1. Adrenocorticosteroids Qing Peng Department of Pharmacology

2. Objectives List at least two representatives of short acting, intermediary acting and long acting glucocorticoids. Indicate the physiological and pharmacological effects of glucocorticoids. Describe Clinical uses and adverse reactions of glucocorticoids.

3. Physiology The natural adrenocortical hormones are steroid molecules produced and released by the adrenal cortex. –zona glomerulosa (15%) → mineralocorticoids: salt-retaining activity –zona facsiculata (78%) → glucocorticoids: intermediary metabolism –zona reticularis (7%) → sex hormones: androgenic or estrogenic activity

4. Secretion of adrenocortical steroids is controlled by the pituitary( 垂体 ) release of corticotropin (ACTH).

8. History of cotisone

9. Glucocorticoids (GC) Pharmacokinetics: 1.Rapidly and completely absorbed when given by oral administration or injection. 2.In plasma : More than 90% bound to circulating proteins, most to corticosteroid –binding globulin. 10% free, available to exert its effect on target cells.

10. 3.Metabolized in the liver, excreted in the urine. 4.C 11 ＝ O (eg, cortisone) → － OH (eg, hydrocortisone, cortisol) activated in the liver.

11. Which drugs should be selected in patients with severe liver dysfunction ？

12. Classifications

15. Pharmacodynamics: 1.Physiologic states: metabolic effects 1)Carbohydrate metabolism: stimulate gluconeogenesis( 糖原异生 ) and glycogen synthesis, increase serum glucose levels. Protein metabolism: catabolism( 分解代谢 )↑, synthesis↓ 2)Fat metabolism: fat redistribution － central obesity 3)Nucleic acid metabolism: induce RNA synthesis 4)Water and salt metabolism: reabsorption of sodium and excretion of potassium, diuresis

16. 2. Increase resistance to stress: Provide energy by raising the glucose levels. Raise blood pressure by enhancing the vasoconstrictor action of adrenergic stimuli on small vessels.(permissive effects: in the absence of which many normal functions become deficient. )

17. Ultra-physiological dose: 3.Anti-inflammatory Effects: gene effects and non- gene effects  effects on the concentration, distribution, and function of peripheral leukocytes; inhibit the functions of tissue macrophages and other antigen-presenting cells.  suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation. 4.Immunosuppressive and anti-hypersensitive Effects:  Suppress the effects of lymphocyte, inhibition of phospholipase A 2  Suppress mast cell degranulation( 脱粒 )

18. 5.Anti-shock Effects : 1)Inhibiting production of inflammatory cytokines; 2)Enhance the body’s tolerance to bacterial endotoxin; 3)Stability of lysosomal membranes, and decrease of myocardial depressant factors.

19. 6.Other Effects: 1)Antipyretic( 退热 ) effect: 2)Blood and hematopoietic( 造血的 ) system: stimulate bone marrow hematopoietic function.  increase the number of platelets and red blood cells.  neutrophil↑, lymphocyte ↓——functions ↓ 3)Nervous system:  Central nervous system excitability↑, behavioral disturbances － initially insomnia and euphoria( 欣快 ) and subsequently depression. 4)Bone: osteoporosis( 骨质疏松 )  antagonize the effect of VitD on calcium absorption.

20. Clinical Uses: 1.Diagnosis and treatment of disturbed adrenal function: 1)Adrenocortical insufficiency: replacement therapyAdrenocortical insufficiency: replacement therapy a.Chronic (Addison’s disease): 20-30 mg/d of hydrocortisone, with increased amounts during periods of stress. Plus a salt-retaining hormone such as fludrocortisone. b. Acute correction of fluid and electrolyte abnormalities and treatment of precipitating factors in addition to large amounts of parenteral hydrocortisone

21. 2)Adrenocortical hypo- and hyperfunction a.Congenital adrenal hyperplasia: disorders characterized by an enzyme defect in the synthesis of cortisol. b. Cushing’s syndrome: treatment after adrenalectomy c. Aldosteronism( 醛固酮增多症 ) : for diagnostic use

23. 3)Use of glucocorticoids for diagnostic purposes: dexamethasone suppression test → diagnosis of Cushing’s syndrome. DXM Morning cortisol Normal : 3mcg/dLCushing’s syndrom: >5mcg/dL DXM Cortisol-producing adrenal tumor: ACTH Ectopic-ACTH producing tumor: ACTH

24. 2.Stimulation of lung maturation in fetus. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone is commonly used to reduce the incidence of respiratory distress syndrome.

25. 3.Non-adrenal Disorders:  suppress inflammatory and immune response. 1)Serious infections or Inflammation: a.Serious acute infection b.Anti-inflammation: to prevent sequela ( 后遗症 )

26. 2) Autoimmune diseases, Organ transplants and Allergic reactions: a.Autoimmune diseases nephrotic syndrome, Lupus erythematosus, thrombocytopenia, rheumatic disorders. b. Organ transplants: rejection reaction↓ c. Allergic reactions

27. 3)Anti-shock: septic shock: early, short duration and large dose Allergic shock: adrenaline + glucocorticoids Hypovolemic shock: fluid supplement + glucocorticoids 4)Hematologic disorders: acute lymphoblastic leukemia (ALL), aplastic anemia, etc. 5)Topical administration : eczema, asthma

28. Adverse Reaction: 1.Long-term, large dose: 1)Digestive system complication: acute peptic ulcers, pancreatitis. 2)infection 3)iatrogenic( 医源性 ) Cushing’s syndrome: 4)Cardiovascular system : hypertension, atherosclerosis( 动脉粥样硬化 ), 5)Osteoporosis, amyotrophy( 肌肉萎缩 ), impaired wound healing, growth retardation,etc. 6)Others: hypomania( 轻躁狂 ), acute psychosis

30. 2.Withdrawal reaction: 1)iatrogenic( 医源性 ) adrenal insufficiency: When corticosteroids are administered for more than 2 weeks, adrenal suppression may occur. 2) rebound phenomenon If the dose is reduced too rapidly in patients receiving glucocorticoids for a certain disorder, the symptoms of the disorder may reappear or increase in intensity

31. Contraindication& Cautions: –Serious psychosis, epilepsy( 癫痫 ) –Active peptic ulcer, freshly gastroenterostomy( 胃肠吻合术 ) –Bone fracture, trauma in plerosis( 修复 ) –Corneal ulcer( 角膜溃疡 ) –Hyperadrenocorticism –Serious hypertension –Diabetes –Pregnant woman –Incontrollable infection by antibacterial agents

32. Usage and Course( 用法与疗程 ): 1.High-dose implosion therapy( 冲击疗法 ):  Hydrocortisone: 200~300mg/d; 3~5 day 2.Common dose long-term therapy:  Controlled dose: Prednisone( 泼尼松 ): p.o. 10~30mg, t.i.d., gradually reduced.  Maintainance dose: cortisol secretion follows a circadian rhythm:  Every morning: (short-acting) cortisone or hydrocortisone  alternate-day morning: (medium-acting) prednisone or prednisolone 3.Small dose replacement therapy:  cortisone 12.5~25mg/d or hydrocortisone10~20mg/d