Pharmacology of corticosteroids

Pharmacology of corticosteroids

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  CORTICOSTEROIDS Dr Mayur Chaudhari AssistantProfessor Department of Pharmacology Government Medical College, Surat
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  Steroids are fastcatching up with antibiotics as the most abused class of drugs today 2
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  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
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   The adrenalproduces 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
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  LEARNING OBJECTIVES  Biosynthesis Actions  Pharmacokinetics and Preparations  Uses  Dosage schedule and withdrawal  ADRs and Contraindications  Precautions during therapy  Contraindications 5
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  ANATOMY 6
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  BIOSYNTHESIS OF ADRENAL HORMONES Mineralocorticoids Glucocorticoids SexHormones 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
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  REGULATION  Synthesized andReleased under influence of ACTH and Pituitary.  Regulated by CRH from hypothalamus and by feedback levels of blood concentrations 8
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  HPA AXIS 9
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  REGULATION Circadian rhythm 10
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  MECHANISM OF ACTION 11
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  ACTIONS • Effect onNa+ Mineralocorticoid • Effect on K+ • Fluid Balance Glucocorticoid • Carbohydrate • Protein and Fat • Other Activities 12
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  MINERALOCORTICOID ACTIONS  Enhancedabsorption of Na+ from DT  increased excretion of K+ and H+.  Similar action on colon, sweat gland and salivary gland. 13
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  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
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  GLUCOCORTICOID ACTIONS CARBOHYDRATE METABOLISM Glycogen deposition in liver  Gluconeogenesis  Inhibit glucose utilization  Hyperglycemia  Insulin resistance, DM like state 15
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  PROTEIN METABOLISM  Breakdownof 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
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  FAT METABOLISM  Permissiveaction due to Glucagon, Growth Hormone, Adrenaline and Thyroxine – Lipolysis.  Increased breakdown of triglycerides.  Redistribution of body fat – Moon face, Buffalo Hump, Fish Mouth. 17
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  CALCIUM METABOLISM  Inhibitionof intestinal absorption and promotion of excretion  Loss of calcium from bone.  Negative calcium balance  Spongy bones – more sensitive. 18
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  WATER EXCRETION ANDSTOMACH  Maintain normal GFR  In adrenal insufficiency capacity is lost – water intoxication  Gastric acid and pepsin secretion enhanced  Aggravate peptic ulcer 19
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  CARDIOVASCULAR SYSTEM  Permissiverole 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
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  SKELETAL MUSCLES  Hypocorticism:Decreased work capacity, weakness  Hypercorticism: Excess Mineralocorticoid .Hypokalemia – Weakness.  Excess glucocorticoid : Muscle wasting, weakness and myopathy 21
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  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
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  LYMPHOID TISSUE  Destructionof 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
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  INFLAMMATION  Prevent migrationof 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
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  INFLAMMATION  Suppress inflammatoryresponse 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
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  IMMUNOLOGICAL ACTION  Inhibitfunction 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
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  IMMUNOLOGICAL ACTION  Impairimmunological 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
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  MISCELLANEOUS  Uricosuric action Nonspecific antipyretic  Structural and functional maturation of fetal lung 28
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  PHARMACOKINETICS  Therapeutically givenby 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
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  PHARMACOKINETICS  Synthetic steroidshave 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
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  HYDROCORTISONE  Rapid butshort acting with significant Mineralocorticoid activity  Used for replacement therapy, shock,  Status asthmaticus and adrenal insufficiency  Topically and as enema for ulcerative colitis 31
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  PREDNISOLONE  More potentthan hydrocortisone, more GC activity  Intermediate duration of action  Less HPA axis suppression  Used for allergic, inflammation  autoimmune diseases, malignancy 32
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  METHYLPREDNISOLONE  More potentand more selective  Retention enema in ulcerative colitis  Pulse therapy in non responsive RA  Renal transplant, pemphigus  Minimal suppression of HPA axis. 33
