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Drugs affecting endocrine system

Drugs affecting endocrine system. Weiwei Hu huww@zju.edu.cn 88208226 Dept. Pharmacology, Medical School, Zhejiang University. Drugs related to adrenocortical hormones Thyroid hormones and antithyroid drugs Insulin and oral hypoglycemic drugs. Cortex: adrenocorticoid Glucocorticoids

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Drugs affecting endocrine system

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  1. Drugs affecting endocrine system Weiwei Hu huww@zju.edu.cn 88208226 Dept. Pharmacology, Medical School, Zhejiang University

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

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

  4. Adrenocorticoid • Glucocorticoids : hydrocortisone, cortisone • Mineralocorticoids： aldosterone，desoxycortone • Sex hormones

  5. 黄山药 穿地龙 薯蓣属植物（黄山药、穿地龙） 提取薯蓣皂苷元合成皮质激素

  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) 1位和2位碳之间改成不饱和的双键: 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: fludrocortosone (氟氢可的松). (3)引入甲基: 6-methylprednisolone,dexamethasone (6甲泼尼龙, 地塞米松). (4) 16引入羟基: 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. binding to glucocorticoid receptor (GR) nuclear translocation binding to GRE or nGRE regulating related gene transcription biological effects (usually slow) Mechanisms of glucocorticoid actions

  11. 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

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

  13. 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

  14. 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↓

  15. 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)

  16. 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.

  17. PAF Lipid-derived autocoids and related drugs

  18. 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:decreasing the transcription and activities of TNF, IL-1, IL-2, IL-5, IL-6, IL-8, etc. c) Inhibiting adhesion molecules d) Inducing the apoptosis of inflammatory cells

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

  20. (4) Effects on immune and allergy

  21. Glucocorticoid drugs • (4) Effects on immune and allergy • Suppressing immuneological functions and allergy • 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 • d) inhibit the allergic mediator production

  22. Examples of glucocorticoid actions: Inhibition of proinflammatoryfactors (AP-1 and NFB)

  23. Glucocorticoid drugs • (4) Effects on immune and allergy • Suppressing immuneological functions and allergy • a) inhibit DNA, RNA and protein synthesis, and induce the DNA degeneration of lymphocytes • b) inducing apoptosis of T and B lymphocytes • c) inhibiting transcription factor － such as nuclear factor B (NF-B) or activating protein-1 (AP-1) activity • d) inhibit the allergic mediator production

  24. Glucocorticoid drugs • (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

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

  26. 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.)

  27. 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

  28. PK – Administration and Absorption • Intravenous • conjugated with phosphate or hemisuccinate to increase solubility • Oral • Prednisolone and prednisone are the most common • Others include methylprednisolone, dexamethasone • Inhalation • Increase local effective dose and decrease systemic toxicity

  29. Glucocorticoid drugs • 3. Clinical uses • (1) Immune diseases • a) autoimmune disorders:rheumatic fever, rheumatic carditis, rheumatic arthritis, osteoarthritis, systemic lupus erythematosus, polyarteritisnodosa, 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.

  30. Glucocorticoid drugs • (2) Severe infection and inflammation • a) acute severe infections:merely suppressing inflammatory manifestations but at times lifesaving • 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.

  31. 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)

  32. 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.

  33. 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

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

  35. 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.

  36. Feedback inhibition of CRH and ACTH by plasma cortisol Circadian rhythm of the secretion of ACTH and cortisol Plasma cortisol

  37. 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.

  38. 糖皮质激素利弊对比

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

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

  41. Case A: Part 1 A 55-year-old male immigrant with no significant past medical history came to the emergency department for evaluation of a 3-day history of dyspnea, non-productive cough, and fever. Physical examination revealed tachypnea(心悸), diffuse end expiratory wheezes. The patient was started empirically on a cephalosporin(头孢菌素) and a macrolide(大环内酯) for community-acquired pneumonia. Given the diffuse wheezing on exam, he was also treated with intravenous corticosteroids.

  42. Case: Part 2 Over subsequent days, the patient deteriorated, developing respiratory failure and requiring transfer to the intensive care unit. Diffuse wheezing persisted. Subsequent chest radiographs and CT scans revealed progressive bilateral diffuse granular opacities. More extensive work-up pursued to evaluate for atypical and fungal pneumonia revealed no culprit organism. Bronchoscopy revealed thick yellow mucus and cultures were sent. Ultimately, bronchial washings demonstrated the larvae of strongyloidesstercoralis (粪类圆线虫). What will you do then? What do you learn from this case?

  43. The Presented Case • Proper therapeutic regimen would have included discontinuing glucocorticoids, and providing appropriate anti-infectives for S. stercoralis: thiabendazole(噻苯咪唑) and ivermectin(伊维菌素)

  44. Glucocorticoids • Glucocorticoids not helpful in Strongyloides stercoralis • Should be considered essentially for acute use, with plans to taper or replace with other medications • Exceptions are chronic or prolonged diseases for which there are no more therapeutic options

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

  46. Future developments • Further separation of their anti-inflammatory effects from the toxicity associated with their metabolic effect, e.g. Deflazacort,a predinisolone derivative with lower lipid solubility, has less activity on bone, carbohydrate and lipid metabolism • Concurrent administration of other drugs to diminish the side effects: e.g. Ca++ and vitamin D supplementation; growth hormone treatment to reverse glucocorticoid-induced growth retardation in children. • Elucidation of downstream pathways may allow the design of new drugs which mimic corticosteroid action, e.g. screening of small molecules that can interact with co regulator proteins or NF-kB transcription factors may represent a promising approach in this effort.

  47. Mineralocorticoid drugs Aldosterone 醛固酮 • Na+ excretion , K+ excretion : edema, hypertension, hypokalemia, etc.

  48. Effects of Aldosterone Cardiac Myocyte Fibroblast Peripheral Artery Kidney Vasoconstriction Potassium Loss Hypertrophy Hyperplasia Endothelial Dysfunction Sodium Retention Collagen Synthesis Norepinephrine Release Hypertrophy Fibrosis Decreased Compliance

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