Class androgens
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1. The document discusses androgens and their role in male physiology and pharmacology. It describes hormones like testosterone and their effects on tissues like the testes, prostate, and muscles. 2. Various androgen therapies are mentioned for conditions like hypogonadism, breast cancer, and osteoporosis. Antiandrogen drugs are also summarized that block androgen receptors for prostate cancer. 3. Biosynthesis and metabolism of testosterone is outlined. Side effects of androgen therapies and indications for antiandrogens are provided. Erectile dysfunction treatments like sildenafil are also briefly described.
Class androgens
- 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC.
- 2. GnRH-gonadotropin release hormone LH-ICSH-Interstitial cell stimulating hormone FSH-inhibin- supresses FSH activin- stimulates FSH synthesis FSH in males-spermatogensis, sertoli cells LH in males-androgen and testosterone in leydig cells SERTOLI cells-gonadal peptides- Inhibin- b and activin FSH germ cell proliferation and maturation in semniferous tubules
- 3. Naturally occurring androgenic hormones are: 1. Testosterone, the principal androgenic hormone produced by the Leydig cells of testis. 2. Dehydroepiandrosterone (DHEA) (Adrenal cortex produces DHEA) 3. Androstenedione The testis produce other hormones like 1) Small quantities of Estradiol 2) Inhibin and 3) Activin
- 4. Testosterone preparations: Use for androgen replacement: - Testosterone I.M; S.C - Testosterone propionate I.M, S.L - Testosterone cypionate I.M; depo I.M - Methyltestosterone O; S.L - Fluoxymestrone O Use for breast cancer: Testolactone (progesterone derivative and aromatase inhibitor)
- 5. Use for anabolism (osteoporosis): Androgen:anabolic ratio=1:2 or 1:3 (promote + ve anabolism and muscular growth but little effect on sex) - Ethylestrenol O - Stanozolol O - Oxandrolone O - Nandrolone decanoate I.M - Methandienone O
- 6. - Estrogens: Diethylstilbesterol; mestranol... - Progestins: Cyproterone acetate - GnRH superagonists (Leuprolide acetate); GnRH antagonists (Ganirelix) - Flutamide; Bicalutamide and Nilutamide - 5α- reductase inhibitors: Finasteride - Ketoconazole - Spironolactone - Gossypol
- 7. Androgenic Steroids CH3 OH O CH3 CH3 O CH3 O CH3 OH O CH3 H Androstendione (Andro) 5a-Dihydro-testosterone Testosterone Structure and Nomenclature (17b-hydroxy-androst-4-en-3-one) 3D-structure (androst-4-en-3,17-dione) (17b-hydroxy-5b-androstan-3-one) 3D-structure
- 8. Androgens Antagonists NH CF3 S F CN O O O CH3OH NH CF3 O CH3 NO2 CH3 O CH3 CH3 OH CH N CH3 CH3 N H O O N H CH3 CH3 CH3 H Danazol (endometriosis) Finesteride (baldness) Bicalutamide (prostate cancer) Flutamide (prostate cancer)
- 9. Biosynthesis and Metabolism of Testosterone CH3 CH3 OH CH3 CH3 CH3 O OH CH3 CH3 OH O CH3 O CH3 O CH3 OH O CH3 H CH3 CH3 H OH OH Cholesterol Pregnenolone Testosterone Androstendione5a-DHTOther metabolites
- 10. 1. 3. 2. hormonal families of the anterior lobe:
- 11. Androgenic Steroids – Physiological Activities Androgenic Activity Growth and development of male sex organs • Important for male sex drive and performance • Development of secondary sexual characteristics • Important role in spermatogenesis Anabolic Activity • Development of muscle mass • Reverse catabolic or tissue-depleting processes
- 12. Transport & MOA of androgens: SHBG 5α-reductase Testosterone 5α-dihydrotestosterone (sex organs) (skeletal muscles) cytosolic; nuclear receptors increase transcription of a specific protein androgen effects DHT is 10 times more potent than testosterone and mediates effects of testosterone on skin and sexual organs (prostate; seminal vesicle, epididymis…)
- 13. - Virilizing=masculinizing effect 1° & 2° sexual characteristics - ↑ Spermatogenesis - ↑ Erythropoiesis - Anabolic or growth promoting effect (bone; skeletal muscles) Pharmacokinetics-Testosterone metabolism: Androsterone Hepatic → 17-ketosteroids Etiocholanolone
- 14. O CH3 CH3 O O H HH Testolactone - Teslac® TESTOLACTONE Indications: palliative therapy in advanced disseminated breast cancer MOA: irreversible inhibitor of the enzyme steroid aromatase that is responsible for the synthesis of estrone from androstenedione Hepatic metabolism Most commonly used androgen for breast cancer. Few or no androgenic side effects - hirsutism Adrenal estrogen depletion – post menopausal women Contraindicated in male breast cancer
- 15. Mild androgenic, anabolic and progestational activity Treatment of endometriosis, fibrocystic disease of breast and premenstrual tension syndrome Used to prevent the attacks of hereditary angioneurotic oedema recurrent oedema of skin and larynx these patients lack endogenous inhibitor of activated first component of complement danazol increases serum conc of C1 Danazol withdrawl after 3-4 monthsrebound fertility Used in hemophiliaproco-agulant factor VIII increased S/E-hot flushes, muscle cramps, teratogenic
