Inflammatory response

Question 1

Definition of inflammatory response

Answer 1

A local response to injurious stimuli which signals pain to reduce further damage

Question 2

What are eicosanoids

Answer 2

C20 signalling molecules derived from arachidonic acid (from membrane phospholipid)
Includes prostanoids - prostaglandins, prostacyclins, thromboxanes

Question 3

Describe enzymatic reactions involved in producing prostaglandins

Answer 3

Membrane phospholipids converted to arachidonic acid by phospholipase A2
Arachidonic acid converted to PG-G by COX 1/2
PG-G converted to PG-H by COX 1/2
PG-H converted to PG-D/E/F/I by specific enzymes

Question 4

Properties of prostaglandin E

Answer 4

Released from BVs and local tissue

Causes vasodilation, hyperalgesia, fever and immunomodulation

Question 5

Describe COX1 enzyme

Answer 5

Constantly synthesised
Expressed in range of tissues (gastric mucosa, renal parenchyma, myocardium)
Narrow mouthed

Question 6

Describe COX2 enzyme

Answer 6

Unregulated in response to inflammatory mediators such as bradykinin
Wide mouthed

Question 7

What’s responsible for NSAIDs therapeutic and adverse effects
Why is this the case

Answer 7

Adverse reaction - COX1 inhibition (lost protective role in maintaining optimal perfusion in tissues - renal and gastric)
Therapeutic action - COX2 inhibition

Question 8

MoA of prostaglandins in causing pain via peripheral nervous system

Answer 8

Injury
Surrounding neurones synthesise PG-E2 which binds to EP1 receptors on C fibres (Gq) causing increased neurotransmitter release
This increases C fibre activity by:
Increasing neuronal sensitivity to bradykinin
Inhibiting K channels and activating Na channels

Question 9

MoA of prostaglandins in causing pain via central nervous system

Answer 9

Sustained peripheral nociception (2 weeks)
Increased cytokines production in dorsal horn cell body increases COX2 synthesis
Increased PG-E2 which binds to EP2 receptors (Gs)
Decreased glycine receptor affinity so increased pain perception

Question 10

MoA of prostaglandins in causing pyrexia

Answer 10

Endotoxins stimulate macrophages to release IL1 which stimulates PG-E2 synthesis in hypothalamus (via COX2 expression)
PG-E2 binds to EP3 receptors (Gi) which increases heat production and decreases heat loss

Question 11

What order kinetics do NSAIDs show

Answer 11

First order in therapeutic range

Question 12

4 main categories of adverse effects of NSAIDs

Answer 12

GI
Renal
Vascular
Hypersensitivity

Question 13

Mechanism of GI side effects with NSAIDs

Answer 13

COX1 inhibition reduces PG-E2 so there is reduced mucosal perfusion, less mucus secretion and more acid production
Leading to ulceration, bleeding, nausea and abdo pain

Question 14

Mechanism of renal side effects with NSAIDs

Answer 14

COX1 inhibition reduces PG-E2 and PG-I2 in renal parenchyma so there is reduced renal perfusion and decreased GFR
Leading to hyperkalaemia and fluid retention

Question 15

Mechanism of vascular side effects with NSAIDs

Answer 15

Inhibition of thromboxane A2 leads to increased bleeding time
Bruising and haemorrhage risk

Question 16

Describe hypersensitivity reactions with NSAIDs

Answer 16

Skin rashes
Asthmatic bronchospasm
Steven Johnson syndrome (immune complex mediated)

Question 17

Describe NSAIDs interaction with other NSAIDs, opiates and low dose aspirin

Answer 17

With other NSAIDs - affect each others protein binding so increased adverse drug reactions
With low dose opiates - treat pain better and less opiate mediated side effects
With low dose aspirin - compete for COX1 inhibition so aspirin loses its cardioprotective function

Question 18

What protein bound drugs can be displaced by NSAIDs and what will be the consequence

Answer 18

Sulphonylureas - hypoglycaemia
Warfarin - haemorrhage
Methotrexate - range of serious adverse drug reactions

Question 19

How does aspirin inhibit COX enzymes

Answer 19

Irreversible inhibition via acetylation

Question 20

Metabolism of aspirin

Answer 20

Short half life

Metabolised to salicylate

Question 21

What order kinetics does aspirin show

Answer 21

First order at low dose

Zero order at high dose

Question 22

Secondary benefits of aspirin

Answer 22

Inhibits thromboxane A2 so prevents atherothrombotic disease
Prophylactic for GI cancer

Question 23

Usual dose for paracetamol and when it needs altering

Answer 23

8x 500mg per day

Lower in liver patients/alcoholics

Question 24

Potential MoA of paracetamol for analgesia

Answer 24

COX inhibition in CNS

Question 25

Paracetamol metabolism at normal dose

Answer 25

First order kinetics
90% undergoes phase 2 conjugation with glucoronide or sulphate
10% undergoes phase 1 oxidation to produce NAPQI which is detoxified by glutathione

Question 26

Metabolism of paracetamol at high dose

Answer 26

Zero order kinetics
Phase 2 conjugation pathway saturated so more NAPQI produced
This is directly hepatotoxic and also depletes glutathione causing secondary oxidative damage to liver

Question 27

Treatment for paracetamol overdose

Answer 27

Look at time vs blood drug level graph, treat above normal risk line
0-4 hours: oral activated charcoal
0-36 hours: IV N-acetylcysteine