Class corticosteroids new

this class is in brief for under graduate understanding and examination purpose

1. CLASS CORTICOSTEROIDS Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1

2. Introduction 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 gluco - and mineralo -corticoids and their synthetic analogues

3. 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 Steroid Class Prototype Physiological effect Mineralocorticoid Aldosterone (z. glomerulosa) Na, K and water homeostasis Glucocorticoid Hydrocortisone or cortisol (z. fasciculata) Corticosterone Glucose and many other homeostasis Adrenal cortex also produces sex steroids – Androgens, Dehydroepiandrosterone (DHEA) – z. reticularis

4. Synthetic glucocorticoids Alcometasone –topical Amcinonide -topical Beclomethosone -top/ inh Budesonide- inh Clobetasol -topical Clocortolone -topical Desonide -topical Dexsoximetasone -top Deflazocart DOCA- Desoxy Corticosterone Acetate Triamcinolone Flucinolone -topical Flunisolide -topical Fluoromethalone-opth Fluticasone- inh /top Halcinonide -top Medrysone-opth Fludrocortisone

5. Biosynthesis Synthesized from cholesterol through a series of enzyme-mediated transformations ACTH stimulates adrenal steroid synthesis Aldosterone synthesis is not stimulated by ACTH but by angiotensin II, although ACTH does stimulate synthesis of aldosterone precursors Circulating Potassium exerts a permissive effect on angiotensin II stimulation; high potassium enhances and low potassium diminishes Corticoids are 21 carbon compounds having cyclopentanoperhydrophenanthrene nucleus

6. Regulation of Synthesis Synthesized and released under influence of ACTH - Ant. Pituitary (HPA axis) • Regulated by CRH( C orticotropin Releasing Hormone) from hypothalamus and by feedback levels of blood concentrations

7. Adrenals Kidney Posterior Pituitary Gland Hypothalamus Anterior Pituitary Gland ACTH Stress Circadian rhythm CRH (-) Glucocorticoids, Catecholamines, etc.. Glucocorticoids, Catecholamines, etc.. Muscle: Net loss of amino Acids (glucose) Liver: Deamination of proteins into amino acids, gluconeogenesis (glucose) Fat Cells: Free fatty acid mobilization Heart rate: Increased Immune system: altered Hypothalamopituitary adrenal (HPA) axis: Negative Feedback

8. Corticosteroids are Gene-Active

9. Stress and the Adrenal Glands

10. Carbohydrate and protein metabolism Gluconeogenesis Peripheral actions (mobilize glucose and glycogen) Hepatic actions Peripheral utilization of glucose Glycogen deposition in liver (activation of hepatic glycogen synthase) Negative nitrogen balance and hyperglycemia

11. Redistribution of Fat-buffalo hump, moon face Promote adipokinetic agents activity (glucagon, growth hormone, adrenaline, thyroxine ) Mobilization of free fatty acids is increased Glucose utilization by adipose tissue and muscle is inhibited Lipid metabolism

12. Mineralocorticoid action Aldosterone  Na reabsorption from the distal convoluted and cortical collecting renal tubules with concomitant increased excretion of K+ and H+ Rapid non-genomic effect through stimulation of Na/H+ exchanger Aldosterone induced proteins Na/K+ ATPase molecules(Na+ pumps) Efflux of K+ from the cell into the lumen

13. Electrolyte and water balance Aldosterone is more important Action on DT and CD of kidney Na + reabsorption Urinary excretion of C a K + and H + ADDISON’S DISEASE -inadequate secretion of adrenal hormone Na+ loss, Shrinkage of ECF Cellular hydration Hypodynamic state of CVS Circulatory collapse, renal failure, death

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

15. Addison's disease: weakness and fatigue is due to Prolonged use: steroid myopathy Skeletal Muscles Needed for maintaining the normal function of Skeletal muscle inadequacy of circulatory system

16. Direct: Mood, Behaviour Brain excitability Insomnia, anxiety, Higher doses lower seizure threshold and may precipitate seizures in epileptic patients Indirect: maintain glucose, circulation and electrolyte balance ICP ( pseudotumour cerebri ) - Rare CNS

17. RBC , platelets and neutrophils in circulation WBC: Lymphocytes, eosinophils , monocytes, basophils Glucocorticoids show marked lytic effect on malignant lymphaltic cells lymphomas GIT- Aggravate peptic ulcer. May be due to: Acid and pepsin secretion immune response to H.Pylori Blood

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

19. Anti-Inflammatory Effect Suppress T-cell activation and cytokine production Suppress mast cell degranulation Decrease capillary permeability indirectly by inhibiting mast cells and basophils Reduce the expression of cyclooxygenase II and prostaglandin synthesis Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A 2 activity

20. Phospholipase A 2 Arachidonic acid (AA) Prostaglandins & thromboxanes Lipoxygenase products (leukotrienes) Cyclooxygenase (COX) Lipoxygenase Inflammatory effects (esp. in asthma) Inflammatory effects (inducible) Homeostatic Functions (stomach mucus) 2.NSAIDS (including aspirin) 3. Zileuton Montelukast , zafirlukast Inflammatory Enzymes: PLA 2 & COX 1. Steroids

