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Adrenocorticosteroids

Adrenocorticosteroids. Adrenal Gland. Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione and dehydroepiadrosterone) Adrenal medulla – catecholamines e.g epinephrine. Adrenal Cortex. Outer zone (zona glomerulosa) – secretes mineralocorticoids

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Adrenocorticosteroids

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  1. Adrenocorticosteroids

  2. Adrenal Gland • Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione and dehydroepiadrosterone) • Adrenal medulla – catecholamines e.g epinephrine

  3. Adrenal Cortex • Outer zone (zona glomerulosa) – secretes mineralocorticoids - receptors for angiotensin II and express aldosterone synthase; do not atrophy • Inner zone (zona fasciculata and reticularis) – secrete glucocorticoids and adrenal androgens - expresses 17α-hydroxylase and 11β-hydroxylase; results in atrophy

  4. ACTH • a peptide of 39 amino acids • amino acids 15 – 18: high affinity binding • amino acids 6 – 10: receptor activation • synthesized from pro-opiomelanocortin (POMC)

  5. ACTH • Stimulates the synthesis and release of adrenocortical hormones • Human ACTH – G-protein coupled receptor family → activates adenyl cyclase → ↑ intracellular cyclic AMP (2nd messenger for most steroidogenesis)

  6. Regulation of ACTH secretion • Hypothalamic – Pituitary – Adrenal axis (HPA axis) - 3 levels of regulation: 1. diurnal rhythm in basal steroidogenesis 2. negative feedback regulation 3. marked increases in steroidogenesis in response to stress

  7. Steroid hormone production • rate limiting step – conversion of cholesterol to pregnanolone • sources of cholesterol: circulating cholesterol (LDL), cholesterol esterase, de novo biosynthesis

  8. Adrenal Cortex • Produce and releases natural adrenocortical hormones • Uses: a. diagnosis and treatment of disorders of adrenal function b. treatment of inflammatory and immunologic disorders

  9. Classification of corticosteroids • They are all C21 hormones.

  10. A. Glucocorticoids • Naturally-occurring: Cortisol • Kinetics: 10-20 mg daily • Normally its production is diurnal with a peak early in the morning followed by a decline and then secondary smaller peak in the late afternoon. Factor such as stress and levels of the circulating steroid influence secretions. • PORMOTE NORMAL METABOLISM: Glucocorticoids favor gluconeogenesis through increasing amino acid uptake by the liver ,kidney and elevating activites.its deficiency may lead to hypoglycemia specially in case of the periods fasting and during stress. 5. INCREASE RESISTANCE TO STRESS.

  11. A. Glucocorticoids 5. INCREASE RESISTANCE TO STRESS. By inc plasma glucose levels glucocorticoids provide the body to energy to combact stress like trauma fright ,infections bleeding or debilitating disease. 6. HAVE ANTI INFLAMMATORY ACTIONS: the most important therapeutic property of glucocorticoids is their ability to dramatically reduce the inflammatory response and to suppress immunity. See pathologist for exact mechanism .

  12. B. Mineralocorticoids 1. Aldosterone – zona glomerulosa - promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules. 2 conversly it decrease the abosorption of the k ions and in that H ion excrete in urine. 3 Enhance sodium reabsorption most in musoca salivary glands. 4 Hypokalemia ,alkalosis OCCUR. -

  13. B. Mineralocorticoids USES: • ADDISON DISEASE. (replacement therapy for primary adrenocortical insufficiency .medication given is hydrocortisone to treat it.20-240mg PO OD. • CUSHING SYNDROME: Cushing syndrome is caused by a hyper secretion of glucocorticoids that results either from excessive release of corticotropin.

  14. Therapeutic Uses: A. Replacement Therapy 1. Adrenal Insufficiency a. Acute adrenal insufficiency ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness, lethargy, hypotension cause: disorder of the adrenal abrupt withdrawal of glucocorticoids at high doses or prolonged use mgt: IV : D5 0.3%NaCl solution Monitor for fluid overload Hydrocortisone (cortisol) 100mg bolus, ffed by 100mg every 8 hrs. ; once stable, may give 25mg IM hydrocortisone every 6-8hrs.; thereafter, same mgt with chronic adrenal insufficiency

  15. 1. Adrenal Insufficiency (cont.) b. Chronic Adrenal Insufficiency (Addison’s disease) ssx:hyperpigmentation, wt. loss, inability to maintain fasting blood sugar, weakness, fatigue, hypotension cause: primary adrenal insufficiency, tuberculosis mgt: Hydrocortisone 20-30mg/day BID Fludrocortisone acetate 0.05 – 0.2mg/day (valuable indicator of adequate replacement: disappearance of hyperpigmentation and resolution of electrolyte abnormalities) -monitor plasma ACTH levels or measure urinary free cortisol; dosage adjustments for stress

  16. Therapeutic Uses (cont.)2. Adrenocortical hypo- and hyperfunctioning a. Congenital Adrenal Hyperplasia ssx: after puberty with infertility, hirsutism, amenorrhea and acne; female; accelerated linear growth but height at maturity is reduced; salt wasters – cause: Genetic disorder; activity of enzymes required for the biosynthesis of corticosteroid is deficient (21 β hydroxylase) mgt: 1st seen as acute adrenal crisis oral hydrocortisone 0.6mg/kg/day BID or TID fludrocortisone acetate 0.05-0.2mg/day treatment in-utero: mothers at risk – glucocorticoid therapy is initiated before 10 weeks gestation ffed by genotyping and sex determination

  17. b. Cushing’s syndrome cause: pituitary adenoma, tumors of the adrenal gland ssx: round, phletoric face, truncal obesity, muscle wasting, thinning, purple striae and easy bruising of the skin, poor wound healing, osteoporosis mgt: surgery hydrocortisone 300 mg IV on the day of the surgery, then maintenance oral dose

  18. B. Stimulation of fetal lung maturation –betamethasone 12mg ffed by 12mg 18-24 hrs. later C.Nonendocrine Diseases 1. Rheumatic disorders – suppress the disease and minimize resultant tissue damage mgt: prednisone 10 mg/kg/day (taper thereafter by decreasing 1mg/kg/day every 2-3 wks) intraarticular injection: triamcinolone acetonide osteoarthritis : intraarticular injections with interval of 2-3 mos. to minimize complications

  19. C. Non-Endocrine Diseases (cont.) 3. Allergic Disease – epinephrine 0.5ml of a 1:1000 solution IM or SQ, repeated every 15 mins up to 3 doses is needed (anaphylaxis) - onset of action of glucocorticoid is delayed

  20. C. Non-Endocrine Diseases (cont.) 4. Bronchial Asthma – role of inflammation in the immunopathogenesis - onset of action is delayed for 6 – 12 hrs. mgt: IV methylprednisolone 60-120mg initially ffed. by oral prednisone 40-60mg daily as the attack resolves inhaled steroids – reduces bronchial hyperreactivity with les suppression of adrenal function (dysphonia or oropharyngeal candidiasis)

  21. C. Non-Endocrine Diseases (cont.) 5. Infectious Disease – P. carinii pneumonia – increases oxygenation and decreases the incidence of respiratory failure and mortality H. influenzae type b meningitis – decrease the long-term neurological impairment 6. Ocular disease – 0.1% dexamethasone - C/I: herpes simplex keratitis (clouding of the cornea) , glaucoma

  22. C. Non-Endocrine Diseases (cont.) 7. Skin diseases – inflammatory dermatoses 8. GIT diseases – inflammatory bowel disease 9. Hepatic diseases – prednisolone – 80% histologic remission in pts. with chronic, active hepatitis 10. Malignancies – ALL, lymphomas 11. Cerebral edema 12. Miscellaneous dis – Sarcoidosis (induce remission), thrombocytopenia (decrease bleeding tendency), organ transplantation, spinal cod injury

  23. D. Diagnostic Application • Dexamethasone suppression test – differentiates Cushing’s syndrome vs. stress and if Cushing’s syndrome, whether it’s an adrenal or a pituitary tumor • Baseline cortisol levels are determined • Dexamethasone 0.5mg every 6hrs x 48 hrs. • Dexamethasone 2 mg every 6 hrs. x 48 hrs.

  24. Toxicity: • Withdrawal of therapy: ssx: fever, myalgias, arthralgias, malaise, pseudomotor cerebri (papilledema) • Continued use at supraphysiologic doses ssx: fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, myopathy, behavioral disturbances, cataracts, growth arrest and fat redistribution, acne, hirsutism, striae, ecchymoses, osteonecrosis, peptic ulcer • Adrenal suppression - >2 wks. Contraindications:peptic ulcer, heart disease or Hpn with CHF, infections, psychoses, diabetes, osteoporosis, glaucoma or herpes simplex infection

  25. Supplemental measures: • Diet rich in potassium and low in sodium • Caloric mgt to prevent obesity • High protein intake • Appropriate antacid therapy • Calcium and vit D, physical therapy • Alendronate biphosphonate

  26. Classification of Adrenocorticosteroids I. Short to medium-acting glucocorticoids: a. Hydrocortisone (cortisol) b. Cortisone c. Prednisone d. Prednisolone e. Methylprednisolone f. Meprednisone

  27. II. Intermediate-acting glucocorticoids a. Triamcinolone b. Paramethasone c. Fluprednisolone III. Long-acting glucocorticoids a. Betamethasone b. Dexamathasone IV. Mineralocorticoids a. Fludrocortisone b. desoxycorticosterone acetate

  28. Addison described :           . general languor and debility          . remarkable feebleness of the heart's action          . irritability of the stomach          . peculiar change of the color of the skin 

  29. Thank You

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