Chapter 32 Adrenocorticosteroids

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Chapter 32 Adrenocorticosteroids
zona glomerulosa mineralocorticoids
Adrenal gland
zona fasciculata glucocorticoids
cortex
zona reticularis adrenal androgens
medulla
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adrenocorticosteroids
mineralocorticoids
glucocorticoids
adrenal androgens
aldosterone desoxycorticosterone
hydrocortisone cortisone
dehydroepiandrosterone
?Structure-activity relationships

• Steroid nucleus is the common structure
• The keto group in C3, carbonyl group in C20, and
  the double bond between C4 C5 are essential for
  both glucocorticoids mineralocorticoids

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aldosterone
3. There is an a-hydroxyl group linked to C17 in
glucocorticoids but not in mineralocorticoids 4.
As for sexual hormones, C20 C21 are usually
absent.
dehydroepiandrosterone
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?Physiological regulation mechanism of
glucocorticoids secretion
_
(Hypothalamus-pituitary-adrenal gland axis)
_

• Hypothalamus
• CRH
• Anterior pituitary
• ACTH
• Adrenal cortex
• Hydrocortisone secretion

CRH corticotropin releasing hormone ACTH
adrenocorticotrophic hormone
_
plasma
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?Pharmacological effects of glucocorticoids

• Metabolic effects
• Permissive effects
• Anti-inflammatory effects
• Immunosuppressive anti-anaphylaxis effects
• Anti-shock effects
• Hematic effects
• Gastrointestinal effects
• Central nervous exciting effects

Physiol
Pharma
Adverse
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?Pharmacological effects
1. Metabolic effects
1) Carbohydrate metabolism
serum glucose??glucogen in liver muscle?
2) Protein metabolism
synthesis ?in liver but ?in lymphoid, connective
tissue, muscle, fat and skin? serum aa ?, urea
nitrogen ?
3) Fat metabolism
lipolysis?, lipogenesis??serum fatty acids
cholesterol ?
4) Electrolyte water
Na retention? , K , Ca2 water excretion?
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?Pharmacological effects
2. Permissive effects
Glucocorticoids enhances the effects of other
hormones such as catecholamine, ACTH, and growth
hormone
3. Anti-inflammatory effects
?Characteristics
1) Strong 2) Nonselective 3) Whole process of
inflammation 4) No antibacterial effect 5) A two
sides sword
Early alleviating rubefaction, tumefaction,
pain Later limiting conglutination, scar
formation
Advantage Disadvantage delaying wound healing
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Basic mechanism of action
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Zinc fingers in glucocorticoid receptor and its
binding to DNA
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• GC bind to GR in the cytoplasm where they
  dimerize and translocate to the nucleus, where
  they bind to GC response elements (GRE) on
  GC-responsive genes, resulting in increasing
  transcription of genes coding for
  anti-inflammatory proteins

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Anti-inflammatory mechanisms
GC increase the synthesis of lipocortin-1, that
has inhibitory effect on phospholipas A2 and
therefore inhibit the production of lipid
mediators as well as inhbit genes coding for
COX-2.
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Anti-inflammatory mechanisms ? ?? transcription
expression of genes for inflammation relateded
proteins their receptors ?? ?? IL-10,
lipocortin-1, neutral endopeptidase ?? ??
phospholipase A2 COX-2?? ?? prostaglandins
leukotrienes ?? ? ? IL-1, 2, 5, 6, 8
TNF-a??inflammation due to cytokines ?Induction
of endonucleases?apoptosis in inflammatory cells
such as eosinophils lymphocytes ? Inhibits
leukocytes (including macrophage) functions
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?Pharmacological effects
4. Immunosuppressive effects anti-anaphylaxis
effects 1) Immunosuppressive effects
Mechanisms ? Inhibits macrophages other
antigen-presenting cells function ? Decreases
circulating lymphocyte number ? Low dose mainly
inhibits cellular immunity, and high dose
inhibits humoral immunity 2) Anti-anaphylaxis
effects Inhibits histamine release by
basophils / mast cells
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?Pharmacological effects
5. Anti shock effect Mechanisms ?
Decreases inflammatory factors release ?
Increases body resistance to the bacterial
endotoxin ? Contracts blood vessel dilated
increases myocardial contractibility ?
Decreases vascular sensitivity to some
vasoconstrictors ? Decreases myocardial
depressant factor generation because of
stabilizing lysosome membrane.
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?Pharmacological effects

• 6. Hematic effects
• Stimulation of hematopoiesis in bone marrow
• red cells?, hemoglobin ?
• platelets ?, fibrinogen ?(in high dose)
• neutrophils increases in number, but
  decreases in function
• 2) Lymphatolysis
• lymphocytes in blood ?

