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Hormonal pharmacotherapy

Hormonal pharmacotherapy. Ján Mojžiš. GLUCOCORTICOIDS AND MINERALOCORTICOIDS. Glu c o c orticoids. well absorbed in GIT ( i.v.; i.m.; locally ) 90% of hydrocortisone is bound to albumin and transcortin (specific corticosteroid binding globulin )

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Hormonal pharmacotherapy

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  1. Hormonal pharmacotherapy Ján Mojžiš

  2. GLUCOCORTICOIDS AND MINERALOCORTICOIDS

  3. Glucocorticoids • well absorbed in GIT (i.v.; i.m.; locally) • 90% of hydrocortisone is bound to albumin and transcortin(specificcorticosteroid binding globulin) • 70% of cortisole – metabolised in liver by microsomal enzymes to hydrocortisone • synthetic corticoids – the same fate • prednisone and methylprednisone (prodrugs) – prednisolone and methylprednisolone • excretion by the kidney as gluco- or sulfoconjugates

  4. Mechanism of action

  5. Glucocorticoids actions  glycogenolysis and gluconeogenesis  protein catabolism and  protein synthesis  lipolysis; redistribution of body fat  intestinal calcium absorption; decreased osteoblast formation and activity  secretion of gastric acid and pepsin CVS – restrict capillary permeability, maintain tone of arterioles and myocardial contractility

  6. Glucocorticoids actions – cont. • CNS – euphoria, insomnia, anxiety, motor activity; high dose –proepileptic effects • blood cells -  of eosinophils, basophils, monocytes, lymphocytes;  in circulating phagocytes -  ability of the body to fight infections • suppression of all types of hypersensitivity

  7. Glucocorticoids actions – cont. • inflammatory responses (basis of the most of their clinical uses); nonspecific action, covers all stages and components of inflammation such as: • increased capillary permeability • local exudation • cellular infiltration • phagocytic activity • collagen deposition • fibroblastic activity • scar formation

  8. Indications A: Replacement therapy 1. acute adrenal insufficieny 2. chronic adrenal insufficieny (Addison´s disease) - hydrocortisone is givent to correct the defficiency; 2/3 morning , 1/3 afternoon; failure of therapy - death

  9. Indications – cont. B: Pharmacotherapy of non-endocrinne diseases 1. Arthritis rheumatoid arthritis, osteoarthritis; rheumatic fever, gout (NSAID are trefered) 2. Collagen disease systemic lupus erythematosus, dermatomyositis, glomerulonephritis (therapy started with high dose) 3. Severe allergic reactions for short period in anaphylaxis, urticaria, angioedema

  10. Indications – cont. 4. Autoimmune diseases haemolytic anemia, trombocytopenia 5. Respiratory tract bronchial asthma, aspiration pneumonia, pulmonary edema 6. Eye large number of inflammatory ocular diseases topically allergic conjuctivitis, iritis, keratitis etc. should not be used in infective conditions 7. Skin topicaly – eczematous skin diseases systemicaly – pemfigus vulgaric, exfoliative dermatitis

  11. Indications – cont. 8. GIT ulcerative colitis, Crohn´s disease corticosteroid are indicated in acute exacerbation 9. CNS cerebral edema due to tumor, meningitis, cerebral/spinal injury 10. malignancies essential in acute lymphatic leukemia Hodgkin´s disease and other lymphomas 11. organ transplantation

  12. Side effects • suppression of immune system (rendering the patient vulnerable to common infections) • osteoporosis (rendering the patient vulnerable to fractures) • peptic ulcer • suppression of growth in children • reproductive problems • edema, hypertension

  13. Side effects– cont. • fragile skin • diabetes mellitus • muscular weakness • delayed healing of wounds and surgical incisions • psychiatric disturbancies • development of cushingoid habitus

  14. Cushing syndrome

  15. SEX HORMONES

  16. sex hormones are necessary for conception, embryonic maturation, and development of primary and secondary sexual characteristics at puberty

  17. Female sex hormones Estrogens • major estrogens - estradiol, estrone, and estriol • at puberty cause growth of breast, accumulation of fat, pubic and auxillary hair growth, femine body contours and behaviour are affected • estrogens are anabolic, maintain bone mass

  18. Actions of estrogens ovaries : stimulate follicular growth; small doses cause an increase in weight of ovary; large doses cause atrophy uterus: endometrial growth vagina: cornification of epithelial cells with thickening and stratification of epithelium cervix: increase of cervical mucous with a lowered viscosity (favoring sperm access)

  19. Actions of estrogens skin: increase in vascularization, development of soft, textured and smooth skin bone: increase osteoblastic activity electrolytes: retention of Na+, Cl- and water by the kidney cholesterol: hypocholesterolemic effect

  20. Receptor Actions in Cells (B. Katzenellenbogen et al. Recent Prog. Horm. Res.,2000)

  21. Therapeutic uses of estrogens a) for replacement therapy in deficient patients b) for contraception c) therapy of prostatic cancer and some brest cancer d) menstrual disorders e) suppression of lactation

  22. Postmenopausal hormone therapy • estrogen therapy is used in women experiencing „hot flashes“, „atrophic vaginitis“ and in women who wish to reduce risk of osteoporosis • the doses of estrogens are approximately 1/5 of doses used in oral contraception • less risk of adverse reactions