- 16. 1. Replacement therapy in men: hypogonadism, impotency; ↓ libido; aging, infertility 2. Anemia: aplastic or other anemia, leukemia; lymphoma (largely replaced by recombinant erythropoietin) 3. Protein anabolic steroids-METHANDIENONE, NANDROLONE, OXYMETHOLONE, STANOZOLOL 4. Osteoporosis(either alone or in conjunction with estrogens. Replaced by bisphosphonates) 5. Angioneurotic edema-danazol 6. Endometriosis and fibrocystic disease of breast- Danazol
- 17. 1. Virilization (masculinization) 2. Hirsutism; acne; menstrual disorders 3. Precocious puberty & hirsutism in children 4. Salt & water retention 5. Jaundice; gall bladder stones (methyltestosterone) 6. Enlargement of prostate 7. Liver cancer
- 19. ANTIANDROGENS
- 20. OSTARINE- Customized response-selective anabolic effect on bones and muscles except androgenic effect on prostate and testis(10:1) -females-increase bone mas and libido without causing virilization, devoid of hepatotoxicity HERSHBERGER ASSAY-for determining the androgen and anabolic ratio(ventral prostate and levator ani muscle of male rats)
- 21. - Carcinoma prostate - Benign hyperplasia of the prostate (Finasteride) - Severe acne and hirsutism (Spironolactone; Cyproterone acetate) - Precocious puberty - Antifertility agents ( contraceptive) (Gossypol) - baldness (Cyoctol=topical antiandrogen; Finasteride) - Female disorders: dysfunctional uterine bleeding, endometriosis advanced breast and ovarian cancers- GnRH agonists and antoagonists - Antiandrogens side effects: ↓ libido; impotency; ↓ spermatogenesis; ↓ ejaculate
- 22. CH3 N H NO2 CF3 O CH3 Flutamide - Eulexin® FLUTAMIDE Indications: metastatic carcinoma of the prostate MOA: non-steroidal anti-androgen inhibits cellular uptake of androgen steroids and inhibits nuclear binding of androgens to their receptors – adrenal hepatic metabolism with renal excretion, 96% protein bound Used with LHRH (GnRH) agonists DEMERITS-photosensitivity, Urine color changes
- 23. NILUTAMIDE-Indications: For use in treatment with surgical castration for metastatic carcinoma of the prostate MOA: non-steroidal anti-androgen that inhibits cellular uptake of testosterone and inhibits nuclear binding to its receptor - adrenal Hepatic metabolism of methyl group produces two enantiomers in which one is major active compound Inhibits a variety of CYP enzymes
- 24. N H CF3 O CH3 CN OH SO2 Bicalutamide - Casodex® F Indications: Advanced prostate cancer MOA: a non-steroidal competitive inhibitor of the cytosolic androgen receptors - adrenal Prostatic carcinoma is androgen sensitive Mixture of enantiomers - stereospecific metabolism occurs; R-enantiomer of the drug is predominate serum drug Drug must be taken in combination with luteinizing- hormone releasing hormone (LHRH)
- 25. pregnant women, infants and young children (somatotropin is more appropriate to produce a growth spurt). male patients with carcinoma of the prostate or breast. renal or cardiac disease predisposed to edema Caution: Several cases of hepatocellular carcinoma have been reported in patients with aplastic anemia treated with androgen anabolic therapy. Erythropoietin and colony-stimulating factors should be used instead.
- 26. Oral therapy- Phoshodiesterase-5 inhibitors-Sildenafil, Tadalafil, Vardenafil Intracavernosal injection therapy-Alprostidil Transcutaneous application therapy-Glycerlyl Trinitrate, Papaverine, Minoxidil, Alprostidil Triple therapy-Alprostidil + Papaverine + Phentolamine Herbal agents-Ginseng, Kava, Ginko biloba
- 27. NO activates guanylyl cyclase which forms cGMP from GTP produces smooth muscle relaxation leading to erection Sildenafil inhibits PD-5 enzyme increases cGMP levels Erectile dysfunction due to organic and psychogenic causes 25-50mg taken 1 hour prior to anticipated sexual activity and beneficial effects lasts for 4hrs after administration P/K-oral bioavailability-40% - Plasma protein binding-95%
- 28. Metabolite-N-desmethyl sildenafil is about 50% potent Elimination –biliary Adverse effects- headache, nasal congesiton, decrease in BP, disturbance in colour vision Drug interaction-concurrent organic nitrates (angina, MI, hypertension) CYP inhibitors such as ketoconazole, itraconazole, cimetidine and erythromycin increase plasma levels of drug Carbamazepine and rifampicin decrease levels of drug Contra-indication- Retinitis Pigmentosa
- 29. Physiology 0f penile erection
- 30. Most useful method for ED before sildenafil Needs repeated self injection into penis- painful Alprostadil-PGE1 analogue , can also be placed in urethra as mini- suppository S/E- low incidence of priapism and fibrosis Triple therapy ( Alprostidil + Papavarine + Phentolamine)- less side effects