1. Drugs affecting endocrine system Huifang Tang Department of pharmacology Email: tanghuifang@zju.edu.cntanghuifang@zju.edu.cn

2. Hypothalamus-pituitary gland: The regulatory center of endocrine system

4. Membrane receptor Nuclear receptor (GCS, TH)

5. Part1 Adrenocorticoid drugs Part2 Insulin and oral hypoglycemic drugs Part3 Thyroid hormones and antithyroid drugs

6. Part1 Adrenocorticoid drugs  Adrenocortical hormones  Mineralocorticoids  Glucocorticoids  (Glucocorticosteroids)  Sex hormones

7. History(1)  In 1849, Addison first appreciated the importance of the adrenal glands  Addison T. On the Constitutional and Local Effects of Disease of the Supra-renal Capsules. London, UK: Samuel Highley; 1855.

9. Structure and function of adrenal cortex. ZonaReticularis Adrenaline ZonaFaseciculata Androgens

10. History(2)  As early as 1912, Cushing described patients with hypercorticism, and later recongized that pituitary basophilism represented the cause of the adrenal overactivity.

12. History(3)  In 1948, the role of hypothalamus in pituitary control was established by Harris.  In 1949, Hench and colleagues demonstrated the dramatic effect of glucocorticoids and ACTH in the treatment of rheumatoid arthritis.

13. Contents  A. Glucocorticoid drugs  B. Mineralocorticoid drugs  C. ACTH and corticosteroid synthetase inhibitors

14. Basic structure of glucocorticoid drugs: Basic structure of glucocorticoid drugs: AB CD 甾 甾体结构 H A. Glucocorticoid drugs

15. Structure and Activity Relationship: (1)1 位和 2 位碳之间改成不饱和的双键 : cortisone  prednisone; cortisone  prednisone; hydrocortisone  prednisolone. hydrocortisone  prednisolone. (2)16  引入羟基 : triamcinolone( 曲安西龙 ). triamcinolone( 曲安西龙 ). (3)6  引入甲基 : 6  -methylprednisone 6  -methylprednisone (6  甲基泼尼松 ). (6  甲基泼尼松 ). (4)9  引入氟原子 : fludrocortosone fludrocortosone ( 氟氢可的松 ). ( 氟氢可的松 ). 1 2 3 4 5 6 7 810 9 12 13 14 15 15 16 16 18 18 19 19 A B C D 基本结构 H A. Glucocorticoid drugs

16. Mechanisms of glucocorticoid actions binding to glucocorticoid receptor (GR) nuclear translocation nuclear translocation binding to GRE or nGRE binding to GRE or nGRE regulating related gene transcription regulating related gene transcription biological effects (usually slow) biological effects (usually slow) A. A. Glucocorticoid drugs

17. Action mode of glucocorticoid drugs CBG: corticosteroid binding globulin S: glucocorticoid steroids GR: glucocorticoid receptor HSP: heat shock protein IP: immunophilin GRE: glucocorticoid- response element

18. Nuclear translocation of glucocorticoid receptors (GR) Dexamethasone was used GR was labeled with green fluorescent protein

19. One of glucocorticoid’s anti-inflammatory actions: Inhibition of proinflammatory gene transcription (AP-1 and NF  B) A. Glucocorticoid drugs

20. Non-genomic mechanisms of action of glucocorticoids. C. Boardman et al. / Pulmonary Pharmacology & Therapeutics 29 (2014) 129e143

21. 1. Pharmacological effects Mechanisms of glucocorticoid actions (1) Effects on metabolisms (2) Permissive action (3) Anti-inflammatory effects (4) Effects on immune and allergy (5) Anti-shock (6) Other effects antipyretic effects effects on blood and blood-forming organs skeletal system CNS effects A. Glucocorticoid drugs

22. (1) Effects on metabolisms ① Glucose metabolism: gluconeogenesis , glucose utilization   blood glucose . ② Protein metabolism: synthesis , degradation . ③ Lipid metabolism: plasma cholesterol , fat redistribution (central obesity: moon face, buffalo hump, etc.). ④ Water and electrolytic metabolism: water excretion , Na+ excretion , K+ excretion , Ca2+ excretion  and absorption . A. Glucocorticoid drugs

23. Weaker action of glucocorticoid drugs (cortisol) on mineralocorticoid receptor

24. (2) Permissive action Potentiating the effects of catecholamines and glucagon (3) Anti-inflammatory effects Acute: inhibiting microvascular leakage leukocyte infiltration Chronic: inhibiting fibroblast proliferation deposition of collagen cicatrization ( 瘢痕形成 ) A. Glucocorticoid drugs

