Lecture 3 Adrenal Glands PDF

Bachelor of Pharmacy (Honours) Year 3, Semester I Academic Session 2023/2024 Lecture 3 Anatomy, physiology and pathophysiology of the adrenal glands Zalina Bt Zahari ([email protected]) 22/10/2023 (10 am – 1 pm...

Bachelor of Pharmacy (Honours) Year 3, Semester I Academic Session 2023/2024 Lecture 3 Anatomy, physiology and pathophysiology of the adrenal glands Zalina Bt Zahari ([email protected]) 22/10/2023 (10 am – 1 pm) (F2F, e-Learning) Contents 3. Anatomy, physiology and pathophysiology of the adrenal glands 3.1. Synthesis and release of adrenocortical hormones 3.2 Naturally occurring glucocorticoids - Mechanism of action, pharmacological actions and therapeutics uses 3.3. Regulation of aldosterone synthesis and release Aims At the end of the lecture session, student will be able to: 1. Explain about the anatomy, physiology and pathophysiology of the adrenal glands in terms of - Synthesis and release of adrenocortical hormones - Naturally occurring glucocorticoids - Mechanism of action, pharmacological actions and therapeutics uses - Regulation of aldosterone synthesis and release The adrenal glands  the outer cortex (derived from mesodermal tissue, account for ~90% of the weight of the adrenals)  the inner medulla (derived from a subpopulation of neural crest)  Anatomy of adrenal glands Localization: the top of the kidney and weighting approximately 5 g each Each adrenal gland is composed of two endocrine components: 1. medulla (inner part) that constitutes 20% of the gland 2. cortex (outer part) that constitutes the remaining 80%. The cortex consists of three zones. The medulla and each of the zones in the cortex each produce different hormones that serve a variety of functions in your body. Functional anatomy and zonation  Adrenal glands cortical substance medullary substance zona zona zona glomerulosa fasciculata reticularis Mineralocorticoid Glucocorticoids: Catecholamines: Sex hormones: s: aldosterone, cortisol, noradrenaline testosterone, deoxycorticoster cortisone, (norepinephrine), estradiol one corticosterone adrenaline The adrenal glands The adrenal cortex  The adrenal cortex The Adrenal Cortex (cont.)  Zonation The glucocorticoids cortisol and corticosterone, and the androgen dehydroepiandrosterone (DHEA), are synthesized in the zona fasciculata and zona reticularis of the adrenal cortex. The mineralocorticoid aldosterone is synthesized in the zona glomerulosa of the adrenal cortex. Molina PE: Endocrine Physiology, 3rd ed. Synthesis of the adrenal cortical hormones Steroidogenic Enzymes  Cortical hormones: Steroid Hormones Synthesis Steroids are derivatives of cholesterol. Steroid hormones are synthesized and secreted on demand (not stored) All steroid hormones have in common the 17-carbon cyclopentano-perhydrophenanthrene nucleus. Additional C can be added at positions 10 and 13 or as a side chain attached to C17. Steroid hormones and their precursors and metabolites differ in 1. number and type of substituted groups, 2. number and location of double bonds, 3. stereochemical configuration. The Secretion of glucocorticoids from the adrenal cortex is regulated by negative feedback involving the CRH secretion by the hypothalamus. CRH then acts on the anterior pituitary to stimulate ACTH secretion, which then stimulates the adrenal cortex into cortisol secretion.  Synthesis of adrenocorticosteroids 1. Uptake of cholesterol by the adrenal cortex is mediated by the LDL receptor. With long-term stimulation of the adrenal cortex by ACTH, the number of LDL receptors increases. Much of the cholesterol in the adrenal is esterified to cholester and stored in cytoplasmic lipid droplets. 2. Upon stimulation of the adrenal by ACTH or cAMP, an esterase is activated, and the free cholesterol formed by CEH is transported into the mitochondria. CEH: neutral cytosolic cholesteryl ester hydrolase  Biochemical actions of adrenocorticosteroids A. Mineralocorticoids: aldosterone  It promotes Na+ reabsorption at the distal convoluted tubules of kidney. Na+ retention is accompanied by corresponding excretion of K+,H+ and NH4+ ions.  Aldosterone exerts the 90% of the mineralocorticoid activity. Cortisol also have mineralocorticoid activity, but only 1/400th that of aldosterone.  Excess aldosterone causes: 1. increases tubular hydrogen ion secretion, with resultant mild alkalosis 2. Increases transcription of Na/K pump 3. Increases the expression of apical Na channels and an Na/K/Cl co-transporter in sweat glands, salivary glands during excessive sweat/saliva loss,& intestinal epithelial cells. 