1. Thyroid hormones and antithyroid drugs Dept of Pharmacology Shi-Hong Zhang ( 张世红 ) shzhang713@zju.edu.cn

2. Front view Thyroid gland

3. Thyroid hormones 1. Uptake of iodide 2. Oxidation of iodide (peroxidase) and iodination and coupling of tyrosine 3. Formation of thyroxine (T 4 ) and triiodothyronine (T 3 ) from iodotyrosine 4. Secretion of thyroid hormones (proteolytic enzymes) 5. Regulation by thyroid stimulating hormone (TSH), T 4, T 3

6. 甲状腺素的生理及药理作用 1 ．维持生长发育 2 ．促进代谢 3 ．提高交感神经系统的敏感性

7. Hypothyroidism cretinism ( 呆小症 ) 瘿 simple goiter ( 单纯性甲状 腺肿 ) Hypothyroidism After treatment

8. 甲状腺素的临床应用 l ． 呆小病 2. 黏液性水肿 3 ．不典型及亚临床型甲状腺功能减退 4. 单纯性甲状腺肿 5. T 3 抑制试验

9. Hyperthyroidism 颤抖 腱反射亢进 心慌，心脏肥大 甲状腺肿大，突眼，情绪激动 多食、腹泻、消瘦

12. Case report A 47-year-old woman consulted her physician because of heart palpitations, tremulousness, weight loss and heat tolerance. Examination: heart rate 110, BP 150/70, diffusely enlarged thyroid glands, wide-eyed stare, lid lag, T4 40 pmol/L,T3 10.6 pmol/L, TSH undetectable, TSI ↑. The diagnosis was Graves’s disease.

13. Case report Continued She was started on treatment with propranolol, 40 mg tid, propylthiouracil ( 丙硫氧嘧啶 ) 200 mg bid. She became euthyroid ( 甲状腺功能正常 ) in 6 weeks, and the propranolol dose was gradually reduced and finally discontinued. She continued receiving a maintenance dose of propylthiouracil (50 mg bid) for 1 year, after which the drug was discontinued.

14. Case report Continued The symptoms of hyperthyroidism recurred 3 years later, and treatment with propranolol and propylthiouracil was reinitiated. However, she developed severe rash over her whole body. Therefore, the treatment was changed with oral Na 131 I for definitive control of her hyperthyroidism.

15. Case report Continued Three months later, the patient complained of lethargy, tiredness, a feeling of coldness at room temperature, puffiness ( 肿胀 ) around the eyes, and constipation. Laboratory testes showed lowered level of T4 and T3, but elevated level of TSH, confirming the diagnosis of hypothyroidism. She was started on levothyroxine 0.1 mg daily, and 6 weeks later, her complaints disappeared. She has remained well on this therapy.

16. Hypothyroidism: – thyroid hormones – iodine and iodides Hyperthyroidism: – antithyroid drugs: thiourea derivatives 硫脲类 iodine and iodides 碘和碘化物  receptor antagonists Radioiodines 放射性碘 : 131 I Therapeutic drugs on thyroid dysfunction

18. 丙硫氧嘧啶 PTU 卡比马唑 甲巯咪唑 MMI Thiourea derivatives Antithyroid drugs 硫脲类

19. Thiourea derivatives 1. Pharmacological effects (1) Inhibiting the formation of thyroid hormones by interfering with iodination: competing peroxidation, then the iodination and coupling Symptom relieving: 2-3 weeks Basic metabolic rate returning: 1-2 months (2) Inhibiting peripheral deiodination of T 4 : T 4  T 3  (propylthiouracil 丙硫氧嘧啶 ) Antithyroid drugs

20. Thiourea derivatives 1. Pharmacological effects (3) Inhibiting glucose metabolism by down- regulating βreceptor (4) Immunosuppression: TSI↓ Antithyroid drugs

21. 2. Clinical uses (1) Non-operative therapy of hyperthyroidism: long duration (1- 2y) (2) Preoperative therapy of hyperthyroidism: combined with iodide (3) Thyrotoxic crisis: combined with larger dose of iodide, propylthiouracil 3. Adverse effects (1) Agranulocytosis (0.2% or up) (2) Hypersensitivity (3) GI reactions (4) Goitrogenic action (goiter): TSH↑ Thiourea derivatives

