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Endocrinology > Adrenal steroids as anti-inflammatory and immunosuppressive drugs > Flashcards

Adrenal steroids as anti-inflammatory and immunosuppressive drugs Flashcards

1
Q

State 4 stimuli for aldosterone release.

A

Angiotensin II
High plasma potassium
Low plasma sodium
Beta-1 stimulation

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2
Q

State some clinical uses of glucocorticoids.

A 
Replacement of adrenocortical insufficiency 
Diagnosis of Cushing’s syndrome (low dose dexamethasone suppression test) 
Inflammatory disease  
Hypersensitivity  
Autoimmune disorders  
Prevent rejection 
Neoplastic disease  
Preterm birth
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3
Q

What is inflammation?

A

Vascular and cellular response to harmful stimuli (it provides powerful defence against pathogens)

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4
Q

State 5 features of inflamed tissue.

A 
Red (rubor) 
Hot (calor) 
Painful (dolor) 
Swollen (tumor) 
Loss of function (function laesa)
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5
Q

What causes these characteristics?

A

Release of inflammatory mediators such as prostaglandins and histamine

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6
Q

Name a type of inflammation of the skin that is a classic reactionto an allergen or injury.

A

Erythema multiforme

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7
Q

What causes this?

A

Histamine release from mast cells

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8
Q

Which types of cells infiltrate tissues in chronic inflammation?

A

Monocytes and lymphocytes

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9
Q

What happens if tissue can’t be repaired completely?

A

Scar tissue is placed instead – this leads to loss of function

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10
Q

State 4 main characteristics of the chronic inflammatory response.

A

Tissue damage
Local repair
Scarring
Impaired tissue function

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11
Q

Name a type of ulcer that is caused by chronic inflammation.

A

Pyoderma gangrenosum

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12
Q

What are the two mechanisms of inflammation?

A 
Innate  
 Non-specific
 Comprises of vascular and cellular events  
 Rapid 
Acquired 
 Specific
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13
Q

What is the first step of the induction phase of lymphocyte activation?

A

Antigen presentation

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14
Q

Describe this step.

A

Antigen presenting cells pick up antigen and present it on its cell surface
Then the APCs are activated and move to the lymph nodes where they encounter CD4+ T cells
They have a unique TCR – when it recognises a complementary antigen, it will bind to it (requires costimulation)
This binding activates the T-helper cell, which starts to release IL-2

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15
Q

What are the autocrine effects of IL-2 on the T-helper cells?

A

It stimulates the generation of a clone of Th0 cells

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16
Q

Which cytokine stimulates the conversion of Th0 cells to Th1 cells?

A

IL-12

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17
Q

Describe 3 possible outcomes of the Th1 cells.

A

Some will release cytokines that activate macrophages
Some will release interferon gamma, which causes differentiation of the Th1 cells into CD8+ T cells –> this develops into cytotoxic T cells
Some Th1 become memory cells

18
Q

Which cytokine is responsible triggers the differentiation of Th0 cells to Th2 cells?

A

IL-4

19
Q

What effect does the IL-4 released by Th2 cells have on B cells?

A

It stimulates B cell proliferation Some of the clones of B cells will mature into plasma cells that produce antibodies NOTE: in the effector phase of lymphocyte action you get cell-mediated and antibody-mediated actions

20
Q

Describe the interaction between Th1 and Th2 cells.

A

Th1 produces cytokines that inhibit Th2 cells

And Th2 cells produce cytokines that inhibit Th1 cells

21
Q

State two classes of drugs used to treat inflammation.

A

Non-steroidal anti-inflammatory drugs (e.g. aspirin)

Steroidal anti-inflammatory drugs

22
Q

Describe the effects of glucocorticoids on vascular events

A

Inhibits the vasodilator response Reduced fluid exudation (so reduces redness, swelling, heat and pain)

23
Q

Describe the effects of glucocorticoids on cellular events.

A

Reduces influx and activity of polymorphonuclear granulocytes
Inhibits recruitment and activity of mononuclear cells
Inhibits angiogenesis
Block clonal proliferation of T cells
Inhibit fibroblast function

24
Q

Which pro-inflammatory mediators do glucocorticoids reduce?

