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Steroids. Overall Organization of the Lecture Series. Structure, Nomenclature, Conformation, Configuration Anti-Hyperlipidemic Agents Androgens Estrogens and Progestins Anti-inflammatory Steroids and Salt Retaining Agents. Anti-inflammatory Agent. Congested Heart Symptoms.

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Steroids


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    1. Steroids Overall Organization of the Lecture Series • Structure, Nomenclature, Conformation, Configuration • Anti-Hyperlipidemic Agents • Androgens • Estrogens and Progestins • Anti-inflammatory Steroids and Salt Retaining Agents MEDC 603 Steroids

    2. Anti-inflammatory Agent Congested Heart Symptoms Examples of Steroid-based Drugs in Use Today Male Sex Hormone Female Sex Hormone MEDC 603 Steroids

    3. Functional Classification of Steroids • Anabolic Steroids - Interact with androgen receptor; enhance muscle mass/athlete’s performance; male sex hormones • Glucocorticoids - regulate metabolism and immune function; anti-inflammatory activity • Mineralocorticoids - maintain blood volume and renal excretion • Progestins - Development of female sex organs and characteristics • Phytosteroids - Plant steroids • Ergosteroids - Steroids of the fungi; vitamin D related MEDC 603 Steroids

    4. CH3 CH3 21 D C 22 20 26 23 B A 25 24 27 Structures of Steroids Structure and Nomenclature of the Steroid Nucleus MEDC 603 Steroids

    5. Configurational Isomers of Steroids Fusion points between rings A B A B trans- configuration cis- configuration MEDC 603 Steroids

    6. D C A B Configurational Isomers of Steroids Fusion points between rings 3 fusion points  23 isomers = 8 MEDC 603 Steroids

    7. Configurational Isomers of Steroids Three dimensional structure of three most common isomers trans-trans-trans cis-trans-trans cis-trans-trans trans-trans-trans cis-trans-cis cis-trans-cis MEDC 603 Steroids

    8. Nomenclature of Steroids a- and b- configuration and numbering MEDC 603 Steroids

    9. Nomenclature of Steroids a- and b- configuration and numbering MEDC 603 Steroids

    10. Nomenclature of Steroids Number of Nuclear Positions and Steroid Classification C-27 skeleton … Cholestanes C-24 skeleton … Cholanes C-21 skeleton … Pregnanes C-19 skeleton … Androstanes C-18 skeleton … Estranes MEDC 603 Steroids

    11. Nomenclature of Steroids Usage of ‘Nor’ terminology C-27 skeleton … Cholestanes 18-Nor C-27 skeleton … 18-nor cholestane C-19 skeleton … Androstanes 19-Nor C-19 skeleton … 19-nor androstane MEDC 603 Steroids

    12. Anti-Hypercholesterolemic Agents • Biosynthesis and Metabolism of Cholesterol • What is arteriosclerosis? - Link between arteriosclerosis and cholesterol • Lipoproteins particles - Structure and classification of lipoprotein particles • Hyperlipidemias - Types and overall strategy to control hyperlipidemias • Anti-hyperlipidemic Agents - Classes • Statins • Fibrates • Bile Acid Sequestrants • Nicotinic Acid • Ezetimibe MEDC 603 Steroids

    13. O CH3 O CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoA OH acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA CH3 -OOC-CH2-C-CH2-CH2-OH OH mevalonate cholesterol Biosynthesis of Cholesterol HMG CoA reductase MEDC 603 Steroids

    14. Metabolism of Cholesterol MEDC 603 Steroids

    15. Arteriosclerosis Arteriosclerosis is excessive formation and deposition of endogeneous products from blood. In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%. MEDC 603 Steroids

    16. Lipoprotein Particles Structure MEDC 603 Steroids

    17. Lipoprotein Particles Classification of lipoprotein particles MEDC 603 Steroids

    18. Transport of Lipoprotein Particles MEDC 603 Steroids

    19. Hyperlipidemia Types of hyperlipidemias N = normal, = increase; = decrease; = slight increase; = slight decrease MEDC 603 Steroids

    20. Biosynthesis Diet LDL-R Cellular Cholesterol Serum Cholesterol Conversion to hormones within cells or storage as granules Bile Acids Re-absorption Intestine Lipoprotein catabolism Feces Strategy for Controlling Hyperlipidemia STATINS HMG CoA reductase Ezetimibe BILE ACID SEQUESTRANTS FIBRATES MEDC 603 Steroids

    21. R R R R Anti-hyperlipidemic Drugs - Statins MEDC 603 Steroids

    22. Anti-hyperlipidemic Drugs - Statins Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin MEDC 603 Steroids

    23. HMG CoA substrate For example, Mevastatin Lovastatin Simvastatin For example, Fluvastatin Atorvastatin Cerivastatin Anti-hyperlipidemic Drugs - Statins Rationale – competitive binding MEDC 603 Steroids

    24. Anti-hyperlipidemic Drugs - Statins Pharmacokinetic properties of statins – case of cerivastatin Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles. MEDC 603 Steroids

    25. Anti-hyperlipidemic Drugs - Fibrates • Older generation drugs; introduced in 1981 • Second most useful anti-hyperlipidemic drugs • Primarily decrease serum triglycerides • Increase lipoprotein catabolism; increase TG usage by the body • Most used in Type III, IV and V hyperlipidemias MEDC 603 Steroids

    26. Anti-hyperlipidemic Drugs – Bile Acid Sequestrants • Anion exchange resins • Water insoluble and inert to digestive enzymes • Not absorbed through the GI tract • Positively charged nitrogens sequester bile acid re-absorption • Lower serum LDL levels • Most useful in type IIa and IIb hyperlipidemias MEDC 603 Steroids