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  TRIAMCINOLONE  Potent andselective glucocorticoid  Used as intraarticular injection DEXAMETHASONE  Potent and highly selective, long acting  Marked HPA suppression  Inflammatory and allergic condition  Shock, cerebral edema. 34
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  FLUDROCORTISONE  Potent mineralocorticoidhaving some GC activity  Replacement therapy in Addison’s disease  Congenital adrenal hyperplasia  Idiopathic hypotension 35
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  THERAPEUTIC USES  Physiologicdoses 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
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  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
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  REPLACEMENT THERAPY ACUTE ADRENALINSUFFICIENCY  IV Hydrocortisone/ Dexamethasone bolus f/b infusion  Monitor CVP  Short term infusion of dopamine CHRONIC ADRENAL INSUFFICIENCY  Hydrocortisone orally  If needed ad fludrocortisone 38
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  REPLACEMENT THERAPY CONGENITAL ADRENALHYPERPLASIA  Hydrocortisone 0.6 mg/kg in divided doses  Fludrocortisone 10-20 µg/kg if salt wasting persist 39
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  MUST KNOW  Biosynthesisand Regulation of Corticosteroids  Mechanism of action of Corticosteroids  Name of commonly used Glucocorticoids  Anti-inflammatory and immunosuppressive actions of Glucocorticoids 40
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  3/09/13 99.16,100,34.62,56,39,38,33,78,94,71,17,29,44,37,81,92,48,10,66,9 ,70,73,21,75,58,53,60,27,20,19,14,22,88,52,89,5,2,86,68,69,28,45, 8,13,26,41,32,54,82,74,98,11,3,47,93,55,91,63,49,30,15,95,64,96,77 ,18,101,76 06/09/13 38,99,16,100,52,40,35,71,78,94,89,86,5,69,2,28,53,58,75,21,70,33, 73,60,92,66,9,37,27,20,19,88,22,14,34,56,62,13,45,85,7,36,49,46,1 1,98,54,50,59,82,3,18,47,30,51,15,23,63,57,61,91,12,93,101,96,95,6 7 41
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  CORTICOSTEROIDS Dr Mayur Chaudhari AssistantProfessor Department of Pharmacology Government Medical College, Surat
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  OBJECTIVES  Pharmacotherapy  AdverseEffects  Contraindications 43
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  GENERAL PRINCIPLES  Singledose is not harmful  Short Courses  Long term use – Hazardous  Initial Dose – According to severity  No abrupt withdrawal  Local Therapy 44
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  Pharmacotherapy 45
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  ARTHRITIDES  Rheumatoid Arthritis Osteoarthritis  Rheumatic fever  Gout 46
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  COLLAGEN DISEASES  SystemicLupus Erythematous  Nephrotic Syndrome  Glomerulonephritis 47
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  SEVERE ALLERGIC REACTIONS Anaphylaxis  Angioneurotic edema  Urticaria  Serum Sickness  Allergic conjunctivitis  Allergic Rhinitis 48
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  AUTOIMMUNE DISEASES  Hemolyticanemia  Idiopathic thrombocytopenic purpura  Active chronic hepatitis 49
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  BRONCHIAL ASTHMA  Statusasthmaticus  Acute asthma exacerbation  Severe chronic asthma 50
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  LUNG DISEASES  Aspirationpneumonia  Pulmonary edema  Lung maturation in fetus 51
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  INFECTION  Severe tuberculosis Lepra reaction  Bacterial meningitis  Pneumocystis carinii pneumonia 52
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  EYE DISEASES  Allergicconjunctivitis  Iritis  Iridocyclitis  Keratitis 53
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  SKIN DISEASES  Eczema Pemphigus vulgaris  Exfoliative dermatitis  Steven Johnson Syndrome 54
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  INTESTINAL DISEASES  Ulcerativecolitis  Crohn’s Disease  Coeliac Disease 55
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   CEREBRAL OEDEMA NEUROCYSTICERCOSIS  MALIGNANCIES  ORGAN TRANSPLANT  SKIN ALLOGRAFT 56
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   SEPTIC SHOCK THYROID STORM  PITUITARY ADRENAL AXIS FUNCTION 57
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  ADVERSE EFFECTS 58
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  MINERALOCORTICOID  Na+ andwater retention  Edema  Hypokalemic alkalosis  Progressive rise in BP 59
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  GLUCOCORTICOID  Cushing’s habitus Fragile skin, Purple Striae  Hyperglycemia  Muscular Weakness  Delayed healing 60
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   Susceptibility toinfection  Peptic Ulceration  Osteoporosis  Posterior Sub capsular cataract  Glaucoma  Growth Retardation  Foetal abnormality 61
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   Psychiatric Disturbances HPA Axis Suppression 62
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  CONTRAINDICATIONS  Peptic ulcer Diabetes mellitus  Hypertension  Viral and fungal infections  Tuberculosis 63
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  CONTRAINDICATIONS  Osteoporosis  Herpessimplex keratitis  Psychosis  Epilepsy  Congestive heart failure  Renal Failure 64
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  SUMMARY  Guidelines foruse of glucocorticoids  Pharmacotherapy  Adverse effects  Contraindications 65