PAMS pharmacology: COX1 and COX2 inhibitors

Question 1

What are the actions of NSAIDs class of drugs ?

Answer 1

These are drugs with analgesic, anti-inflammatory, antipyretic, anti-platelet properties.

Question 2

What is the principle mechanism by which NSAIDs act ?

Answer 2

They inhibit the Cyclooxygenase enzyme which is responsible for converting arachidonic acid to Prostaglandin H2 or PGH2.

Question 3

what are the prostaglandin subforms to which PGH2 is converted by the tissue specific isomerases ?

Answer 3

PGD2, E2, F2, I2 ( prostacyclin), and TxA2.

Question 4

What are the functions of PGD2?

Answer 4

Vasodilation and chemotaxis

Question 5

What are the functions of PGE2 ?

Answer 5

• Vasodilation
• spinal neuronal sensitization to pain.
• Fever induction
• Inhibition of stomach acid secretion.
• Increase uterine contraction and GFR.

Question 6

What is the function of PGF2 ?

Answer 6

Induce uterine contraction

Question 7

What is the function of PGI2 or prostacyclin?

Answer 7

• Vasodilation
  Spinal neuronal pain sensitization.
• Inhibit platelet aggregation and stomach acid secretion.
• Increase GFR

Question 8

What are the functions of thormboxane A2?

Answer 8

Increase vasoconstriction and platelet aggregation.

Question 9

What is the difference between the physiological action of COX-1 and COX-2 enzymes ?

Answer 9

COX-1 mediates homeostatic functions. Whereas COX-2 is expressed in response to inflammation.

Question 10

What are the pharmacological effects of COX-01 inhibitors ?

Answer 10

• Increases stomach acid secretion and GFR by inhibiting PGE2 and PGI2
• Reduces uterine contraction by inhibiting PGF2 and PGE2.
• Increases platelet aggregation by inhibiting PGI2.
• Decreases platelet aggregation by inhibiting TXA2.

Question 11

What are the pharmacological effects of COX-02 inhibitors ?

Answer 11

• Increases vasoconstriction by inhibiting PGD2, E2and I2.
• increases vasodilation by inhibiting TXA2.
• Desensitise spinal neurones to pain by inhibiting PGE2 and PGI2.
• Inhibits fever by inhibiting PGE2.

Question 12

What are prostaglandins ?

Answer 12

They are also called eicosanoids or porstanoids they are molecules with a very short half-life. They are the main local mediators of inflammation and act on many cells to produce many effects.

Question 13

What are the Gynaecological & Obstetric uses of prostanoids or Prostaglandin analogs ?

Answer 13

misoprostol ( stable PGE2 analog) can be used to induce labour and prevent post-partum haemorrhage.

Question 14

What is the use of prostaglandin analogs in GI disease ?

Answer 14

Misoprostol a PGE2 analog can be used to prevent GI bleeding in patients taking NSAIDs

Question 15

What is the cardiovascular use of Prostaglandin analog?

Answer 15

Iloprost; a stable PGI2 analogue can be used to inhibit platelet aggregation during dialysis.

Question 16

What is the mechanism of NSAIDs induced anti-inflammatory effect ?

Answer 16

Reduction in prostaglandin production and reduced vasodilation reduces edema and inflammation.

Question 17

What is the mechanism of NSAIDs induced anti-pyretic effects ?

Answer 17

Reduction in prostaglandin production resets the hypothalamic thermostat threshold to the normal range.

Question 18

What is the mechanism of NSAIDs induced analgesic effect ?

Answer 18

reduced prostaglandin production peripherally and its reduced effect on spinal pain centres induces analgesia.

Question 19

What is the mechanism of NSAIDs induced anti-platelet effect ?

Answer 19

Reduction in TXA2 causes anti-platelet effects.

Question 20

What is the manifestation of NSAIDS gastric side effects?

Answer 20

Gastric ulcers, nausea, bleeding.
*Increased risk in older age (>60)

*Increased risk if existing ulcer.

*Increased risk with higher dose and duration.
*Increased risk if concurrent drug use (anti-platelet/coagulant, glucocorticoid).

*Approx 10% of arthritis patients taking NSAIDs will be hospitalised for GI toxicity.

Question 21

What is the mechanism of NSAIDs induced GI side effects ?

Answer 21

The inhibition of PGE2 which is responsible for reducing gastric acid secretion and stimulation of bicarbonate and mucin secretion by the epithelial cells causes gastric acid hyper secretion and peptic ulcers.

