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Hormones V. Geršl According to:

Hormones V. Geršl According to: - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed. - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower: Pharmacology, 6th ed. R.A.Howland, M.J.Mycek: Lippincott ’ s Illustrated Reviews: Pharmacology,3rd ed.

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Hormones V. Geršl According to:

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  1. Hormones • V. Geršl • According to: • - H.P.Rang, M.M.Dale, J.M.Ritter, P.K.Moore: Pharmacology, 5th ed. • - H.P.Rang, M.M.Dale, J.M.Ritter, R.J.Flower: Pharmacology, 6th ed. • R.A.Howland, M.J.Mycek: Lippincott’s Illustrated Reviews: Pharmacology,3rd ed. • B.G.Katzung: Basic and clinical pharmacology, 10th ed.

  2. H O R M O N E S The nervous system and the endocrine system are the two mechanisms coordinating body functions and transmitting messages between individual cells and tissues. The nervous system communicates by eletrical impulses (act within milliseconds). In contrast, the endocrine system releases hormones into the blood stream, which carries these chemical messengers to target cells through the body. Much broader range of response times than do nerve impulses, from seconds to days or longer to cause a response that may last for weeks or month. Systems are closely interrelated.

  3. Adrenocorticosteroid Hormones

  4. OVERVIEW The adrenal gland – cortex, medulla. Medulla - secretes epinephrine; Cortex - steroid hormones-adrenocorticosteroids= glucocorticoids and mineralocorticoids, and the adrenal androgens. Cortex– 3 zones that synthesize various steroids from cholesterol and then secrete them. The outer (zona glomerulosa) - mineralocorticoids (aldosterone) - responsible for regulating salt and water metabolism. Production is regulated by the renin-angiotensin system. The middle (zona fasciculata) - glucocorticoids (e.g., cortisol) The inner (zona reticularis) - adrenal androgens (e.g., dehydroepiandrosterone). Adrenal glucocorticoids serve as feedback inhibitors of ACTH and CRF secretion.

  5. Secretion by the two inner zones and, to some extent, the outer zone - controlled by pituitary corticotropin (ACTH), which is released in response to the hypothalamic corticotropin-releasing hormone (CRH = CRF corticotropin-releasing factor). • Glucocorticoids - feedback inhibitors of ACTH and CRH. • replacement therapy; • treatment of asthma and other inflammatory diseases (e.g., rheumatoid arthritis); • treatment of severe allergic reactions; • treatment of some cancers.

  6. Regulation of corticosteroid Hypothalamus Stress Corticotropin- releasing factor Anterior pituitary Corticotropin (ACTH) ADRENAL CORTEX Zona glomerulosa Aldosterone Zona fasciculata Cortisol Androgens Zona reticularis (according to Lippincott´s Pharmacology, 2006 ADRENAL MEDULLA

  7. Hypothalamus Regulation of synthesis and secretion of adrenal corticosteroids CRF ADH Long negative feedback loop Short negative feedback loop Anterior pituitary Exogenous ACTH ACTH Metyrapone mitotane Renin-angiotensin system Adrenal cortex Mineralocorticoids Glucocorticoids Exogenous mineralocorticoids (e.g. fludrocortisone) Exogenous glucocorticoids (e.g. prednisolone) Peripheral actions (metabolic, anti-inflammatory, immunosuppressive) Peripheral actions on salt and water metabolism

  8. Summary of adrenal corticosteroids ADRENAL CORTICOSTEROIDS CORTICOSTEROIDS Beclomethasone Betamethasone Cortisone Desoxycorticosterone Dexamethasone Fludrocortisone Hydrocortisone Methylprednisolone Paramethasone Prednisolone Prednisone Triamcinolone INHIBITORS OF ADRENOCORTICOID BIOSYNTHESIS OR FUNCTION Aminoglutethimide Eplerenone Ketoconazole Metyrapone Mifepristone Spironolactone Trilostane (according to Lippincott´s Pharmacology, 2006

  9. ADRENOCORTICOSTEROIDS Bind to specific intracellular cytoplasmic receptors in target tissues. Glucocorticoid receptor- widely distributed in the body; Mineralocorticoid receptor- excretory organs (kidney, colon, salivary and sweat glands). The receptor-hormone complex translocates into the nucleus, where it attaches to gene promoter elements, acting as a transcription factor to turn genes on or off, depending on the tissue. This requires time to produce an effect. Other glucocorticoid effects (e.g., interaction with catecholamines to mediate dilation of vascular and bronchial musculature or Ijpolysis) -effects are immediate.

