Anti-inflammatory Drugs

Question 1

NSAID characteristics

Answer 1

analgesic, anti-inflammatory, anti-pyretic

Question 2

NSAID mech of action

Answer 2

Inhibition of COX

Question 3

Types of COX

Answer 3

COX-1: constitutive enzyme

COX-2 : Induced at site inflmmation

Question 4

Why are newer NSAID’s preferred

Answer 4

Selective for COX-2 v. older which is unselective and binds mainly to COX-1 -> less toxicity on GI track but cardiovascular side effects are a problem

Question 5

Anti-pyretic effect of NSAIDS mec of action

Answer 5

1. exogenous pyrogens are engulfed by macrophages to make endogenous pyrogens e,g, IL1. TNFa
2. Endogenous pyrogen leads to PGE2 formation in hypothalamus
3. PGE resets body’s thermostat to higher level
   - > NSAIDS inhibit PGE2 -> normal level

Question 6

How do NSAID’s provide analgesisa?

Answer 6

Since PGE2 sensitises sensory nerves at site of inflammation -> lower pain threshold + CNS effect -> inhibit PGE2 = reverse

Question 7

NSAID’s inhibit formation of XYZ which does ABC

Answer 7

X = PGE2
Y = PGD2 
Z = PGI2 
A = Decrease HR 
B = decrease rednesss 
C = decrease oedema of inflammation

Question 8

How does PGE2 interact with COX-1 and what happens when this is inhibited?

Answer 8

PGE2 from COX-1 in stomach inhibits gastric acid secretion + promotes protective mucus formation + bicarbonate release
-> when inhibited -> mucosa ulcerates + bleeds

Question 9

Only natural steroid

Answer 9

hydrocortisone

Question 10

Why might I use a synthetic compound over hydrocortisone?

Answer 10

1. improve potency

2. improve selectivity

Question 11

Steroid examples

Answer 11

Prednisolene, betamethascine, glutocorticoids

Question 12

Steroids general mech:

Answer 12

1. anti-inflammatory
   i) early events: vaso D, oedema, leucocyte, infiltration + activation
   ii) later) cell proliferation, macrophage activity, fibroblast activity, angiogenesis
2. Immunosppressive

Question 13

Steroids also suppress

Answer 13

Production of autocoids e.g. PG’s, LT’s, TX’s -> histamine release from basophil inhibited

Question 14

Glucocorticords characteristics

Answer 14

Lipid soluble, easily cross cell membrane and binds GR which causes loss of hsp complex -> reveals translocation + DNA binding region on GR -> receptor enters nucleus

Question 15

Once in nucleus, steroid mechanism of action:

Answer 15

1. Binds G regulatory element + activating gene transcription of anti-inflammatory proteins e.g. Lipocortin-1 (calcium reg. annexin), IKB
2. Binds GRE -> neg. regulate pro-infl. gene transcription e.g. IL-1
3. Transexpression of NFKB at DNA
4. Direct bind soluble TF’s/ transactivators

Question 16

Steroid effects:

Answer 16

1. Synthesis/ suppression of proteins - not immediate
2. Anti-inflammatory -> after hours
3. Decrease cox products
4. decrease lipocygenase products
5. decrease leucocyte infiltration + activation
6. decrease bronchoconstriction
7. decrease COX2, NOS, adhesion and cytokines

Question 17

Tumour necrosis factor (TNFa) characteristics

Answer 17

• Cytokine ( 3 x 17KDa protein trimer)

- key regulatory in chronic inflammatory diseases

Question 18

TNFa effects

Answer 18

1. Cytokine synthesism angiongenesis
2. Acute phase protein release - fibroblast
3. cytotoxic. cytostatic for cells
4. activates granulocytes + macrophages
5. bone metabsorption by osteoclasts
6. inhibits collagen synthesis + promotes breakdown
7. Activates endothelial cells