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BIMM118 Steroid-based Drugs Adrenocortical Hormones.

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Presentation on theme: "BIMM118 Steroid-based Drugs Adrenocortical Hormones."— Presentation transcript:

1 BIMM118 Steroid-based Drugs Adrenocortical Hormones

2 BIMM118 Adrenocortical Hormones Adrenal gland: Medulla: –produces Epinephrine (stimulated by sympathetic impulse) Cortex: –Zona glomerulosa – produces Aldosterone (stimulated by Angiotensin II and ACTH) –Zona fasciculata – produces Glucocorticoids (stimulated by ACTH = Corticotropin) –Zona reticularis – produces Androgens (physiological role unclear)

3 BIMM118 Adrenocortical Hormones Steroid hormone synthesis: Pregnenolone synthesis is rate-limiting step C21 hydroxylase: –Prevents hydroxylation of C17 (-> c) => Only mineralocorticoids C17 hydroxylase: –Hydroxylation of C17 (-> f, g) can be followed by hydroxylation of C11 and C21 (-> h, j, k) => Sex hormones and glucocorticoids P450 C17  hydroxylase: –Produces 17-Keto-steroids (-> l) => Sex hormones

4 BIMM118 Adrenocortical Hormones Steroid hormone classification: Progesterone: –C21 –C 3: =O –C17: -OH or =O Mineralocorticoids: –C21 –C21: -OH –C3: =O Glucocorticoids : –C21 –C21, C17: -OH –C 3: =O –C11: -OH or =O Estrogens : –C18 –C17: -OH or =O –C 3: -OH Androgens : –C19 –C17: -OH –C 3: =O

5 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Inhibit all phases of inflammatory reaction Promote fetal development (lungs) Inhibit NF  B nuclear translocation => transcription of proinflammatory mediators is prevented Upregulate lipocortin => inhibits PLA 2 => no PG and LT synthesis Undesirable effects of increased GC: –Immune suppression –Increased glucose release (=> “steroid diabetes”) –Glucose coverted to fat => adiposity –Increased protein catabolism => muscle atrophy –Salt and water retention (increased GC lead to reduction in ACTH => decreases levels of aldosterone) => hypertension –Osteoporosis

6 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Adrenal cortex failure (= Addison’s disease) Lack of GC production: –Chronic fatigue and muscle weakness. –Loss of appetite, inability to digest food, and weight loss. –Low blood pressure (hypotension) –Blotchy, dark tanning and freckling of the skin (feedback missing => increased corticotropin) –Blood sugar abnormalities –Inability to cope with stress Adrenal cortex tumors (= Cushing Syndrome) GC overproduction –Upper body obesity –“Buffalo hump” –Red, round face –Hypertension –Water retention –Thin skin and bruising –Poor wound healing

7 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Clinical uses: Allergic Rhinitis Rheumatoid Arthritis Asthma Multiple Sclerosis Carpal Tunnel Syndrome Dermatitis COPD Osteoarthritis Gout Psoriasis Inflammatory Bowel Disease Sinusitis Lupus Erythematosus Many conditions flare up if GC therapy is discontinued due to adreno-corticol atrophy

8 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Hydrocortison (= Cortisol) –Main glucocortocoid in humans –Also binds mineralocorticoid receptor (Cortison does NOT) –Used for replacement therapy (Addison’s Disease) –Otherwise mostly topical application due to sodium-retaining effects

9 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Prednisone –Inactive until converted to Prednisolone –Drug of choice for systemic application –Lower sodium-retaining effects Prednisolone Prednisone

10 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Triamcinoline –Stronger anti-inflammatory (5x) than cortisol –No sodium-retaining effect Halogenated GC Betamethasone Dexamethasone –30x more potent than cortisol –No water and sodium retaining effects

11 BIMM118 Adrenocortical Hormones Glucocorticoids (GC): Administration –Oral –Nasal –Cutaneous –IV –Inhalation

12 BIMM118 Steroid-based Drugs Sex Steroids

13 BIMM118 Sex Steroids Female reproductive cycle –Gonadotropin Releasing Hormone (GnRH) = Gonadoliberin stimulates release of –Follicle stimulating hormone (FSH) = Follitropin and –Luteinising Hormone (LH) = Lutropin which trigger production of –Estrogens (E) and Gestagens (G) which in turn negatively regulate –Pituitary (E+G) and Hypothalamus (G) hormone production

14 BIMM118 Sex Steroids Female reproductive cycle –Cycle length varies from days Menstruation 3-6 days –First (= Proliferative) phase: Variable (7-21 days) FSH and LH promote follicle development One follicle becomes the Graafian follicle (the rest degenerate) Graaffian Follicle: –Consists of thecal and granulosa cells which surround the ovum FSH-stimulated granulosa cells produce estrogens from androgen precursors generated by LH-stimulated thecal cells Estrogens are responsible for the proliferative phase: increase in thickness and vascularity of endometrium; secretion of protein+ carbo-rich mucus Constant low estrogen inhibits LH/FSH production BUT high estrogen cause surge of LH production => swelling and rupture of Graafian follicle = Ovulation

