(7.1) NSAIDs

Question 1

What’s the mechanism of action of NSAIDs

Answer 1

• NSAIDs competitively block COX enzymes 1 & 2, which are involved in:
• Arachidonic Acid -> Prostaglandin H2

Question 2

How do COX 1&2 enzymes different in their structures and roles?

Answer 2

• COX 1: small binding site; produce PGH in many organs all the time to enhance perfusion
• COX 2: large binding site, activated by Bradykinin at injury site (therapeutic target)

Question 3

How do Prostaglandins induce pain centrally?

Answer 3

• Binds to EP2 receptor (GsA) on C-fibres in Dorsal Horn
• +Adenyl Cyclase -> + PKA
• Inhibition of Glycine receptors -> reduced Inhibitory potential -> Increased pain

Question 4

How do Prostaglandins induce pain peripherally?

Answer 4

• Binds to EP1 receptor (GqA) on C-fibres

- +Na channels & - K channels -> hyperexcitibility -> Increased pain

Question 5

How do Prostaglandins induce pyrexia?

Answer 5

• Macrophages -> IL-1 -> Hypothalamus -> release Prostaglandin
• Binds to EP3 receptor (GiA) at injured site -> -Adenyl Cyclase -> -cAMP -> +[Ca2+]i -> heat production

Question 6

Name one example of a long acting and a short acting NSAIDs.

Answer 6

• Long: Naproxen

- Short: Ibuprofen

Question 7

What does it mean by NSAIDs exert dose-dependent kinetics?

Answer 7

• Low dose shows First Order Kinetic (conc is proportional to metabolism, e.g. linear Log[drug] to time graph)
• High dose shows Zero Order Kinetic (metabolism is constant at any drug conc.)

Question 8

List 4 ADRs of NSAIDS and how are they produced?

Answer 8

Actions on COX 1 enzymes, reducing Prostaglandin at organs:

• GI: ulceration, haemorrhage, perforation (Prostaglandin normally -> +Neck cell to produce mucus & +Epithelial cell to produce HCO3-)
• Renal: -perfusion & -GFR (Prostaglandin normally -> vasodilation of Afferent arterioles)
• Vascular: bleeding, bruising, haemorrhage (Prostaglandin normally -> +Thromboxane A -> Platelet aggregation
• Hypersensitivity -> rashes or bronchospasm in asthmatics

Question 9

Why do you need to be careful when prescribing NSAIDs to a patient who’s on Sulphonylureas?

Answer 9

NSAIDs heavily bind to plasma proteins -> displace Sulphonylureas -> Hypoglycaemia

Question 10

What is the mechanism of action of Aspirin?

Answer 10

Acylation of COX enzymes e.g. non-reversible

Question 11

Suggest 4 indications of Aspirin.

Answer 11

• Athero-thrombotic disease: Post-MI & Stroke (-Prostaglandin -> -Thromboxane A -> -Platelet aggregation)
• Colon cancer
• Pain

Question 12

Describe the metabolism of Paracetamol at therapeutic level and why is it dangerous if overdosed?

Answer 12

• Therapeutic level -> 90% straight into Phase II
• 10% enters Phase I -> Oxidation -> NAPQI -> conjugate with Glutathione
• If overdose -> Glutathione depleted -> unconjugated NAPQI -> Toxic

Question 13

How can you treat Paracetamol overdose?

Answer 13

• IV N-Acetylcysteine
• IV Charcoal
• Oral Methionine