  10. A lipid-soluble steroid diffuses across the cell membrane, and binds to a cytoplasmic receptor. Gene regulation by glucocorticoids Corticosteroid TARGET CELL Corticosteroid Inactive receptor CYTOSOL Activated receptor complex Receptor forms a dimer NUCLEUS Glucocorticoid response element Promoter Gene DNA Binding to a glucocorticoid response element stimulates or inhibits the activity of an adjacent promoter, which initiates or inhibits transcription of a gene. mRNA mRNA Changes in amounts of specific proteins (according to Lippincott´s Pharmacology, 2006) Biologic effects

  11. A. Glucocorticoids • Cortisol- the principal human glucocorticoid. • Diurnal production- a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon. • Factors (e.g., stress, levels of the circulating hormone influence secretion). • The effects of glucocorticoids: • Promote normal intermediary metabolism: • Effects on metabolism, water and electrolyte balance: • - carbohydrate metabolism:Stimuate gluconeogenesis by both  • amino acid uptake via the liver and kidney and promoting increased • activity of gluconeogenic enzymes. Gluconeogenesis from AAs • after splitting the proteins. Hyperglycaemia »»» steroid diabetes !

  12. b. Stimulation of protein catabolism (except in the liver), decreased protein synthesis, particularly in muscle (adynamy, hypodynamy)c. Stimulation of lipolysis, redistribution of fat characteristic for Cushing´s syndrome. Thus, provide the building blocks and energy that are needed for glucose synthesis. [Note: Glucocorticoid insufficiency may result in hypoglycemia (e.g., during stressful periods or fasting).] Lipolysis - a consequence of the glucocorticoid augmenting the action of growth hormone on adipocytes, causing  in the activity of hormone-sensitive lipase. Glucocorticoids have some mineralocorticoids actions (»»» sodium and water retention and potassium loss) !!Decrease in calcium absorption from GIT, increase in calcium excretion via kidney »»» osteoporosis !!

  13. d. Increase resistence to stress: By  plasma glucose levels they provide • the body with the energy it requires to combat stress caused by, e.g. • trauma, fright, infection, bleeding, or disease. • Also cause a rise in blood pressure, by enhancing the vasoconstrictor • action of adrenergic stimuli on small vessels. • Note: Individuals with adrenal insufficiency may also respond to severe • stress by becoming hypotensive. • e. Alter blood cell levels in plasma: • in eosinophils, basophils, monocytes, and lymphocytes. • blood levels of hemoglobin, erythrocytes, and polymorphonuclear leukocytes. • Note:The decrease in circulating lymphocytes and macrophages  • a decreased ability of the body to fight infections !!

  14. f. Anti-inflammatory and immunosupresssive action:The most important therapeutically - ability to dramatically reduce the inflammatory response and to suppress immunity. The exact mechanism iscomplex and incompletely understood:-  and inhibition of peripheral lymphocytes and macrophages- indirect inhibition of phospholipase A2 (due to the steroid-mediated elevation of lipocortin 1 = annexin), which blocks the release of arachidonic acid.- COX-II synthesis is availability of PGS. - Interference in mast cell degranulation results - histamine and capillary permeability.-  in inducible NO synthesis.The most pronounced activity in the tissues of mesenchymal origin –i.e.,  in lymphocytes,  activity of fibroblasts, chondroblasts and osteoblasts reduced healing and repair.

  15. g. Negative feedback effects on the anterior pituitary and hypothalamus: inhibition of ACTH and CRF  inhibition of further glucocorticoid synthesis and atrophy of the adrenal cortex !!! After prolonged therapy it takes many months to return to normal function. Also inhibition of TSH production, whereas growth hormone production is increased.

