W1 5 Anti-inflammatory steroids

Question 1

Where are corticosteroids synthesised?

Answer 1

Middle layer of adrenal cortex

Question 2

What are corticosteroids split into?

Answer 2

Glucocorticoids and mineralocorticoids

Question 3

What is the endogenous glucocorticoid?

Answer 3

Cortisol

Question 4

What is cortisol synthesised from?

Answer 4

Cholesterol. Retains 4 ring chemical structure.

Question 5

What compound is made chemically to mimic cortisol?

Answer 5

Hydrocortisone

Question 6

What chemical properties of hydrocortisone make it differ from cortisol?

Answer 6

Position of side-groups increase selectivity to gluco and mineralocorticoids
Fluoridation increases half-life of drugs
Double bond in ring increases potency

Question 7

What actions does cortisol have?

Answer 7

Anti-inflammatory actions

Question 8

What axis is cortisol part of?

Answer 8

Hypothalamus-pituitary adrenal axis - HPA axis

Question 9

Describe the negative feedback loop involving cortisol - PG46

Answer 9

Hypothalamus releases CRH stimulating the anterior pituitary gland to release ACTH, stimulating the adrenal gland to release cortisol.
Cortisol negatively feedbacks on the HPA to decrease its own production
It acts on many tissues to have metabolic effects
Pro-inflammatory mediators flow to HPA axis to generate cortisol and limit inflammation
Chronic stimulation of cortisol might shut down the HPA system, causing atrophy
Stress, inflammation, immune system all can cause the system to release cortisol

Question 10

What is the implication of being a steroid for absorption?

Answer 10

Steroids are lipophilic and easily absorbed in the gut
Not in plasma freely, so are bound to a carrier protein

Question 11

Which proteins are steroids bound too?

Answer 11

Transcortin is a specific carrier protein. It has a high affinity for steroids but low capacity.
Majority are bound to albumin. It has a high capacity but low affinity.

Question 12

Once in the tissues, the steroid freely diffuses into the cell cytoplasm, where the glucocorticoid receptor is located. What are the different domains of a glucocorticoid receptor?

Answer 12

Ligand binding domain - where steroid will bind
DNA binding domain - related to an action
HSP binding domain - anchors it to the cytoplasm

Question 13

What happens as the steroid binds to the receptor?

Answer 13

The binding to the HSP is broken and thus free the receptor to allow it to move into the nucleus.

Question 14

What happens once the steroid is inside the nucleus?

Answer 14

Can turn a gene on = trans activation - upregulates anti-inflammatory mediators
Can bind to genes and turn them off = transrepression - down regulates the pro-inflammatory mediators

Question 15

How long does the typical steroid anti-inflammatory effect take?

Answer 15

6-8hrs

Question 16

Do anti-inflammatory drugs need an initiating stimulus to work?

Answer 16

No, anti-inflammatory drugs will work independent of initiating stimulus

Question 17

What happens to the body in an inflammatory response? PG48

Answer 17

We would have PLA2 breaking down phospholipids to make arachidonic acid, and COX2 to make prostanoids, which would have an inflammatory effect.

Question 18

What would a glucocorticoid do (to genes) to have an anti-inflammatory effect? PG48

Answer 18

Stimulate annexin-1 production which would inhibit PLA2 and stop the formation of arachidonic acid. (trans activation)
Stop the formation of COX2 (trans repression)
Annexin-1 can also inhibit the inflammatory response and promote recovery

Question 19

What non-genomic response can steroids have?

Answer 19

Stabilise lysosomal membranes. Prevents the release of pro-inflammatory enzymes from damaged cells.

Question 20

What are some examples of short-acting (<12hrs) glucocorticoids?

Answer 20

Hydrocortisone, cortisone

Question 21

What are some examples of intermediate-acting (12-36hrs) glucocorticoids?

Answer 21

Prednisolone
Prednisone
Triamicinalone

Question 22

What are some examples of long-acting (>36hrs) glucocorticoids?

Answer 22

Dexamethasone
Betamethasone
Paramethasone

Question 23

What uses do glucocorticoids have outside of dentistry?

Answer 23

Allergies, asthma, cancer

Question 24

How are glucocorticoids delivered for allergies like allergic rhinitis or dermatitis/eczema?

Answer 24

Usually aerosol or cream = ability to give a high local dose

Question 25

How are glucocorticoids delivered in asthma?

Answer 25

Inhalation of direct local access

Question 26

Are allergies and asthma treated chronically with glucocorticoids?

Answer 26

Yes chronic treatment, but delivery means there will be small systemic effect

Question 27

Briefly describe the role of glucocorticoids in cancer

Answer 27

(Not really important card - skip) Curative role for lymphoid cancers to stop lymphocyte proliferation and cause immune suppression Non-curative role as anti-emetic

Question 28

Uses of glucocorticoids in dentistry

Answer 28

Oral ulcerations - eg denture induced trauma Pulpal hypersensitivity Post-operative sequelae - to reduce post-surgical oedema

Question 29

Advantages of glucocorticoids

Answer 29

Easily absorbed into the GI tract and locally into skin/mucous membranes

Question 30

Disadvantages of glucocorticoids

Answer 30

Lack of specificity - have multiple effects Are an anti-inflammatory but also have metabolic effects

Question 31

What are the adverse effects of glucocorticoids?

Answer 31

Chronic use causes same symptoms as Cushing’s disease

Question 32

What will chronic GC use cause?

Answer 32

Chronic GC use will chronically suppress the HPA axis and chronically reduce ACTH, leading to adrenal atrophy. Consider adrenal insufficiency. Sudden withdrawal will lead to adrenal crisis - a medical emergency.

Question 33

Symptoms of Cushing’s disease

Answer 33

Hyperglycaemia Moon face Increased susceptibility to infection Oedema CNS irritability Personality changes Osteoporosis Thin skin Purple striae Bruises Thin extremities

Question 34

What has similar features to adrenal crisis?

Answer 34

Addisons disease

Question 35

What are the features of adrenal crisis/addisons?

Answer 35

Hypoglycaemia, renal shutdown (decreased sodium and increased potassium), profound fatigue, dehydration, vascular collapse (cause hypotension), GI disturbances, weakness, weight loss Pg50

Question 36

What are the adverse immune effects of chronic GC use and their implications?

Answer 36

Immune suppression - increased risk of infection Wound healing Skin/mucosa thinning - wound repair impaired

Question 37

Why does chronic GC use cause hyperglycaemia?

Answer 37

Glucocorticoids increase blood glucose levels, stimulating gluconeogenesis

Question 38

Why does chronic GC use cause osteoporosis?

Answer 38

Reduced Ca absorption from the gut and increase calcium secretion from the kidneys

Question 39

List all the metabolic implications of chronic GC use

Answer 39

Hyperglycaemia, myopathy, osteoporosis, body fat distribution, fluid retention, electrolyte balance (high sodium low potassium)

Question 40

What are the dental implications of chronic GC treatment?

Answer 40

Increased risk of infection from dental procedures Impaired wound healing Adrenal insufficiency - book surgery in morning for diurnal variation Invasive surgery - requiring complete replacement ‘steroid cover’ - GA normally produce cortisol. If suppressed then not making it and so need cover.