Pharmacology of corticosteroids

Notes on pharmacology of corticosteroids which can be helpful for pharmacy students and fresh graduates

1. Pharmacology of Corticosteroids Dalia K. Zaafar Lecturer of Pharmacology

2. Adrenal cortex steroidal hormones corticosteroids are any class of steroidal hormones produced in the adrenal cortex. They are two types, glucocorticoids and mineralocorticoids. Glucocorticoids: corticosterone and cortisol Mineralocorticoids: aldosterone

3. Adrenal cortex steroidal hormones Glucocorticoid: a word derived from “ gluco se + cort ex + ster oid ” to reflect their: a) role in regulating glucose metabolism, b) adrenal cortex origin, and c) steroidal structure. Endogenous glucocorticoids are part of the feedback mechanism the body utilizes to reduce immune activity (inflammation). Exogenous glucocorticoids are used to treat diseases caused by an overactive immune system (e.g. allergies, asthma, autoimmune diseases & sepsis). Glucocorticoids are distinguished from mineralocorticoids and sex steroids that have different receptors, target cells and effects.

4. Adrenal cortex steroidal hormones Mineralocorticoid: a class of steroid hormones that cause retention of sodium and water. Aldosterone is the most important endogenous mineralocorticoid. Aldosterone's physiological role is essential in maintenance of adequate fluid volume needed for normal cardiac output and arterial blood pressure. Without adequate levels of mineralocorticoids, diminished cardiac output can result in fatal shock. Elevated levels of aldosterone associated with long term stimulation of the Renin-Angiotensin-Aldosterone-System (RAAS) is involved in the development of vascular remodeling and systolic heart failure.

5. Hypothalamus Pituitary Adrenal Axis

6. Glucocorticoid action Action on CHO, fats and protein metabolism Insulin resistance, hyperglycemia and gluconeogenesis Break down of protein, muscle wasting and excess urea production Redistribution of body fat: moon face and buffalo hump

7. Glucocorticoid action

8. Glucocorticoid action Action on calcium metabolism Inhibition of intestinal absorption and promote excretion of calcium Loss of calcium from bones Negative calcium balance

9. Glucocorticoid action Action as an immunosuppressive and anti-inflammatory agent Inhibition of T- lymphocyte action, so suppress delayed hypersensitivity reaction Inhibit inflammation by inhibiting synthesis prostaglandins (inhibit phospholipase A2 and COXII expression) Inhibit mast cells, basophils and eosinophils degranulation Inhibits neutrophils and macrophage migration

10. Glucocorticoid action More specifically glucocorticoids cause Upregulation of anti-inflammatory genes Downregulation of pro-inflammatory genes

11. Glucocorticoid action Structural and functional maturation of fetal lung CNS anti stress agent Stimulate pepsin and gastric acid secretion

12. Pharmacokinetics Hydrocortisone undergoes a high first pass metabolism Synthetic corticosteroids are highly bioavailable after oral administration Glucocorticoids bound to corticosteroid binding globulin CBG Can be given orally, IV, IM, topically Synthetic steroids are reduced in liver into active compounds

13. Therapeutic uses 1- inflammation such as asthma Beclomethasone, budesonide, flunisolide and fluticasone are examples of inhaled steroids. Oral candidiasis, thrush and hoarse voice are the main side effects of inhaled corticosteroids

14. Therapeutic uses

15. Adverse Effects Hyperglycemia and diabetes Central obesity, moon face and buffalo hump Weight gain Osteoporosis Poor wound healing Hypertension Cataract

16. Therapeutic uses 2- Cancer treatment such as lymphoma By increasing rate of apoptosis in malignant lymphatic tissue 3-Organ graft as an immunosuppressor 4- In allergy and autoimmune diseases 5- Stimulation of fetus lung maturation

17. Therapeutic uses 6- Addison’s disease (adreno-cortical insufficiency) Fludrocortisone is administered to replace aldosterone and prednisone or methyl prednisolone is administered to replace cortisole A disorder that occurs when adrenal glands produce too little cortisol and too little aldosterone. Signs and symptoms: Extreme fatigue, Weight loss and decreased appetite, hyperpigmentation of skin, Low blood pressure, hypoglycemia, gastrointestinal symptoms, Muscle or joint pains, Irritability and Depression

18. Therapeutic uses 6- Addison’s disease (adreno-cortical insufficiency)

19. Adrenocortical over-activity (Cushing’s) CUSHINGOID is a useful way to remember GC side effects C cataract formation and glaucoma U ulcers S skin: stria, thinning, bruises H hypertension and hyperglycemia I infections

20. Adrenocortical over-activity (Cushing’s) N necrosis: avascular necrosis of femoral head G glycosuria O osteoporosis and obesity I immunosuppression D diabetes

21. Glucocorticoids synthesis inhibitors 1- Aminoglutethimide Block the enzymatic conversion of cholesterol into pregnenolone in steroid synthesis resulting in a decrease in the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens Block the conversion of androgen to estrogen by inhibiting aromatase enzyme Used in ttt of Cushing’s, prostate and breast cancer

22. Glucocorticoids synthesis inhibitors 2- Ketoconazole (Antifungal drug) Block the enzymatic conversion of cholesterol into pregnenolone in steroid synthesis resulting in a decrease in the production of adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens Used in ttt of Cushing’s and prostate cancer

23. Glucocorticoids synthesis inhibitors 2- Metyrapone Selectively blocks cortisol biosynthesis by inhibiting 11β- hydroxylase enzyme This mainly results in an increase in ACTH production by the pituitary, In addition to a marked increase in adrenocortical secretion of their precursors, 11-desoxycortisol and deoxycorticosterone in plasma and in urine. So metyrapone is used as a diagnostic test, and occasionally used in Cushing’s ttt.

24. Glucocorticoids antagonist 1- Mifepristone A steroid which binds strongly to progesterone receptor & inhibits activity of progesterone High doses exerts anti-glucocorticoids activity Used in induction of early abortion and can be used for adrenal carcinoma

25. Glucocorticoids antagonist 2- Mitotane In addition to its inhibitory action on corticosteroid synthesis, it has a direct and selective cytotoxic effect on the adrenal cortex. So it causes adrenal atrophy and used in adrenal carcinoma

26. Fludrocortisone A mineralocorticoid used for regulation of fluid and electrolyte balance Acts on distal renal tubule increasing Na+ reabsorption and k+ excretion. Can cause hypokalemia as a side effect so contraindicated with pot. lowering drugs as loop and thiazide diuretics. Taken orally and used (with glucocorticoids) in ttt of adrenal insufficiency

27. Mineralocorticoid antagonists 1- Spironolactone competitively inhibits mineralocorticoid receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention. Used in ttt of hyperaldosteronism (Conn’s syndrome) Used in ttt of heart failure, hypertension As a K+ sparing diuretic Used in ttt of hirsutism in females (anti-androgenic activity)

28. Mineralocorticoid antagonists 2- Eplerenone Similar to spironolactone with a more specific action on mineralocorticoid receptor (no anti-androgenic effect) Used in ttt of hyperaldosteronism, heart failure, hypertension As a K+ sparing diuretic