  16. C. Therapeutic uses of the adrenal corticosteroids Semisynthetic derivates of the glucocorticoids - vary in their anti-inflammatory potency, the degree to which they cause Na retention, and the lenght of time of activity. 1. Replacement therapy of primary adrenocortical insufficiency (Addison´s disease): caused by adrenal cortex dysfunction. HYDROCORTISONE(hye droe KOR ti sone - identical to the natural cortisol) is given to correct the deficiency. The dosage is divided so that two thirds of the normal daily dose is given in the morning, and one third in the afternoon. Note: The goal is to approximate the daily hormone levels resulting from the circadian rhythm exhibited to cortisol (plasma levels to be maximal around 8 A.M. and then to decrease throughout the day to their lowest level around 1 A.M !!! FLUDROCORTISONE (floo droe KOR ti sone) - a synthetic mineralocorticoid with some glucocorticoid activity, may also be necessary to raise the mineralocorticoid activity to normal levels.

  17. 2. Replacement therapy for secondary or tertiary adrenocortical insufficiency: Caused by a defect either in CRF production by the hypothalamus or ACTH production by the pituitary. Note: the adrenal synthesis of mineralocorticoids is less impaired. The adrenal cortex responds to ACTH by synthesizing and releasing the adrenal corticosteroids. Hydrocortisone is also used. 3. Diagnosis of Cushing´s syndrome: Caused by a hypersecretion of glucocorticoids (either excessive release of ACTH or to an adrenal tumor). Dexamethasone suppression test - used to diagnose the cause. It suppresses cortisol release in pituitary-dependent Cushing´s syndrome, but it does not suppress release from adrenal tumors. 4. Replacement therapy for congenital adrenal hyperplasia (CAH): Resulting from an enzyme defect in the synthesis of one or more adrenal steroids hormones »»» administration of sufficient corticosteroids necessary to normalize the patient´s hormone levels.

  18. 5. Relief of inflammatory symptoms:Glucocorticoids dramatically reduce the manifestations of inflammations (e.g., rheumatoid and osteoarthritis inflammations, inflammatory conditions of the skin), including the redness, swelling, heat, and tenderness that are commonly present at the inflammatory site. Decreased production of PGS and leukotrienes - believed to be central to the anti-inflammatory action.Furthermore, the effect is associated with their effects on the distribution, concentration, and function of leukocytes. These include an  in the concentration of neutrophils, a  in lymphocytes (T and B cells), basophils, eosinophils, and monocytes, and an inhibition of the ability of leukocytes and macrophages to respond to mitogens and antigens. Also their abilities to reduce the amount of histamine released by basophils and to inhibit the activity of kinins and NO synthesis.Note: The ability of glucocorticoids to inhibit the immune response is also a result of the other actions.

  19. 6. Treatment af allergies: In the treatment of the symptoms of drug, serum, and transfusion allergic reactions, bronchial asthma, and allergic rhinitis. These drugs are not, however, curative. Note:In aerosol - a significant advance in asthma. Applied topically to the respiratory tract through inhalation  it minimizes systemic effects and allows to reduce or eliminate the use of oral steroids. 7. Immunosupressive activity and used (prevention of rejection of organs after transplantation) 8. Hematological disorders (lymphatic leukaemia, haemolytic anaemia) 9. GIT diseases (ulcerative colitis, inflammatory bowel disease) 10. Nephrotic syndrome and other autoimmune diseases. 11. Topically in dermatology (ekzema ...) 12. Acceleration of lung maturation: Respiratory distress syndrome – a problemin premature infants. Fetal cortisol is a regulator of lung maturation.  Beclomethasone administered i.m. to the mother 48 hours prior to birth followed by a second dose 24 hours before delivery.