4. Expands ECF volume The four mechanisms of aldosterone secretion Decreasing blood volume or pressure by Renin-angiotensin mechanism – kidneys release renin, which is converted into angiotensin II that in turn stimulates aldosterone release Plasma low concentration of sodium and high potassium – directly influences the zona glomerulosa cells ACTH – causes small increases of aldosterone during stress Atrial natriuretic peptide (ANP) – inhibits activity of the zona glomerulosa  Biochemical actions of adrenocorticosteroids B. Glucocorticoids: Cortisol 1. Effects on glucose metabolism: They promote gluconeogenesis. They work in tandem with insulin from the pancreas to maintain blood glucose levels 2. Effects on lipid metabolism: They increase lipolysis in adipose tissue and reduce synthesis of TG. 3. Effects on protein and nucleic acid metabolism: They promote transcription and protein synthesis in liver. They also cause catabolic effects in extrahepatic tissues results in enhanced degradation of protein. 4. Effects on water and electrolyte metabolism: Deficiency of them cause increased production of ADH which can decrease glomerular filtration rate causing water retention in the body. The inverse relationship between cortisol and AVP may account for the nonosmotic change in AVP in patients with disorders of glucocorticoid secretion. 5. Effects on immune system: Cortisol suppress the immune response directly and indirectly by affecting most cells that participate in immune reactions and inflammatory reactions. This is one of the reasons why strong corticosteroids (prednisone, prednisolone, etc.) are used with all diseases involving inflammatory processes, including auto-immune diseases. 6. Effects on CVS: Cortisol could control the contraction of the walls of the mid-sized arteries in increasing blood pressure, but this hypertensive effect is moderated by calcium and magnesium. It also directly affects the heart by regulating sodium and potassium in the heart cells and increasing the strength of contraction of the heart muscle. 7. Effects on CNS: The changes of behavior, mood, and decreased memory. These occur because the brain is affected by both too little and too much cortisol.   Steroid transport  Free cortisol is active.Normally less than 15% of circulating cortisol is free.  unbound cortisol and its metabolites are filterable at the glomerulus. Increased quantities of free steroid are excreted in the urine  About 70% of blood cortisol is bound to a carrier protein called corticosteroid-binding globulin CBG. Another 15% is bound to albumin, the remaining 15% exists free in solution.  CBG binding is reduced in areas of inflammation, thus increases the local concentration of free cortisol.  Sex Corticosteroids (Testosterone, Estradiol)  Sex Corticosteroids take part in the development of the secondary sexual characters  in the libido regulation.  The concentration of sex corticosteroids changes within 24 hours: max at 19-21 o'clock in the evening; minimum at 3 o'clock in the morning.  The Secretion of glucocorticoids from the adrenal cortex is regulated by negative feedback involving the CRH secretion by the hypothalamus. CRH then acts on the anterior pituitary to stimulate ACTH secretion, which then stimulates the adrenal cortex into cortisol secretion.  Stress  Adrenal glands are the anti-stress glands of the body.  There are four major categories of stress: 1. Physical stress: such as overwork, lack of sleep, athletic overtraining. 2. Chemical stress: environmental pollutants, allergies to foods, diets high in refined carbohydrates, endocrine gland imbalances. 3. Thermal stress: over-heating or over-chilling of the body 4. Emotional and mental stress During stress cortisol must simultaneously provide more blood glucose, mobilize fats and proteins for a back-up supply of glucose, modify immune reactions, heartbeat, blood pressure, brain alertness and nervous system responsiveness. If cortisol level cannot rise in response to these needs, maintaining your body under stress is nearly impossible.  short term stress response Adrenal medulla releases epinephrine (adrenaline) and norepinephrine Stimulates rapid mobilization of metabolic resources: increased heart rate, BP, blood glucose  "Rapid response" Fasting People have considerable difficulty when on a prolonged fasting. During a fasting, the body will call on the adrenals to produce glucocorticoids to maintain blood glucose level which is adequate for normal level of activity. The glucocorticoids can elevate blood glucose by breaking down protein into carbohydrates through the process of gluconeogenesis.  Fasting People have considerable difficulty when on a prolonged fasting. During a fasting, the body will call on the adrenals to produce glucocorticoids to maintain blood glucose level which is adequate for normal level of activity. The glucocorticoids can elevate blood glucose by breaking down protein into carbohydrates through the process of gluconeogenesis. Genetic defects in adrenal steroidogenesis Transport of adrenal steroids in blood Transport of adrenal steroids in blood Metabolism of adrenal steroids Regulation of the synthesis of adrenal steroids The main actions of ACTH on steroidogenesis  Glucocorticoids Cortisol (very potent, accounts for about 95 percent of all glucocorticoid activity) Corticosterone (provides about 4 percent of total glucocorticoid activity, but much less potent than cortisol) Cortisone (almost as potent as cortisol) Prednisone (synthetic, four