NSAIDS and Pain Processing

Question 1

What are eicosanoids?

Answer 1

Small lipid molecules derived from arachidonic acid

Question 2

What is the rate limiting step in the production of eicosanoids?

Answer 2

Release of AA by phospholipase A

Question 3

List three examples of eicosanoids

Answer 3

Prostaglandins
Thromboxanes
Leukotrienes

Question 4

What drives the synthesis of eicosanoids?

Answer 4

Stimuli such as cell death
Eicosanoids have a role in inflammation
Present at tissue damage site

Question 5

Which two fatty acids metabolise eicosanoids?

Answer 5

COX1 and COX2

Question 6

Describe co enzymes COX1 and COX2

Answer 6

COX1- constitutive, expressed all the time, in most tissues (platelets)
normal physiological wellbeing
COX2- Induced in activated inflam cells- IL1/TNF gamma produce prostaglandin inflam mediators

Question 7

List the 4 cyclic endoperoxides

Answer 7

PGI2- vasodilator- IP receptor 
PDG2- vasodilator DP receptor
TXA2- vasoconstrictor TP receptor
PGF2- acts on FP receptor
PGE2- EP receptor

Question 8

How does inflammation occur

Answer 8

Inflam due to release of PGE2 and PGI2- gen by local tissue and bv
Mast cells release PGD2

Question 9

What is the main effect of chronic inflammation?

Answer 9

Increase in macrophages/monocytes

Question 10

What is the main effect of PGD2, PGI2, PGE2?

Answer 10

Powerful vasodilators

Increase blood flow to inflammation and leakiness of bv

Question 11

How is itch produced?

Answer 11

Prostanoid synergises with histamine

Question 12

How is pain produced?

Answer 12

Prostanoid synergises with bradykinin

Question 13

Why is there redness?

Answer 13

Increased blood flow to the area

Question 14

Describe bradykinin

Answer 14

Synthesised de novo during tissue damage
Made in vasculature by activated enzymes
PG sensitive nociception
Activate nociceptors by B1 and B2 receptors, increase PG prod, enhance nociceptor response to BK

Question 15

What are the three main uses of NSAIDs?

Answer 15

Anti inflammatory- decrease vasodilation and oedema
Anti pyretic- decrease body temp. NSAIDs reset thermostat in hyp. Block changes in hyp by PG
Analgesic- for pain assoc with inflam/tissue damage eg arthritis, muscle pain, toothache

Question 16

What are NSAIDs used in combination with?

Answer 16

Opioids to decrease chronic pain post op/cancer

Question 17

What are the clinical uses of NSAIDs?

Answer 17

Short term- Ibuprofen, aspirin, paracetamol
Long term- naproxen, piroxicam
Chronic/acute inflam- lupus, gout, rheum arthritis- high dose
Decrease temp in fever

Question 18

How does aspirin work?

Answer 18

Irreversible inactivation of COX1/2
Oralm rapid absorp, 75% metab in liver
1st order elimination, half like of 48 hours
Antiplatelet drug in MI therapy+ CVA prophylaxis

Question 19

What are the main side effects of NSAIDs

Answer 19

GI effects- gastric ulcers- bleeding
Dyspepsia, bloating, diarrhoea, nausea, vomiting
Skin rash, dizzy, deaf, tinnitus, viral encephalitis in kids
Toxic dose- uncompensated resp and metabolic acidosis

Question 20

How does paracetamol work?

Answer 20

Analgesic, antipyretic, anti inflam
Metab in liver- 2-4 hours, few side effects- kidney damage with high dose
Toxic dose- nausea and vom and liver damage

Question 21

How do selective COX2 inhibitors work

Answer 21

VIOXX, Merck- risk of heart attack, stroke, CV death

Celecoxib- 375 fold selective for COX2