NSAIDs

Question 1

What is a drug?

Answer 1

A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.

Question 2

Drugs are generally derived from…?

Answer 2

Plants or animals, created synthetically, or produced by genetic engineering.

Question 3

What are medicines?

Answer 3

Contain drug/s plus other agents e.g. preservatives, bulking agents, solvents

Question 4

What happens in Phase 1 trials?

Answer 4

First time in humans - a small number of healthy volunteers (50-200) take part to examine the pharmacologic actions and safe dosage range of a drug, how it is absorbed, distributed, metabolised and excreted.

Question 5

What happens in Phase 2 trials?

Answer 5

Studies in volunteers (100-400) with the disease to assess if the drug has any effect and at what doses.

Question 6

What happens in Phase 3 trials?

Answer 6

Determine efficacy; Randomised controlled trials of the drug among 1000-3000 highly-selected individuals with the disease. Compare the drug to placebo or to an alternative treatment.

Question 7

What are the limitations of phase 3 trials?

Answer 7

Restricted population studied
Numbers are limited
Women and older people with multiple diseases often excluded
Children excluded
Duration of study limited
No information on benefits, risks, outcomes associated with long-term us
Outcome studied may be a surrogate not the clinical outcome of interest
Studies are not powered to determine adverse effects so knowledge about safety is very limited
People taking the drug are unlikely to all be like the phase 3 study population

Question 8

What are phase 4 studies?

Answer 8

Studies of safety/pharmacovigilance

Question 9

NSAIDs are effective as…?

Answer 9

Analgesics and for reducing inflammation

Question 10

What was the first NSAID?

Answer 10

Aspirin

Question 11

What was already being used in Roman times to treat inflammation?

Answer 11

Plants containing salicylic acid and its derivatives, e.g. willow bark

Question 12

When was salicylic acid first synthesised?

When was it first registered?

Answer 12

1859

1899

Question 13

How many aspirin tablets are consumed each year?

Answer 13

10 to the 11, e.g. 32,000 tons

Question 14

When was the mechanism of action of aspirin first known?

Answer 14

1970s

Question 15

Which NSAIDs prescription rate has increased significantly recently?

Answer 15

Naproxen

Question 16

What is the Cyclo-oxygenase enzyme (Cox) involved in?

Answer 16

Prostaglandin synthesis from arachidonic acid and oxygen

Question 17

What are the actions of prostaglandins?

Answer 17

Pyretic
Pro-inflammatory
Hyperalgesic
Inhibit gastric acid	secretion
Generated by	platelets
Contract	the uterus
Increase	renal blood flow

Question 18

What are the actions of aspirin?

Answer 18

Antipyretic, anti-inflammatory, analgesic, GI side effects, anti-platelet effect, delays labour and may lead to kidney problems

Question 19

What did John Vane demonstrate in 1971?

Answer 19

That aspirin, salicylate and indomethacin blocked the production of PGs in vitro.

Question 20

When was ibuprofen launched (prescription only)?

When did it become available over the counter?

Answer 20

1969

1983

Question 21

Which COX enzyme has physiological functions?

Which has an inflammatory role?

Answer 21

COX-1 (constitutive)

COX-2 (inducible)

Question 22

What are the three broad categories of COX inhibition mechanisms?

Answer 22

Category 1 - rapid competitive reversible binding of COX-1 and COX- 2 (e.g. ibuprofen)
Category 2: rapid, lower-affinity reversible binding followed by time-dependent, higher-affinity, slowly reversible binding of COX-1 and COX-2 (e.g. diclofenac)
Category 3: rapid reversible binding followed by covalent modification of COX-1 and/or COX-2 (non-competitive, irreversible) (e.g. aspirin).

Question 23

Why is low-dose aspirin cardio-protective?

Answer 23

It falls into category 3, where there is irreversible covalent modification. Platelet COX-1 is irreversibly inhibited for the lifetime of the platelet hence aggregation inhibited.

Question 24

Give some examples of COX-2 selective NSAIDs.

Answer 24

Rofecoxib and celecoxib

Question 25

Inhibition of COX-1 and -2 by a non-selective NSAID

Answer 25

NSAID blocks entrance channel to COX-1

Binding/transformation of Arachidonic Acid prevented

Question 26

Inhibition of COX-2 by a COX-2 selective NSAID

Answer 26

Fits into COX-2 side pocket

Too bulky to fit into COX-1 entry channel so Arachidonic Acid can reach COX-1 site for transformation

Question 27

What is the major unwanted adverse effect of COX-1 inhibition?

Answer 27

Loss of gastric protection, causing ulcers and bleeding

Question 28

Why was Rofecoxib withdrawn voluntarily from the market in 2005?

Answer 28

Pharmacovigilance studies and other randomised controlled trials revealed cardiovascular risk problems.

Question 29

Which NSAID should not be prescribed for people with ischaemic heart disease?

Answer 29

Diclofenac (non-selective but potent COX-2 inhibitor)

Question 30

Which NSAIDs are associated with an increased risk of CVS disease?

Answer 30

Rofecoxib, diclofenac, high-dose ibuprofen and celecoxib

Question 31

Which NSAID appears to have a neutral risk for CVS disease at high and low doses?

Answer 31

Naproxen (suppresses platelet thromboxane production)

Question 32

Why do all NSAIDs appear to be associated with increased heart failure risk in vulnerable individuals?

Answer 32

Impact on homeostasis/intravascular fluid volumes