Chapter 39. Adrenocorticosteroids

Transcription

1 Chapter 39 Adrenocorticosteroids

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3 - The adrenal glands are located on the top of both kidneys. - Each adrenal gland consists of medulla and cortex.

4 Adrenal cortex corticoid Glucocorticoid, GC Mineralocorticoid

5 Adrenal cortex Composed of 3 layers (zones) outer zone (zona glomerulosa) produces aldosterone (mineralocorticoid) middle zone (zona fasciculata) produces cortisol (glucocorticoids) GC inner zone (zona reticularis) produces corticosterone and androgens

6 Aldosterone (mineralocorticoid) outer Cortisol (glucocorticoids) Adrenal cortex Androgens (sex hormones) center

7 Adrenal Gland Regulation hypothalamus (HPT) pituitary (PIT) corticotropin releasing hormone (CRH) adrenocorticotropic hormone (ACTH) ACTH is a stimulates of : - 1) the synthesis and secretion of cortisol - 2) the growth of the adrenal gland When cortisol levels increase, this shuts off CRH and ACTH secretion.

8 O Chemical structure and structure-activity relationships 1 The common structure of adrenocortical hormones: 4 circums: A B C D Carbon C3: carbonyl group Basic structure: steroid core 21 CH 2 OH C4-5 :double bond C20 :carbonyl group A 5 R B C C 17 D O

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10 Adrenal cortex corticoid Glucocorticoids, GCs Mineralocorticoid

11 Glucocorticoids---overview Glucocorticoids are similar to hormones that your adrenal glands produce to fight stress associated with illnesses and injuries. They reduce inflammation and affect the immune system.

12 Glucocorticoids---overview You may need them to treat: Arthritis Asthma Autoimmune diseases such as lupus and multiple sclerosis Skin conditions such as eczema and rashes

13 Glucocorticoids---overview Steroids are strong medicines, and they can have side effects, including weakened bones and cataracts. Because of this, you usually take them for as short a period as possible.

14 Injection, orally, Topical glucocorticoid inhalers

15 GLUCOCORTICOIDS (GCs) Mechanisms of action G-R

16 Mechanisms of action : Most of the known effects of the GCs are mediated by widely distributed GC receptors, which regulate the transcription of the target genes.

17 GC receptors Tau 1 DNA binding domain ligand binding domain (eg, steroids) N Zn Zn C HSP90 binding domain Consist of 800 amino acids. Taul: in the N-end (nitrogen), regulating domain, related to transcription gene. DNA binding domain (zinc-fingers): related to the control of transcription gene activation and dimeric formation. HSP90 binding domain: bind with HSP90. Ligand binding domain: C-end (carbon), bind with steroids.

18 Anti-inflammatory effects Mechanisms of action GCs Bind to the Receptors, GCs interact with ngre to inhibit transcription of some cytokines related to chronic inflammation, such as IL-l, TNF a, GM-CSF, IL-3, IL-4, IL-5, IL-6, IL-8, and potently suppress the cytokinemediated inflammation.

19 1. Physiological effects of GCs

20 Physiological effects: A. Carbohydrate metabolism GCs increase liver glycogen, muscle glycogen deposition and blood glucose levels.

21 Physiological effects: B. Protein metabolism GCs increase the protein breakdown and inhibit the synthesis of protein. So, Long-term use of GCs can result in growth arrest, muscle wasting, thinning of skin, osteoporosis, atrophy of lymph tissue, delay of wound-healing.

22 Physiological effects: C. Lipid metabolism GCs increase lipolysis, and inhibit lipid synthesis. So, Long-term use of GCs can cause redistribution of body fat. Redistribution of body fat from extremities (ie. arms and legs) to neck, face and abdomen.

23 Physiological effects: D. Water and electrolyte metabolism The GCs also possess Mineralocorticoids activity, i.e. natrum retension and potassium excretion. Excessive GCs lower the blood calcium level, and the bone will be osteoporosis in the long-term therapeutic use of GCs.