22. Iodine and iodides 1. Pharmacological effects (1) Small doses: simple goiter (2) Larger doses: inhibiting the release of thyroid hormones (proteolysis  ) and synthesis After iodide use, the thyroid vascularity is reduced, and the gland becomes much firmer, the cells become smaller. Antithyroid drugs

23. 2. Clinical uses (1) Simple goiter (2) Preoperative therapy of hyperthyroidism: combined with thiourea derivatives (3) Thyrotoxic crisis: combined with thiourea derivatives (propylthiouracil) Lugol’s solution 卢戈氏液 : 5% iodine and 10% potassium iodide Antithyroid drugs

24. 3. Adverse effects (1) Acute effects: hypersensitivity, angioedema, swelling of the larynx (2) Chronic intoxication (iodism) (3) Thyroid dysfunction: exacerbation of hyperthyroidism, goiter Antithyroid drugs

25. 25 Radioiodines 131 I, 125 I, 123 I Destroying thyroid tissue: βray Careful use for hyperthyroidism and differentiated thyroid carcinoma Radioactive iodine uptake test Antithyroid drugs

26.  receptor antagonists 1. Pharmacological effects (1) Heart:  1 block (2) CNS: relieving anxiety (3) Presynaptic  2 receptor: NE release  (4) Decrease T3: inhibiting deiodination of T4 2. Clinical uses Adjuvant therapeutic drug Antithyroid drugs

27. Pancreatic hormones & antidiabetic drugs

28. 胰高血糖素 胰岛素 生长抑素

29. Overview of Glucose Regulation by insulin Amended from Dinneen SF. Diabetes Med. 1997;14(suppl 3):S19-24. Insulin secretion Glucose disposal ↑ Persistent Hepatic Glucose Output ↓ Glucose absorption lipogenesis↑ lipolysis↓ Glycogenesis ↑

30. Different forms of diabetes mellitus

31. “Beta-cell failure” prediabetic metabolic syndrome

32. Symptoms of diabetes

33. Complications of diabetes mellitus Acute complications –Diabetic ketoacidosis ( 酮症酸中毒 ) –Hyperosmotic nonketotic coma ( 高渗性非酮症性昏迷） Chronic complications –Cardiovascular diseases –Renal damage –Retinal damage –Nerve degeneration –Infection –Myopathy –etc.

35. 糖尿病视网膜血管增生 正常视网膜

36. Pharmacological therapy  Insulin  Oral hypoglycemic drugs  Insulin secretagogues ( 促胰岛素分泌药 ):  Sulfonylureas 磺酰脲类  Meglitinides (Non-SU) 格列奈类  GLP-1 agonists and DPP-4 inhibitors  Insulin sensitizers 胰岛素增敏剂 :  Thiazolidinediones (TDs ，噻唑烷二酮类 )  Biguanides 双胍类  α-glucosidase inhibitors α- 葡萄糖苷酶抑制剂  Amylin analogue 胰淀粉样多肽类似物  Aldose reductase inhibitor 醛糖还原酶

37. Case report A 45-year-old man first consulted his physician because of nocturia, mild thirst, and some fatigue. At the time, he was somewhat overweight and sedentary in his habits. Laboratory tests showed an elevated fasting blood glucose level of 15 mmol/L, glucose but no ketones in the urine. Diabetes was diagnosed and he was placed on diabetic diet low in free sugar and fat. Two months later, he was found to have higher fasting blood glucose, 2-hr postlunch glucose, glycosylated hemoglobin (HbA1C). Therefore, He was started on glyburide 5mg before breakfast and 5 mg before dinner, but the blood glucose remained elevated. The dosage was therefore raised to 10 mg twice daily, and this achieved a good result.

38. Case report After 3 years, he developed unstable angina pectoris, and the blood glucose and HbA1C levels were again found to be elevated. Addition of metformin to his treatment produced some improvement, but his cardiac symptoms gradually worsened over the next 3 years. He showed intermittent glycosuria and proteinuria. His weight had fallen to a normal level. His physician therefore decided to transfer him to insulin therapy, started on a regimen of 22 units of Lente insulin and 12 units of regular insulin every morning before breakfast. The dosage was gradually raised to 35 units according to the glucose level in the blood and urine. During the next year he had three mild hypoglycemic reactions. He was found to have stable background retinopathy, mild nephropathy and mild numbness and tingling in both feet, but the blood pressure remained normal.

