreases the numbers of circulating lymphocytes, monocytes, eosinophils and basophils but increase polymorphs

16. Actions of Glucocorticoids 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

17. Glucocorticoids - anti-inflammatory and immunosuppressive effects Suppress inflammatory response to all noxious stimuli: Pathogens, chemical, physical and immune mediated stimuli, hypersensitivity Underlying cause of disease is not corrected Reduction in cardinal signs of inflammation Anti-inflammatory effects are non-specific and covers all components of inflammation: Effects on concentration, distribution and functions of peripheral leukocytes - increased neutrophils & their activity In macrophages: reduction of arachidonic acid metabolites (mediators) like PG, LT and PAF synthesis that results from activation of phospholipase A2 Basis of exogenous use of most clinical uses

18. 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.

19. Glucocorticoids – 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) 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

20. Important agents Injectable: Dexamethasone Methylprednisolone Betamethasone Prednisolone Hydrocortisone Triamcinolone Oral: Betamethasone Fludricortisone Prednisolone Prednisone Methylprednisolone

21. Important agents Topical: Betamethasone Flucinolone Clobetasol Mometasone Inhalation: Beclomethasone Flunisolode Budesonide

22. 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

23. PREDNISOLONE More potent than hydrocortisone, more GC activity Intermediate duration of action Less HPA axis suppression Used for allergic, inflammation Autoimmune diseases, malignancy

24. 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.

25. FLUDROCORTISONE Potent mineralocorticoid having some GC activity Replacement therapy in Addison's disease Congenital adrenal hyperplasia Idiopathic hypotension

26. Therapeutic Uses Physiologic doses of corticosteroids are used for replacement therapy Supraphysiologic doses are used for their anti- inflammatory effects Immunosuppressive effects in organ transplant patients and those with autoimmune disorders

27. Replacement Therapy Adrenal insufficiency - acute/chronic Abrupt withdrawal of steroid therapy Chronic infections – Tuberculosis Autoimmune adrenal disease Surgery, Haemorrhage and AIDS Cortisol Congenital adrenal hyperplasia Congenital disorder due to deficiency of 21- hydroxylse enzyme - no cortisol but ACTH – increased androgen production

28. Acute adrenal insufficiency IV replacement of sodium chloride and fluid IV hydrocortisone 100 mg stat followed by 100 mg every 8 Hrs - maximal daily rate of secretion(alternatively, dexamethasone can be used) Chronic adrenal insufficiency Hydrocortisone Prednisolone or dexamethasone long acting Fludrocortisone for mineralocorticoid effects Congenital adrenal hyperplasia Hydrocortisone 0.6 mg/kg in divided doses - to maintain feedback suppression

29. Anti-inflammatory Uses For suppression of inflammatory components in Rheumatoid arthritis as adjuvant with NSAIDs in severe cases Osteoarthritis - NSAIDs, intra-articular injection Rheumatic fever - severe cases with carditis and CHF Gout - NSAID failed cases and colchicine failed cases intra-articular injection Vasculitis disorders: Polyarteritis nodosa

30. Intra-articular steroids Can be used in inflammatory & non inflammatory diseases Knee joint Shoulder joint Tennis

31. Autoimmune disease Autoimmune haemolytic anaemia Idiopathic thrombocytopenic purpura Active chronic hepatitis, alcoholic hepatitis (prednisolone 1-2 mg/kg/day given till remission followed by gradual withdrawal or low dose maintenance)

32. Renal diseases Nephrotic syndrome in children Renal disease secondary to SLE Renal sarcoidosis Glomerulonephritis - membranous type (Life saving importance - usually given in large doses followed by tapering to maintenance dose)

33. Organ Transplant Combined with other immunosuppressants - cyclosporin, azathioprine For prolonged use: Prednisolone or methylprednisolone are used - Intermediate duration of action - Can be easily tapered - Can be converted to an alternate regime

34. Allergic Disorders Exhibit a delayed response in allergies (1-2 hrs even in IV injection) In anaphylaxis, angioneurotic oedema and serum sickness etc. - adrenaline is the choice Seasonal allergies, bee sting, drug allergies - Allergic reactions can be suppressed by corticosteroids as supplements Intranasal administration in allergic rhinitis - budesonide and flunisolide

35. Infectious Diseases Indicated only in severe infective diseases to tide over crisis or present complications AIDS and pneumocystis carinii pneumonia In haemophilus influenza meningitis to reduce neurological complications Tubercular meningitis Lepra reaction Septicaemia

36. Skin disease The largest application of steroid therapy Topical forms are widely used in many eczematous skin diseases Systemic therapy are also required and may be life saving in - Pemphigus vulgaris - Exfoliative dermatitis - Stevens-Johnson syndrome

37. Bronchial Asthma The increased recognition of the immunological and inflammatory nature of Bronchial asthma has led to the use of corticosteroids In severe asthma attacks IV hydrocortisone Methylprednisolone Oral prednisolone Acute attacks: Inhaled beclmethasone, budesonide, flunisolide alone or combined with beta-2 agonists/ipratropium Oral steroids

38. GIT Inflammatory conditions of intestine like Ulcerative colitis Crohn's disease Coeliac disease (oral therapy or retention enema with hydrocortisone)May mask the major complications like perforation and peritonitis

39. Other uses Antiemetic - with ondansetron Acute mountain sickness Aspiration pneumonia, pulmonary oedema from drowning Hyperthyroidism - thyroid storm

40. Adverse effect Mineralocorticoids Sodium and water retention Edema Hypokalemic alkalosis Progressive rise in bp

41. Glucocorticoids Cushing’s habitus Fragile skin, purple striae Hyperglycemia Muscular weakness Delayed healing Susceptibility Peptic ulceration Glaucoma Posterior sub capsular cataract Growth retardation Foetal abnormality Psychiatric disturbance HPA axis suppression

42. Contraindication Peptic ulcer Diabetes mellitus Hypertension Viral & fungal infections Tuberculosis Osteoporosis Herpes simple keratitis Psychosis Epilepsy Congestive heart failure Renal failure

43. Thank You.