8.2.1 NSAIDs I

Question 1

What are prostanoids?

Answer 1

Active lipid mediators that regular inflammatory response

Question 2

What are some examples of prostanoids?

Answer 2

PGE2
PGF2 alpha
PGD2
TXA2

PG-prostaglandin

Question 3

How are prostanoids synthesised?

Answer 3

Arachadonic acid incorporated into phospholipids

Arachadonic phospholipid complex catalysed by COX1 and COX2 to form prostanoids

Produced on demand

Question 4

How do prostanoids have fine local control?

Answer 4

Due to short half-lives

Question 5

What do PGE2 and PGI2 do?

Answer 5

PGE2
Contributes to regulation of acid secretion in parietal cells

PGI2
PRostacyclin-contributes to maintenance of blood flow and mucosal repair

Question 6

How do prostanoids act?

Answer 6

Act locally at GPCRs, action depends on receptor type and location

Question 7

How are actions of prostanoids enhanced?

Answer 7

Enhanced by local autacoids e.g. bradykinin and histamine

Question 8

Which prostanoids must have a fine balance between them?

Answer 8

TXA2 and PGI2 as they have opposing vascular effects

Important for haemodynamic and thrombogenic control

TXA2- vasoconstriction and platelet aggregation

PGI2- vasodilation and inhibition of platelet aggregation

Question 9

What does an imbalance in prostanoids lead to?

Answer 9

Significant role in hypertension, MI and stroke risk

Question 10

What diet cause higher levels of TXa3 and PGI3?

Answer 10

Diet rich in fish oils “Mediterranean diet”

Better prostanoids, lower incidence of CVD

Question 11

What are the two functional isoforms of cyclooxygenase enzymes?

Answer 11

COX-1-active across most tissues
COX-2-mostly in chronic inflammation, constitutively in brain, kidney and bone

Question 12

Complete the table

Answer 12

Question 13

What are the structural difference between COX-1 and COX-2?

Answer 13

COX-2 has a larger and more flexible substrate channel than COX-1

COX-2 has a large space at the site where inhibitors bind

Question 14

What are NSAIDs used for mainly?

Answer 14

Analgesic and anti-inflammatory effects

Question 15

What is the single common mode of action of NSAIDs ?

Answer 15

Inhibition of COX

Reduces synthesis of:
- Prostaglandin
- Prostacyclin
- Thromboxane

Competes with arachidonic acid for hydrophobic site of COX enzymes

Question 16

What is the mechanism of NSAIDs for analgesia?

Answer 16

Inhibition of COX reduces peripheral pain fibre sensitivity due to blocking of PGE2

Reduction of PGE2 in dorsal horn
Reduction of neurotransmitter release
Decreased excitability of neurones in pathway to brain

Question 17

When is the full analgesic effect of NSAIDs acheived?

Answer 17

Efficacious after first dose

Full analgesia after several days dosing

Question 18

What is the mechanism of action of NSAIDs for reducing inflammation?

Answer 18

NSAIDs reduce production of prostaglands released at site of injury

PGs normally released causing vasodilation(post-capillary venules), increasing permeability leading to vasodilation and oedema

Question 19

What is the effect of NSAIDs on underlying chronic conditions?

Answer 19

Little effect

Give symptomatic relief with COX inhibition

Question 20

What is the mechanism of NSAIDs reducing pyrexia?

Answer 20

PGE2 critical component in the preoptic area of the hypothalamus

Can still be stimulated by cytokines

Inhibition of hypothalamic COX2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature

Question 21

How are NSAIDs differentiated?

Answer 21

By their selectivity

High prevalnce of ADRs attributed to COX1 selective inhibitiors

COX2 selective inhibitors inhibitor COX2 with much greater selectivity than COX1

Question 22

Give some examples of NSAIDs and their COX selectivity

Answer 22

Aspirin

Ibuprofen
Naproxen
Diclofenac

Celecoxib
Etoricoxib

CoxiB
B is 2nd in the alphabet so if it ends in coxib its more selective for COX2

Question 23

What are the GI considerations of NSAIDs?

Answer 23

Dyspepsia
Nausea
Peptic ulceration
Bleeding
Perforation
Exacerbation of IBD

Relative risk of GI bleed increases by 1-10x depending on NSAID

Question 24

Why do NSAIDs cause GI issues?

Answer 24

Inhibiton of COX enzymes leads to reduced prostaglandin synthesis causing:
- Decreased mucus and bicarbonate secretion
- Increased acid secretion
- Decreased mucosal blood flow causing enhanced cytotoxicity and hypoxia

Question 25

When should you not use NSAIDs?(GI)

Answer 25

Elderly
Prolonged use
Smoker
Alchol
History of peptic ulceration
Helicobacter pyrloi

Question 26

What are some important drug to drug interactions with NSAIDs? (GI)

Answer 26

Aspirin
Glucocorticoid steroids
Anticoagulants (PPI should be considered)

Question 27

What are some adverse drug reactions of NSAIDs? (Renal)

Answer 27

• Reversible decrease in GFR, decreased renal blood flow
  Therapeutic dose in healthy person- less issues
• Prostaglandins inhibit sodium absorption in the collecting duct, NSAIDs inhibit this causing increase in Na+, H2O, BP

Question 28

When should you not use NSAIDs? (Renal)

Answer 28

CKD
Heart failure

More likely to have low GFR and rely on prostaglandins for vasodilation of the afferent arteriole to maintain GFR pressure and renal perfusion

Question 29

What are some important drug to drug interactions with NSAIDs? (Renal)

Answer 29

ACEi
ARBs
Diuretics