39. A. Insulin

40. Frederick Sanger (1918- )

41. A. Insulin 1. Pharmacological effects (1) Carbohydrate metabolism: reducing blood glucose levels by glycogenolysis , glycogen synthesis , gluconeogenesis , glucose transport . (2) Lipid metabolism: fat synthesis , lipolysis , plasma free fatty acids , ketone bodies . (3) Protein metabolism: active transport of amino acids , incorporation of amino acids into protein , protein catabolism 

42. Mechanism of insulin actions: Interacting with insulin receptor

43. 2. Clinical uses (1) Insulin-dependent patients with diabetes (type 1) (2) Insulin-independent patients: failure to other drugs (3) Diabetic complications: diabetic ketoacidosis ( 酮症 酸中毒 ), hyperosmotic nonketotic coma （高渗性非酮症性昏迷） (4) Critical situations of diabetic patients: fever, severe infection, pregnancy, trauma, operation (5) Others: promotion of K + uptake into the cells A. Insulin

44. 3. Preparations Fast-acting insulin Regular insulin 正规胰岛素 Monocomponent insulin 单组分胰岛素 High solubility Can be given intravenously Start working 0.5-1h after injection, reach peak 2-4h, and last 5-7h. A. Insulin

45. 3. Preparations Intermediate-acting insulin Neurtral protamine hagedorn (NPH) 中性精蛋白锌胰岛素 Isophane insulin 低精蛋白锌胰岛素 Globin zinc insulin 珠蛋白锌胰岛素 Start working 1-1.5h after injection, reach peak 8-12h, and last 24h. A. Insulin

46. 3. Preparations Long-acting insulin Protamine zinc insulin (PZI) 鱼精蛋白锌胰岛素 Start working 4-8h after injection, reach peak 14-20h, and last 24-36h. A. Insulin

47. 3. Preparations Mixed insulin Human insulin isophane 低精蛋白锌胰岛素 + Human insulin 人胰岛素 Start working 0.5h after injection, reach peak 2-12h, and last 16-24h. A. Insulin

48. 3. Preparations Fast-acting insulin analogs Insulin aspart 门冬胰岛素 Insulin lispro 赖脯胰岛素 Start working 5-15 minutes after injection, reach peak at 1h, and last ~4 hours. Used for IDDM and NIDDM with high postlunch glucose. A. Insulin

49. 3. Preparations Super-long acting insulin analogs Insulin glargine 甘精胰岛素 Onsets 1-2 h after injection and continues to work for as long as 24 hours. Used to treat type 1 or type 2 diabetes mellitus. Less soluble than native human insulin at physiological pH, and precipitates in skin following subcutaneous injection, resulting in delayed absorption. A. Insulin

51. For patients who eat meals out, may consider use of an insulin pen. Most insulins now available as pen

52. Insulin Pump and Glucose Monitoring Insulin Pump – “Open Loop” Patient sets basal infusion rate and superimposed boluses Continuous Glucose Monitor “Closed Loop” insulin pump system is ultimate goal: infusion rate adjusted based on input from continuous glucose monitor.

53. 4. Adverse effects (1) Hypersensitivity: treated with H 1 receptor antagonist, glucocorticoids (2) Hypoglycemia: adrenaline secretion (sweating, hunger, weakness, tachycardia, blurred vision, headache, etc.), treated with 50% glucose (3) Insulin resistance: acute, chronic (4) Lipoatrophy and lipohypertrophy (5) Weight gain (6) Refractive errors ( 屈光不正 ) (7) Edema A. Insulin

54. B. Oral hypoglycemic drugs  Insulin secretagogues （促胰岛素分泌药） :  Sulfonylureas 磺酰脲类  Meglitinides (Non-SU) 格列奈类 ( 苯丙胺酸衍生物 )  GLP-1 agonists and DPP-4 inhibitors  Insulin action enhancers 胰岛素增敏剂 :  Thiazolidinediones (TDs ，噻唑烷二酮类 )  Biguanides 双胍类  α-glucosidase inhibitors α- 葡萄糖苷酶抑制剂  Amylin analogue 胰淀粉样多肽类似物  Aldose reductase inhibitor 醛糖还原酶

55. Sulfonylureas （磺酰脲类） Tolbutamide (D860) 甲苯磺丁脲 Chlorpropamide 氯磺丙脲 Gliburide 格列本脲 ( 优降糖 ) Glipizide 格列吡嗪（美吡达） Gliclazide 格列齐特 ( 达美康 ) B. Oral hypoglycemic drugs