times as potent as cortisol) Methylprednisone (synthetic, five times as potent as cortisol) Dexamethasone (synthetic, 30 times as potent as cortisol) Mechanism of action of glucocorticoids  Effects of glucocorticoids Metabolic effects - Catabolic, antianabolic, diabetogenic effects the anti-inflammatory action of glucocorticoids Effects on the immune system - Maintenance of the vascular response to norepinephrine Glucocorticoids and stress - Regulation of glucocorticoid secretion  Effects of cortisol on carbohydrate metabolism Stimulation of gluconeogenesis – Cortisol increases the enzymes required to convert amino acids into glucose in the liver cells – Cortisol causes mobilization of amino acids from the extrahepatic tissues mainly from muscle Decreased glucose utilization by cells Elevated blood glucose concentration and “adrenal diabetes.”  Effects of cortisol on protein metabolism Reduction in cellular protein increases liver and plasma proteins increased blood amino acids diminished transport of amino acids into extrahepatic cells enhanced transport into hepatic cells  Effects of cortisol on fat metabolism Mobilization of fatty acids Obesity caused by excess cortisol Cortisol is important in resisting stress and inflammation Anti-inflammatory effects of high levels of cortisol cortisol prevents the development of inflammation by stabilizing lysosomes and by other effects Cortisol causes resolution of inflammation Cortisol blocks the inflammatory response to allergic reactions  Mineralocorticoids Aldosterone (very potent, accounts for about 90 percent of all mineralocorticoid activity) Deoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted) Corticosterone (slight mineralocorticoid activity) 9α-Fluorocortisol (synthetic, slightly more potent than aldosterone) Cortisol (very slight mineralocorticoid activity, but large quantity secreted) Cortisone (slight mineralocorticoid activity)  Effects of mineralocorticoides The physiological action of aldosterone is to stimulate sodium reabsorption in the kidneys by the distal tubule and collecting duct of the nephron and to promote the excretion of potassium and hydrogen ions. Aldosterone secretion is stimulated by an increase in the potassium concentration in extracellular fluid, caused by a direct effect of potassium on zona glomerulosa cells Regulation of aldosterone secretion  Hypercorticism Causes: ACTH or adrenal tumor symptoms: – muscle weakness and atrophy – accumulation and redistribution of fat (facies lunata) – hyperglycaemia – immunity disorders – osteoporosis – hypertension – hypokalaemia – alkalosis Cushing’s syndrome, Cushing’s disease Hyperadrenalism – hypercortisolism. Causes: Adenomas of the anterior pituitary that secrete large amounts of ACTH, which causes adrenal hyperplasia and excess cortisol secretion; Abnormal function of the hypothalamus that causes high levels of CRH, which stimulates excess ACTH release; “ectopic secretion” of ACTH by a tumor elsewhere in the body, such as an abdominal carcinoma; adenomas of the adrenal cortex  Cushing’s syndrome, Cushing’s disease Signs and symptoms: mobilization of fat from the lower part of the body, with concomitant extra deposition of fat in the thoracic and upper abdominal regions, giving rise to a buffalo torso. an edematous appearance of the face, acne and hirsutism (“moon face”) hypertension, hyperglycemia, severe muscle weakness, large purplish striae, severe osteoporosis with consequent weakness of the bones. Cushing’s syndrome, Cushing’s disease buffalo hump, moon face striae rubrae Primary aldosteronism - Conn’s syndrome Hyperadrenalism – hyperaldosteronism Causes: a small tumor of the zona glomerulosa cells or hyperplastic adrenal cortices that secrete aldosterone rather than cortisol Signs and symptoms: Hypokalemia, occasional periods of muscle paralysis, mild metabolic alkalosis Hypertension, headaches a decreased plasma renin concentration  Adrenogenital syndrome An occasional virilizing adrenocortical tumor secretes excessive quantities of androgens that cause intense masculinizing effects throughout the body: In females: virile characteristics growth of a beard a much deeper voice occasionally baldness masculine distribution of hair on the body and the pubis growth of the clitoris to resemble a penis deposition of proteins in the skin especially in the muscles to give typical masculine characteristics  Adrenogenital syndrome In the prepubertal male: a virilizing adrenal tumor causes the same characteristics as in the female plus rapid development of the male sexual organs. In the adult male: the virilizing characteristics of adrenogenital syndrome are usually obscured by the normal virilizing characteristics of the testosterone secreted by the testes. The excretion of 17-ketosteroids (derived from androgens) in the urine may be 10  Hypocorticism Causes: ACTH or destruction of AG symptoms: – fatigue – anorexia – hypoglycaemia – natriuresis, dehydratation – hypotension – hyperkalaemia, hyponatriaemia – metabolic acidosis – hyperpigmentation