NSAIDs

Question 1

Examples of prostanoids + their actions

Answer 1

• Prostaglandins: vasodilators
• Prostacyclin (PGI2): vasodilator | prevent platelet aggregation
• Thromboxane: platelet granule > initiation of platelet aggregation | vasoconstrictor
• PGE2: good for stomach > regulation of a stomach acid

Question 2

How are prostanoids produced?

Answer 2

Produced locally on demand from arachnoid acid

Question 3

Role of prostanoids in the GI system

Answer 3

• PGE2: regulation of acid secretion in parietal cells
• prostacyclin: maintenance of blood flow + mucosal repair

Question 4

How do prostanoids signal?

Answer 4

Act locally via many GPCRs

Question 5

What is a consequence of imbalance of prostanoids?

Answer 5

Hypertension
MI
Stroke

Question 6

Why is the Mediterranean diet suggested to lower incidence of CVD?

Answer 6

• diet is rich is fish oil
• proposed to lead to conversion of thromboxane + PGI3 (better prostanoids)

Question 7

What are the two functional isoforms of cyclooxygenase enzymes?

Answer 7

COX-1
COX-2

Question 8

Compare the haemostatic function of COX-1 + COX-2

Answer 8

COX-1:
- GI protection
- platelet aggregation
- vascular resistance
.
COX-2:
- renal homeostasis
- tissue repair + healing
- uterine contractions
- inhibition of platelet aggregation

Question 9

Compare the pathological functions of COX-1 + COX-2

Answer 9

COX-1:
- chronic inflammation
- chronic pain
- hypertension
.
COX-2:
- chronic inflammation
- chronic pain
- fever
- blood vessel permeability

Question 10

Compare the active sites in COX-1 + COX-2

Answer 10

COX-2 has a larger + more flexible binding site

Question 11

What is the common mode of action of NSAIDs?

Answer 11

Inhibition of COX
- decrease prostaglandin, prostacyclin + thromboxane synthesis
- compete with arachidonic acid for site of COX enzymes

Question 12

What are three general actions of NSAIDs?

Answer 12

Analgesia
Anti-inflammatory
Antipyretic

Question 13

How do NSAIDs work as analgesics?

Answer 13

• COX inhibition
• decreases PGE2 synthesis in dorsal horn
• decrease neurotransmitter release > decrease excitability of neurone in pain relay pathway
• inhibition reduces peripheral pain fibre sensitivity

Question 14

How do NSAIDs work as anti inflammatories?

Answer 14

• COX inhibition
• reduce production of prostaglandins released at site of injury
• reduces vasodilation + swelling

Question 15

How do NSAIDs work as antipyretics?

Answer 15

Inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated > reduced temperature

Question 16

Outline NSAID COX selectivity

Answer 16

COX1 selectivity
- aspirin
- ibuprofen
- naproxen
- diclofenac
- celecoxib
- etoricoxib
COX2 selectivity

Question 17

What are GI adverse drug reactions of NSAIDs?
What is this due to?

Answer 17

• dyspepsia
• nausea
• peptic ulceration
• bleeding + perforation
• exacerbation of IBD
  .
• decreased prostaglandins
• reduction in mucosal blood flow > hypoxia
• reduction in mucous + bicarb secretion > increased acid secretion

Question 18

What are important drug drug interactions of NSAIDs in relation to GI ARDs?

Answer 18

• aspirin
• Glucocortioid steroids
• anticoagulants
  (PPI should be considered as additional drug)

Question 19

What are renal adverse drug reactions of NSAIDs?
What is this due to?

Answer 19

• reversible decreases in renal blood flow + GFR
  .
• reduction in prostaglandins
• reduced vasodilation of afferent arteriole
• reduced blood supply

Question 20

What are important drug drug interactions of NSAIDs in relation to renal ARDs?

Answer 20

ACEi
ARBs
Diuretics

Question 21

Examples of selective COX-2 inhibitors

Answer 21

Celecoxib
Etoricoxib

Question 22

Difference in selective COX2 inhibitors + non selective ADRs

Answer 22

• less GI ADRs
• renal ADRs similar

Question 23

Effect of thromboxane + prostacyclin on CVS

Answer 23

Thromboxane is generally bad
Prostacyclin is generally good

Question 24

How does NSAID use effect MI risk?

Answer 24

• All NSAIDs (but baby aspirin) increase risk of MI
• possibly due to decrease in prostacyclin

Question 25

What are considerations/possible contraindications of NSAIDs?

Answer 25

- CVD - renal function - GI disease - DDIs - level of pain, pyrexia + inflammation - 3rd trimester of pregnancy

Question 26

What are indications for NSAID use?

Answer 26

- inflammatory conditions - osteoarthritis - post op pain - Menorrhagia - low dose aspirin for platelet aggregation inhibition - topical use on cornea

Question 27

What is the mechanism of action of paracetamol?

Answer 27

COX-2 selective inhibition in CNS

Question 28

How can NSAIDs increase free plasma conc. of other drugs?

Answer 28

Competitively displaced other bound drugs > increase free drug conc.

Question 29

What builds up in paracetamol overdose?

Answer 29

NAPQI

Question 30

What is used to treat paracetamol overdose? How does it work?

Answer 30

**N-acteylcysteine** - replaces glutathione which is protective agaisnt NAPQI

Question 31

Difference in action of COX-1 + COX-2 inhibition in relation to platelet aggregation

Answer 31

- COX-1inhibitors decrease thromboxane > decrease platelet aggregation - COX-2 selective inhibitor’s decrease PGI > unopposed aggregatory effects

Question 32

Why can NSAIDs exacerbated CKD? Why do ACEi/ARB compound this?

Answer 32

- NSAID use > reduction in prostaglandins > reduction in vasodilation > reduced GFR + renal blood flow - in CKD, there is a greater reliance on PG for vasodilation + renal perfusion . - ACEi/ARBs cause vasodilation > increase renal blood flow

Question 33

Describe how NSAIDs should be prescribed

Answer 33

Lowest effective dose for shortest time necessary

Question 34

Presentation + consequences of paracetamol overdose

Answer 34

- asymptomatic at first - N+V + abdo pain in first 24 hours - maximal liver damage occurs at 3-4 days

Question 35

What NSAID is most selective for COX2?

Answer 35

Etoricoxib

Question 36

What are mechanisms by which NSAIDs can cause GI ADRs?

Answer 36

- Decreased mucous secretion - Decreased bicarbonate secretion - Reduced mucosal blood flow - Inhibtion of PGE2 + PGI2 cause them