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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 11/9/2018 MEDC 603 Steroids
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Examples of Steroid-based Drugs in Use Today
Male Sex Hormone Female Sex Hormone Congested Heart Symptoms Anti-inflammatory Agent 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Structures of Steroids
Structure and Nomenclature of the Steroid Nucleus CH3 A B C D 20 21 22 23 24 25 26 27 11/9/2018 MEDC 603 Steroids
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Configurational Isomers of Steroids
Fusion points between rings A B A B trans- configuration cis- configuration 11/9/2018 MEDC 603 Steroids
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Configurational Isomers of Steroids
Fusion points between rings A B C D 3 fusion points 23 isomers = 8 11/9/2018 MEDC 603 Steroids
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Configurational Isomers of Steroids
Three dimensional structure of three most common isomers trans-trans-trans cis-trans-trans trans-trans-trans cis-trans-trans cis-trans-cis cis-trans-cis 11/9/2018 MEDC 603 Steroids
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Nomenclature of Steroids
a- and b- configuration and numbering 11/9/2018 MEDC 603 Steroids
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Nomenclature of Steroids
a- and b- configuration and numbering 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Biosynthesis of Cholesterol
CH3-C-SCoA OOC-CH2-C-CH2-C-SCoA O OH CH3 acetyl coenzyme A hydroxy-3-methyl-glutaryl-CoA HMG CoA reductase cholesterol -OOC-CH2-C-CH2-CH2-OH OH CH3 mevalonate 11/9/2018 MEDC 603 Steroids
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Metabolism of Cholesterol
11/9/2018 MEDC 603 Steroids
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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%. 11/9/2018 MEDC 603 Steroids
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Lipoprotein Particles
Structure 11/9/2018 MEDC 603 Steroids
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Lipoprotein Particles
Classification of lipoprotein particles Composition Density Size Chylomicrons TG >> C, CE Low Large VLDL TG > CE IDL CE > TG LDL CE >> TG HDL High Small 11/9/2018 MEDC 603 Steroids
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Transport of Lipoprotein Particles
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Hyperlipidemia Types of hyperlipidemias I IIa IIb III IV V Lipids
Cholesterol N- Triglycerides N Lipoproteins Chylomicrons VLDL LDL HDL N = normal, = increase; = decrease; = slight increase; = slight decrease 11/9/2018 MEDC 603 Steroids
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Strategy for Controlling Hyperlipidemia
STATINS Diet Biosynthesis HMG CoA reductase Ezetimibe Cellular Cholesterol LDL-R Serum Cholesterol Bile Acids Intestine Re-absorption Lipoprotein catabolism Conversion to hormones within cells or storage as granules Feces BILE ACID SEQUESTRANTS FIBRATES 11/9/2018 MEDC 603 Steroids
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Anti-hyperlipidemic Drugs - Statins
11/9/2018 MEDC 603 Steroids
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Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin Fluvastatin Rosuvastatin Pitavastatin 11/9/2018 MEDC 603 Steroids
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Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding For example, Mevastatin Lovastatin Simvastatin Fluvastatin Atorvastatin Cerivastatin HMG CoA substrate 11/9/2018 MEDC 603 Steroids
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Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin Bioavail. Dosage (mg) Protein Binding Metabolites Atorvastatin ~14% 10 – 80 >98% Active Cerivastatin ~60% 0.2 – 0.3 >99% Fluvastatin ~24% 98% Lovastatin ~5% >95% Pravastatin ~17% 10 – 40 ~50% Simvastatin ~95% 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. 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Steroid Hormones Overall Mechanism of Steroid Hormone Action
(intracellular) (intranuclear) proteins Intracellular effects extracellular effects transcription translation dimerization DNA (extracellular) 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Androgenic Steroids - Physiological Activities
Andro is available over the counter!! 11/9/2018 MEDC 603 Steroids
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Biosynthesis and Metabolism of Testosterone
Cholesterol Pregnenolone Testosterone Other metabolites 5a-DHT Androstendione 11/9/2018 MEDC 603 Steroids
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Structure Activity Relationships in Androgens
Anabolic Androgenic Testosterone (injectable) Testosterone esters (injectable) R = COCH2CH propionate = CO(CH2)5CH enanthate = COCH2CH2(C5H9) cypionate 11/9/2018 MEDC 603 Steroids
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Structure Activity Relationships in Androgens
Anabolic Androgenic 17a-methyl Testosterone (oral) Fluoxymesterone (oral) 11/9/2018 MEDC 603 Steroids
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Structure Activity Relationships in Androgens
Anabolic Androgenic Nandrolone (injectable) Oxymetholone (oral) 11/9/2018 MEDC 603 Steroids
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Structure Activity Relationships in Androgens
Anabolic Androgenic Stanozolol (oral) Dromostanolone (oral) 11/9/2018 MEDC 603 Steroids
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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) 11/9/2018 MEDC 603 Steroids
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Androgens Antagonists
Danazol (endometriosis) Finesteride (baldness) Bicalutamide (prostate cancer) Flutamide (prostate cancer) 11/9/2018 MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Estrogenic Steroids Structure and Nomenclature of Natural Estrogens
Estradiol Estrone Estriol intramuscular intramuscular oral 100% % % estr-1,3,5-triene- 3,17b-diol 3-hydroxy-estr-1,3,5 -triene-17-one estr-1,3,5-triene- 3,16a,17b-triol 11/9/2018 MEDC 603 Steroids
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Progesterone Progesterone (Progest-4-ene-3,20-dione) 11/9/2018
MEDC 603 Steroids
