T1 L14 Pharmacology of immunology

Question 1

Describe the discovery of aspirin

Answer 1

Rev Edmund Stone (1763)
 - White willow (Salix alba)
 - Used bark to treat fever and joint pain 
Felix Hoffman (Bayer)(1899)
 - Acetylsalicylic acid ‘aspirin’

Question 2

Give examples of NSAIDs

Answer 2

Aspirin
Paracetamol
Propionic acid derivatives
Arylalkanoic acids
Oxicams
Fenamic acids
Butazones
Coxibs

Question 3

How are phospholipids converted to arachidonic acid?

Answer 3

Phospholipases

Question 4

How is arachidonic acid converted to leukotrienes?

Answer 4

Lioxygenases

Question 5

How is arachidonic acid converted to prostaglandin H2?

Answer 5

Cyclo-oxygenases

Question 6

What can prostaglandin H2 be converted to?

Answer 6

Thromboxanes
Prostaglandins
Prostacyclins

Question 7

What is arachidonic acid?

Answer 7

Polyunsaturated 20 carbon lipid which is either metabolised into leukotrienes of prostaglandin H2 depending on tissue and inflammatory stimuli.

Question 8

What are thromboxanes involved in?

Answer 8

Platelet aggregation and small vessel tone

Question 9

What are prostacyclines involved in?

Answer 9

Vasodilator properties

Question 10

What are prostaglandins involved in?

Answer 10

Bronchial tone
Vascular tone
Sensitivity of nerve fibres

Question 11

What is the NSAID mechanism?

Answer 11

Inhibits cyclo-oxygenase

Prevents conversion of arachidonic acid to prostaglandin H2

Question 12

What are the 3 isoforms for cyclo-oyxygenase?

Answer 12

COX-1
COX-2
COX-3

Question 13

What is COX-1 involved in?

Answer 13

Constitutes expression for all tissues
Stomach, kidney, platelets, vascular endothelium
inhibiting has an anti-platelet activity

Question 14

What is COX-2 involved in?

Answer 14

Induced in inflammation
Injury, infection, neoplasia
Inhibition leads to analgesia and anti-inflammatory actions

Question 15

What is COX-3 involved in?

Answer 15

CNS

Inhibited specifically by paracetamol leading to antipyretic and analgesic effects

Question 16

What are the indications for NSAID therapy?

Answer 16

As mild analgesics 
 - mechanical pain
 - minor trauma
 - headaches, dental pain, dysmenorrhoea
Potent analgesics
 - peri-operative pain
 - ureteric colic
Anti-inflammatories 
 - gout
 - inflammatory arthritis

Question 17

Why is aspirin use for pain and inflammation limited?

Answer 17

GI toxicity
Tinnitus
Reye’s syndrome

Question 18

What is Reye’s syndrome?

Answer 18

Severe, sudden hepatic failure in children

Question 19

Describe the metabolism of paracetamol

Answer 19

Phase II conjugation reaction in liver to paracetamol sulphate and glucuronide which is then excreted.
Excess paracetamol is shunted to phase I oxidation reaction to produce NAPQI which causes hepatic necrosis

Question 20

What does the treatment for paracetamol toxicity rely on?

Answer 20

Provision of substrates which body can use to synthesis glutathione

Question 21

What do prostaglandins E2 and I2 do in the GI tract?

Answer 21

Decrease acid production
Increase mucus production
Increase blood supply

Question 22

What is the effect of the inhibition of prostaglandins in the gut?

Answer 22

Irritation
Ulcers
Bleeding

Question 23

What are the risk factors for an upper GI bleed?

Answer 23

Previous GI bleed
Age
Chronic disease e.g. rheumatoid disease
Steroids

Question 24

Describe the changes in glomerular blood flow caused by NSAIDs

Answer 24

Decrease in glomerular filtration rate
Sodium retention
Hyperkalaemia
Papillary necrosis

Question 25

Why do 10% of asthmatics experience bronchoconstriction following NSAID?

