Clucocorticoids

1. Clucocorticoids

4. Some characrteristics of synhetic glukocorticoids

5. Effects of glucocorticoids 1. Physiologic effects  increase protein breakdown, leading to a negative nitrogen balance,  stimulation of gluconeogenesis  increase of blood glucosa level,  increase plasma fatty acids and ketone body formation,  increase of kalium excretion (increased protein catabolism),  increase of Na+ and water retention. 2. Anti-inflammatory effect  inhibition of antigen response,  inhibition of PLA2 decrease of prostanoids production,  inhibition of cytokine production (IL-1, IL-2, TNF-),  inhibition of vascular permeability.

7. 3. Immunologic effects  decrease of circulating lymphocytes, monocytes, eosinophils and basophils,  increase of circulating neutrophils,  chronic therapy results in ivolution of all lymphoid tissue. Other effects  inhibition of plasma ACTH and possible adrenal atrophy,  inhibition of fibroblast growth and collagen synhesis,  stimulation of acid and pepsin secretion,  altered CNS responses, influencing mood and sleep paterns, enhanced neuromuscular transmission

8. SIDE EFFECTS UF GC  iatrogenic Cushing´s disease  adrenal suppresion,  hyperglycemia,  osteoporosis, peptic ulcer, cataracte and increased intraocular pressure,  edema,  hypertension, increased susceptibility to infection and poor wound healing,  muscle weaknes and tissue loss,

9. Therapeutic uses of GC CVS:rheumatic carditis, myocarditis  Respiratory system:asthma, pulmonary fibrosis  Gut:exacerbation of inflammatory bowel disease  CNS:prevention of scarring and cerebral oedema produced by surgery, head injures and tumours, exacerbation of sclerosis multiplex  Renal:nephrotic syndrome  Musculoskeletal system: rheumatoid arthritis and other collagen-diseases  Eye:prevention of scarring following surgery and uveitis  Skin:eczema, severe inflammatory skin conditions  Endocrine: replacement therapy in Adison´s disease Immune system:anaphylactic shock, prevention of transplanted organ rejection  Blood:autoimmune anaemia and thrombocytopenia, leukeamia and Hodkin´s disease

10. Inhibitors of corticoid synthesis •  Metyrapone, Trilostane- predominantly inhibits terminal step in cortisol and aldosterone production. •  Ketoconazole, Aminoglutethimide- inhibitors of cytochrome P450. •  Mitotane - inhibits steroidogenesis at the ACTH regulated step.

12. Estrogenes and androgenes

13. ESTROGENS

14. Naturaly estrogens • Estradiole (most potent), testosterone is the precursor • Estrone and Estriole are produced in the liver from 17 -estradiol • Synthetic estrogens • Ethinylestradiol • Mestranol • Diethylstilbestrol (nonsteroidal) • Mechanism of action  Estrogens bind to specific intracelular receptors  Interacts with specific DNA sequences and alter the transcription rate of genes  These changes leads to the specific protein synthesis within a target cells

15. Pharmacokinetic Estradiol is extensively (98%) bound to sex steroid-binding globulin and to serum albumin  Estrogens are metabolized in the liver (by conjugation) • Metabolites are excreted in the urine (10% undergou enterohepatic circulation) • Actions  Growth and development - development and maturation of external genitalia, growth of breast, myometrium  Menstrual cycle  Systemic metabolizm - promote positive nitrogen balance, increase triglycerides, tend decrease cholesterol - decrease total serum proteins, increase level of transferin, and thyroid- binding globulins, plasminogen, fibrinogen and coagulation factors ( VII-X) - decrease bone resorption •  Influence libido and

17. Therapeutic uses - Hypogonadism - Menstrual abnormalities - Postmenopausal therapy • Oral contraception Hormone replacement therapy • The principal indication for such therapy is to suppress hot flashes and treat atrophy of the urogenital tissues, which may manifest as dry vagina. • For women with a uterus, estrogen therapy must be combined with progestin therapy to prevent the induction of endometrial cancer. • Like contraceptives, hormone therapy is available as oral tablets, transdermal patches, and vaginal rings and tablets.

24. Oral contraception 1. Combination Estrogen–Progestin Contraception

25. Side effects(combinedpills) Cardiovascular system  venous thromboembolic disease,  myocardial infarction,  hypertension.  Carcinoma  increased risk of cervical and breast carcinoma,  pill protects against endometrial and ovarian malignancy.  Liver  rarely, cholestatic jaundice, hepatic tumours.  Others  headache, menstrual irregularity in the first months of treatment

26. Contraindication  history of the thromboembolic disease,  breast, endometrial and liver carcinoma,  hyperlipidaemia. Use with caution  diabetes mellitus,  hypertension,  migraine.

27. 1. Progestin-Only Contraception • The two progestin-only oral contraceptives available, commonly referred to as the “mini-pill,” are norgestrel and norethindrone. • Medroxyprogesterone acetate 104 mg for Subcutaneous injection or 150 mg intramuscular injection- can be given every 3 months 2. Emergency (Morning-After) Contraception Oral levonorgestrel 0.75 mg, given as soon as possible after the exposure and repeated in 12 hours. 3. Male Contraception - the goal of male contraception would be to suppress endogenous production of sperm reversibly, generating a state of azoospermia (parenteral testosterone enanthate plus daily oral levonorgestrel)

28. Androgens

29. Naturaly androgens • Testosterone- is synthesised in the Leydig cellsunder the influence of LH Synhetic androgens • Methyltestosterone • Fluoxymesterone • Stanozolol • Nandrolone-with highes anabolic action Actions Stimulate the differentiation and development of wolffian structures: epiddymis, seminal vesicles, prostate and penis Stimulate the development and maintanance of male semale secundary sexual characteristics  Anabolic actions-growth at puberty, increase in muscle mass, positive nitrogen balance  Behavioral effects-aggressiveness and icreased libido

31. Uses -Prepubertal and postpubertal hypogonadism -Anemia-stimulate secretion of erythropoetine - Androgen-dependent breast cancers -Illicit use by athlets (increase the extent and rate of muscle formation) Adverse effects -Decreased testicular function, altered plasma lipids (increased LDL, decreased HDL) -Masculinization in women -Increase of plasma fibrinolytic activity (bleeding with concomitant anticoagulants) -Long-term use is assotiated with liver tumors -Are contraindicated in patients with carcinoma of prostate, or hepatic, renal and cardiovascular disease. Antiandrogens • Flutamide, Finasteride-in the treatment of prostatic carcinoma • Cyproterone-decrease sexual drive in men. • Are usefulin treating precocious puberty.

32. Progestins

33. Naturaly progestins • Progesterone-is synthesized by ovaries, testes and adrenals Synhetic progestins • Norethisterone • Medroxyprogesterone • Norgestrel Actions Mechanism of action: as for estrogens. Prior estrogen action is required for the synthesis of progesterone receptors Slow the mitotic activity of the estrogen stimulated uterus, cause the vascularization of the endometrium Induce a more glandular appearance and function Slightly decrease triglycerides and and HDL and increase LDL

34. Progestins

35. Therapeutic uses - Oral contraception (alone or in the combination) - Treatment of endometrial cancer - To delay menstruation (for surgical or postoperative reasons) • Combination with estrogenes – replacement therapy • Anti-progestins Mefepristone-for use to induce medical abortion in the first trimester