15 BIMM118 Sex Steroids Female reproductive cycle –Second (= Secretory) phase: Secretory phase constant (~ 14 days) LH-stimulated ruptured follicle develops into Corpus luteum which secrets Progesterone Progesterone (Pg) is responsible for the secretory phase: endometrium becomes suitable for implantation; mucus thickens Thermogenic effects of Pg => body temperature increase 0.5º C Without implantation: Pg secretion stops => menstruation is triggered With implantation: continued Pg production which (via inhibition of LH and FSH prod.) blocks further ovulation Chorion (“precursor” of placenta) secretes human chorionic gonadotropin (HCG) which maintains endometrium lining throughout pregnancy (HCG -> see pregnancy test)

16 BIMM118 Sex Steroids Female reproductive cycle

17 BIMM118 Sex Steroids Estrogens All produced from androgen precursors Three main endogenous estrogens: Estradiol –Primary estrogen in humans –Breast development –Improving bone density –Growth of the uterus –Accelerating bone maturation and epiphyses closure –Development of the endometrium to support pregnancy –Promoting vaginal mucosal thickness and secretions –Increase HDL Estrone Estriol –only during pregnancy (made by fetus)

18 BIMM118 Sex Steroids Estrogens –Estrogens induce expression of progesterone receptors –Progesterone inhibits expression of estrogen receptors –Two types of estrogen receptors => potential for selective drugs Estradiol –Not suitable for oral administration (rapid hepatic elimination) => stable derivatives: Ethinylestradiol Diethyl-Stilbestrol –Stilbene derivative

19 BIMM118 Sex Steroids Estrogens Mestranol –Used in oral contraceptives –Inactive => Cleavage of C3-methoxy group yields ethinylestradiol Raloxifene –Selective estrogen receptor modifier (=SERM) –Antiestrogenic effects on breast and endometrium –Estrogenic effects on bone and lipid metabolism => use in postmenopausal osteoporosis Clinical uses of estrogens: –Replacement therapy (Turner syndrome; menopause) –Contraception –Cancer therapy

20 BIMM118 Sex Steroids Anti-Estrogens Tamoxifen –Antiestrogenic effects on mammary tissue –Weak estrogenic effects on bone and lipid metabolism Clomiphene –Inhibits estrogen binding in the pituitary => prevention of negative feedback=> ovulation Clinical uses of anti-estrogens: –Breast cancer therapy (Tamoxifen) –Infertility (Clomiphen)

21 BIMM118 Sex Steroids Progesterons Progesterone –Inhibits rhythmic contractions of the myometrium –Not suitable for oral administration (rapid hepatic elimination) => stable derivatives: Hydroxyprogesterone Medroxyprogesterone

22 BIMM118 Sex Steroids Progesterons Testosterone derivatives with progesterone activity: Norethindrone Norgestrel Desogestrel

23 BIMM118 Sex Steroids Anti-Progesterons Mifepristone (RU486) –developed during the early 1980s by the French company Roussel Uclaf –while investigating glucocorticoid receptor antagonists, they discovered compounds that blocked the similarly shaped progesterone receptor. Further refinement led to the production of RU 486 –Clinical testing of mifepristone as a means of inducing medical abortion began in France in Results from these trials showed that when used as a single agent, mifepristone induced a complete abortion in up to 80% of women up to 49 days’ gestation. –Addition of small doses of a prostaglandin analogue (=> see misoprostol) a few days later to stimulate uterine contractions, a complete medical abortion is achieved in nearly 100 percent of women –approved in the US in 2000 for the termination of early pregnancy (defined as 49 days or less)

24 BIMM118 Sex Steroids Male reproductive system –Gonadotropin Releasing Hormone (GnRH) = Gonadoliberin stimulates release of –Follicle stimulating hormone (FSH) (Stimulates Sertoli cells => promotes gametogenesis) and –Luteinising Hormone (LH) = Interstitial Cell Stimulating Hormone (ICSH) which triggers production of –Testosterone (T) (by Leydig cells) which in turn negatively regulates –Pituitary and Hypothalamus hormone production

25 BIMM118 Sex Steroids Androgens Testosterone –Primary androgen in humans –Possesses androgenic and anabolic effects: Androgenic effects: Growth and development of male sex organs Important for (male) sex drive and performance Development of secondary sexual characteristics Important role in spermatogenesis Anabolic effects: Development of muscle mass Reverse catabolic or tissue-depleting processes Dihydro-Testosterone –Active metabolite –Mediates most of testosterone actions

