Clucocorticoids

Some characrteristics of synhetic glukocorticoids

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.

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

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,

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

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

Estrogenes and androgenes

ESTROGENS

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

Pharmacokinetic 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 Actions  Growth and development - development and maturation of external genitalia, growth of breast, myometrium - development and maturation of external genitalia, growth of breast, myometrium  Menstrual cycle  Systemic metabolizm - promote positive nitrogen balance, increase triglycerides, tend decrease cholesterol - 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 - decrease bone resorption  Influence libido and  Influence libido and

Therapeutic uses 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. 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. 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. Like contraceptives, hormone therapy is available as oral tablets, transdermal patches, and vaginal rings and tablets.

Oral contraception 1. Combination Estrogen–Progestin Contraception Oral contraception 1. Combination Estrogen–Progestin Contraception

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

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

1. Progestin-Only Contraception The two progestin-only oral contraceptives available, commonly referred to as the “mini-pill,” are norgestrel and norethindrone. 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 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. 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)

Androgens Androgens

Naturaly androgens Testosterone- is synthesised in the Leydig cellsunder the influence of LH Testosterone- is synthesised in the Leydig cellsunder the influence of LH Synhetic androgens Methyltestosterone Methyltestosterone Fluoxymesterone Fluoxymesterone Stanozolol Stanozolol Nandrolone-with highes anabolic action Nandrolone-with highes anabolic actionActions  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

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

Progestins Progestins

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

Progestins Progestins

Therapeutic uses 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 Anti-progestins Mefepristone-for use to induce medical abortion in the first trimester Mefepristone-for use to induce medical abortion in the first trimester