    27. Anti-hyperlipidemic Drugs – Nicotinic Acid • Administered in large doses (0.5 to 6 grams daily) • Reduces triglycerides and total cholesterol • Increases biliary secretion of cholesterol, but not bile acids • Useful in Type IIa, IIb, III, IV and V hyperlipidemias MEDC 603 Steroids

    28. Anti-hyperlipidemic Drugs – Ezetimibe • Approved in October 2002 • Reduces serum LDL, TC, and TG and increases HDL • Prevents the absorption of cholesterol from diet • Useful in Type IIa, IIb, III, IV and V hyperlipidemias MEDC 603 Steroids

    29. Androgenic Steroids Overall Organization of the Topic • Overall mechanism of steroid hormone action • Structure of male sex hormones - Testosterone, androstendione, and 5a-dihydrotestosterone • Nomenclature of androgenic steroids • Physiological activities - Androgenic and anabolic activities • Biosynthesis and metabolism of testosterone • Structure activity relationships - Generalizations • Androgen antagonists - Finasteride, danazol, bicalutamide and flutamide MEDC 603 Steroids

    30. (intranuclear) dimerization DNA (intracellular) transcription translation proteins Intracellular effects extracellular effects Steroid Hormones Overall Mechanism of Steroid Hormone Action (extracellular) MEDC 603 Steroids

    31. Androgenic Steroids Structure and Nomenclature Testosterone Androstendione (Andro) (17b-hydroxy-androst-4-en-3-one) 3D-structure (androst-4-en-3,17-dione) 5a-Dihydro-testosterone (17b-hydroxy-5b-androstan-3-one) 3D-structure MEDC 603 Steroids

    32. Androgenic Steroids – Physiological Activities Primarily two activities – Androgenic and Anabolic • 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 MEDC 603 Steroids

    33. Androgenic Steroids - Physiological Activities Andro is available over the counter!! MEDC 603 Steroids

    34. Biosynthesis and Metabolism of Testosterone Testosterone Cholesterol Pregnenolone Other metabolites Androstendione 5a-DHT MEDC 603 Steroids

    35. Structure Activity Relationships in Androgens Anabolic Androgenic Testosterone 1 1 (injectable) Testosterone 1 1 esters (injectable) R = COCH2CH3 propionate = CO(CH2)5CH3 enanthate = COCH2CH2(C5H9) cypionate MEDC 603 Steroids

    36. Structure Activity Relationships in Androgens Anabolic Androgenic 17a-methyl Testosterone 1 1 (oral) Fluoxymesterone 1 1 (oral) MEDC 603 Steroids

    37. Structure Activity Relationships in Androgens Anabolic Androgenic Nandrolone 2.5 1 (injectable) Oxymetholone 2.5 1 (oral) MEDC 603 Steroids

    38. Structure Activity Relationships in Androgens Anabolic Androgenic Stanozolol 3 1 (oral) Dromostanolone 4 1 (oral) MEDC 603 Steroids

    39. Structure Activity Relationships in Androgens 17a-methyl testosterone (10-50 mg/day) Ethylestrenol (4 mg/day) Oxandrolone (5-10 mg/day) Methenolone acetate (20 mg /wk) Norethandrolone 10-30 mg/day Chlorotestosterone acetate (20 mg / wk) MEDC 603 Steroids

    40. Androgens Antagonists Danazol (endometriosis) Finesteride (baldness) Bicalutamide (prostate cancer) Flutamide (prostate cancer) MEDC 603 Steroids

    41. Female Sex Hormonal Steroids Overall Organization of the Topic • Structure and nomenclature - Estradiol, estrone, estriol, and progesterone • Biosynthesis and metabolism of estradiol and progesterone • Synthetic estrogens - Schuler’s hypothesis • Estrogen antagonists - clomiphene and tamoxifen • Synthetic progestins • Progesterone antagonists MEDC 603 Steroids

    42. Estrogenic Steroids Structure and Nomenclature of Natural Estrogens Estradiol Estrone Estriol intramuscular intramuscular oral 100% 33% 1.6% 3-hydroxy-estr-1,3,5 -triene-17-one estr-1,3,5-triene- 3,16a,17b-triol estr-1,3,5-triene- 3,17b-diol MEDC 603 Steroids

    43. Progesterone Progesterone (Progest-4-ene-3,20-dione) MEDC 603 Steroids

    44. Female Sex Steroids Physiological Activity of Natural Estrogens • Reproduction and development of female sex organs • Role in ovulation and pregnancy • Role in bone density modulation Physiological Activity of Progesterone • Maintenance of Pregnancy • Inhibition of follicular maturation and ovulation • Prevention of spontaneous uterine contractions MEDC 603 Steroids

    45. Biosynthesis and Metabolism of Estradiol and Progesterone cholesterol pregnenolone testosterone estriol estrone estradiol conjugation to glucuronides, sulfates, etc…. MEDC 603 Steroids

    46. Synthetic Estrogenic Estradiol look-alikes ….. agonists MEDC 603 Steroids

    47. Synthetic Estrogenic Diethyl-Stilbestrols (DES) Ethinyl-estradiol R = H Diethylstilbestrol Mestranol R = CH3 Chlorotrianisene Dienestrol MEDC 603 Steroids

    48. Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens MEDC 603 Steroids

    49. Synthetic Estrogenic MEDC 603 Steroids

    50. Estrogen Antagonists Triphenylethylene Derivatives – Inverse Agonists Chlorotrianisene (estrogenic) MEDC 603 Steroids