NSAID

Question 1

What can Arachidonic acid be converted into and by what?

Answer 1

Lipoxins by 15-lipoxygenase
Prostanoids by Cyclooxygenase
Leukotrienes by 5-lipoxygenase

Question 2

What are the different type of prostanoids?

Answer 2

Prostacyclin
Classical prostaglandins
Thromboxane

Question 3

What is the effect of Prostacyclin?

Answer 3

Vasodilation
inhibit platelet aggregation

Question 4

What is the effect of classical prostaglandins?

Answer 4

Increase vascular permeability and pain

Question 5

What is the effect of thromboxanes?

Answer 5

Vasoconstriction and platelet aggregation

Question 6

What are the effects of Aspirin?

Answer 6

1. Analgesic
   2.Anti-pyretic (by blocking prostaglandin)
   3.Anti platelet

Question 7

Explain the “analgesic ceiling” effect of Aspirin

Answer 7

Production of prostaglandin (which causes pain) is blocked by Aspirin. –> this sensitive the nociceptive fibres to stimulation by other inflammatory mediator, making them more sensitive to other compounds like Bradykinin and leukotrienes which can result in pain sensation

Question 8

Explain why Aspirin is antiplatelet even though it inhibits production of prostacyclin (inhibits platelet aggregation)

Answer 8

Aspirin inhibits both Prostacyclin (which inhibits platelet aggregation) and Thromboxane A2 ( which promotes platelet aggregation)

PGI2 can be restored by synthesis of new COX enzyme which takes a few hours while TXA2 can only be restored by the formation of new platelets which takes 1-2 weeks

Net effect of inhibit platelet aggregation

Question 9

Aspirin is a ____ (reversible/irreversible) COX inhibitor

Answer 9

Irreversible

Question 10

What can aspirin be used for?

Answer 10

Aspirin is used at low dose as a blood thinner in cardiovascular diseases

Question 11

What are the adverse effect of aspirin?

Answer 11

COX inhibition –> Salicylate toxicity when at high doses ( GI intolerance and tinnitus)

Always linked to Reye’s Syndrome. Children with viral infection could develop encephalitis (swelling of brain), hepatomegaly. Contraindicated in children

Question 12

When is aspirin given in children?

Answer 12

Kawasaki Syndrome when there is high risk of cardiovascular complications including aneurysm and impaired blood flow to periphery.

Question 13

What are some adverse effect of typical NSAIDS?

Answer 13

PGE2 (prostaglandin)
- Reduce gastric acid section
-increase mucosal blood flow
-increase secretion of mucus
- increase secretion of bicarbonate

Ulcer formation and haemorrhage risk in chronic users

Inhibition of PGE 2
- Sodium and water retention
- Peripheral edema
- Hypertension

Inhibition of PGI 2
- Suppression of renin/aldosterone secretion
- Hyperkalemia
- Acute renal failure

Other effects
- Bronchospasm in asthmatics due to excess leukotrienes due to “back damping effect
- Failure of haeomostasis, bruising
- Pseudo-allergic reaction: rashes, swelling, itching, nasal
congestion, anaphylactic shock

Question 14

What are the typical NSAID and what are they used for?

Answer 14

Typical NSAIDS:

1. Naproxen
   a. More effective in women (higher free fraction) used for dysmenorrhea
2. Indomethacin
   a. Strongly anti-inflammatory due to additional steroid-like phosphlipase A inhibition
   b. But CNS adverse effects (confusion, depression, psychosis)
3. Diclofenac
   a. Short plasma half-life, therefore low GI risk
   b. Long half-life in synovial fluid, used for inflammatory joint disease

Question 15

What are the main function of COX-1 and COX-2?

Answer 15

Constitutive COX-1: responsible for house keeping, physiological function
- production of TbA2,PGI2,PGE2

Inducible COX-2: Inflammation
- production of PGI2 and PGE2

Question 16

Why do we use COX-2 selective inhibitors?

Answer 16

Since COX-2 do not produce TXA2, Prescence of TXA2 allows for platelet aggregation –> lower risk of bleeding due to increase clotting –> lower risk of peptic ulcer

This is preferred over to non selective COX inhibitors which stop TXA2 production , increasing risk of bleeding and peptic ulcer

Question 17

What are some COX-2 selective inhibitor?

Answer 17

Celecoxib
Etoricoxib
Meloxicam
Diclofenac

Question 18

What is a major contraindication of COX-2 inhibitor (including non-selective) NSAID?

Answer 18

Contraindicated in third trimester of pregnancy

Question 19

What are some unwanted effects of COX-2 inhibition?

Answer 19

• Renal toxicity (COX-2 in kidney)
• Delayed follicular rupture during ovulation
• Thrombosis due to increased COX-1 activity and TxA 2 production
• Premature closure of ductus arteriosus in late pregnancy
• Impairment of wound healing (exacerbation of ulcers)

Question 20

What is the mechanism of action of Paracetamol?

Answer 20

CNS-Selective COX inhibition

Question 21

Why is acetaminophen (paracetamol) used more commonly now?

Answer 21

Good antipyretic, spares GI tract, few AE and Se, few DDI

Question 22

Disadvantages of paracetamol

Answer 22

-weak anti inflammatory
-overdose cause liver damage
- allergic reaction