  20. Some therapeutic indications for the use of glucocorticoids in nonadrenal disorders (according to Katzung BG: Basic and clinical pharmacology, 2007)

  21. (according to Katzung BG: Basic and clinical pharmacology, 2007)

  22. D. Pharmacology • Naturally occurring adrenal corticosteroids and derivates - readily • absorbed from GIT. Selected compounds can also be administered • i.v., i.m., or topically. Bound to plasma proteins: most to corticosteroid- • binding globulin (the remainder to albumin). Metabolized by the liver • microsomal oxidizing enzymes. Conjugated to glucuronic acid or sulfate; • excreted by the kidney. • Note: The half-life may increase dramatically in hepatic dysfunction. • 2. In determining the dosage of adrenocortical steroids, many factors need • to be taken into consideration, incl. activity, duration of action, type • of preparation …. • When large doses of the hormone are required over an extended period of • time (more than 2 weeks), suppression of the hypothalamic-pituitary- • adrenal (HPA) axis occurs. • To prevent this adverse effect, a regimen of alternate-day administration • of the adrenocortical steroid may be useful. This schedule allows the HPA • axis to recover function on the days the hormone is not taken

  23. The only glucocorticoid that has no effect on the fetus in pregnancy = prednisone.It is a prodrug that is not converted to the active compound, prednisolone, in the fetal liver. Any prednisolone formed in the mother is biotransformed to prednisone by the fetus.

  24. Routes of administration and elimination of corticosteroids IM Cortisone Desoxycorticosterone Triamcinolone IV, IM Dexamethasone Hydrocortisone Methylprednisolone Prednisolone (according to Lippincott´s Pharmacology, 2006

  25. Glucocortifcoids 1 Hydrocortisone 1 0.8 Anti-inflammatory effect Cortisone 0.8 Salt-retaining effect 4 Prednisone 0.3 5 Prednisolone 0.8 5 Methylprednisolone 0.5 5 Triamcinolone 0 35 Betamethasone 0 30 Dexamethasone 0 10 Paramethasone 0 Mineralocorticoids 10 Fludrocortisone 125 0 Deoxycorticosterone (according to Lippincott´s Pharmacology, 2006 20

  26. Comparison of the main corticosteroid agents (using hydrocortisone as a standard) Approximatelly relative potency in clinical use: Duration of action after oral dose Comments Compound Anti-inflammatory Sodium-retaining Drug of choice for replacement therapy Hydrocortisone 1 1 S (cortisol) Cheap; inactive untill converted to hydrocortisone; not used as anti-inflammatory because of mineralocorticoid effects Cortisone 0.8 0.8 S Corticosterone 0.3 15 S Drug of choice for systemic anti-inflammatory and immunosuppressive effects Prednisolone 4 0,8 I Inactive until converted to prednisolone Prednisone 4 0,8 I Anti-inflammatory and immunosuppressive Methylprednisolone 5 Minimal I Relatively more toxic than others Triamcinolone 5 None I

  27. Dexamethasone 30 Minimal L Anti-inflammatory and immunosuppressive, used especially where water retention is undesirable, e.g. cerebral oedema; drug of choice for suppression of ACTH production Anti-inflammatory and immunosuppressive, used especially where water retention is undesirable Betamethasone 30 Negligible L Anti-inflammatory and immunosuppressive; effective topically and as an aerosol Beclometasone + - - diproprionate Anti-inflammatory and immunosuppressive; effective topically and as an aerosol Budesonide + - - Deoxycortone Negligible 50 - Fludrocortisone 15 150 S Drug of choice for mineralocorticoid effects Endogenous mineralocorticoid Aldosterone None 500 S

  28. Some commonly used natural and synthetic corticosteroids for general use (according to Katzung BG: Basic and clinical pharmacology, 2007)

  29. Some commonly used natural and synthetic corticosteroids for general use (according to Katzung BG: Basic and clinical pharmacology, 2007)

  30. E. Adverse effects • Osteoporosis, impaired synthesis of collagen ( impaired wound • healing) and myopathy that results from protein catabolism. • Note: Impaired growth in children is probably caused by the same • action. • 2. Edema, hypertension, and congestive heart failure due to salt and • water retention can occur. • 3. The CNS effects range from euphoria to psychoses inclidung suicidal • tendencies. May cause a psychological dependency. • 4. May cause stimulation of peptic ulcers. • 5. Corticosteroids may cause development of iatrogenic Cushing´s • syndrome, including redistribution of body fat, puffy face, increased • body hair growth, acne, insomnia and increased appetite.

