CORTICOSTEROIDS Steroids are fast catching up with antibiotics

CORTICOSTEROIDS

Steroids are fast catching up with antibiotics as the most abused class of drugs in doctor's black bag. High doses of corticosteroids and other immunosuppressive agents cause AIDS Mohammed Ali Al-Bayati Ph. D Corticosteroids were voted Allergen of the Year in 2005 by the American Contact Dermatitis Society

HISTORY • Tadeusz Reichstein together with Edward Calvin Kendall and Philip Showalter Hench were awarded the Nobel Prize for Physiology and Medicine in 1950 for their work on hormones of the adrenal cortex. • Lewis Sarett of Merck & Co. was the first to synthesize cortisone.

Biosynthesis • Steroid hormones are produced from cholesterol • Synthesis requires many oxidative enzymes located in mitochondria and endoplasmic reticulum. • The hypothalamic-pituitary axis controls adrenal steroid production through ACTH release • ACTH binds to its receptor and activates adenylyl cyclase and production of c. AMP • c. AMP activates protein kinases which converts cholesterol esters into free cholesterol • Cholesterol is transported to mitochondria by St. AR (steroidogenic acute regulatory protein) • rate-limiting step in steroid hormone production is the transport of free cholesterol from the cytoplasm into mitochondria

Biosynthesis

Basal secretions Group Hormone Daily secretions 5 – 30 mg 2 – 5 mg • Cortisol • Corticosterone Mineralocorticoids • Aldosterone 5 – 150 mcg • 11 - deoxycorticosterone Trace Sex Hormones • Androgen • DHEA 15 – 30 mg • Progestogen • Progesterone 0. 4 – 0. 8 mg Trace • Oestrogen • Oestradiol Glucocorticoids From Essential of Pharmacotherapeutics, ed. FSK Barar. P. 351

Pharmacological Actions 1. Carbohydrate 8. Stomach 2. Protein 9. Blood 3. Lipid 10. Anti-inflammatory 4. Electrolyte & water 11. Immunosuppressant 5. CVS 12. Respiratory system 6. Sk. Muscle 13. Growth & Cell Division 7. CNS 14. Calcium metabolism

Actions: Carbohydrate and protein metabolism Negative nitrogen balance & hyperglycaemia • Gluconeogenesis • Peripheral utilization of glucose • Glycogen deposition in liver (activation of hepatic glycogen synthase)

Actions: Lipid metabolism • Redistribution of Fat • Buffalo hump • Moon face

Actions: Electrolyte and water balance • Aldosterone is more important • Act on D. T. & C. D. of kidney – Na+ reabsorption – Urinary excretion of K+ and H+

Actions: Cardiovascular system • Restrict capillary permeability • Maintain tone of arterioles • Myocardial contractility sensitize blood vessels to the action of catecholamines & angiotensin

Actions: Skeletal Muscles Needed for maintaining the normal function of Sk. muscle Addison's disease: weakness & fatique is due to inadequacy of circulatory system Prolonged use: Steroid myopathy

Actions: CNS • Direct: – Mood – Behaviour – Brain excitability • Indirect: – maintain glucose, circulation and electrolyte balance • Excess of GC levels leads to neuroses and psychoses.

Actions: Stomach Aggravate peptic ulcer. May be due to – Acid & pepsin secretion – immune response to H. Pylori

Actions: Blood RBC: Hb & RBC content (erythrophagocytosis ) WBC: Lymphocytes, eosinophils, monocytes, basophils

Actions: Anti-inflammatory • Recruitment of WBC & monocyte- macrophage into affected area & elaboration of chemotactic substances • Lipocortin • TNF from phagocytic cells • IL 1 from monocyte-macrophage • Formation of Plasminogen Activator • fibroblastic activity • Expression of cyclo-oxygenase II

Corticosteroids Return Lipocortin Phospholipids Phospholipase A 2 Arachidonic acids lipoxygenase Cycylooxygenase Leukotriene Prostaglandins, Thromboxane Prostacyclins PAF by lipocortin

Anti-inflammatory actions of corticosteroids Corticosteroid inhibitory effect Return

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 • Transplant rejection: antigen expression from grafted tissues, delay revascularization, sensitisation of T lymphocytes etc.

