S8.1 NSAIDs

Question 1

What is the inflammatory response?

Answer 1

A protective response to injurious stimuli to reduce risk of further damage to organism.

Question 2

What are the substances involved in the inflammatory response?

Answer 2

Autacoids - bradykinin, histamine, cytokines

Eicosanoids - prostaglandins

Question 3

How are prostaglandins formed?

Answer 3

Phospholipids converted to arachidonic acid, which is metabolised by COX 1 to PG G, which is metabolised by COX 2 to PG H.
From PG H we can produce specific PGs, PG E most important in mediating inflammatory response.

Question 4

What is the action of prostaglandins?

Answer 4

Prostaglandins bind to GPCRs, the action usually involves synergising effects of other autacoids.
They cause pain, pyrexia and inflammation, which NSAIDs can prevent.

Question 5

How do NSAIDs cause analgesic effects?

Answer 5

Decreased synthesis of PGE2 in the dorsal Horn leads to reduced neurotransmitter release, and therefore reduced excitability of pain relay neurones

Question 6

How do NSAIDs cause anti-inflammatory effects?

Answer 6

Following injury, there’s increased release of PGE2 which results in swelling. NSAIDs inhibit COX enzymes leading to reduced PGE2 synthesis. This reduces inflammation but little effect on the underlying condition.

Question 7

How do NSAIDs cause anti-pyretic effects?

Answer 7

Cytokines act on the hypothalamus to stimulate PGE2 release. NSAIDs inhibit hypothalamic COX2 enzymes, reducing PGE2

Question 8

What are the features of COX1 enzymes?

Answer 8

PG synthesis by COX-1 has a major cytoprotective role (in gastric mucosa, myocardium, renal parenchyma, and ensures local perfusion).
Most of the ADRs of NSAIDs are caused by COX-1 inhibition

Question 9

What are the features of COX2 enzymes?

Answer 9

Is expressed during injurious stimuli. The main therapeutic effects of NSAIDs come via COX-2 inhibition.

Question 10

Describe GI ADRs of NSAIDs

Answer 10

COX 1 PGE2 usually stimulates protective mucus production and inhibits acid secretion, thus inhibition to PGE2 production will result in damage to the stomach.
Can lead to ulceration, gastric bleeding.

Question 11

Describe renal ADRs of NSAIDs

Answer 11

PGE2 maintains renal blood flow, if PGE2 reduced by NSAIDs then GFR shall drop, hypertension can also occur.

Question 12

Describe vascular ADRs of NSAIDs

Answer 12

NSAIDs cause increased risk of prolonged bleeding time, haemorrhage, and increased bruising

Question 13

Describe some other ADRs of NSAIDs

Answer 13

Hypersensitivity reactions (SJ syndrome)
Reye's syndrome: brain/ liver injury

Question 14

Describe some DDIs of NSAIDs

Answer 14

With aspirin - competes with COX1 binding sites interfering with aspirins cardioprotective role.
With sulphonylureas - can get hypoglycaemia
With warfarin - can get increased bleeding
With methotrexate - can get hepatic toxicity

Question 15

Describe the features of aspirin

Answer 15

Only NSAID which irreversibly inhibits COX enzymes via acetylation (not by competitive blocking).
Also acts as an as an anti-platelet as it prevents thromboxane A2 production

Question 16

Describe the toxicology of paracetamol at normal doses?

Answer 16

Paracetamol shows linear PKs. 90% enters phase 2 conjugation forming glucuronide and sulphate, rest enters phase 1 oxidation to produce NAPQI.
NAPQI is very reactive and toxic, it is detoxified by phase II conjugation with glutathione.

Question 17

Describe the toxicology of paracetamol at high doses >10g?

Answer 17

Pharmacokinetics becomes zero order.
Phase II metabolism becomes saturated which leads to increase in phase I production of NAPQI. Increase in NAPQI will deplete the glutathione levels.

Question 18

What is the treatment for paracetamol overdose?

Answer 18

IV N-acetylcysteine or oral methionine (to replenish glutathione levels).