CPT15 - NSAIDs

Question 1

4 features of eicosanoid synthesis

Arachidonic Acid
Endoperoxides
COX-1 Enzyme
COX-2 Enzyme

Answer 1

1. ) Arachidonic Acid - produced from phospholipids
   - derived primarily from dietary linoleic acid
   - enzyme involved is phospholipase A2
   - found throughout the body esp muscle, brain and liver
2. ) Endoperoxides - unstable intermediates
   - arachidonic acid –> endoperoxides –> prostanoids
   - COX enzymes converts them into prostanoids
3. ) COX-1 Enzyme
   - constitutively active across most tissues
4. ) COX-2 Enzyme
   - inducible mostly in chronic inflammation
   - increased activity in the brain, kidneys, and bone
   - has a larger substrate binding site than COX-1 so some drugs can be selective to COX-2

Question 2

3 types of prostanoids

Prostaglandins
Prostacyclin
Thromboxane A2
PGI2 and TXA2 Balance

Answer 2

1. ) Prostaglandins - PGE2, PGF2-alpha, PGD2
   - involved in pain, pyrexia, and inflammation
   - action is often enhanced by local autacoids such as bradykinin and histamine
2. ) Prostacyclin - PGI2
   - vasodilator and inhibits platelet aggregation
   - it is cytoprotective for the CVS
3. ) Thromboxane A2 - TXA2
   - vasoconstrictor and activates platelet aggregation
   - it is generally bad for the CVS
4. ) PGI2 and TXA2 Balance - opposing vascular effects
   - balance for haemodynamic and thrombogenic control
   - imbalance –> hypertension, MI, stroke etc.

Question 3

6 features of NSAIDs

Examples x6
Mechanism
COX-2 Selectivity
Usage x6
Caution x3
Side Effects (IGRAB)

Answer 3

1. ) Examples - aspirin, ibuprofen, naproxen, diclofenac
   - celecoxib and etoricoxib are COX-2 selective
2. ) Mechanism - competitive inhibition of COX enzymes
   - ↓prostaglandin, prostacylin and thromboxane synthesis
3. ) COX-2 Selectivity - aspirin is least selective
   - less GI ADRs but similar renal ADRs
   - doesn’t inhibit prostacyclins, leaving TXA2 unopposed which can be bad for the CVS
4. ) Usage - pain, fever, inflammation
   - arthritis, menorrhagia, opioid sparing
   - long term usage could be prescribed with a PPI (omeprazole)
5. ) Caution
   - asthma: can cause bronchospasm in 10-20% of patient with asthma
   - heart failure: can cause fluid retention exacerbating heart failure
   - GI risk factors: elderly, smoking, alcohol, H. pylori
   - GI diseases: peptic ulcers, IBD
   - with other drugs: PPI, anticoagulants, ACEi (also ↓GFR)
6. ) Side Effects - IGRAB
   - Interactions w/ other medication e.g. warfarin
   - Gastric ulceration, Renal impairment
   - Asthma sensitivity, Bleeding risk
   - fluid retention

Question 4

3 functions of NSAIDs

Answer 4

1. ) Analgesia - local peripheral action at site of pain
   - ↓PGE2 synthesis in DH –> ↓neurotransmitter release -> ↓excitability of neurones in pain relay pathway
   - full analgesia occurs after several days of dosing
2. ) Anti-Inflammatory - inhibits prostaglandins
   - leads to ↓inflammation (vasodilation, swelling)
   - symptomatic relief, little effect on underlying condition
3. ) Antipyretic - inhibits COX-2 in the hypothalamus
   - prostaglandins can act on the thermoregulatory centre and increase the temp set point to cause a fever
   - PGE2 can be stimulated by pyrogens (cytokines)
   - therefore, ↓PGE2 leads to reduction in temperature

Question 5

2 main side effects of NSAIDs

GI ADRs
Renal ADRs

Answer 5

1. ) GI ADRs - nausea, peptic ulcers, bleeding, perforation
   - ↓mucus and ↓HCO3 –> ↑acid secretion
   - ↓mucosal blood floow –> hypoxia and cytotoxicity
   - exacerbation of IBD
2. ) Renal ADRs - ↓GFR and ↓renal blood flow
   - prevents vasodilation of AA (↓PGE2/PGI2)
   - ↑sodium absorption in CD (inhibition of prostaglandins)
   - ADRs in underlying CKD and heart failure

Question 6

3 main drug interactions with NSAIDs (protein-binding)

Answer 6

1. ) Sulfonylureas - can lead to hypoglycaemia
2. ) Methotrexate - hepatotoxicity, leukopenia, RA
3. ) Warfarin - increases risk of bleeding