Question 22

What are the strategies to avoid GI toxicity of NSAIDs?

Answer 22

*Reduce dose/duration of NSAID.

*Patient selection.

*Co-administer gastric protectant (misoprostol, PPI)
*Coxibs

Question 23

What is the effect of aspirin on COX activity ?

Answer 23

Aspirin irreversibly binds to the COX enzyme and it has a half life of 7 days, ergo, its anticoagulation effect can prolong for 7 days.

Question 24

What is the NSAIDs side effect on coagulation?

Answer 24

It inhibits the activity of thromoboxine A2. Therefore, it can cause bleeding by reducing platelet aggregation. The management is to stop the drug.

Question 25

What is the mechanism of cardiovascular adverse effects of NSAIDs ?

Answer 25

The cardiovascular adverse effects increases with age, pre-exciting conditions, dose and duration. All NSAIDs except Naproxin and low dose aspirin tend to increase BP by inhibiting the activity of PGI2 and TXA2 action on the vascular endothelial cells. Which may lead to cardiovascular necrosis, MI, and stroke.

Question 26

What should the ideal mode of administration of NSAIDS in a patient on aspirin ?

Answer 26

Aspirin should be given two hours prior to NSAIDs.

Question 27

What are the side effects of IV NSAIDs ?

Answer 27

*Renal Effects *Liver effects *Allergy *CNS effects (headache, dizziness) *Bronchospasm *Skin reaction (rash or photosensitivity) *Tinnitus and hearing loss (aspirin-specific).

Question 28

What are the benefits and side effects of COX2 inhibitors?

Answer 28

Reduced GI toxicity Reduced bleeding effects More compatible with aspirin BUT still cardiovascular side effects

Question 29

What is the mechanism of action of aspirin ?

Answer 29

It irreversibly inhibits COX-1 and COX2 enzymes. Excessive consumption can cause salicylism.

Question 30

Why is aspirin is not recommended for children ?

Answer 30

Risk of Rey syndrome

Question 31

What is the main side effect of Aspirin ?

Answer 31

GI toxicity and increased bleeding time.

Question 32

What is the mechanism of action of ibuprofen?

Answer 32

It reversibly inhibits COX-1 and 2 enzymes. It can reduce the effect of aspirin, if you take them together. Therefore aspirin should be taken two hours before ibuprofen.

Question 33

What is Diclofenac ?

Answer 33

It is the most potent broad spectrum NSAIDs. It can inhibit COX enzymes, May inhibit lipooxygenease pathway, and may inhibit phospholipase A2 as well. The main side effect is GI toxicity secondary to longterm use.

Question 34

What is celecoxib ?

Answer 34

It is a selective COX two inhibitor. It has increased risk of CV side effects and decreased risk of GI side effects.

Question 35

What are semi selective NSAIDs ?

Answer 35

They have strong affinity for COX2 and weak affinity for COX1. Therefore, use with caution in patients with CV risk.

Question 36

What are some examples of semi selective NSAIDs?

Answer 36

Meloxicam, Diclofenac, Etodolac, Indomethacin, and Piroxicam.

Question 37

What are non-selective NSAIDs ?

Answer 37

They have decreased risk for CV events and increased risk for GI events. examples: Ibuprofen and Naproxen.

Question 38

What are irreversible non-selective inhibitors ?

Answer 38

It has cardio-protective effects at low dose and increased risk for GI bleeding.

Question 39

What is paracetamol and its mechanism of action ?

Answer 39

Its mechanism of action is still debated. It may selectively inhibit COX-3 and prevent hypothalamic prostaglandin synthesis. It may also scavenger the ROS required for COX. It is metabolised in the liver and has low therapeutic index. It has analgesic and anti-pyretic effects, but no anti-inflammatory effects.

Question 40

How to treat Paracetamol overdose?

Answer 40

The drug is basically converted to mercaptopuric acid by glutathione. In overdose (2 to 3 times the normal dose) the glutathione stores get depleted and the drug converts to protein adducts causing hepatotoxicity. The treatment is gastric lavage and N-acetylecystine.

Question 41

Why is Ibuprofen considered an NSAIDs of choice with Warfarin ?

Answer 41

All though it is highly plasma protein bound like warfarin. It does not displace warfarin. Therefore, it does not alter warfarin's effectiveness.