Adrenal steroids as anti-inflammatory and immunosuppressive drugs

Question 1

State 4 stimuli for aldosterone release.

Answer 1

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

Question 2

State some clinical uses of glucocorticoids.

Answer 2

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

Question 3

What is inflammation?

Answer 3

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

Question 4

State 5 features of inflamed tissue.

Answer 4

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

Question 5

What causes these characteristics?

Answer 5

Release of inflammatory mediators such as prostaglandins and histamine

Question 6

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

Answer 6

Erythema multiforme

Question 7

What causes this?

Answer 7

Histamine release from mast cells

Question 8

Which types of cells infiltrate tissues in chronic inflammation?

Answer 8

Monocytes and lymphocytes

Question 9

What happens if tissue can’t be repaired completely?

Answer 9

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

Question 10

State 4 main characteristics of the chronic inflammatory response.

Answer 10

Tissue damage
Local repair
Scarring
Impaired tissue function

Question 11

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

Answer 11

Pyoderma gangrenosum

Question 12

What are the two mechanisms of inflammation?

Answer 12

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

Question 13

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

Answer 13

Antigen presentation

Question 14

Describe this step.

Answer 14

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

Question 15

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

Answer 15

It stimulates the generation of a clone of Th0 cells

Question 16

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

Answer 16

IL-12

Question 17

Describe 3 possible outcomes of the Th1 cells.

Answer 17

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

Question 18

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

Answer 18

IL-4

Question 19

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

Answer 19

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

Question 20

Describe the interaction between Th1 and Th2 cells.

Answer 20

Th1 produces cytokines that inhibit Th2 cells

And Th2 cells produce cytokines that inhibit Th1 cells

Question 21

State two classes of drugs used to treat inflammation.

Answer 21

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

Steroidal anti-inflammatory drugs

Question 22

Describe the effects of glucocorticoids on vascular events

Answer 22

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

Question 23

Describe the effects of glucocorticoids on cellular events.

Answer 23

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

Question 24

Which pro-inflammatory mediators do glucocorticoids reduce?

Answer 24

Histamine
Eicosanoids
Complement components
Nitric oxide

Question 25

Describe the effect of glucocorticoids on anti-inflammatory proteins.

Answer 25

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

Question 26

What effect do glucocorticoids have on extracellular matrix proteins?

Answer 26

Reduced matrix protein production | Enhanced production of degrading enzymes

Question 27

Describe how glucocorticoids have their effects.

Answer 27

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

Question 28

What are eicosanoids?

Answer 28

Metabolites of arachidonic acid

Question 29

How is arachidonic acid produced?

Answer 29

Arachiconic acid is produced from membrane phospholipids by phospholipase A2

Question 30

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

Answer 30

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)

Question 31

Describe how glucocorticoids inhibit eicosanoid synthesis

Answer 31

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

Question 32

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

Answer 32

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

Question 33

Name three glucocorticoid drugs.

Answer 33

Hydrocortisone Prednisolone Dexamethasone

Question 34

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

Answer 34

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

Question 35

Describe the plasma protein binding of these 3 drugs.

Answer 35

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

Question 36

Describe the metabolism of glucocorticoid drugs.

Answer 36

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

Question 37

State the duration of action of the 3 drugs.

Answer 37

``` Hydrocortisone = 8 hours Prednisolone = 12 hours Dexamethasone = 40 hours ```

Question 38

State three broad clinical uses of glucocorticoid treatment.

Answer 38

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

Question 39

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

Answer 39

Osteoporosis

Question 40

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

Answer 40

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

Question 41

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

Answer 41

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