Actions: Growth & Cell division • Inhibit cell division or synthesis of DNA • Delay the process of healing • Retard the growth of children

Actions: Calcium metabolism • Intestinal absorption • Renal excretion • Excessive loss of calcium from spongy bones (e. g. , vertebrae, ribs etc)

Actions: Respiratory system • Not bronchodilators • Most potent and most effective anti-inflammatory • Effects not seen immediately (delay 6 or more hrs) • Inhaled corticosteroids are used for long term control

Classification (Glucocorticoids) SHORT ACTING t 1/2 <12 hours INTERMEDIATE ACTING t 1/2 12 -36 hours LONG ACTING t 1/2 > 36 hours Hydrocortisone Prednisolone Dexamethazone Methylprednisolone Betamethazone Triamcinolone

Classification Injectable Betametasone Hydrocortisone Dexamethasone Methylprednisolone Prednisolone Triamcinolone Oral Betamethasone Fludricortisone Methylprednisolone Prednisolone Topical Betamethasone Clobetasol Flucinolone Mometasone Inhalational Beclomethasone Budesonide Flunisolide

Adverse Effects

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Adverse Effects • • • High blood sugar High blood pressure Vertigo Blurred vision Female balding Menstrual irregularities Hirsutism Severe depression Cognitive impairment Emotional instability Easy fatiguability

Adverse Effects • • • Fluid & electrolyte disturbances Precipitation of Diabetes mellitus Increased susceptibility to infections Peptic ulcers Osteoporosis Myopathy Behaviour changes Cataracts Growth arrest

Therapeutic Uses

Replacement Therapy Adrenal insufficiency –Acute/ Chronic • – Abrupt withdrawal of steroid therapy • – Chronic infection-Tuberculosis • – Autoimmune adrenal disease • – Surgery • – Haemorrhage • – AIDS • • Congenital adrenal hyperplasia Replacement therapy: • – IV Replacement of sodium chloride and fluid • – IV Hydrocortisone 100 mg stat followed by 100 mg every 8 hours • Chronic insufficiency - Addison’s Disease • – Hydrocortisone • – Prednisolone or dexamethasone-long acting • – Fludrocortisone for mineralocorticoid effects

Anti-inflammatory/ immunosuppressive • In diseases with autoimmune and inflammatory components • Myasthenia gravis • Rheumatic disorders • SLE • Hemolytic anemia • Rheumatoid Arthritis – Controversial because of adverse effects of chronic usage.

Organ transplant • Combined with other immunosuppressants • Cyclosporin, azathioprine

Renal Disease • Nephrotic syndrome in children • Glomerulonephritis

Allergic Disorders • • Exhibit a delayed response in allergies Seasonal allergies, bee stings, drug allergiesallergic response can be suppressed by administration of corticosteroids as supplements.

Bronchial Asthma In severe asthmatic attacks • – Iv Hydrocortisone /Methylprednisolone • – Oral prednisolone Acute attacks • Oral steroids / Inhaled beclomethasone, • budesonide, flunisolide alone or combined with β 2 agonists/ipratropoium

Infectious Diseases • AIDS and Pneumocystis carinii pneumonia • Tubercular meningitis • Lepra reactions

Ocular Diseases • Important drug therapy for suppressing inflammation in eye and preservation of sight. • Topical steroids are use for conditions of the anterior chamber • Systemic steroids for posterior chamber. • • Dexamethasone topical 0. 1 % • • Prednisolone oral • • Contraindicated in viral infections, fulminant bacterial infections, fungal infections, injuries and glaucoma.

Skin Diseases • • The largest application of steroid therapy Topical forms are commonly used • – Allergic conditions • – Eczema • – Psoriasis • – Pemphigus