56. 1. Pharmacological effects 1) Increase insulin release: blocking ATP sensitive K + channel, Ca 2+ inflow  Sulfonylureas

57. 1. Pharmacological effects 2) Increase receptor affinity to insulin (long- term use) 3) Promote glucose uses （ 促进合成糖原和脂肪 ） 4) Increase sensitivity of  cells to glucose 5) Anti-uretic effect (Chlorpropamide 氯磺丙脲 ) 6) Anti-platelet effect (Gliclazide 格列齐特 ) Sulfonylureas

58. 2. Clinical uses (1) Insulin-independent diabetic patients (type 2): alone or combined with insulin (2) Diabetes insipidus ( 尿崩症 ): Chlorpropamide ( 氯磺丙脲 ): anti-uretic hormone (ADH)  Sulfonylureas

59. 3. Adverse effects (1) GI reactions (2) CNS reactions （ 嗜睡、眩晕 ） (3) Hypoglycemia: especially in elderly, hepatic or renal insufficiencies (4) Others: leukopenia ( 白细胞减少 ), cholestatic jaundice ( 胆汁郁积性黄疸 ), hepatic damage Sulfonylureas

60. 4. Drug interactions (1) Potentiation of hypoglycemic effects replacement in plasma protein binding: salicylic acid, sulfates, indomethacin, penicillin, warfarin, etc. inhibition of hepatic microsomal enzymes: chloramphenicol, warfarin (2) Attenuation of hypoglycemic effects induction of hepatic microsomal enzymes: phenytoin, phenobarbital, etc. interactions in pharmacodynamics: glucagon, thiazides, etc. Sulfonylureas

61. Act by binding to SUR1 on beta cells to promote insulin secretion. Repaglinide ( 瑞格列奈 ) and Nateglinide ( 那格列奈 ) are current agents in class. Efficacy of repaglinide appears to be similar to SU’s Major advantage is rapid onset and offset, can dose just prior to meals with better post-prandial control. Low risk to induce hypoglycemia. Are additive with metformin ( 二甲双胍 ). Used for type 2 patients. Non-SU Insulin Secretagogues

62. Hepatic metabolism permits use in patients with impaired renal function. Major side effect is hypoglycemia. Many drug interactions. Most concerning is gemfibrozil ( 吉非罗齐 ) which increases repaglinide ( 瑞 格列奈 ) concentration and may result in prolonged effect. Cost may be an issue (1 or 2 mg tabs: $122.09/month at drugstore.com) Non-SU Insulin Secretagogues

63. GLP-1: glucogons-like protein-1 Exenatide ( 依可那肽 ): GLP-1 agonist ， stimulates insulin secretion, only available as injection. Sitagliptin ( 西他列汀 ), Vildagliptin ( 维格列 汀 ): DPP-4 inhibitor. GLP-1 agonists and DPP-4 inhibitors

65. Insulin action enhancers Thiazolidinediones (TZDs) 噻唑烷酮类化合物 Rosiglitazone 罗格列酮 Pioglitazone 吡格列酮 Biguanides （双胍类） Metformin 二甲双胍 B. Oral hypoglycemic drugs

66. 1. Pharmacological effects Selective agonists for nuclear peroxisome proliferator activated receptor-  (PPAR , 过氧化物酶 增殖体激活受体  ), increasing glucose transport into muscle and adipose tissue. (1) Lowering insulin resistance (2) Lipid metabolism regulation: TG, free fatty acid  (3) Preventive effects on diabetic vascular complications (VEGF ↓) (4) Improve  cell function (adiponectin 脂联素 ↑) Thiazolidinediones

68. 2. Clinical uses Used for treatment of insulin-resistant diabetic patients or type 2 patients; Delayed onset of action – takes 8-12 weeks to achieve maximal effect; Absence of hypoglycemia when used as monotherapy; No reliance on renal excretion Thiazolidinediones

69. 3. Adverse effects Edema: at higher doses and used with insulin, in older patients, patients with multiple medical problems, patients with underlying CAD or CHF Headache Myalgia ( 肌痛 ) GI reactions Hepatic damage (troglitazone). Contraindicated with Class III or IV heart failure or significant liver disease. Thiazolidinediones