25. a) Increasing inflammation related proteins or enzymes inducing lipocortin( 脂皮素 ), inhibiting phospholipase A 2 activity, decreasing mediators: PGs, LTs, PAF inducing angiotension-convertion enzyme,ACE) inducing vasocortin( 血管皮素 ), decreasing microvascular permeability inhibiting the expression of PLA 2, COX-2, inducible NOS, etc. b) Inhibiting cytokinins: decreasing the transcription and activities of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc. c)Inhibiting adhesion molecules: decreasing the transcription and activities ofICAM-1, E-selectin etc. d) Inducing the apoptosis of inflammatory cells A. Glucocorticoid drugs

26. (4) Effects on immune and allergy Suppressing immunological functions and allergy a) inducing apoptosis of T and B lymphocytes b) inhibiting transcription factor activity(eg. AP- 1, NF  B): A. Glucocorticoid drugs

28. (5) Anti-shock Septic shock a) improving cardiovascular functions b) inhibiting the production of inflammatory factors c) stabilizing lysosome membrane: decreasing the release of myocardial depressant factor (MDF) d) increasing the tolerance to endotoxin from bacteria A. Glucocorticoid drugs

29. (6) Other effects a) antipyretic effects b) effects on blood and blood-forming organs red cell  ; lymphocytes  ; neutrophils  (function  ); eosinophils  ; platelets  c) skeletal system: osteoporosis d) CNS: increasing excitability (elevated mood, euphoria, insomnia, restlessness, increased motor activity) A. Glucocorticoid drugs

30. 2. ADME and properties of commonly used drugs Cortisone and prednisone are reduced and transformed to hydrocortisone and prednisolone (active forms) in the liver Metabolism will be increased by hepatic enzyme inductors (phenobarbital, phenytoin, rifampine, etc.) A. Glucocorticoid drugs

31. Commonly used drugs Short-acting: hydrocortisone (cortisol) 氢化可的松 cortisone 可的松 Intermediate-acting: prednisone 泼尼松, 强的松 prednisolone 泼尼松龙, 强的松龙 Long-acting: dexamethasone 地塞米松 Topical: fluocinolone 氟轻松 A. Glucocorticoid drugs

32. Cortisone可的松 Hydrocortisone氢化可的松Cortisol Prednisone泼尼松 Prednisolone泼尼松龙 Fluocinolone氟轻松 地塞米松 H

34. 3. Clinical uses (1) Immune diseases a) autoimmune disorders: reumatic fever, reumatic carditis, rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus, polyarthritis nodosa, nephritic syndrome, etc. b) rejection of organ transplantation c) allergic diseases: urticaria, serum sickenss, contact dermatitis, drug allergic reactions, chronic severe asthma, status asthmaticus, angioneurotic edema, etc. A. Glucocorticoid drugs

35. (2) Severe infection and inflammation a) acute severe infections: merely suppressing inflammatory manifestations but at times lifesaving Causion: ① combination with effective anti-microbial drugs; ② Large dose; ③ short term administration ! Usually be not used in viral and fungal infections except for those with cerebral edema or severe systemic symptoms b) prevention of sequelae ( 后遗症 ) of some types of inflammation, such as in brain, heart, eye, joint, etc. A. Glucocorticoid drugs

36. (3) Septic shock: Causion: larger dose, short-term, and combined with antimicrobial drugs. Causion: larger dose, short-term, and combined with antimicrobial drugs. (4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia ( 再生障碍性贫血 ),, hemolytic anemia, leukocytopenia, thrombocytopenia, etc. (5) Topical applications: skin, eye, respiratory tract, joint (local injection) (6) Some types of tumors: breast and prostatic cancers, acute lymphocytic leukemia, etc. A. A. Glucocorticoid drugs

37. 4 、 Adverse effects of glucocorticoid drugs: Effects resulting from continued used of large doses A. A. Glucocorticoid drugs

38. 4. Adverse effects (1) Effects resulting from continued used of large doses a) Hypercorticism-like syndrome: central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; etc. b) Increasing susceptibility to infections: Causion: specfic antimicrobial drugs should be administered with GCs c) Ingestive system: peptic ulcers, etc. A. Glucocorticoid drugs