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?Pharmacological effects
7. Gastrointestinal effects gastric acid ?,
pepsin ? ?peptic ulcer 8. Central nervous
exciting effects Euphoria, excitation,
insomnia Anoia induced occasionally
High dose induces convulsion in chidren.
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Representative Glucocorticoids

• Natural
• hydrocortisone cortisone
• Synthetic
• prednisone prednisolone
  
• methylprednisolone triamcinolone
• dexamethasone betamethasone
• fluocilonone beclometasone

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?Structure-activity relationships
Changing single bond between C1 C2 into the
double, the anti-inflammatory effect enhances and
salt water effects weakens e.g.
cortisone? prednisone, hydrocortisone ?
prednisolone
1.
Adding a -CH3 to C6, the anti-inflammatory effect
enhances more e.g. prednisolone?
6-methyl-prednisolone
2.
3.
Adding a -F to C9 at aposition, and adding a
-CH3 or -OH to C16 the anti-inflammatory effect
enhances and salt- retaining effects weakens
further. e.g. hydrocortisone?fludrocortisone?de
xamethasone triamcinolone
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Structure-activity relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity life

hydrocortisone 1 1
120 min
cortisone 0.8
0.8 30 min
prednisone 4
1 60 min
prednisolone 4
0.6 115-212 min
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Structure-Activity Relationships
Anti- Salt-
Plasma inflammatory retaining
half activity activity
life
4 0 78-188
min
6a-methyl-prednisolone
triamcinolone 5
0 200 mim
dexamethasone 30
0 110-210 min
betamethasone 35
0 300 min
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beclomethasone
fluocilonone
Anti-inflammatory and salt- retaining effects
both enhanced obviously
Anti-inflammatory effect is strong lasting
Local use for skin diseases
Use via nasal spray for asthma
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Clinical use 1. Adrenocortical insufficiency
Addisons disease, anteriorhypopituitarism ,
post-subtotal bilateral adrenalectomy . 2. Acute
serious infections adjuvant Bacteria
infection fulminant dysentery, bacterial
meningitis, toxic pneumonia, heavy typhoid, acute
miliary tuberculosis, scarlatina, septicemia
Virus infection heavy infectious hepatitis,
epidemic parotitis, measles, Japanese
encephalitis
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Clinical use 3. Sequelae of some inflammation
conglutination or scar pyogenic meningitis,
encephalitis, pericarditis, rheumatic heart
disease, traumatic arthritis, testitis, iritis,
keratitis, burn. 4. Autoimmunity diseases
allergic diseases 1) Autoimmunity diseases
rheumatic fever, rheumatic myocarditis, rheumatic
arthritis, rheumatoid arthritis, systemic lupus
erythematosus , polyarteritis nodosa,
dermatomyositis, nephrotic syndrome, etc. 2)
Organ transplantation rejection
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Clinical use 4. Autoimmunity diseases allergic
diseases 3) Allergic diseases urticaria,
pollenosis, serum sickness, angioneurotic edema,
allergic rhinitis, asthma, etc. 5. Shocks 1)
Septic shock early, short, large dose. 2)
Anaphylactic shock the support drugs 3)
Cardiogenic shock 4) Hypovolemic shock
transfusion first
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Clinical use 6. Hematic diseases acute
lymphoblastic leukemia, aplastic anemia,
granulocytopenia, thrombocytopenia, allergic
purpura syndrome 7. Local use on skin
contact dermatitis, eczema, anus tickle,
psoriasis, neurodermatitis Hydrocortisone,
prednisolone fluocilonone prefered
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• Adverse Effects
• Complications during chronic uses
• Cushings syndromes
• body obesity, rounded face, increased fat
  around the neck, thinning arms legs, acne,
  hirsutism, edema, hypokalemia, hypertension,
  diabetes.
• 2) Inducement or aggravation of infections
• 3) Complications of digestive system
• inducement or aggravation of peptic ulcer
• pancreatitis, sebaceous hepatitis appeared
  occasionally

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• Adverse Reactions
• Complications during chronic uses
• 4) Complications of cardiovascular system
• hypertension, atherosclerosis.
• 5) Osteoporosis, sweeny and wound healing delay
• 6) Other complications
• anoia, teratogenesis
• 2. Withdraw
• 1) Iatrogenic adrenal insufficiency
• 2) Original disease relapse or aggravation

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Contraindications Patients with
peptic ulcer, heart disease, heavy hypertension
with heart failure, infectious disease such as
varicella, tuberculosis, and psychoses, epilepsy,
osteoporosis, diabetes, or glaucoma carefully
used or forbidden! In summary,
decision caution both need for the use of
glucocorticoids evalue advantges disadvantages
of using glucocorticoids before use .
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?Pharmacokinetics 1. Absorption Oral or
injective administration easily absorbed. 2.
Transport gt90 of hydrocortisone reversibly
bound to protein if its total concentration in
plasma lt 25µg 2 plasma proteins
cortisosteroid-binding globulin (CBG)
albumin. 3. Distribution The concentration in
liver is high. 4. Metabolism Activity-lose for
all activation for some are performed in liver
O in C11 replaced by OH in liver are
essential for getting activities. e.g.
cortisone?hydrocortisone prednisone
?prednisolone. 5. Excretion kidney
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Dosage schedule

• Low dosage for replacement therapy
• Addisons disease, anteriorhypopituitarism
  , post subtotal bilateral adrenalectomy
• cortisone12.525 mg/d, or hydrocortisone
  1020 mg/d.
• Universal dosage for long term therapy
• inflammations, rheumatoid arthritis,
  lymphoma, lymphoblastic leukemia
• Started with prednisone 1020 mg, 3/d
  gradually decreased to the maintenance dose after
  obtained the initial effect.
• High dosage for implosive therapy
• Serious infections hydrocortisone i.v.d.
  200-300 mg, 1 g/d.
• Shocks hydrocortisone v.d. 1 g, 4-6 g/d.