70. 1. Pharmacological effects Increasing glucose uptake in fat tissues and anaerobic glycolysis in skeletal muscles Decreasing glucose absorption in gut and glucagon release 2. Clinical uses Mild insulin-independent patients with obesity Major advantages: Lack of weight gain; Absence of hypoglycemia; Low cost with generic prep. 3. Adverse effects Severe lactic acidosis, malabsorption of vitamin B 12 and folic acid Biguanides ( 双胍类 )

71. Alpha-Glucosidase inhibitors Acarbose-Precose 阿卡波糖 Miglitol-Glyset 米格列醇 Voglibose 伏格列波糖 B. Oral hypoglycemic drugs

72. Alpha-Glucosidase inhibitors Acarbose is an oligosaccharide, whereas miglitol resembles a monosaccharide. Miglitol （米格列醇） is fairly well-absorbed by the body, as opposed to acarbose. Reducing intestinal absorption of starch ( 淀粉 ), dextrin ( 糊精 ), and disaccharides ( 二糖 ) by inhibiting the action of intestinal brush border  -glucosidase. Acarbose also blocks pancreatic alpha-amylase ( 淀粉酶 ). Used for diabetes mellitus type 2, particularly with regard to postprandial hyperglycemia.

73. Must be taken at the start of main meals to have maximal effect. Efficacy will depend on the amount of complex carbohydrates in the meal. Absence of hypoglycemia when used as monotherapy. Side effects: gastrointestinal side effects such as flatulence and diarrhea; voglibose, in contrast to acarbose, has less of GI side effects and more economical. Alpha-Glucosidase inhibitors

74. Amylin analogues Mechanism of action: –Inhibits postprandial glucagon secretion, thereby reducing hepatic glucose production –Slows gastric emptying –Promotes satiety  reduces caloric intake Pramlintide (Symlin 普兰林肽 ) is the only amylin analog on the market As adjunct therapy for patients with type 1 or 2 diabetes to control postprandial glucose Increases the risk of severe hypoglycemia Main side effect is nausea. Riddle and Drucker. Diabetes Care 2006; 29:435-49. B. Oral hypoglycemic drugs

75. Alsose reductase –Aldose reductase activity increases in those tissues that are not insulin sensitive, including lenses, peripheral nerves and glomerulus. –Epalrestat ( 依帕司他 ) inhibits aldose reductase. –Delay the progression of diabetic neuropathy and ameliorate the associated symptoms of the disease. B. Oral hypoglycemic drugs

76. Type II Diabetic Medications MedicationSite of Action/Mechanism Side-Effects Sulfonylurea (eg. glyburide) Augments insulin secretion, binds SUR Hypoglycemia, caution renal insufficiency, elderly Thiazolidinediones (eg. rosiglitazone) PPARγ receptor/increased insulin sensitivity Liver, LE edema, congestive heart failure, MI Biguanide (metformin)Reduced hepatic gluconeogenesis GI upset, Lactic acidosis (very rare), only use if creatinine<1.5 mg/dl Glinides (repaglinide)Bind SUR, short actionHypoglycemia, caution in renal insufficiency Alpha-glucosidase inhibitors (acarbose) Inhibits brush border enzyme/Reduce glucose absorption Flatulence, diarrhea Incretins/GLP-1 (exenatide)Stimulates insulin, delays gastric emptying, satiety Nausea, vomiting (given by injection) DPP4 Inhibitors (vildagliptin) Inhibits GLP1 breakdownGI side effects

78. Adrenocorticoids & adrenocortical antagonists

79. Adrenocortical hormones –Glucocorticoids (Glucocorticosteroids) –Mineralocorticoids –Sex hormones

80. Structure and function of adrenal cortex Zona Reticularis Adrenaline Zona Faseciculata Androgens

81. ACTH Regulation of glucocorticoids ‒

82. Plasma glucocorticoids

83. Basic structure of glucocorticoid drugs AB CD 甾体结构 H A. Glucocorticoid drugs 1 2 3 4 5 6 7 8 9 10 12 13 14 15 16 18 19

