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Adrenocorticoids & adrenocortical antagonists

Adrenocorticoids & adrenocortical antagonists. Huifang Tang Email: tanghuifang@zju.edu.cn. History(1). In 1849, Addison first appreciated the importance of the adrenal glands

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Adrenocorticoids & adrenocortical antagonists

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  1. Adrenocorticoids & adrenocortical antagonists Huifang Tang Email: tanghuifang@zju.edu.cn

  2. 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.

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

  4. Adrenocortical hormones • Mineralocorticoids: aldosterone • Glucocorticoids (Glucocorticosteroids): cortisol • Sex hormones: androgens

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

  6. 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.

  7. Contents • A. Glucocorticoid drugs • B.Mineralocorticoid drugs • C. ACTH and corticosteroid synthetase inhibitors

  8. A. Glucocorticoid drugs Basic structure of glucocorticoid drugs: 甾 H C D A B 甾体结构

  9. A. Glucocorticoid drugs 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. (2)16引入羟基: triamcinolone(曲安西龙). (3)6引入甲基: 6-methylprednisone (6甲基泼尼松). (4)9引入氟原子: fludrocortosone (氟氢可的松). 基本结构 19 H 12 18 16 13 D C 14 15 1 9 2 10 8 A B 3 5 7 4 6

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

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

  12. 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

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

  14. A. Glucocorticoid drugs 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

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

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

  17. A. 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)

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

  19. A. Glucocorticoid drugs a) Increasing inflammation related proteins or enzymes inducing lipocortin, inhibiting phospholipase A2 activity, decreasing mediators: PGs, LTs, PAF inducing vasocortin, decreasing microvascular permeability inhibiting the expression of PLA2, 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 d) Inducing the apoptosis of inflammatory cells

  20. A. Glucocorticoid drugs (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):

  21. A. 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

  22. A. Glucocorticoid drugs (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)

  23. A. Glucocorticoid drugs 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.)

  24. A. 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

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

  26. A. Glucocorticoid drugs 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.

  27. A.Glucocorticoid drugs (2) Severe infection and inflammation a) acute severe infections:merely suppressing inflammatory manifestations but at times lifesaving Causion:①combination with effective anti-microbial drugs; ②Large dose; ③short 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.

  28. A.Glucocorticoid drugs (3) Septic shock: 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.

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

  30. A.Glucocorticoid drugs 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.

  31. A.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

  32. ‒ ACTH Suppression of hypothalamic-pituitary-adrenal axis andglucocorticoid drugs

  33. A. Glucocorticoid drugs (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.

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

  35. A.Glucocorticoid drugs 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

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

  37. Action of aldosterone on mineralocorticoid receptor

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

  39. C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors • 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

  40. 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

  41. C. Adrenocorticotropic hormone and corticosteroid synthetase inhibitors • 2. Corticosteroid synthetase inhibitors • Mitotane米托坦 • Metyrapone 美替拉酮 • Aminoglutethimide 氨鲁米特 • Used for adrenocortical tumors or hypercorticism

  42. 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

  43. 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 • levels 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

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