21. Effect on immune response of

22. Inhibit cell division or synthesis of DNA Delay the process of healing Retard the growth of children CALCIUM METABOLISM Intestinal absorption Renal excretion Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs) Growth and Cell division

23. Play important role in development of foetal lungs  surfactant Most potent and most effective anti-inflammatory Effects not seen immediately (delay 6 or more hrs ) Inhaled corticosteroids are used for long term control THYROID HORMONE Inhibit TSH pulsatility and nocturnal surge of this hormone Respiratory system

24. Replacement Therapy

25. 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

26. Replacement Therapy Acute adrenal insufficiency IV replacement of sodium chloride and fluid IV hydrocortisone 100 mg stat followed by100 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

27. 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 Vasculitic disorders: Polyarteritis nodosa

28. Intra-articular Steroids Can be used in inflammatory Non-inflammatory diseases Knee joint Shoulder joint Tennis elbow Carpal tunnel syndrome Triamcinolone: used for severe asthma and for local joint inflammation (intra-articular inj .)

29. Autoimmune diseases 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) ITP

30. 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) SLE

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

32. 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

33. 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 Beclomethasone - dipropionate , budesonide: pass membranes poorly; more active when applied topically (severe eczema for local anti-inflammatory effects) than orally; used in asthma, (aerosol).

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

35. Ocular Diseases Important drug therapy for suppressing inflammation in eye and preservation of sight Topical instillations are used for conditions of the anterior chamber – allergic conjunctivitis, iritis , iridocyclitis and keratitis etc. Systemic steroids for the posterior chamber Dexamethasone topical 0.1% Prednisolone oral Contraindicated  in viral, fulminant bacterial infections, fungal infections and injuries

36. Skin Diseases 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 Pemphigus vulgaris

37. 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

38. Malignancy Essential for combined chemotherapy of Acute lymphatic leukemia Hodgkin's and other lymphomas Hormone responsive breast carcinoma Symptomatic relief in other advance malignancies by improving appetite and controlling secondary hypercalcaemia

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

40. Cerebral Oedema Cerebral oedema due to tumors (neoplasms) Traumatic and post stroke oedema  Dexamethasone or betamethasone is preferred because no Na+ retaining activity) Other CNS conditions - spinal chord injury, Bell`s palsy and neurocysticercosis  Oral Prednisolone is the preferred drug

41. Steroid therapy Once daily dosing is usually preferred for oral glucocorticoids Large steroid doses are administered in divided doses to reduce local GIT effects In order to mimic the normal diurnal cycle and reduce the risk of adrenal suppression, GCs should be given in the morning between 6-10 AM Alternate day therapy allows the HPA axis to recover on off days Single dose Steroid

42. Withdrawal of Steroid Therapy Taper the dose to reduce GC dose by 2.5-5 mg of prednisolone equivalent daily Once the GC dose is reduced to 5 mg of prednisolone equivalent, the patient may be switched to a shorter acting agent for further tapering Intermediate acting corticosteroids allow for more flexible dosing schedule Have potent glucocorticoid effects Causes lesser suppression of HPA axis Prednisolone , methylprednisolone and triamcinolone have a half life of 12-36 Hrs , are available in a number of dosage forms

43. Adverse Effects Two types: From abrupt withdrawal Chronic therapeutic use of high dose Withdrawal Flare up of underlying disease Suppression of HPA axis and acute adrenal insufficiency Increased ICT and papilloedema

44. Other Important Adverse Effects Fluid and Electrolyte Disturbance – Na and water retention Precipitation of Diabetes mellitus – hyperglycemia Increased susceptibility to infections – immune response suppression Peptic ulceration – bleeding & perforation Osteoporosis – flat spongy bones Osteonecrosis – avascular necrosis of head of femur, humorous etc. Myopathy – weakness of muscles Cataract – posterior sub capsular Glaucoma – prolonged topical therapy Growth retardation – in children

45. Pseudotumor cerebri (Intracranial hypertension) Glucocorticoids Mineralocorticoids Amiodarone Vitamin A Oral contraceptives Tetracyclines

46. Contraindications Peptic ulcer Hypertension and Diabetes mellitus Viral and fungal infections Tuberculosis and other diseases Osteoporosis Epilepsy and psychosis CHF and renal failure

47. Adrenocorticosteroid Inhibitors METYRAPONE: 11 beta-hydroxylase enzyme inhibitor – used in Cushing`s syndrome and test of pituitary efficiency AMINOGLUTETHEMIDE: Stops conversion of cholesterol to pregnelone (Medical adrenalectomy ) – Breast cancers MIFEPRISTONE: Progesterone antagonist SPIRONOLACTONE: Aldosterone antagonist KETOCONAZOLE: Inhibits synthesis of all hormones in testes and adrenal cortex – used in Cushing`s syndrome and also in hirsutism in female

48. Thank you Download slides from Authorstream /presentations/ raghuprasada Slideshare /presentations/ raghuprasada Youtube / raghuprasada