24 Long-term use of Glucocorticoids can cause

25 2. Pharmacological effects of GCs

26 1. Anti-inflammatory effects GCs can prevent or suppress all kinds of inflammation caused by physical, chemical, biological, and immunological stimuli.

27 Anti-inflammatory effects In the early stage of inflammation GCs suppress the exudation, edema, phagocytosis, improve early inflammatory symptoms such as redness, swelling, hot. In the late stage of inflammation GCs suppress the proliferation of capillaries and fibroblasts, delay the formation of granulation tissue, prevent the tissue adhesion or scar formation. The function of the late stage of inflammation is an important cause of tissue rehabilitation.

28 Anti-inflammatory mechanism of GCs GCs bind to receptors anchored in the target cells, affecting gene transcription which are concerned with inflammation and exert the function of anti-inflammation.

29 2. Immunosuppressive effects Inhibit many types of immune responses. Small dosage of GCs ---- inhibit cellular immunity. Large dosage of GCs ----inhibit the B lymphocyte transforming into plasma cells, decrease the production of antibodies, interfere with humoral immunity.

30 3. Anti-shock effects Super high-dose of GCs is widely used for all kinds of severe shock, especially the therapy of toxic shock. May be related to the following factors: * (a) Dilating contracted blood vessels, and strengthening the cardiac contractility; * (b) Reducing the sensitivity of blood vessels to some vesselcontracting substances, improving the state of shock; * (c) Stabilizing of lysosome membrane and suppressing myocardial depressing factor formation; * (d) increasing the tolerance of human body to endotoxin.

31 4. Other effects Effects on central nervous system (CNS) Adrenal insufficiency caused marked psychiatric depression. Increased amounts of GCs often produce behavioral disturbances in humans initially insomnia and euphoria and subsequently depression. Large doses of GCs may induce convulsion in children.

32 4. Other effects Effects on gastrointestinal tract GCs increase the secretion of gastric acid and pepsin, improve the appetite, promote the digestion. But large dosage of GCs can induce or aggravate ulcer.

33 4. Other effects Effects on blood system GCs stimulate the hemopoiesis of the bone marrow, increase the levels of Red Blood Cell (RBC) and hemoglobin (Hb). Large doses of GCs increase the blood levels of platelet and the fibrinogen.

34 4. Other effects Effects on fetal lungs GCs have important effects on the development of the fetal lungs. The structural and functional changes in the lungs near term, are stimulated by GCs.

35 Pharmacological effects of GCs

36 Pharmacological effects of GCs 1. Anti-inflammatory effects 2. Immunosuppressive effects 3. Anti-shock effects 4. Other effects Effects on central nervous system (CNS) Effects on gastrointestinal tract Effects on blood system Effects on fetal lungs

37 3. Therapeutic applications of GCs

38 1. Chronic adrenocortical insufficiency Replacement treatment Addison s disease

39 Addison s disease Definition Addison's disease is a disorder that occurs when the adrenal glands do not produce enough of their hormones.

40 Addison s disease Symptoms: Hyperpigmentation--- increased skin pigmentation of creases, nipples. weakness, fatigue and anorexia, weight loss. nausea, vomiting and diarrhea.

41 Treatment Treatment with replacement corticosteroids will control the symptoms of this disease. However, you will usually need to take these drugs for life. People often receive a combination of glucocorticoids (cortisone or hydrocortisone) and mineralocorticoids (fludrocortisone).

42 Treatment The health care provider may increase the medication dose in times of: Infection Injury Stress

43 2. Severe infections or inflammations 1) Severe acute infections 2) Prevention of some inflammatory sequela

44 3. Autoimmune and allergic diseases Autoimmune disease: Such as rheumatic fever, systemic lupus erythematosus (SLE), nephropathy syndrome etc. Combination use of GCs is recommended to avoid the untoward effects.

