Adrenocorticosteroids

Qing Peng

Department of Pharmacology

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.

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

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

History of cotisone

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.

3. Metabolized in the liver, excreted in the urine.

4. C11 ＝ O (eg, cortisone)→ － OH (eg, hydrocortisone, cortisol) activated in the liver.

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

Classifications

• 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

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. )

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 )

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.

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.

• 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

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

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

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 .

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 )

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

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

• 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

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

• 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

• 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