in primary Addison’s disease  Primary Addison’s disease Hyperpigmentation of the skin may be seen, as well as darkening of the palmar skin creases (e.g., of the hands), nipple, and the inside of the cheek (buccal mucosa), old scars may darken, sites of friction, the vermilion border of the lips, and genital skin. In secondary and tertiary forms of adrenal insufficiency, skin darkening does not occur, as ACTH is not overproduced. Classic darkening of the skin due to increased pigment as seen in Addison's disease The adrenal medulla  The adrenal medulla The catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) are synthesized and secreted by the chromaffin cells of the adrenal medulla Catecholamines interact with four adrenergic receptors (α1,α2 and β1,β2) that mediate the cellular effects of the hormones Catecholamines have rapid, widespread effects.  The adrenal medulla Stimuli such as injury, anger, pain, cold, strenuous exercise, and hypoglycemia generate impulses in the cholinergic preganglionic fibers innervating the chromaffin cells, resulting in the secretion of catecholamines To counteract hypoglycemia, catecholamines stimulate glucose production in the liver, lactate release from muscle, and lipolysis in adipose tissue Catecholamine physiologic effects  Catecholamine-mediated responses to hypoglycemia  Hypercatecholamin e states Cause: chromaffin-cell tumors = catecholamine producing endocrine neoplasms (e.g. pheochromocytoma) Symptoms: – hypertension (paroxysmal) – hyperglycaemia – Hypermetabolism Treatment: Diazepam, a non-selective beta blocker, other antihypertensive drugs, antipsychotics  References 1. Brunton L, Knollman B, Hilal-Dandan R. (2017) Goodman & Gilman’s The Pharmacological Basis of Therapeutics.. 13 ed. New York: McGraw-Hill Education. 2. Katzung BG, Trevor AJ. (2015) Basic & Clinical Pharmacology. 13 ed. New York: McGraw Hill. 3. Guyton and Hall Textbook of Medical Physiology/ Hall JE, — 11 ed. 4. A Textbook of Clinical Pharmacology and Therapeutics/ Ritter JM, Lewis LD, Mant T GK and Ferro A — 5th ed. 5. Medical Pharmacology at a Glance, / Michael J. Neal. 8t ed Companion website: www.ataglanceseries.com/pharmacology 6. Lee Ellen Copstead & Jacquelyn L Banasik (2013). Pathophysiology, 5th Edition, St Louis. Elsevier 7. Essentials of anatomy and physiology/Valerie C. Scanlon, Tina Sanders. — 5th ed. 8. Principles of Anatomy and Physiology/ Tortora GJ, Derrickson BH. — 12 ed. 9. Ritter J, Flower R, Henderson G, Loke YK, MacEwan D, Rang H. (2020) Rang & Dale's Pharmacology. 9 ed. United Kingdom: Elsevier Churchill Livingstone. Summary 1. Explain about the anatomy, physiology and pathophysiology of the adrenal glands in terms of - Synthesis and release of adrenocortical hormones - Naturally occurring glucocorticoids - Mechanism of action, pharmacological actions and therapeutics uses - Regulation of aldosterone synthesis and release  Extra activity (1) Anatomy and Physiology of the Adrenal Glands 1. Visit the website, https://www.youtube.com/watch?v=-d-9gRgz9pY - Please write short notes on the anatomy and physiology of the adrenal glands based on this video. - You may do further literature search to enhance your understanding and answer  Extra activity (2) Adrenal Gland Disorders 1. Visit the website, https://www.msdmanuals.com/home/quick-facts- hormonal-and-metabolic-disorders/adrenal-gland-disorders - Please write short notes on the adrenal gland disorders based on this article. - You may do further literature search to enhance your understanding and answer  Extra activity (3) Adrenal Cortex: Synthesis and Secretion 1. Visit the website, https://www.youtube.com/watch?v=lq_s0bgC5L4 - Please write short notes on the synthesis and release of adrenocortical hormones based on this video. - You may do further literature search to enhance your understanding and answer  Extra activity (4) Glucocorticoids - Mechanism of action, pharmacological actions and therapeutics uses 1. Visit the website, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744986/ Please write short notes on the glucocorticoids pharmacology and their application in the treatment of childhood-onset systemic lupus erythematosus based on this article. - You may do further literature search to enhance your understanding and answer  Extra activity (5) Glucocorticoids - Mechanism of action, pharmacological actions and therapeutics uses 1. Visit the website, https://www.youtube.com/watch?v=sSP6QrTvPlo - Please write short notes on the pharmacology of glucocorticoids based on this video. - You may do further literature search to enhance your understanding and answer  Extra activity (6) Regulation of aldosterone synthesis and release 1. Visit the website, https://www.youtube.com/watch?v=wPy-6OyLIZA - Please write short notes on the Aldosterone: Regulation of Secretion and Effects based on this video. - You may do further literature search to enhance your understanding and answer  Thank you for your attention Acknowledgements AP Dr Azyyati Mohd Suhaimi Adapted from: Mdm Aslinda Jamil