A

Histamine
Eicosanoids
Complement components
Nitric oxide

25
Q

Describe the effect of glucocorticoids on anti-inflammatory proteins.

A

Enhanced production of anti-inflammatory proteins e.g. annexin-1

26
Q

What effect do glucocorticoids have on extracellular matrix proteins?

A

Reduced matrix protein production

Enhanced production of degrading enzymes

27
Q

Describe how glucocorticoids have their effects.

A

They pass into the cell through the lipid membrane, bind to the glucocorticoid receptor and the glucocorticoid-receptor complex moves to the nucleus where it influences protein transcription

28
Q

What are eicosanoids?

A

Metabolites of arachidonic acid

29
Q

How is arachidonic acid produced?

A

Arachiconic acid is produced from membrane phospholipids by phospholipase A2

30
Q

Describe how arachidonic acid can be metabolised to produce various important products.

A

Arachidonic acid can be converted by lipoxygenes to leukotrienes and HETEs
It can be converted by cyclooxygenase (COX1 and COX2) to endoperoxides (prostacyclin, prostaglandins and thromboxane)

31
Q

Describe how glucocorticoids inhibit eicosanoid synthesis

A

Glucocorticoids induce synthesis of annexin-1, which then inhibits phospholipase A2
Glucocorticoids also reduce the expression of COX2

32
Q

Describe how glucocorticoids inhibit the induction and effector phases of lymphocyte activation.

A

They inhibit the expression of cytokine genes (such as IL-2)
By inhibiting IL-2, glucocorticoids inhibit the generation of a clone of Th1 cells
It also inhibits the activation of macrophages (because macrophages are activated by IL-2 released from Th1 cells)
They also have some effect of antibody-mediated reactions because blocking the first IL-2 step will reduce the number of Th0 and, hence, Th2 cells produced –> reduced activation of B-lymphocytes
Glucocorticoids target many other cytokines other than IL-2

33
Q

Name three glucocorticoid drugs.

A

Hydrocortisone
Prednisolone
Dexamethasone

34
Q

Why is hydrocortisone generally only used for short-term use?

A

It has quite profound mineralocorticoid effects so has a large side-effect profile when used in high doses

35
Q

Describe the plasma protein binding of these 3 drugs.

A

Hydrocortisone is the most plasma protein bound (90-95%) – it binds to corticosteroid binding globulin (CBG) and albumin
Prednisolone is less plasma protein bound – it binds to CBG
Dexamethasone is the least plasma protein bound – it does NOT bind to CBG and binds to albumin weakly NOTE: CBG is also sometimes called transcortin

36
Q

Describe the metabolism of glucocorticoid drugs.

A

Hepatic metabolism
The drug is conjugated and made more water soluble
It is excreted in the bile and urine

37
Q

State the duration of action of the 3 drugs.

A 
Hydrocortisone  = 8 hours  
Prednisolone = 12 hours  
Dexamethasone = 40 hours
38
Q

State three broad clinical uses of glucocorticoid treatment.

A

Anti-inflammatory and immunosuppressive (e.g. rheumatoid arthritis)
Neoplasm (e.g. to reduce cerebral oedema in patients with brain metastases, elevate mood in terminally ill patients, anti-emetic treatment with chemotherapy)
Pregnancy – to mature the foetal lung before growth - this reduces the chances of infant respiratory distress syndrome

39
Q

What is one of the most serious consequences of Cushing’s that is particularly bad in the elderly?

A

Osteoporosis

40
Q

Describe some ways in which you can minimise the unwanted effects of glucocorticoids.

A

Use locally where possible
Intermittent therapy
Use glucocorticoid receptor selective glucocorticoids
Use minimum effective dose
Recommend that patients carry a steroid dependence card

41
Q

When taking someone off glucocorticoid therapy, why must you withdraw the steroids slowly?

A

Long-term glucocorticoid therapy will suppress the HPA axis and, hence, inhibit ACTH production
This leads to adrenal atrophy so the adrenals have lost their capability to respond to stress
The dose of glucocorticoids must be reduced slowly to allow time for the adrenals to recover
If the glucocorticoids are suddenly withdrawn, it could lead to an adrenal crisis

Endocrinology (18 decks)

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