  31. 6. Withdrawal from the drugs can be a serious problem, because hypothalamic-pituitary-adrenal suppression. Abrupt removal - an acute adrenal insufficiency syndrome that can be lethal. This fact, coupled with the possibility of psychological dependence and the fact that withdrawal might cause an exacerbation of the disease, means that the individual schedule for withdrawal may be based on trial and error. The patient must be carefully monitored. 7. Hypercoagulability, raised intracranial pressure, glaucoma, fever. 8. Suppression of response to infection. 9. Suppression of endogenous glucocorticoid synthesis.

  32. Euphoria (though sometimes depression or psychotic symptoms and emotional lability) Effects of prolonged glucocorticoid excess: iatrogenic Cushing´s syndrome. Italicised effects are particularly common. Less frequent effects, related to dose and duration of therapy, are shown in brackets. (Benign intracranial hypertension) Buffalo hump (Cataracts) Moon face, with red (plethoric) cheeks (Hypertension) Increased abdominal fat Thinning of skin (Avascular necrosis of femoral head) Also: Osteoporosis Tendency to hyperglycaemia Negative nitrogen balance Increased appetite Increased susceptibility to infection Obesity Thin arms and legs: muscle wasting Easy bruising Poor wound healing (according to Rang and Dale, Pharmacology, 2007)

  33. Glucocorticoids • Drugs used: hydrocortisone, prednisolone and dexamethasone. • Metabolic actions • On carbohydrates: decreased uptake and utilisation of glucose and increased gluconeogenesis; this causes a tendency to hyperglycaemia. • On proteins: increased catabolism, reduced anabolism. • On fat: a permissive effect on lipolytic hormones, and a redistribution of fat, as in Gushing's syndrome.

  34. Regulatory actions • On hypothalamus and anterior pituitary: a negative feedback – a reduced release of endogenous glucocorticoids. • On vascular events: reduced vasodilatation, decreased fluid exudation. • On cellular events: • ― in areas of acute inflammation: decreased influx and activity of leucocytes • ― in areas of chronic inflammation: decreased activity of mononuclear cells, • decreased proliferation of blood vessels, less fibrosis • ― in lymphoid areas: decreased clonal expansion of T and B cells and decreased • action of cytokine- secreting T cells. • On inflammatory and immune mediators: • ― decreased production and action of cytokines including many interleukins, • tumour necrosis factor-g, granulocyte-macrophage colony-stimulating factor • ― reduced generation of eicosanoids • ― decreased generation of IgG • ― decrease in complement components in the blood. • Overall effects: reduction in chronic inflammation and autoimmune reactions but also decreased healing and diminution in the protective aspects of the inflammatory response.

  35. Mechanism of action of the glucocorticoids • Interact with intracellular receptors; the resuIting steroid-receptor complexes dimerise (form pairs) then interact with DNA to modify gene transcription: inducing synthesis of some proteins and inhibiting synthesis of others. • For metabolic actions, most mediator proteins are enzymes, e.g. cAMP-dependent kinase, but not all actions on genes are known. • For anti-inflammatory and immunosuppressive actions, some actions at the level of the genes are known: • ― inhibition of transcription of the genes for COX-2, cytokines(e.g. interleukins), cell adhesion molecules and inducible form of NO synthase • ― block of vitamin D3-mediated induction of the osteocalcin gene in • osteoblasts and modification of transcription of the collagenase genes • ― icreased synthesis of annexin-1 - an important factor in negative feedbackon the hypothalamus and anterior pituitary and may have anti- • inflammatory actions. • Some non-genomic (rapid) effects of glucocorticoidswere observed.

  36. Pharmacokinetics and unwanted actions of the glucocorticoids • Administration can be oral, topical and parenteral. The drugs are bound to corticosteroid-binding globulin in the blood and enter cells by diffusion. They are metabolised in the liver. • Unwanted effects are seen mainly with prolonged systemic use as anti-inflammatory or immunosuppressive agents (in which case all the metabolic actions are unwanted), but not usually with replacement therapy. • The most important are: ― suppression of response to infection • ― suppression of endogenous glucocorticoid synthesis • ― metabolic actions • ― osteoporosis • ― iatrogenic Cushing's syndrome

  37. Inhibitors of adrenocorticoid biosynthesis Several substances - useful inhibitors of the synthesis of adrenal steroids: metyrapone, aminoglutethimide, ketoconazole, trilostane, spironolactone, and eplerenone. Mifepristone competes with glucocorticoids for the receptor.

