NSAIDs

Question 1

What do NSAIDs do?

Answer 1

inhibit the production of prostanoids by COX enzymes

Question 2

What three things are classified as prostanoids?

Answer 2

• prostaglandins
• thromboxane
• prostacyclin

Question 3

How many known prostanoid receptors are there?

Answer 3

• 10 known
• naming based on agonist potency
• physiological and pro-inflammatory effects

Question 4

How many receptors can PGE2 activate?

Answer 4

4 (EP1, EP2, EP3 and EP4)

this is via cAMP-dependant and independent downstream mechanisms

Question 5

What are the unwanted actions of PGE2?

Answer 5

• increased pain perception
• increased body temperature
• acute inflammatory response
• immune responses
• tumorigenesis
• inhibition of apoptosis

Question 6

WHat do PGE2 analogues do?

Answer 6

• lower the pain threshold

Question 7

By what mechanisms do COX inhibitors raise the pain threshold?

Answer 7

suggested involvement of EP4 receptors and endocannabinoids
-there is cross-talk between prostanoids and the endocannabinoid receptors so there is neuromodulation

COX inhibitors raise the pain threshold by blocking the production of PGE2

Question 8

What does PGE2 do?

Answer 8

resets the body’s thermostat

it is important in acute inflammation and in sustaining and maintaining chronic inflammation

Question 9

What are the effects of NSAIDS on renal blood flow?

Answer 9

-cause renal toxicity

-constrict the afferent arteriole
reduce renal artery flow
reduce glomerular filtration rate

if you look at the urine of patients taking NSAIDS you see the epithelial calls have been sloughed off and come out in the urine

Question 10

How is PGE2 involved in gastric cytoprotection?

Answer 10

• downregulates HCL secretion in the stomach
• lots of PGe2 produces less acid and stimulates the production of mucus and bicarbonate
• the mucus protective layer acts as a physical barrier to the acid and stops it from damaging the cell surface

Question 11

What does reducing PGE2 with NSAIDS lead to an increased risk of?

Answer 11

• increased risk of ulceration

Question 12

What do most COX products cause?

Answer 12

-bronchodilation

Question 13

Why should NSAIDS not be taken by asthmatics?

Answer 13

inhibition of COX favours the production of leukotrienes which are bronchoconstrictors

Question 14

What serious unwanted effects can NSAIDs have?

Answer 14

• cardiovascular

there is an increase in incidence of MI and stroke in patients that use NSAIDs chronically

• vasoconstriction
• salt and water retention
• hypertension

Question 15

What are the effects of NSAIDs comparing analgesic use and anti-inflammatory use

Answer 15

analgesic: occasional and relative low risk of side effects

anti-inflammatory: often sustained, higher doses, relatively high risk of side effects

Question 16

Which isoform of COX does ibuprofen and indomethacin inhibit? With what effect

Answer 16

• inhibits both COX-1 and COX-2

- analgesic, anti-pyetic and anti-inflammatory actions

Question 17

What is the effect of Celecoxib?

Answer 17

• selectively inhibits COX-2

- it has less effect on COX-1 mediated processes, leading to a decrease in the incidence of ulceration

Question 18

What do COX-1 and COX-2 inhibitors increase the risk of?

Answer 18

COX-1 selective NSAIDS increase the GI risk

COX-2 selective NSAIDs increase the CVS risk

Question 19

Outline the mechanism by which COX-2 selective NSAIDs increase CVS risk

Answer 19

• inter with the balance of prostacyclin and thromboxane, which will increase the risk of thrombosis

Question 20

Why can all NSAIDs contribute to CVS risk?

Answer 20

-increase the production of oxygen free radicals that affect multiple pathways and can contribute to CVS disease

Question 21

What strategies are used to limit the GI side effects?

Answer 21

• administer the NSAID with omeprazole or other proton pump inhibitor
• minimise use in patients with other risk factors and reduce them where possible e.g. alcohol consumption
• minimise use in patients with GI ulceration history

Question 22

What is unique about aspirin?

Answer 22

• selective for COX-1 and irreversible

- analgesic, anti-inflammatory and anti-pyretic

Question 23

How does aspirin affect platelet aggregation?

Answer 23

at high dose it will reduce prostacyclin and thromboxane production

Question 24

Why can endothelial cells replenish COX compared to platelets?

Answer 24

-they are nucleated so they can resynthesize COX and maintain prostacyclin production

Question 25

What are the anti-platelet actions of aspirin due to?

Answer 25

• COX-1 inhibition which suppresses thromboxane A2 production by platelets
• covalent binding irreversibly inhibits platelet COX-1

Question 26

What are the major side effects of aspirin?

Answer 26

• gastric irritation and ulceration
• bronchospasm in sensitive asthmatics
• prolonged bleeding times
• nephrotoxicity

side effects are more likely because it inhibits COX covalently

Question 27

What happens to paracetamol in an overdose?

Answer 27

• during metabolism a toxic metabolite Is formed which usually is mopped up by glutathione
• in an overdose there is depletion of glutathione stores
• the toxic metabolite binds to any -SH- group they can find , which leads to hepatic cell death

Question 28

What is the antidote for paracetamol poisoning?

Answer 28

• add a compound with -SH- groups
  -usually IV acetylcysteine
  occasionally oral methionine

Question 29

Why is paracetamol not classed as a NSAID?

Answer 29

it does not have anti-inflammatory effect