Understanding Drugs Affecting Endocrine System

1. Drugs affecting endocrine system Weiwei Hu huww@zju.edu.cn 88208227 Dept. Pharmacology, Medical School, Zhejiang University

2. Drugs related to adrenocortical hormones • Thyroid hormones and antithyroid drugs • Insulin and oral hypoglycemic drugs

4. Cortex: adrenocorticoid • Glucocorticoids • (Glucocorticosteroids) • Mineralocorticoids • Sex hormones • Medulla:epinephrine • norepinepherine

5. Adrenocorticoid • Glucocorticoids : hydrocortisone (cortisol), cortisone • Mineralocorticoids： aldosterone, desoxycortone

6. Basic structure of adrenocorticoid drugs 甾核结构 Cortisone (可的松) Hydrocortisone (氢化可的松) aldosterone (醛固酮)

7. 基本结构 Prednisone (泼尼松) Structure and Activity Relationship • 1位和2位碳之间改成不饱和的双键 • (抗炎↑水钠潴留↓ 半衰期↑): • cortisone  prednisone • hydrocortisone  prednisolone Cortisone (可的松) Prednisolone (泼尼松龙) Hydrocortisone (氢化可的松, Cortisol)

8. (地塞米松) Structure and Activity Relationship (2) 9引入氟原子(抗炎↑ 、水钠潴留↑): fludrocortosone (氟氢可的松). (3)引入甲基(抗炎↑水钠潴留↓ 半衰期↑): 6-methylprednisolone,dexamethasone (6甲泼尼龙, 地塞米松(16),倍他米松(16)). (4) 16引入羟基(抗炎↑水钠潴留↓): triamcinolone(曲安西龙). 基本结构 Fludrocortisone (氟氢可的松) Triamcinolone (曲安西龙)

9. Non-gene modulation Gene modulation (GCS, TH)

10. 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

11. Glucocorticoid drugs • (1) Effects on metabolisms • a) Carbohydrate:blood glucose ↑: gluconeogenesis ↑, glycolysis↓, glucose utilization↓ • b) Protein:synthesis ↓, degradation ↑ • c) Lipid: long term use:plasma cholesterol ↑, fat redistribution (central obesity: moon face, buffalo hump) • d) Water and electrolytic:Na+ excretion ↓, K+ excretion ↑, Ca2+ excretion↑and absorption↓

12. Glucocorticoid drugs • (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)

13. Glucocorticoid drugs • a) Inhibiting inflammation related proteins or enzymes • inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF • inhibiting the expression of PLA2, COX-2, inducible NOS,etc. • inducing ACE, degrade bradykinin.

14. PAF Lipid-derived autocoids and related drugs

15. Glucocorticoid drugs • a) Inhibiting inflammation related proteins or enzymes • inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF • inhibiting the expression of COX-2, inducible NOS,etc. • inducing ACE, degrade bradykinin. • b) Inhibiting cytokines:TNF, IL-1, IL-2, IL-5, IL-6, IL-8, etc. c) Inhibiting adhesion molecules d) Inducing the apoptosis of inflammatory cells

16. Glucocorticoid drugs • (4) Effects on immune and allergy • Suppressing immunological functions • 1) 抑制巨噬细胞对抗原的吞噬和处理 • 2) 使敏感动物的淋巴细胞破坏解体 (大鼠、小鼠、家兔) • 3) 干扰淋巴组织在抗原作用下的分裂和增殖，阻断致敏T细胞诱发的单核巨噬细胞的募集

17. Glucocorticoid drugs • (4) Effects on immune and allergy • Suppressing immunological functions • a) inhibit DNA, RNA and protein synthesis, and induce the DNA degeneration of lymphocytes • b) inducing apoptosis of lymphocytes • c) inhibiting transcription factor nuclear factor B (NF-B) activity and increase expression of I B a

18. Glucocorticoid drugs • (4) Effects on immune and allergy • Suppressing allergic reaction • inhibit the allergic mediator • (histamine, 5-HT, bradykinin) • production from mast cells

19. Glucocorticoid drugs • (5) Anti-shock • Septic shock • a) improving cardiovascular functions, decrease the sensitivity to vasoconstrictor substance • 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

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

21. Glucocorticoid drugs • 2. ADME and properties of commonly used drugs • Binding to corticosteroid-binding globulin (CBG, 皮质激素运载蛋白) in the plasma • 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.)

22. Glucocorticoid drugs 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

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

25. Glucocorticoid drugs • (2) Severe infection and inflammation • a) acute severe infections:merely suppressing inflammatory manifestations • Causion: combination with effective antimicrobial drugs ! • Usually not used in viral infections except for those with cerebral edema or severe systemic symptoms • b) prevention of sequelae of some types of inflammation, such as in brain, heart, eye, joint, etc.

26. Glucocorticoid drugs • (3) Septic shock: larger dose, short-term, combined with antimicrobial drugs • (4) Hemological diseases: acute lymphocytic leukemia, lymphomas, aplastic anemia, hemolytic anemia, leukocytopenia, thrombocytopenia, etc. • (5) Replacement therapy • (6) Topical applications: skin, eye, respiratory tract, joint (local injection)

27. Glucocorticoid drugs • 4. Adverse effects • (1) Effects resulting from continued used of large doses • a) Hypercorticism-like syndrome (医源性肾上腺皮质功能亢进):central obesity (moon face, buffalo hump, etc.); hypertension; glycosuria, hypokalemia; muscular atrophy, etc. • b) Increasing susceptibility to infections: • specific antimicrobial drugs should be administered with GCs • c) Digestive system:peptic ulcers, etc.

