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Androgens - drdhriti

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A power point presentation on “Adrogens and anti androgenic drugs” suitable for undergraduate level MBBS students

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Androgens - drdhriti

  1. 1. Androgens, Anabolic Steroids and Antiandrogens Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. Introduction • Normally, testes are responsible for male characters • Testes Functions: 1. Production of Androgenic hormones 2. Spermatogenesis occurring within the seminiferous tubules • Androgens are the substances which cause development of secondary sex characters in the castrated male
  3. 3. Classification - Androgens • Natural Androgens: – From Testes: • Testosterone (5-12 mg daily) • Dihydrotestosterone (more active) by 5 α-reductase – From Adrenal cortex: (weak androgens) • Dehydroepiandrosterone • Androstenedione {Females testosterone: 0.25 – 0.5 mg/day (ovary + adrenals)} • Androsterone – metabolite of testosterone • Synthetic androgens: Submaximal andrgenic and Cholestatic jaundice – Methyltestosterone, Fluoxymesterone – 17-alkyl substituted derivatives – Orally effective: Testosterone undecanoate and Mesterolone – Lipid soluble esters: Propionate and enanthate salts
  4. 4. Testosterone • Produced from cholesterol primarily by Leydig cells in testes • Secreted at adult levels during 1st trimester1, during neonatal life2, continually after puberty3 • Converted by 5 α-reductase to the more potent, 5α-dihydrotestosterone (DHT), which is responsible for many of the responses to testosterone in the urogenital tract (e.g. prostate gland hyperplasia) • Binds to and activates a single androgen receptor (AR) • Androgen receptors are present in many tissues including reproductive tissue, skeletal muscle, brain, kidney etc. 1 2 3
  5. 5. Testosterone 17-alkyl substitution Methyltestosterone Fluoxymesterone • All androgens contain a Testosterone structures • Testosterone has 19-carbons and in general its a steroidal structure
  6. 6. Cholesterol Pregnenolone Progesterone Corticosterone 11-Desoxy- corticosterone 18-Hydroxy- corticosterone ALDOSTERONE 17-α- Hydroxy pregnenolone 11- Desoxy- cortisol 17- Hydroxy progesterone 21,β hydroxylase CORTISOL 11,β hydroxylase Dehydro-epi androsterone Andro- stenedione Oestrone Oestriol TESTOSTERONE OESTRADIOL ACTH
  7. 7. Regulation of Secretion • Testosterone secretion - Leydig`s cell of testes • Pulsatile LH – Pituitary • FSH – only Spermatogenesis • High testosterone – inhibits LH (atrophy) • Oestrogen – feedback inhibition • Inhibin – FSH inhibition • Plasma level of Testosterone: 0.3 to 1 mcg/dl (male) 20 to 60 ng/dl (female)
  8. 8. Pharmacological Actions - Testosterone Androgenic Effects: • In the foetus, testosterone promotes development of male reproductive tract – internal genitalia, vas deferens, epididymis and external genitalia (sex differentiation) • During puberty, testosterone promotes development of : – primary sexual characteristics (e.g. enlargement of penis, scrotum and testes) – secondary sexual characteristics (e.g. male body shape, axillary/pubic hair, deeper pitch of voice, thickening of skin – greasy, loss of subcutaneous fat) – Adulthood: Baldness, BHP, Prostatic cancer Testes: Promotion of spermatogenesis and maturation of sperm • Moderately high dose causes testicular atrophy by inhibiting Gn secretion • Higher doses: direct sustaining effect and less marked atrophy
  9. 9. Testosterone – anabolic effects • Pubertal spurt of growth at puberty – both boy and girl • Bone growth – thickness and length • Oestrogen from testosterone – fuse of bones and mineralization • Muscle building – if aided by exercise • Positive nitrogen, minerals and water balance – increase in weight • Increase in appetite • Acceleration of erythropoiesis
  10. 10. Androgens – Targets of Action
  11. 11. Mechanism of Action Androgen receptor: • Both, testosterone and DH testosterone – act via Androgen receptors (AR) – nuclear receptor super family • Ligand binding and DNA binding domains • Mutations in AR: Incomplete sexual development – Kennedy`s disease: in spinal and bulbar muscle atrophy Estrogen Receptor: • Teststerone converts to estrogen by CYP19 • Deficiency of CYP19 and estrogen receptor – failure to fuse long bones, osteoporosis etc.
  12. 12. T DHT DHT- R T- R R R T- R Nucleus 90% 10% 5- α reductase cytoplasm
  13. 13. Androgen - Pharmacokinetics • Absorption: undergoes high first pass metabolism. Therefore IM injections or synthetic preparations are used • Transport: highly protein bound in plasma to albumin & sex hormone binding globulin (SHBG) (98%, SHBG, albumin) • Metabolism: – by liver enzymes : androsterone & etiocholanolone – excretion by urine after conjugation – small quantity of oestrogen also produced from testosterone, but not from fluoxymesterone and Dihydrotestosterone
  14. 14. Therapeutic Uses of Androgens • Androgen replacement therapy (ART) • ART uses derivatives of testosterone, rather than synthetic Androgens, because they are safe, effective and easy to monitor 1. Androgen deficiency: clinical diagnosis confirmed by hormone assays – is usually caused by • underlying testicular disorders (high LH, but low testosterone levels) • hypothalamic-pituitary disorders (low LH and low testosterone levels) • Goal: Mimic the normal testosterone concentration as closely as possible (serum concentration monitoring) • If untreated, does not shorten life expectancy, but is associated with significant morbidity (ambiguous genitalia, delayed puberty & infertility) • Treated by androgen replacement therapy (ART), usually for the remainder of life. The aim is to restore tissue androgen exposure by using the natural androgen testosterone
