Lecture 4- Therapeutics for inflammation

Question 1

what are H1 receptor antagonists commonly known as?

Answer 1

Anti-histamines

Question 2

what do histamines do?

Answer 2

• increase vascular permeability

- release pro-inflammatory mediators- eosinophils, adhesion molecules etc.

Question 3

how many classes of histamine receptor are there?

Answer 3

2 (H1 and H2)

Question 4

how many generations of anti-histamines have there been?

Answer 4

3

Question 5

what was a major side-effect of anti-histamine generation 1?

Answer 5

sedation (drowsy)

Question 6

what changed from generation 1 to generation 2 of anti-histamine side-effects?

Answer 6

no sedating effects but could react with other chemical such as grapefruit juice to give cardiotoxic effects

Question 7

what changed from generation 2 to generation 3 of anti-histamines?

Answer 7

non sedating and non-cardio toxic

however they still bind to muscarinic receptors which can cause blurred vision and dry mouth

Question 8

what are the 3 actions of NSAIDs?

Answer 8

1) anti-inflammatory
2) analgesic
3) anti-pyretic (reduce fever)

Question 9

how do NSAIDs have an anti-inflammatory effect?

Answer 9

decrease in PGE2 and PGI1 to inhibit oedema

Question 10

how do NSAIDs have an analgesic effect?

Answer 10

decrease prostaglandin sythesis, less sensitisation of nociceptors to bradykinin and 5-HT

Question 11

how do NSAIDs have an anti-pyretic effect?

Answer 11

prevents IL-1 from releasing prostaglandins in te CNS so doesn’t elevate the hypothalamic set point for body temp

Question 12

what’s the worst anti-inflammatory NSAID?

Answer 12

salicylic acid

Question 13

what’s the best anti-inflammatory NSAID?

Answer 13

flurbiprofen

Question 14

is paracetamol anti-inflammatory?

Answer 14

unknown/ contraversial subject

Question 15

what 2 important enzyme families do NSAIDs have an effect on to cause side-effects?

Answer 15

COX-1

COX-2

Question 16

by what mechanism do NSAIDs inhibit COX enzymes?

Answer 16

they prevent the binding of arachidenate to the active site of the COX enzyme

Question 17

how are NSAIDs distinguished?

Answer 17

by their Cox selectivity, rather than chemical class

Question 18

what are the 4 classes of NSAIDs with examples?

Answer 18

Selective COX-1 inhibitor- low dose aspirin
Non- selective COX inhibitors- ibuprofen and high dose aspirin
Selective COX-2 inhibitors- meloxicam
Highly selective COX-2 inhibitors- celeboxib

Question 19

where does most of the knowledge about steroidal anti-inflammatory drugs come from?

Answer 19

observation of naturally produced steroids in the body

Question 20

is natural cortisol produced at a steady speed or does it fluctuate?

Answer 20

it fluctuates throughout the day

however, it increases in stressful situations like illness

Question 21

what chemical to anti-inflammatory steroids mimic?

Answer 21

cortisol

Question 22

show the natural glucocorticoid production and feedback

Answer 22

CRH (corticotropin releasing hormone)–>anterior pituitary –> releases ACTH (adrenocorticotropic hormone) –> adrenal glands (on kidney) –> circulating glucocorticoids –> stops CRH poduction from hypothalamus

Question 23

what type of feedback is there in natural glucocorticoid production?

Answer 23

negative

Question 24

what are the 3 actions of exogenous glucocorticoids (steroid anti-inflammatories)?

Answer 24

• suppress immune system (intended, therefore not side effect)
• increase blood glucose
• reduce bone formation

Question 25

give 2 examples of exogenous glucocorticoids

Answer 25

- hydrocortisol (external)- excema | - prednisolone

Question 26

what's the mechanism of actions of steroid anti-inflammatories on cells?

Answer 26

- they're lipophilic, so can enter cells - bind to cytoplasmic receptors - causes dimerisation - receptor-steroid dimer moves into nucleus - it interacts with HRE (hormone response element) - will lead to either up or down- regulation of mRNA production to either increase anti-inflammatory agents or decrease pro-inflammatory agents

Question 27

what effects do anti-inflammatory drugs have on immune cells?

Answer 27

- reduced migration of neutrophils into tissue from BVs - reduced activation of WBCs - reduced T-helper proliferation and fibroblasts e.g. collagen

Question 28

what effects do anti-inflammatory drugs have on immune chemical mediators?

Answer 28

reduced production of mediatiors such as- cytokines, TNF, cell-adhesion molecules, histamine, NO synthase, complement proteins increased synthesis of IL-10 and annexin-1 which are anti-inflammatory chemicals

Question 29

give some side-effects of steroid anti-inflammatories:

Answer 29

``` candidas bruising weight changes/ fat redistibution osteoporosis adrenal suppression ```

Question 30

what effect do steroid hormones have on HPA axis?

Answer 30

negative effect

Question 31

why can't patients come straight off most steroid drugs?

Answer 31

takes a while before the HPA axis returns to normal so need to come of slowly to prevent dangerous withdrawal symptoms

Question 32

what's the difference between NSAIDs and DMARDs?

Answer 32

NSAIDs only reduce symptoms caused by inflammation, whereas DMARDs can affect the progression of an inflammatory disease over several months

Question 33

what type of drugs do DMARDs include?

Answer 33

immunosuppressants antimalarials gold salts

Question 34

what's an important example of an immunosuppressant DMARD?

Answer 34

Methotrexate

Question 35

what does methotrexate do to cells?

Answer 35

pauses them in S-phase

Question 36

overall, what negative thing is happening in gout?

Answer 36

increased plasma urate/uric acid which deposits as crystals in synovial joints to cause pain and stiffness

Question 37

what, immune-system wise is uric acid?

Answer 37

a DAMP which stimulates the production of IL-1

Question 38

what's the acute treatment for gout?

Answer 38

- NSAIDs - corticosteroids - colchicine- reduces neutrophil mobility

Question 39

what's the long-term treatment for gout?

Answer 39

- uricosuric agents- act on kidney to increase uric acid secretion - xanthine oxidase inhibitors- increase uric acid levels in urine, therefore less in plasma

Question 40

what are anti-cytokine drugs used to treat?

Answer 40

rheumatoid arthiritis/ other inflammatory arthritis'

Question 41

what do anti-cytokine drugs target?

Answer 41

TNF and ILs (cytokines)

Question 42

why are anti-cytokine drugs expensive?

Answer 42

they are biologics (come from a living organism)

Question 43

what's a negative long-term effect of anti-cytokine drugs?

Answer 43

increased risk of infection

Question 44

what does PPAR stand for?

Answer 44

Peroxisome Proliferator Activated Receptor (agonist)

Question 45

give 2 examples of PPARs

Answer 45

- fibrates | - thiazolidinediones

Question 46

what do PPARs do?

Answer 46

reduce expression of cytokines, chemokines, cell adhesion molecules, TLRs etc.

Question 47

what are the 3 subtypes of PPARs?

Answer 47

alpha beta/delta gamma

Question 48

what's a major pathology PPARs are used to treat?

Answer 48

atherosclerosis

Question 49

what is it important to balance when treating inflammatory diseases?

Answer 49

the anti-inflammatory effects of drugs with the host's need for inflammation for immune system function