Anti-inflammatory and immunosuppresant drugs

Question 1

What are the different categories of analgesic drugs?

Answer 1

Opiates
NSAIDs (non-steroid anti-inflammatory drugs)
Local anaesthetics
Specific (others!) such as sumatriptan

Question 2

What are some examples of NSAIDs?

Answer 2

Aspirin
Ibuprofen
Paracetamol

Question 3

What are the 3 effects of NSAIDs?

Answer 3

Analgesia
Anti-inflammatory
Anti-pyretic

Question 4

How are prostaglandins synthesised?

Answer 4

Phospholipids to arachidonic acid by phospholipase A2.

Then arachidonic acid to prostaglandins by cyclooxygenase.

Question 5

What do NSAIDs do to prostaglandin synthesis?

Answer 5

Inhibit synthesis at the cyclooxygenase level

Question 6

How do NSAIDs work as analgesics?

Answer 6

Low to moderate pain (throbbing) to be counteracted.

Work by preventing Prostaglandin synthesis and therefore these PGs cannot sensitise sensory nerves.

Question 7

How do NSAIDs work as anti-inflammatory drugs?

Answer 7

Prevent PG synthesis

Question 8

How do NSAIDs work as an Anti-pyretic?

Answer 8

Pyrogens (IL-1) released by macrophages.

These cause PG release in the hypothalamus.

Question 9

What is the purpose of using anti-pyretics?

Answer 9

Prevent or reduce fever

Question 10

What are the 3 main mechanisms of action of NSAIDs?

Answer 10

Irreversible inhibition of cyclooxygenase (COX) by drugs such as aspirin

Reversible inhibition of COX by drugs such as ibuprofen

Reversible non-competitive inhibition of COX by drugs such as paracetamol.

Question 11

Why is paracetamol as an NSAID the odd one out?

Answer 11

Paracetamol is not Anti-inflammatory (therefore not an NSAID)
However there may be a different target at the site of inflammation.

Question 12

What is the benefit of taking paracetamol?

Answer 12

Paracetamol is “kinder” on the stomach compared to aspirin or ibuprofen.

Question 13

What is the function of the inner most layer of the gut?

Answer 13

Mucosa forms a protective layer from HCL (stomach acid).

In the presence of PGs the mucosa divides more regularly.

Question 14

Why would drugs such as aspirin cause an upset stomach?

Answer 14

Aspirin permenantly inhibits COX and therefore PGs decrease. This means the mucosa gets thinner and hence stomach acid (HCl) can burn through the mucosal layers.

Question 15

Why does paracetamol not upset the stomach as much as aspirin?

Answer 15

Paracetamol mops up free radicals and therefore reduces COX required and hence reduces PGs. Therefore HCl burns through again leading to an inflammatory response. This means there are more free radicals and this concentration is too high for paracetamol to have an effect therefore PGs start being produced again and the mucosa divides more regularly.

Question 16

What is COX-1?

Answer 16

Constitutive enzyme ubiquitously expressed and is responsible for gut effects.
(inhibition would be bad)

Question 17

What is COX-2?

Answer 17

Induced expression inflammatory cells responsible for inflammation.
(inhibition would be good)

Question 18

What is the similarity between COX-1 and COX-2?

Answer 18

They share 60% of sequence identity

Question 19

What type of drug would be used as a COX-2 inhibitor?

Answer 19

Rofecoxib (Vioxx)

withdrawn drug

Question 20

What was the problem with Vioxx

Answer 20

Lead to an increased risk of cardiovascular diseases such as strokes and myocardial infarctions.

Question 21

What are drugs such as celecoxib and etoricoxib used to treat?

Answer 21

Osteoarthritis and rheumatoid arthritis.

Question 22

What issues are non-selective COX inhibitors likely to cause?

Answer 22

GIT bleeding

Question 23

Why is paracetamol considered unsafe?

Answer 23

Due to the way paracetamol is metabolised, slightly higher concentrations than recommended can be lethal.

Question 24

How is paracetamol metabolised in overdose??

Answer 24

Mixed function oxidase (P450) has a high Km. (therefore need high concentrations)
This generates N-acetyl-p-benzoquinone imine (toxic metabolite) which will destroy the liver cells leading to hepatic failure and potentially death.

Question 25

How is paracetamol metabolised when it is taken at the recommended dose?

Answer 25

metabolised by glucuronide conjugation which has a low Km and therefore the P450 system is not engaged as much and toxic metabolites aren’t produced.

Question 26

How can Paracetamol overdose attempt to be treated?

Answer 26

Via acetylcysteine (IV) or methionine (po) as this increases glutathione