26 BIMM118 Sex Steroids Androgens Testosterone –Hepatic elimination after oral administration –Also short half-life after injection => ester derivatives: Proprionate, enanthate, cypionate… Fluoxymesterone –Hepatic elimination after oral administration R

27 BIMM118 Sex Steroids Anabolic Androgens Testosterone derivatives: anabolic effects dominant Nandrolone –Injection Stanozolol –oral administration

28 BIMM118 Sex Steroids Anabolic Androgens Dehydroepiandrosterone (DHEA) –Popular item in health food stores: DHEA was prescription only until recently when changes in federal law labeled it as a nutritional supplement (DHEA sales now equal that of melatonin) –Is actually a testosterone precursor –Supposedly by maintaining youthful DHEA levels one can improve mood, memory, energy and libido, while preserving lean body mass and counteracting the effects of stress hormones. –DHEA may have serious side effects: If it abnormally increases testosterone, then testosterone side effects may be expected, including acne, testicular atrophy and increased risk of prostate cancer. Women taking excessive doses of DHEA have reported acne and facial hair. –DHEA can also be converted into estrogen, so high levels of DHEA can lead to estrogen side effects as well, including gynaecomasty and increased risk of breast cancer. –DHEA is often marketed as an anabolic steroid: This is misleading since as an androgen precursor its metabolism will produce testosterone which has anabolic properties

29 BIMM118 Sex Steroids Anti-Androgens Flutamide –Non-steroidal receptor antagonist –Used in prostate cancer treatment Finasteride –Inhibits 5  -reductase => prevent conversion of testosterone into the more potent dihydrotestosterone (DHT) –Used to treat prostate gland enlargement and hair loss (bald man have higher average levels of DHT)

30 BIMM118 Sex Steroids GnRH analogs/modifiers Danazol –Inhibits GnRH release => no FSH/LH production => no steroid production –Used to treat endometriosis (growth of endometrial tissue outside of the uterus) Synthetic GnRH (Gonadorelin, Buserelin, Leuprorelin…) –Up to 200x more potent than GnRH –If given in pulses (s.c.) stimulate gonadotropin release => induce ovulation –If given continously they desensitize the GnRH receptors => gonadal suppression (“medical castration”) –Used in sex hormone-dependent conditions (prostate, breast cancer; endometriosis; uterine fibroids…) –Side effects: menopausal symptoms

31 BIMM118 Sex Steroids Oral Contraceptives History –1937: Investigators demonstrated that the female hormone progesterone could halt ovulation in rabbits –1949: Scientists at the University of Pennsylvania achieved the production of synthetic progestins –1953: Margaret Sanger, Katherine McCormick and Gregory Pincus team up to develop a reliable contraceptive –1950s: Large scale testing of “the pill” was successful –1960: FDA approves first oral contraceptive (Early pill formulations contained up to 150 micrograms (mcg) of estrogen!) –1982/84: Introduction of the bi- and tri-stage formulation –1988: FDA recognized several severe long-term side effects (high estrogen!) –Currently used by 16 mill. women in the US (40% of women between 18 and 24

32 BIMM118 Sex Steroids Oral Contraceptives Either combination estrogen/progesterone of progesterone alone Combination pills: –Highly effective –Estrogen component is mostly ethinylestradiol, sometimes mestranol –Progesterone component varies –21 day cycle with 7 day break (causes withdrawal bleeding) –Can be mono- or biphasic Mechanism: –Estrogen inhibits FSH secretion (neg. feedback loop!) => suppression of follicle development –Progesterone inhibits LH secretion (neg. feedback loop!) => inhibition of ovulation; also increases mucus viscosity –Both steroids alter endometrium => prevent implantation

33 BIMM118 Sex Steroids Oral Contraceptives Estrogen Progesterone

34 BIMM118 Sex Steroids Contraceptives “Mini Pill”: –Contains only a progesterone (Levonorgestrel, Ethynodiol…) –Used when estrogen in contraindicated (e.g. thrombosis) –Taken daily without interruption –Acts mainly by increasing viscosity of mucus (Mucolytica in cough medicine can cause failure) –Less reliable than combination pill Postcoital contraceptives (“Morning after pill”) –High dose of progesterone (Levonorgestrel) –Must be taken within 72 hrs –Nausea and vomiting are common side effects Depot and patch formulations –Injection of oily depot formulations every 3 month –Transdermal delivery systems

35 BIMM118 Sex Steroids Oral Contraceptives Side effects: –Thrombosis –Hypertension –Intermittent bleeding –Weight gain –Depression –Nausea –Loss of libido Drug interactions: –Steroids are metabolized by P450 enzymes –Minimal dose of steroid is used to prevent risk of thrombosis –Any increase in clearance by P450-inducing drugs can result in contraception failure –Frequent cause of OC failure is diarrhea (diminished time for absorption)

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