39. d) Cardiovascular system: hypertension, arteriosclerosis e) Myopathy and osteoporosis: vertebral compression fractures, spontaneous fractures, especially in postmenopausal women f) CNS: behavioral disturbances, induction of epileptic seizures g) cartarcts( 白内障 ): well established complication of glucocorticoid therapy. Children appear to be particularly at risk. slit-lamp examination h) Inhibition or arrest of growth in children A. Glucocorticoid drugs

40. Suppression of hypothalamic- pituitary-adrenal axis and glucocorticoid drugs ‒ ACTH

41. (2) Withdrawal syndrome a) Suppression of hypothalamic-pituitary-adrenal axis b) Exacerbation of the underlying diseases (rebound) (3) Contraindications psychiatric disorders; epilepsy; active peptic ulcers; fractures; hypercorticism; severe hypertension; diabetes mellitus; viral or fungal infections, etc. A. Glucocorticoid drugs

42. Balance the ratio of benefit / risk before the use of GCs !!! A. Glucocorticoid drugs

43. 5. Applications (1) Replacement therapy: usually using hydrocortisone (2) Prompt intensive treatment: i.v. gtt hydrocortisone, dexamethasone (3) Long-term therapy: oral prednisone or prednisolone morning single dose alternate-day therapy Notes: for less severe and less sustained patients; less suppression on hypothalamic-pituitary-adrenal (HPA) axis (4) Tipical applications: skin; eye; respiratory tract A. Glucocorticoid drugs

44.  Aldosterone 醛固酮  Na + excretion , K + excretion  : edema hypertension hypokalemia, etc. used for adrenocortical dysfunction with imbalance of water and electrolytes B. Mineralocorticoid drugs

45. Action of aldosterone on mineralocorticoid receptor

46. Mineralocorticoid receptor signal transduction.  MR: mineralocorticoid receptor;  HRE: hormone responsive element.  AIP: Aldosterone induced protein AIP

47. C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

48.  1. Adrenocorticotropic hormone (ACTH)  Used for diagnosis of adrenocortical function  inhibition of secretion of adrenocortical hoemones after long-term glucocorticoid drug use  Easily inducing allergy to ACTH C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

49.  Extraadrenal effects of Adrenocorticotropic hormone (ACTH)  In larger doses, ACTH cause a number of metabolic changes in adrenalectomized animals, including ketosis,lipolysis,hypoglycemia( immediately after treatment), and resistance to insulin(later after treatment)  Hyperpigmentation: ACTH activated the MSH receptor on melanocytes. C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

50. Diagnosis of H-P-A Axis status: Adrenocortical function test Cosyntropin  synthetic ACTH used as adrenal cortical stimulant  Normal response: plasma cortisol levels are elevated  Abnormal response: plasma cortisol level are unchanged

51.  2. Inhibitor of the biosythesis  Mitotane 米托坦 --o,p'-DDD, an adrenocorticolytic agent  Corticosteroid synthetase inhibitors inhibit cytochrome P450 enzymes involved in adrenocorticosteroid biosynthesis Metyrapone 美替拉酮 Aminoglutethimide 氨鲁米特 Ketoconazole 酮康唑 target: different steroid hydrolases  Used for adrenocortical tumors or hypercorticism  Common rsik: precipitating acute adrenal insufficiency C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

52. 3 、 Antiglucocorticoids （抗糖皮质激素药） mifepristone (RU-486) 米非司酮  Antiprogestagen, can terminate early pregnacy.  At higher doses, it also inhibits the glucocorticoid receptor, blocking the feedback regulation of HPA axis and secondarily increasing endogenous ACTH and cortisol levels  Potential clinicla use: hypercorticism C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

55. Cortisol Suppression Tests  Principle  Based on the ability of exogenous cortisol to exert (-)  feedback on hypothalamus-pituitary release of ACTH  Can’t measure with cortisol itself (exogenous would just  replace endogenous)  Must use a more potent glucocorticoid derivative  usually dexamethasone

56. Diagnosis of H-P-A Axis status: H-P suppression test  Dexamethasone:  used to evaluate the basis for elevated cortisol levels in individuals with suspected pituitary adenoma (Cushing’s disease)  Normal response in Cushing’s disease: plasma ACTH and cortisol, urine 17-OH corticosteroid l evels are reduced  Abnormal response in cortisol-producing adrenal tumor (low ACTH) or ectopic ACTH-producing tumors (high ACTH):  plasma ACTH and cortisol, urine 17-OH corticosteroid levels are unchanged