  23. FDA

  24. Primary hypogonadism • estrogen therapy (in combination with progestin) stimulates development of secondary sex characteristic in young women (11-13 years of age) with hypogonadism

  25. Estrogens: direct effects on the vascular wall

  26. Treatment of metastatic breast cancer • if estrogen receptors can be demonstrated in the neoplastic tissue - administration of large doses of estrogens may lead to arrest or regression of breast tumor growth

  27. Pharmacology • naturally occuring estrogens and their derivates - well absorbed from GIT, skin, mucous membranes, and also if given intramusculary • significant first-pass effect • synthetic estrogens (ethinyl estradiol, mestranole) -well absorbed, metabolized more slowly • inactive metabolits are eliminated in urine

  28. Adverse reactions • nausea and vomiting • breast tenderness, endometrial hyperplasia, postmenopausalbleeding • hyperpigmentation, hypertension, migraine headache • edema - sodium and water retention • decreased bile flow - cholestasis and gallbladder diesease

  29. Contraindications • estrogen-dependent neoplasia • thromboembolic disease • liver disease • coronary or cerebral arterial diesease

  30. Antiestrogens • modify or oppose the action of estrogens • tamoxifen, clomiphene • they have been used to treat infertility • tamoxifen is currently used in the treatment of breast cancer in postmenopausal women • side effect - ovarian enlargement

  31. Female sex hormones Progestins • most important progestin - progesterone • mechanism of action - similar to estrogen • therapeutic uses • major clinical use – contraception • other - control of uterine bleeding, endometrial carcinomas

  32. PROGESTERONE Natural hormone secreted by the corpus luteum and theplacenta it is also an important intermediate in steroid biogenesis in all tissues that produce steroids (testes, adrenal cortex) Intestinal absorption is quite erratic; must be micronized formost effective absoption

  33. Pharmacology • rapid absorption after administration by any route • short half-life - rapidly metabolized • synthetic progestins (medroxyprogesterone, norethindrone) are less rapidly metabolized

  34. Adverse reactions • weight gain • edema • depression • rare thrombophlebitis and pulmonary embolism

  35. Antiprogestin • mifepristone - progestin antagonist • in early pregnancy - abortus of the fetus • side effect - uterine bleeding

  36. Ligands for Progesterone Receptor

  37. Oral contraceptives– cont. Combinationpills • products containing estrogen + progestin - most common oral contraceptives • the pills are taken for 21 days followed by a 7-days withdrawal period to induce menses

  38. Oral contraceptives– cont. Progestin pills • only progestin is present (norethindrone, norgestrel) • less effective than combination pills • may produce irregular menstrual cycle Progestin implants • subdermal capsules (levonorgestrel) - long term contraception • six capsules are placed subcutaneously in upper arm - progestin is slowly released - contraceptive protection approximately 5 years

  39. Oral contraceptives– cont. Postcoital contraception • high doses of estrogen (diethylstilbestrole) is administered within 72 hours of coitus and continued twice daily for 5 days • should be reserved for unexpected or accidental exposure only (rape, condom rupture) – higher failure rate and side effects

  40. Adverse effects Major adverse effects • breast fullness, depression, dizziness, edema, headache, nausea, vomiting Cardiovascular • in women who smoke and over 35 years of age • thromboembolism, thrombophlebitis, hypertension, myocardial infarction, coronary thrombosis Metabolic • decreased dietary carbohydrate absorption • abnormal glucose tolerance test • progestin causes increase LDL and decrease HDL - estrogen has the opposite effect

  41. Male sex hormones • Androgens prototype is testosterone (produced by interstitial cells of testis) • main function: development and maintenance of primary and secondary sex characteristics in males (androgenic) • protein retention (anabolic action) • other naturally occuring androgens: androsterone, isoandrosterone, dehydroandrosterone, dehydroisoandrosterone

  42. Physiological effects of testosterone • enlargement of testes, penis and scrotum • pubic and axillary hair • bone growth • red cell mass increase • skeletal muscle mass increase • larynx enlarges - deepening of the voice • increase in sebaceous glands - often cause of acne • beard development

  43. Uses for androgens • replacement therapy in hypogonadism • delayed puberty • cryptorchidism • metastatic breast cancer in women • postpartum breast pain/engorgement • male climacteric

  44. Pharmacology • testosterone cannot be given orally - first-pass effect • inactive metabolits are excreted in urine • testosterone is administered intramuscularly • testosterone derivate (fluoxymesterone) has longer half-life • it may be given orally

  45. Adverse effects infemales • masculinization • growth of facial hair • deepening of the voice • acne • excessive muscle development • menstrual irregularity • contraindicated in pregnancy - virilization of female fetus

  46. Adverse effects –cont. in males • gynecomastia (conversion testosterone to estradiol in patints vith liver disease) • decreased spermatogenesis • painful erection at the beginig of the therapy in children • growth disturbances • abnormal sexual maturation

  47. Adverse effects –cont. • androgens increase serum LDL and lower HDL levels • they can cause fluid retention - edema • use of anabolic steroids by athletes - premature closing of the epiphysis of the long bone • hepatic abnormalities, jaundice • hepatic carcinoma – longterm therapy with methyltestosterone • increased agression

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