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Adrenocorticosteroids
Qing Peng
Department of Pharmacology
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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.
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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
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• Secretion of adrenocortical steroids is controlled by the pituitary(垂体 ) release of corticotropin (ACTH).
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History of cotisone
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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.
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3. Metabolized in the liver, excreted in the urine.
4. C11 = O (eg, cortisone)→ - OH (eg, hydrocortisone, cortisol) activated in the liver.
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Which drugs should be selected in patients with severe liver dysfunction?
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Classifications
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• 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
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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. )
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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 A2
Suppress mast cell degranulation(脱粒 )
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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.
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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.
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• Clinical Uses:1. Diagnosis and treatment of disturbed
adrenal function:
1) Adrenocortical 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
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2)Adrenocortical hypo- and hyperfunctiona. 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
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3) Use of glucocorticoids for diagnostic purposes: dexamethasone suppression test → diagnosis of Cushing’s syndrome.
DXM
Morning cortisol
Normal : 3mcg/dL Cushing’s syndrom: >5mcg/dL
DXM
Cortisol-producing adrenal tumor: ACTH
Ectopic-ACTH producing tumor: ACTH
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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 .
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3. Non-adrenal Disorders: suppress inflammatory and immune response. 1) Serious infections or Inflammation:
a. Serious acute infectionb. Anti-inflammation: to prevent sequela (后遗症 )
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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
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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
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• 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
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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
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• 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
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• 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