28. Glucocorticoid drugs • 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 • h) skin

29. Adverse effects of glucocorticoid drugs Effects resulting from continued used of large doses

30. Glucocorticoid drugs • (2) Withdrawal syndrome • a) iatrogenic adrenocortical insufficiency: 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.

31. 防治方法： 1）缓慢停药 2）停药前给予ACTH 5-7d 3）停药后1年内遇到手术或感染给予足量GCS 4）早晨7-8时给药 Feedback inhibition of CRH and ACTH by plasma cortisol Circadian rhythm of the secretion of ACTH and cortisol Plasma cortisol

32. Glucocorticoid drugs • (2) Withdrawal syndrome • a) iatrogenic adrenocortical insufficiency: 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.

33. Glucocorticoid drugs • (4) notes • 低糖、低盐、高蛋白饮食、补钾 • 必要时用抗糖尿病、高血压药物 • 儿童、绝经期妇女（补充蛋白质、维生素D、钙盐）

34. 糖皮质激素利弊对比

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

36. Glucocorticoid drugs • 5. Applications • (1) Low dose－replacement therapy:原发性肾上腺皮质功能减退(Addison’s disease)、继发性肾上腺皮质功能减退(脑垂体前叶功能减退、肾上腺次全切除、肾上腺危象) usually using hydrocortisone, cortisone • (2) Prompt intensive treatment :急性、重度i.v. gtt hydrocortisone, dexamethasone，short-term, 防止急性消化道出血

37. Glucocorticoid drugs • 5. Applications • (3) Long-term therapy:oral • for less severe and sustained patients (自身免疫性疾病等); • morning single dose (hydrocortisone, cortisone); • alternate-day therapy (prednisone or prednisolone) • less suppression on hypothalamic-pituitary-adrenal (HPA) axis • Prednisolone 10-30mg/d获得疗效后逐渐减量，维持最小有效剂量 • STOP：1)维持量已减至正常基础需要量、病情稳定者; • 2)疗效差 • 3)有严重副作用或并发症 • (4) Topical applications:skin; eye; respiratory tract

38. Glucocorticoid drugs • 5. Applications • 合理应用原则: • 严格掌握适应症、禁忌症 • 合理选择、足量、足疗程 • 逐步减量，以防旧病复发及肾上腺皮质功能不全 • 及时应用其他辅助药物（ACTH、补钾、补钙、补蛋白质、低钠、低糖）

39. Thyroid hormones and antithyroid drugs

40. Metabolism of thyroid hormones 1.Uptake of iodide 2.Activation of iodide (peroxidase), and iodination of tyrosine 3.Formation of thyroxine (T4) and triiodothyronine (T3) from iodotyrosine 4.Secretion of thyroid hormones (proteolytic enzymes) 5.Regulation by thyroid stimulating hormone (TSH), T4, T3

41. Regulation of the secretion of thyroid hormones (feedback inhibition)

42. Pharmacology of thyroid hormones • 1. Normalizing growth and development • 2. Promoting body metabolism • 促进氧化、增加氧耗、提高基础代谢率、产热增多 • 3. Enhancing sympathetic activity • 4. Cardiovascular effect

43. Clinical uses of thyroid hormones • 1. Treatment of hypothyroidism PRIMARY HYPOTHYROIDISM • Hoshimoto’s thyroiditis-most common • Irradiation of thyroid • Surgical removal SECONDARY HYPOTHYROIDISM • 5% of cases. • Pituitary or hypothalamic neoplasm • Congenital hypopituitarism • Pituitary necrosis

44. Common signs and symptoms Cretinism:a situation induced by a insufficiency of thyroid hormone at birth and during minority, • execute growth, twined facial features, increased tongue and mental detainment Adult: • Fatigue, weakness, weight gain, cold intolerance • Coarse, dry hair, dry and rough pale skin, hair loss • Muscle cramps and frequent muscle aches • Constipation(便秘) • Depression, Memory loss • Abnormal menstrual cycles, decreased libido • Myxedema:describes a specific form of cutaneous and dermal edema secondary to increased deposition of connective tissues, as seen in various forms of hypothyroidism

45. Thyroid Hormone Replacement • Levothyroxine (左甲状腺素) is commonly used • It can cause increases in resting heart rate and blood pressure. So replacement should start at low doses in older and patients at risk for cardiovascular compromise • In case of pituitary hypofunction, give hydrocortisone (prevent adrenocortical insufficiency) before T3 • Myxedema Coma (Below normal temperature, decreased breathing, low blood pressure, low blood sugar, unresponsiveness): T3 (fast) and hydrocortisone

46. Clinical uses of thyroid hormones • 2. Simple goiter (单纯性甲状腺肿) Supply iodide--iodide deficiency Thyroid hormones Surgery—nodule • 3. Treat after thyroid cancer surgery to reduce TSH level to inhibit recurrence of cancer

47. Antithyroid drugs

48. Hyperthyroidism • Graves Disease is the most common cause of hyperthyroidism (60-80%) of all cases. • Graves Disease is caused by an abnormal immune system response that attacks the thyroid gland, and it causes too much production of thyroid hormones. • Antibodies serve as agonists to the TSH receptors on the thyroid’s surface, causing thyroid growth and activation of hormone synthesis and secretion. • Signs and Symptoms: Hyperthyroidism, Exophthalmos, Goiter • Thyroid crisis: Exacerbation of features of hyperthyroidism- hyperpyrexia, confusion, coma, muscle weakness, arrhythmias, cardiac failure, shock, vomiting, diarrhea

49. Symptoms of the patient with hyperthyroidism

50. Therapy for Hyperthyroidism • antithyroid drugs:thiourea derivatives • iodine and iodides •  receptor antagonists • radioiodines:131I • surgery subtotal thyroidectomy