84. Structure (1) 1 位和 2 位碳之间改成不饱和的双键 ( 抗炎作用增加，对糖代谢的影响 增加，对电解质代谢下降 ): cortisone  prednisone ( 泼尼松，强的松 ); hydrocortisone  prednisolone ( 泼尼松龙 ). (2) 16  引入羟基 ( 抗炎作用增强 ): triamcinolone ( 曲安西龙 ). (3) 6  引入甲基 ( 抗炎作用增强，作用时间延长 ): 6  -methylprednisone (6  甲基泼尼松 ). (4) 9  引入氟原子 ( 抗炎和水钠潴留作用增强 ): fludrocortosone ( 氟氢可的松 ). 1 2 3 4 5 6 7 810 9 12 13 14 15 16 18 19 A B C D 基本结构 H A. Glucocorticoid drugs

85. Cortisone ( 可的松 ) Prednisone ( 泼尼松 ) ( 地塞米松 ) Hydrocortisone ( 氢化可的松, Cortisol) Prednisolone ( 泼尼松龙 ) Fluocinolone ( 氟轻松 )

86. 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

87. 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

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

90. Genetic 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

91. Nuclear translocation of glucocorticoid receptors (GR) Dexamethasone

92. Examples of glucocorticoid actions: Inhibition of proinflammatory gene transcription (AP-1 and NF  B)

93. 1. Pharmacological effects (1) Effects on metabolism (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

94. (1) Effects on metabolism ① Glucose metabolism: gluconeogenesis , glucose oxidation and 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: Na+ excretion , K+ excretion , Ca2+ excretion  and absorption . A. Glucocorticoid drugs

95. Weaker action of glucocorticoid drugs (cortisol 氢化可的松 ) on mineralocorticoid receptor

96. (2) Anti-inflammatory effects 1) Acute a) Increasing anti-inflammatory proteins and enzymes inducing lipocortin ( 脂皮素 ), inhibiting phospholipase A 2 activity, decreasing mediators: PGs, LTs, PAF inducing vasocortin ( 血管内皮素 ), decreasing microvascular permeability inhibiting the expression of COX-2, inducible NOS, etc. b) Inhibiting cytokines: decreasing the transcription and activities of TNFα, IL-1, IL-2, IL-5, IL-6, IL-8, etc. c) Inhibiting adhesion molecules d) Inducing apoptosis of inflammatory cells A. Glucocorticoid drugs

97. (2) Anti-inflammatory effects Chronic: inhibiting fibroblast proliferation deposition of collagen cicatrization ( 瘢痕形成 ) A. Glucocorticoid drugs

98. (3) Suppressive effects on immune and allergy a) inducing apoptosis of T and B lymphocytes b) inducing DNA degradation of T and B lymphocytes c) Inhibiting DNA and protein synthesis of T and B lymphocytes d) inhibiting transcription factor activity (eg. AP-1, NF-  B e) Inhibiting mast cells (anti-allergic) (4) Permissive action Potentiating the effects of catecholamines and glucagon A. Glucocorticoid drugs

99. (5) anti-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

100. (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

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

102. 3. Clinical uses (2) Severe infection and inflammation a) acute severe infections: merely suppressing inflammatory manifestations but at times lifesaving Caution: 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

103. 3. Clinical uses (3) Septic shock: Caution: 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. (7) Replacement therapy A. Glucocorticoid drugs

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

105. 4. Adverse effects 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) Inhibition or arrest of growth in children A. Glucocorticoid drugs

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

108. 4. Adverse effects (2) Withdrawal syndrome a) Suppression of hypothalamic-pituitary-adrenal axis iatrogenic hypocortisolism, adrenal crisis 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

109. Balance the ratio of benefit/risk before the use of GCs !

110. 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) Topical applications: skin; eye; respiratory tract A. Glucocorticoid drugs

111. Some indications for the use of glucocorticoids

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

114. Action of aldosterone on mineralocorticoid receptor

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

116. Adrenocorticotropic hormone ( 促肾上腺皮质 激素 ACTH) 1.Used for diagnosis of adrenocortical function 2.Stimulating secretion of adrenocortical hormones after long-term glucocorticoid drug use 3.Easily inducing allergy to ACTH C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors

117. 2. Corticosteroid synthetase inhibitors Mitotane 米托坦 : induces cellular necrosis of the zona fasiculata and the zone reticularis Metyrapone 美替拉酮 : inhibits 11  -hydroxylation, reduces cortisole and corticosterone Aminoglutethimide 氨鲁米特 : blocks the first step of corticosteroid synthesis Used for adrenocortical tumors or hypercorticism C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors