1. ADRENAL GLANDS

2. Objectives At the end of this lecture, the student should be able to: Describe the physiology of adrenal hormones secretion. Determine the synthesis of adrenal hormones. Recognize the functions of the adrenal hormones. State the pharmacological actions and therapeutic principles of corticosteroids. Identify the side effects of steroid abuse. State the importance of steroid tapering after prolonged use.

3. About 5x3 cm in size, combined weight in an adult human ranges from 7 to 10 grams.

5. Anatomy and Function Capsule Cortex (outer) has 3 zones: 1- Zona glomerulosa : mineralocorticoids, mainly aldosterone, responsible for the regulation of BP. It affects the distal convoluted tubule and collecting duct of the kidneymineralocorticoids aldosteroneregulation of distal convoluted tubule collecting duct of the kidney (increased reabsorption of Na + and excretion of both K + and H + ions). 2- Zona fasciculata: glucocorticoids, such asglucocorticoids 11-deoxycorticosterone11-deoxycorticosterone, corticosterone, andcorticosterone cortisolcortisol.

6. 3- Zona reticularis: produces androgens, mainly dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione (the precursor to testosterone) in humans.androgens dehydroepiandrosteroneDHEA sulfateandrostenedione testosterone Medulla (core of the gland) It secretes norepinephrine and epinephrine. Catecholamines (aa tyrosine ), water-soluble, the major hormones underlying the fight-or-flight response.tyrosinefight-or-flight response Receives input from the sympathetic nervous system through preganglionic fibers originating in the thoracic spinal cord from T5–T11.sympathetic nervous systempreganglionic fibersthoracic spinal cord Cortisol also promotes epinephrine synthesis.

7. History 1855 – Addison's diseaseAddison's disease 1856 – Adrenal glands essential for life 1930 – Cortex > medulla 1932 – Cushing’s syndrome 1949 – Steroids in rheumatoid arthritis 1952 – Aldosterone

9. Basal secretions GroupHormoneDaily secretions GlucocorticoidsCortisol5 – 30 mg Mineralocorticoids Aldosterone5 – 150 mcg Sex Hormones Androgen Progestogen Oestrogen DHEA Progesterone Oestradiol 15 – 30 mg 0.4 – 0.8 mg Trace From Essential of Pharmacotherapeutics, ed. FSK Barar. P.351

11. Cholesterol Pregnenolone Progesterone Corticosterone 11-Desoxy- corticosterone 18-Hydroxy- corticosterone ALDOSTERONE 17-α- Hydroxy pregnenolone 11- Desoxy- cortisol 17- Hydroxy progesterone 21,β hydroxylase CORTISOL 11,β hydroxylase Dehydro-epi androsterone Andro- stenedione Oestrone Oestriol TESTOSTERONEOESTRADIOL ACTH

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

13. Actions: Carbohydrate and protein metabolism Gluconeogenesis - In the liver (synthesis of glucose from aa and glycerol ).liver - Mobilization of amino acids from extrahepatic tissues as substrates for gluconeogenesis.extrahepatic - Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy and the released glycerol provide another substrate for gluconeogenesis.fat breakdownlipolysisglycerol Peripheral utilization of glucose - Inhibition of glucose uptake in muscle and adipose tissueadipose Glycogen deposition in liver (activation of hepatic glycogen synthase) Negative nitrogen balance & hyperglycemia

14. Redistribution of Fat Buffalo hump Supraclavicular fat Moon face Promote adipokinetic agents activity (glucagon, growth hormone, adrenaline, and thyroxin) Actions: Lipid metabolism

15. Aldosterone is more important, acts on D.T. & C.D. of kidney – Na + reabsorption – Urinary excretion of K + and H + – Glucocorticoids assist in the normalization of extracellular fluid volume by regulating body’s action to atrial natriureteric peptide. – Cortisol reduces the capacity of osteoblasts to produce new bone tissue and decreases the absorption of calcium in the GIT.osteoblasts Actions: Electrolyte and water balance

16. Restrict capillary permeability Maintain tone of arterioles Myocardial contractility Actions: Cardiovascular system Mineralocorticoids induced hypertension Na+ sensitize blood vessels to the action of catecholamines & angiotensin

17. Addison's disease: weakness & fatigue is due to Prolonged use: Actions: Skeletal Muscles Needed for maintaining the normal function of Sk. muscle inadequacy of circulatory system Steroid myopathy, weakness, reduced muscle mass and repair

18. Direct: – Mood (euphoria) – Behavior, psychosis – Brain excitability – Significant impact on vigilance (attention deficit disorder) and cognition (memory).vigilanceattention deficit disordercognition Actions: CNS ICP (pseudotumor cerebri)pseudotumor cerebri

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

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

21. Recruitment of WBC & monocyte- macrophageWBC & monocyte- into affected area & elaboration of chemotactic substances Lipocortin TNF from phagocytic cells IL1 from monocyte-macrophage Formation of Plasminogen Activator Fibroblastic activity Expression of cyclooxygenase II Actions: Anti-inflammatory

22. Phospholipids Arachidonic acids lipoxygenase Cycylooxygenase Leukotriene Prostaglandins, Thromboxane Prostacyclins Suppress Phospholipase A2 Lipocortin- 1 Corticosteroids PAF by lipocortin

23. Anti-inflammatory actions of corticosteroids Corticosteroid inhibitory effect

24. 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 (graft rejection & delayed hypersensitivity). Transplant rejection: antigen expression from grafted tissues, delay revascularization, sensitization of T lymphocytes.

25. Main pathogens of concern in glucocorticoid-induced immunodeficiency:pathogens Legionella micdadeiLegionella micdadei, Listeria monocytogenes, Mycobacterium tuberculosis, NocardiaListeria monocytogenesMycobacterium tuberculosisNocardia asteroidesasteroides, Salmonella species, Staphylococcus aureus, StreptococciSalmonellaStaphylococcus aureusStreptococci AspergillusAspergillus, Blastomyces, Candida albicans and nonalbicans species, CoccidioidesBlastomycesCandida albicansCoccidioides immitis immitis, Cryptococcus neoformans, Histoplasma capsulatum. Penicillium marneffei,Cryptococcus neoformansHistoplasma capsulatumPenicillium marneffei Pseudallescheria boydiiPseudallescheria boydii, ZygomycosisZygomycosis AdenovirusAdenovirus, Cytomegalovirus, Herpes simplex virus, Human papillomavirus,CytomegalovirusHerpes simplex virusHuman papillomavirus InfluenzaInfluenza/parainfluenza, Respiratory syncytial virus, Varicella zosterparainfluenzaRespiratory syncytial virusVaricella zoster Other CryptosporidiosisCryptosporidiosis/lsospora bellilsospora belli Pneumocystis carinii Strongyloides stercoralis Toxoplasma gondii

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

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

28. 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. Actions: Respiratory system