  15. 15. Uses – contd. 2. Hypopituitarism – Monitoring at anticipated time of puberty 2. AIDS related muscle wasting 3. Hereditary angioneurotic edema (methyltestosterone) 4. Ageing Misuse: involves prescription with no acceptable medical indication • Examples of misuse include: – male infertility – male sexual dysfunction or impotence – “male menopause” (andropause) no convincing evidence that androgen therapy is either effective treatment or safe for older men unless there is frank androgen deficiency
  16. 16. Androgens – Adverse Effects • Virilization: – may occur in women receiving relatively high doses for prolonged periods, such as for estrogen-dependent mammary carcinoma • Cholestatic Jaundice – may be produced by steroids possessing a 17-alkyl substituted group • Priapism (sustained erection) • Oligospermia • Oedema--via promotion of salt and water retention • Precocious puberty and short stature • Acne • Hepatic carcinoma````` • Gynaecomastia
  17. 17. Anabolic Steroids • Synthetic androgens – higher anabolic but lower androgenic activity (1: 3 ratio) – decreased virilizing effect • Similar anabolic effect, same receptors and same androgenic effects • Examples: – Nandrolone propionate 10-25 mg/ml (10 – 50 mg IM/week) – inj. Durabolin – Nandrolone decanoate 25-100 mg/ml (25- 100mg/week) – inj. Decadurabolin – Stanazolol (2 mg tablets (2-6 mg/day)
  18. 18. Anabolic Steroids – Therapeutic uses 1. Catabolic states: Acute illness, severe trauma, major surgery 2. Renal insufficiency 3. Osteoporosis 4. Suboptimal growth in boys 5. Anaemia: haemolytic and malignancy associated 6. Performance enhancement
  19. 19. Anti-androgens • Danazol • Cyproterone acetate • Flutamide • Finasteride, Bicalutamide
  20. 20. Danazol • Ethisterone derivative effective orally • Weak androgenic, anabolic, progestational & glucocorticoid action • Also Labeled as impeded/attenuated androgen: – Induces some androgen specific mRNA production • Prominent effect – – suppression of Gn (FSH and LH) secretion from Pituitary - FSH & LH release in both sexes decrease – inhibition of testicular/ovarian function directly – Directly by inhibition of steroidogenic enzymes – Results in endometrial atrophy and ammenorrhoea • Half life – 12-18Hrs • Preparations: – 50. 100 and 200 mg. tablets – Dose is 200 – 600 mg/day
  21. 21. Danazol – contd. • Uses: – Endometriosis : 3-6 months course – Menorrhagia – Fibrocystic breast disease – Hereditary angioneurotic oedema – Gynecomastia – Infertility • Side effects: Dose related • Amenorrhea (High doses) • Androgenic effects - Decreased breast size, hirsutism, weight gain etc. • Hot flashes, night sweating, cramps • Loss of libido in men
  22. 22. Cyproterone acetate • Direct antiantiandrogenic action • Progesterone like activity – inhibits LH causing antiandrogenic action • Competes with dihydroteststerone for intracellular receptor Uses: • Precocious puberty in Boys • Inappropriate sexual behaviour in men • Virilization in women • Limited use
  23. 23. Flutamide • Non-steroidal and no hormonal activity but specific antiandrogenic action • Active metabolite “2-hydroxyflutamide” causes competitive block Androgen action – Accessory sex organs and Pituitary • Increased LH secretion by blocking feedback inhibition • Plasma testosterone level may increase – to overcome direct antiandrogenic effect • Uses: – Cancer of prostate along with GnRH agonist – Female hirusitism • ADRs: Gynaecomastia and breast tenderness and also liver damage • Dose: 250 mg tds.
  24. 24. Finasteride • MOA: Competitive inhibitor of 5 α-reductase – Selective of 5 α-reductase type-2 isoenzyme – Mainly acts on urogenital tract (prostate) – DHT level lowered but not plasma Testosterone level • Uses: 1. Benign prostatic hypertrophy – decrease in prostate volume, improved urinary flow, reversion of disease progression – Withdrawal results in regrowth – prolonged therapy 1. Male pattern baldness – Kinetics: effective orally, metabolized in liver (t1/2 – 4-6 hrs) – Side effects: loss of libido, impotence, decreased ejaculation – Doses: 5 mg OD (BHP) or 1 mg OD in baldness
  25. 25. Erectile Dysfunction Drugs PDE-5 Inhibitors: Sidenafil, tadalafil – Nitric oxide (NO) pathway
  26. 26. Sidenafil • Absorbed orally and half-life is 4 Hrs • Inhibits PDE5 in the corpus cavernosa of the penis • 50 mg 1 h before sexual activity • Potentiate nitrate’s hypotension activity • Ketoconazole, erythromycin, Verapamil increases its level – due to CYP3A4 inhibition • renal & hepatic disease increases its level • Side effects: – headache, flushing, dyspepsia, myalgia, loose motion – Colour vision impairement (PDE6) – NAION – Fall in BP and precipitation of MI – Patient with Nitrates for angina • Other Uses: Pulmonary hypertension
  27. 27. Summary 1. Testosterone – Pharmacological action, MOA, Pharmacokinetics, Uses and its preparations 2. Anabolic steroids and uses 3. Antiandrogens – details of Danazol and Flutamide 4. PDE – 5 inhibitors, MOA and Adverse effects
  28. 28. Thank you

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