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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 11/9/2018 MEDC 603 Steroids
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Biosynthesis and Metabolism of Estradiol and Progesterone
cholesterol pregnenolone testosterone estriol estrone estradiol conjugation to glucuronides, sulfates, etc…. 11/9/2018 MEDC 603 Steroids
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Synthetic Estrogenic Estradiol look-alikes ….. agonists 11/9/2018
MEDC 603 Steroids
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Synthetic Estrogenic Diethyl-Stilbestrols (DES)
Ethinyl-estradiol R = H Diethylstilbestrol Mestranol R = CH3 Chlorotrianisene Dienestrol 11/9/2018 MEDC 603 Steroids
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Synthetic Estrogenic Schuler’s Hypothesis for Synthetic Estrogens
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Synthetic Estrogenic 11/9/2018 MEDC 603 Steroids
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Estrogen Antagonists Triphenylethylene Derivatives – Inverse Agonists
Chlorotrianisene (estrogenic) 11/9/2018 MEDC 603 Steroids
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Selective Estrogen Receptor Modulators (SERM)
– tissue specific activity …. Estrogenic for bone growth; anti-estrogenic for uterine endometrial growth 11/9/2018 MEDC 603 Steroids
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?? ?? ?? Predict the Metabolism of Progesterone Progesterone
5b-metabolite ?? ?? ?? 6a-hydroxy progesterone 20a/b-hydroxy metabolite 11/9/2018 MEDC 603 Steroids
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Typical Progesterone Agonists
17a-hydroxy progesterone caproate Derivatize ring D Derivatize rings A & D Medroxyprogesterone acetate Megestrol acetate Chlormadinone acetate 11/9/2018 MEDC 603 Steroids
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Unusual Progesterone Agonists
Testosterone Derivatives Ethisterone Dimethisterone Norethisterone Norethindrone Norgestimate Norgestrel 19-Nor-testosterone Derivatives 11/9/2018 MEDC 603 Steroids
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Progesterone Antagonist
Mifepristone Onapristone 11/9/2018 MEDC 603 Steroids
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Steroidal hormones synthesized by the adrenal glands
Adrenocorticoids Steroidal hormones synthesized by the adrenal glands An inner medulla, which is a source of the catecholamines epinephrine and norepinephrine. An outer cortex, which secretes several classes of steroid hormones (glucocorticoids and mineralocorticoids, plus a few others). 11/9/2018 MEDC 603 Steroids
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Adrenocorticoids Hydrocortisone Aldosterone Hemi-acetal form
(11b,17a,21-trihydroxy-pregn-4-ene-3,20-dione) Hemi-acetal form Aldehyde-alcohol form Aldosterone (11b,21-dihydroxy-pregn-4-ene-3,18,20-trione) 11/9/2018 MEDC 603 Steroids
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Adrenocorticoids Biological Activities 1. Glucocorticoid Activity
1.1 Effects on Metabolism Stimulation of gluconeogenesis, particularly in the liver Mobilization of amino acids from extrahepatic tissues Inhibition of glucose uptake in muscle and adipose tissue Stimulation of fat breakdown in adipose tissue 1.2 Effects on Inflammation and Immune Function Anti-inflammatory properties Immunosuppressive properties 1.3 Other Effects of Glucocorticoids Multiple effects on fetal development (promote maturation of the lung) Miscellaneous effects (Excessive glucocorticoid levels affect many systems, e.g., inhibition of bone formation, suppression of calcium absorption and delayed wound healing.) 2. Mineralocorticoid Activity 2.1 Effect on Electrolytes 2.1.1 Increased re-absorption of sodium 2.1.2 Increased renal excretion of potassium Effect on Water 2.2.1 Increased re-absorption of water 11/9/2018 MEDC 603 Steroids
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Adrenocorticoids Disease States
Addison's disease: Affects about 1 in 100,000 people; caused by adrenal in-sufficiency (90%); typical by auto-immune disorders; both cortisol and aldostertone hormones are lacking. Cushing's disease: Affects about 10 to 15 million people / yr; caused by adrenal hyper-activity (cortisol); typical because of tumor growth exposure to prednisone for asthma, rheumatoid arthritis, lupus or other inflammatory diseases Conn's syndrome: May affect 15% of patients with high blood pressure; caused by hyper production of aldosterone; inability of adrenal cortex to carry out 17a-hydroxylation; hypertension, loss of potassium in the urine, muscle weakness and passing of large volumes of urine (polyuria) 11/9/2018 MEDC 603 Steroids
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Biochemical Mechanism of Action
Cortisol Aldosterone Anti-inflammatory Action Mineralocorticoid Action Receptor Receptor Lipocortin Aldosterone- induced protein Phospholipase A2 Cell membrane phospholipids Prostaglandins leucotrienes Regulates Na+-K+-ATPase Pump Na+ Influx 11/9/2018 MEDC 603 Steroids
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Metabolism of Adrenocorticoids
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Structure-Activity Relationships
Anti Salt Plasma inflammatory retaining half activity activity life Hydrocortisone m Cortisone m Prednisone m 11/9/2018 MEDC 603 Steroids
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Structure-Activity Relationships
Anti Salt Plasma inflammatory retaining half activity activity life Prednisone m Prednisolone m 11/9/2018 MEDC 603 Steroids
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Structure-Activity Relationships
Anti Salt Plasma inflammatory retaining half activity activity life Prednisolone m 6a-methyl m prednisolone Triamcinolone m 11/9/2018 MEDC 603 Steroids
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Structure-Activity Relationships
Anti Salt Plasma inflammatory retaining half activity activity life Dexamethasone m Betamethasone m 11/9/2018 MEDC 603 Steroids
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Structure-Activity Relationships
Anti Salt Plasma inflammatory retaining half activity activity life Aldosterone m 11-deoxy m corticosterone Fludrocortisone m 11/9/2018 MEDC 603 Steroids
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