  38. 1. Metyrapone: [me TEER ah pone] - used for tests of adrenal function and can be used for the treatment of pregnant women with Gushing syndrome. It interferes with corticosteroid synthesis by blocking the final step (11-hydroxylation) in glucocorticoid synthesis, leading to an increase in 11-deoxycortisol as well as adrenal androgens and the potent mineralocorticoid 11-deoxycorticosterone. The adverse effects include salt and water retention, hirsutism, transient dizziness, and gastrointestinal disturbances. 2. Aminoglutethimide:- inhibits the conversion of cholesterol to pregnenolone --- the synthesis of all hormonally active steroids is reduced. It has been used therapeutically in the treatment of breast cancer to reduce or eliminate androgen and estrogen production. [Note: Tamoxifen has largely replacedaminoglutethimide]. In these cases, it is used in conjunction with dexamethasone. However, it increases the clearance of dexamethasone. Aminoglutethimidemay also be useful in malignancies of the adrenal cortex to reduce the secretion of steroids. Recent studies indicate it is an aromatase inhibitor.

  39. 3. Ketoconazole: [kee toe KON ah zole] is an antifungal agent that strongly inhibits all gonadal and adrenal steroid hormone synthesis. It is used in the treatment of patients with Gushing syndrome. 4. Trilostane: [TRYE loe stane] reversibly inhibits 3-hydroxysteroid dehydrogenase and, thus, affects aldosterone, cortisol, and gonadal hormone synthesis. Its side effects are gastrointestinal. 5. Mifepristone: At high doses - a potent glucocorticoid antagonist as well as an antiprogestin. It forms a complex with the glucocorticoid receptor, but the rapid dissociation of the drug from the receptor leads to a faulty translocation into the nucleus. Its use is presently limited to treatment of inoperable patients with ectopic ACTH syndrome. Further substance: MITOTANE - derivative of DDT, decreases synthesis mainly by a cytotoxic action »»» used only in inoperable tumours of the adrenal cortex.

  40. MINERALOCORTICOIDS Water and electrolyte homeostasis: Help control the body´s water volume and concentration of electrolytes, especially sodium and potassium. ALDOSTERONE, causing a reabsorption of Na, bicarbonate, and water. Decreases reabsorption of K, which is then lost in urine. Note:Elevated aldosterone levels may cause alkalosis and hypokalemia, whereas retention of sodium and water leads to an increase in blood volume and blood pressure.

  41. Mineralocorticoids Fludrocortisone - given orally to produce a mineralocorticoid effect. It: ― increases Na+ reabsorption in distal tubules and increases K+ and H+ efflux into the tubules ― acts, like most steroids, on intracellular receptors that modulate DNA transcription causing synthesis of protein mediators ― is used with a glucocorticoid in replacement therapy.

  42. Inhibitors of biosynthesis 1. Spironolactone: This antihypertensive drug competes for the mineralocorticoid receptor  inhibits Na reabsorption in the kidney. It can also antagonize aldosterone and testosterone synthesis. It is effective against hyperaldosteronism. Spironolactone is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. Adverse effects: hyperkalemia, gynecomastia, menstrual irregularities, and skin rashes. 2. Eplerenone: [e PLEA en one] - binds to the mineralocorticoid receptor – i.e.,aldosterone antagonist. This specificity avoids the unwanted side effects of spironolactone. It is approved as an antihypertensive.

  43. THYROID HORMONES They facilitate normal growth and maturation - by maintaining a level of metabolism in the tissues. Two major hormones - triiodothyronine (T3; the most active form), and thyroxine (T4). Inadequate secretion of the hormone (hypothyroidism) - bradycardia, poor resistance to cold, and mental and physical slowing (in children, this can cause mental retardation and dwarfism). Hyperthyroidism – tachycardia, cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production can occur. [Thyroid gland also secretes calcitonin-a serum Ca-lowering hormone.]