Answer 25

Arachidonic acid is shunted down 5-lipoxygenase pathway as COX pathway is inhibited by aspirin

Question 26

Give examples of non-selective NSAIDs

Answer 26

Ibuprofen Naproxen Diclofenac Indometacin

Question 27

What is diclofenac widely prescribed for?

Answer 27

Severe, short-term analgesia

Question 28

How is GI toxicity prevented when using NSAIDs?

Answer 28

Treat with gastroprotective drugs - misoprostol Avoid in renal failure and adjust dose if necessary

Question 29

What are COX-2 inhibitors?

Answer 29

Selective inhibition of COX-2 | Anti-inflammatory and analgesic

Question 30

What are some examples of coxibs?

Answer 30

Celecoxib Etoricoxib Foecoxib Valdecoxib

Question 31

When are COX-2 inhibitors indicated instead of non-selective NSAIDs?

Answer 31

Patients at high risk of developing gastroduodenal ulceration, perforation or bleeding After an assessment of cardiovascular risk

Question 32

What functions does cortisol influence?

Answer 32

``` Carbohydrate and protein metabolism Fluid and electrolyte balance Lipid metabolism Psychological effects Bone metabolism Profound modulator of immune response ```

Question 33

How do steroids reduce immune activation?

Answer 33

Alter gene expression in numerous cell types Steroid receptors found in cytoplasm complexed with heat-shock protein Hsp90. Steroids cross cell membrane and bind to complex releasing Hsp90. Steroid receptor complex crosses nuclear membrane. In nucleus, steroid receptor binds to specific gene regulatory sequences and activates transcription

Question 34

Describe immunomodulation by steroids

Answer 34

Cell trafficking - lymphopenia, monocytopeniaa - neutrophilic and impaired phagocyte migration Cell function - T-cell hyporesponsiveness - inhibited B-cell maturation - decreased IL-1, IL-6 and TNF alpha production - widespread inhibition of Th1 and Th2 cytokines - inhibition of COX - impaired phagocyte killing - decrease collagenases, elastases

Question 35

What is the clinical use of steroids?

Answer 35

Suppress inflammation - asthma, Crohn's, Eczema, MS, sarcoid, allergy, rheumatoid arthritis, SLE Suppress specific immunity - graft rejection

Question 36

Describe the potency, lipid solubility, systemic and topical use of hydrocortisone

Answer 36

Low potency Good lipid solubility Systemic use as replacement Topical use for skin and joints

Question 37

Describe potency, lipid solubility, systemic and topical use of prednisolone

Answer 37

Medium potency Good lipid solubility Systemic use as anti-inflammatory Topical use for enema

Question 38

Describe potency, lipid solubility, systemic and topical use of beclomethasone

Answer 38

Medium potency Poor lipid solubility No systemic use Topical use for asthma, Crohn's

Question 39

Describe potency, lipid solubility, systemic and topical use of dexamethasone

Answer 39

High potency Good solubility Systemic use for cerebral oedema No topical use

Question 40

Describe potency, lipid solubility, systemic and topical use of triaminiclone

Answer 40

High potency Poor lipid solubility No systemic use Topical use in skin and joints

Question 41

What are the early side effects of steroid therapy?

Answer 41

Weight gain Glucose intolerance Mood change Suppression of ACTH release

Question 42

What are the later effects of chronic steroid use?

Answer 42

``` Proximal muscle weakness Osteoporosis Skin changes Body shape changes Hypertension Cataracts Adrenal suppression ```

Question 43

Describe the increased risk of infection with steroids

Answer 43

Early risk of phagocytic defects - bacterial infection e.g. S.aureus, enteric bacteria - fungal infection e.g. candida, aspergillus Later risks of cell-mediated defects - intracellular pathogens e.g. TB, varicella, listeria, pneumocystis