Dr Sanjeewani Fonseka Department of Pharmacology Adrenal steroids Dr Sanjeewani Fonseka Department of Pharmacology

Objectives Recall the physiological effect of adrenocortical steroids Describe the anti- inflammatory and immunosuppressive effects of glucocorticoids Compare the relative potency, glucocorticoid/mineralocorticoid activity and duration of action of commonly available steroid drugs List clinical uses and adverse effects of glucocorticoid drugs Explain the principles underling replacement therapy in adrenocortical insufficiency Describe the precautions that can be taken to minimize the adverse effects of long-term steroid therapy

Endogenous Glucocorticoids Hydrocortisone Corticosterone

Corticosteroids are Gene-Active

Glucocorticoids Kinetics: Well absorbed orally Bound to corticosteroid-binding globulin and albumin Distributed all over the body & passes the BBB In the liver, cortisol is reversibly converted to cortisone & conjugated with glucuronic & sulfuric acid Excreted in urine as 17-hydroxy corticosteroids

Action of glucocorticoids Metabolic Anti-inflammatory Immunosuppressive

Actions Stomach Carbohydrate Blood Protein Anti-inflammatory Lipid Immunosuppressant Growth and Cell Division Calcium metabolism Carbohydrate Protein Lipid Electrolyte and H2O CVS Skeletal Muscle CNS

Carbohydrate metabolism Gluconeogenesis Peripheral actions (mobilize glucose and glycogen) Hepatic actions Peripheral utilization of glucose Glycogen deposition in liver (activation of hepatic glycogen synthase) hyperglycemia

protein metabolism Negative nitrogen balance Decreased protein synthesis Increased protein breakdown

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

Lipid metabolism Redistribution of Fat

Electrolyte and water balance Act on DT and CD of kidney Na+ reabsorption Urinary excretion of K+ and H+

CNS Direct Indirect Mood Behavior Brain excitability maintain glucose, circulation and electrolyte balance

Stomach Acid and pepsin secretion immune response to H.Pylori

Blood RBC: Hb and RBC content (erythrophagocytosis) WBC: Lymphocytes, eosinophils, monocytes, basophils Polymorphonucleocytes

Actions on inflammatory cells Recruitment of N, monocytes, macrophage into affected area Action of fibroblasts T helper action Osteoblast osteoclast

Inflammatory mediators Reduced cytokines Reduced complement Reduced histamine

Anti-inflammatory actions of corticosteroids Corticosteroid inhibitory effect

Growth and Cell division 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 bones (e.g., vertebrae, ribs, etc) Osteoporosis

Pharmacological Actions synthetic glucocorticoids are used because they have a higher affinity for the receptor have little or no salt-retaining properties.

Clinical uses Replacement therapy Immunosuppressive / anti-inflammatory therapy Neoplastic disease

Types of Steroids Replacement Therapy glucocorticoid (hydrocortisone) mineralocorticoid (fludrocortisone)

Anti-inflammatory Therapy Short acting: hydrocortisone Intermediate acting: prednisolone, methylprednisolone, triamcinolone Long acting: dexamethasone

Preparations 1 1.0 0.8 4 5 0.3 Intermediate acting 10 - 15 7 Drug Anti-inflam. Salt retaining Topical Cortisol 1 1.0 Cortisone 0.8 Prednisone 4 Prednisolone 5 0.3 Methylpredni- solone Intermediate acting Triamcinolone Paramethasone 10 - Fluprednisolone 15 7

Preparations Long acting 25-40 10 30 Mineralocorticoids 250 20 Drug Anti-inflam. Salt retaining Topical Long acting Betamethasone 25-40 10 Dexamethasone 30 Mineralocorticoids Fludrocortisone 250 DOCA 20

Side effects Not seen in replacement therapy Seen if used for anti-inflammatory property Excess of physiological actions

Iatrogenic Cushing’s syndrome

Adverse effects (long term) Glucose intolerance Acne Hypertension, edema Susceptibility to infection (TB, fungal) Myopathy Behavior & mood changes

Adverse effects (long term) Avascular necrosis of bone Cataract Peptic ulcer Skin atrophy, delayed wound healing Growth retardation (children) Suppression of HPA axis

Drug interactions Estrogens - decrease prednisone clearance Phenobarbital, phenytoin, and rifampicin - increase metabolism of glucocorticoids May cause digitalis toxicity secondary to hypokalemia Monitor for hypokalemia with co-administration of diuretics

Read Monitoring while on steroids Pregnancy and steroids Infections and long term steroid Surgery and steroids

Summary

long term steroids Monitor BP, electrolyte and blood sugar Advise moderate exercise Bone protection measures Gastric protection if needed

Give morning dose Every other day Minimum effective dose Steroid sparing agents

Read Mineralocorticoids – action, side effects, clinical uses