45 Allergic diseases: Such as urticaria, hay fever, serum fever, hypersensitivity rhinitis, asthma, allergic shock, etc.

46 4. Anti-shock therapy Super high-dose of GCs is widely used for all kinds of severe shock, especially the therapy of toxic shock. GCs can be applied to infectious toxic shock in a high dosage, with immediately withdrawal after taking effects. GCs are the second-line drugs for allergic shock. For the treatment of hypovolemic shock, super large dosage of GCs should be used.

47 5. Hematologic disease GCs can be applied to: acute lymphatic leukemia aplastic anemia allergic purpura

48 6. Topical administration Topical administration of GCs is applied to contact dermatitis, eczema.

49 4. Adverse effects of GCs

50 Adverse effects a). Adverse effects caused by long-term and overdose therapy b). Withdrawal reactions

51 a). Adverse effects caused by longterm and overdose therapy 1. Hyperadrenalism-like syndrome Disappear automatically after drug withdrawal.

52 Adrenocortical hyperfunction Cushing s syndrome Due to excess production/administration of GCs * Redistribution of body fat from extremities (i.e. arms and legs) to neck, face and abdomen. *Muscle wasting, thinning, poor wound healing, and osteoporosis. *Mental disorders, hypertension, and diabetes.

53 Treatment of Cushing s syndrome This disorder is treated by surgical removal of the tumor producing ACTH or cortisol, irradiation of the pituitary tumor, or resection of one or both adrenals. These patients must receive large doses of cortisol during and following the surgical procedure. The dose must be reduced slowly to normal replacement levels, since rapid reduction in dose may produce withdrawal symptoms.

54 a). Adverse effects caused by long- term and overdose therapy 2. Induction or aggravation of infections This is mainly caused by the inhibition of the body recovery ability. 3. Gastrointestinal complications GCs promote the secretion of gastric acid and pepsin, inhibit secretion of gastric mucin, and decrease the resistance of gastrointestinal mucosa, which induce or aggravate the ulcers.

55 b). Withdrawal reactions 1. Adrenal cortex atrophy and insufficiency * For long-term application patient, rapid withdrawal of GCs will cause adrenal cortex atrophy and insufficiency due to the negative feedback inhibition of ACTH secretion. * The recovery of adrenal function is related to dosage, duration of drug application and individual differences. * The recovery of pituitary ACTH secretion function takes 3-5 months after drug withdrawal; the recovery of response of adrenal cortex to ACTH takes 6-9 months or more, which are the reasons that the sudden withdrawal of GCs should always be avoided.

56 b). Withdrawal reactions 2. Rebound phenomena Discontinuing or rapid extenuation of GCs can lead to original diseases recurring or deteriorating.

57 5. Dosage schedules of GCs

58 A. High dose bolus therapy This method is used in serious toxic infections and all kind of shock. B. Common dose, long-term therapy This administration method is used in desmosis, nephropathy syndrome, obstinate asthma, etc. C. Alternate-day therapy

59 C. Alternate-day therapy * The secretion of cortex hormone is featured with day-night rhythm.

60 Fluctuations in plasma ACTH and glucocorticoids throughout the day in a normal girl. ACTH and glucocorticoid rises in the morning, before awakening from sleep.

61 C. Alternate-day therapy * The climax of secretion is 8-10 AM. According to this rhythm, alternate-day therapy for chronic diseases with long-term administration can be adopted, i.e., the total dosage of a day or two days is given one time in the alternate-day morning. For it is the time of the highest tide of the hormone secretion, the suppression of adrenal cortex is slight.

62 Adrenal cortex corticoid Glucocorticoids, GCs Mineralocorticoid

63 Mineralocorticoids: Mineralocorticoids play a critical role in regulating concentrations of minerals - particularly sodium and potassium - in extracellular fluids. loss of these hormones leads rapidly to lifethreatening abnormalities in electrolyte and fluid balance.