1. Adrenocorticoids & adrenocortical antagonists
Huifang Tang

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.

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

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

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

8. 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.

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

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

11. 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

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

13. Mechanisms of glucocorticoid actions
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)

14. 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

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

16. 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

17. 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.

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

19. 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)

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

21. 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

22. 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):

24. 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

25. 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)

26. 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.)

27. 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

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

30. 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.

31. 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.

32. 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.

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

34. 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.

35. 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

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

37. 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.

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

39. 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

40. 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

41. Action of aldosterone on mineralocorticoid receptor

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

43. 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

44. 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

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

49. 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

50. 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):
levels are unchanged

51. 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