  44. Thyroid hormone synthesis and secretion: TSH action - mediated by cAMP  stimulation of iodide (I2) uptake. Oxidation to iodine (I-) by a peroxidase - followed by iodination of tyrosines on thyroglobulin. [Antibodies to thyroid peroxide = diagnostic for Hashimoto thyroiditis.] Condensation of 2 iodotyrosine T4 or T3, bound to the protein released following proteolytic cleavage of the thyroglobulin. A. Synthesis: - uptake of plasma iodide by the follicle cells - iodination of tyrosine (MIT and DIT) - two molecules are coupled »»» T3 and T4 - binding to globulin »»» colloid (thyroglobulin), the storage form of thyroid hormone. - release of active hormones (after proteolysis of thyroglobulin) into blood

  45. Biosynthesis of thyroid hormones (according to Lippincott´s Pharmacology, 2006 PLASMA THYROID CELL COLLOID OH CH2 OH Tyrosine residues Synthesis of thyroglobulin 2 Propylthiouracil Methimazole CH2 Amino acids Thyroglobulin Elevated iodide Uptake of iodide ion 1 H2O2 Peroxidase I2 I- I- 3 Iodination I OH OH CH2 HO I I I I OH I O O I I I I I 4 Condensation I CH2 CH2 CH2 CH2 HO Proteolytic release of hormones 5 C H H NH3+ C NH3+ I O COO- COO- I I Propylthiouracil Methimazole Triidothyronine Thyroxine (T3) (T4) CH2

  46. Regulation of secretion: Secretion of TSH by the anterior pituitary is stimulated by the hypothalamic TRH. Feedback inhibition of TRH occurs with high levels of circulating thyroid hormone. [Note: At pharmacologic doses, dopamine, somatostatin, or glucocorticoids can also suppress TSH secretion.] Most of T3and T4 is bound to thyroxine-binding globulin in the plasma. B. Mechanism of action T4 and T3 must dissociate from thyroxine-binding plasma proteins prior to entry into cells (by diffusion or by active transport). In the cell, T4 is enzymatically deiodinated to T3, which enters the nucleus and attaches to specific receptors activation of thereceptors promotes the formation of RNA and subsequent protein synthesis, which is responsible for the effects of T4.

  47. Actions of thyroid hormonesinteraction intracellulary with receptor causing DNA-directed mRNA and protein synthesis/1/ affecting metabolism ( in basal metabolism rate, heat production, increase in oxygen consumption, callorigenic action, modulation of action of other hormones - e.g. catecholamines, increase in cardiac rate ...)/2/ affecting growth and development (particularly necessary for normal growth and maturation of CNS, skeletal development ...)

  48. C. Pharmacokinetics T4 and T3- absorbed after oral administration. Food, Ca preparations, and Al-containing antacids  absorption of T4 but not T3. T4 is converted to T3 by one of two distinct deiodinases, depending on the tissue. The hormones are metabolized through the microsomal P450 system. Drugs that induce the P450 enzymes (phenytoin, rifampin, phenobarbital)accelerate metabolism of hormones.

  49. Enzyme induction can increase the metabolism of the thyroid hormones T3 = triiodothyronine; T4 = thyroxine T3 T4 P-450 Phenytoin Rifampin Phenobarbital P-450 Enzyme induction P-450 Metabolites (according to Lippincott´s Pharmacology, 2006

  50. D. Treatment of hypothyroidism Usually results from autoimmune destruction of the gland or the peroidase and is diagnosed by elevated TSH. It is treated with LEVOTHYROXINE (T4) [leh vo thye ROK sin] or TRIIODOTHYRONINE(LIOTHYRONINE)The drug is given once daily because of its long half-life. Steady state is achieved in 6-8 weeks. adverse effects: - related to T4 levels - signs of hyperthyroidism (risk of precipitating AP, dysrhythmias, cardiac failure, nervousness, heart palpitations and tachycardia, intolerance to heat, unexplained weight loss).

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