NSAIDs

Mx methods + correlation to intensity of pain

Intensity of pain	Mx methods
Pain rating 1-3 ( mild )	NSAIDs  Non-pharmacological + adjuvants
Pain rating 4-6 ( moderate )	Non-opioids ( NSAIDs ) + weak opioid  Non-pharmacological + adjuvants
Pain rating 7-10 ( severe )	Strong opioids  Non-pharmacological + adjuvants

Process of acute inflammation

2 phases : 

Vascular: 

1. Injured cells + sensory neurons + resident immune cells release chemical mediators 

2. Chemical mediators cause vasodilation + permeability of vessels increase 

3. Influx of plasma proteins to facilitate inflammation 

Cellular: 

1. Plasma proteins cause blood clotting;  complement + kinin production 

2. Complement system + chemokines attract WBC to injury site 

3. Macrophages + neutrophils enter tissue through leaky blood capillaries 

Macrophages ingest invading pathogens + cellular debris 

→ release cytokines to induce fever ( enhancement of inflammation )

Effects of acute inflammation + major cellular contributors

Effects	Major cellular / molecular contributors
Redness  Heat  Swelling  Pain  Decreased function  Fever ( systemic )	Plasma proteins  Kinins + compliments  Chemokines Neutrophils  Macrophages

What is chronic inflammation

Inability to remove cause of inflammation w/ inflammatory response 

→ inflammation lasting longer than 2 weeks

Effects of chronic inflammation + major cellular contributors

Effects	Major cellular / molecular contributors
Local tissue damage  High fibroblast activity  → deposition of fibrin + formation fibrotic tissue	Lymphocytes  Monocytes

Role of inflammatory mediators

	Role
Eicosanoids	Pro-inflammatory e.g.  Vasodilation  Increase vascular permeability Chemotaxis  Promotes release of other mediators  E.g.  Prostaglandins/ leukotrienes, thromboxane
Histamine	Mediate allergic reactions ( only one that is stored in mast cells )
Platelet activating factor + C5a

Production process + effects of cytokines

1. Damage to phospholipid bilayer of cells which stores arachidonic acid 

2. Inflammatory stimulus activates phospholipase A2 + release arachidonic acid 

3. Arachidonic acids is released into cytoplasm + converted into leukotrienes by 5-Lipoxygenase/ prostaglandins + thromboxane by COX-1 + COX-2 

4. Prostaglandins are released to neighbouring cells + bind to receptors → effect of prostaglandins is based on which receptors they bind to 

MOA of corticosteroids

1. Indirect inhibition of phospholipase A2 through annexin-1 ( protein ) 

• Glucocroticoid binds to receptors on cell membrane → migrates through phospholipid layer → nuclear membrane → binding to receptor on DNA → increase transcription for annexin 1; reduction in transcription of COX enzymes 

• Effect: reduction of PLA2 activity + prevention of production of all subsequent steps → reduced inflammation 

Adverse effects of steroidal anti-inflammatory drugs

1. Higher chance of developing cataracts in arthritic patients ( longer term use ) 

2. Suppression of HPA axis → long term use of glucocorticoids signals to brain that there is high levels of cortisol in body → sudden stop in glucocorticoids can lead to low levels of cortisol in body as body needs time to adjust + produce cortisol → reduction in ability to regulate glucose levels + stress response ( be alert ) 

3. Stomach irritation 

4. Cushing syndrome + hypertension 

5. Vertebrae osteoporosis 

MOA general of NSAIDs + benefits

General mechanisms of NSAIDs 

1. Inhibition of cyclo-oxygenase enzymes → inhibition of prostaglandin synthesis 

→ Inflammation reduction 

Benefits of NSAIDs:

1. Anti-inflammatory 

2. Anti-pyretic: X increase in prostaglandins due to IL-1 → temperature set point X get elevated 

3. Analgesic: less sensitisation of nociceptors by prostaglandins 

Aspirin: effects of COX-1/ 2 + results

Effects on COX-1 + COX-2	Results
Acetylation w/ COX → irreversible inhibition	Analgesic for pain + fevers  Antipyretic → reduction in fever Anti-inflammatory for arthritis  Antiplatelet activity → inhibition of platelet thromboxane synthesis → slows clotting

Side effects of aspirin 

1. Higher risk of internal/ excessive bleeding 

2. Slows renal blood flow ( nephrotoxicity ) 

3. CNS effects → tinnitus/ confusion /delirium / convulsions

4. Gastric irritation: gastric ulceration 

5. Reye’s syndrome: fatty degeneration of liver + swelling of brain → contraindicated in 12 year old

Ibuprofen: effects of COX-1/ 2 + results

Effects on COX-1 + COX-2	Results
Competitive reversible inhibitor of COX-1 + 2  → slightly COZ- selective	More anti-inflammatory  Anti-pyretic  Menstrual pain ( more effective )  Rheumatoid arthritis ( effective )  Safe for children

Side effects of ibuprofen

1. Increase risk of thrombosis 

2. Some gastric irritation

COX-2 selective antagonists: effects of COX-1/ 2 + results

Effects on COX-1 + COX-2	Results
COX-2 selective → less associated COX-1	Rheumatoid + osteoarthritis  Patients w/ GI disturbances

COX-2 selective antagonists side effects

1. Increased risk of heart attacks + strokes 

→ balance bwt prostacyclin ( vasodilator + inhibitor of platelet aggregation produced w/ help from COX-2  ) + thromboxane ( vasoconstrictive + cause platelet aggregation → produced by COX-1) affected → increase in platelet aggregation + vasoconstriction 

2. Increased risk of GI bleeding ( COX-2 can heal gastric ulcers → slower healing ) 

3. Hypersensitivity reactions e.g. skin reactions 

4. Renal effects: increased blood pressure in kidneys + fluid retention

Paracetamol : effects of COX-1/ 2 + results

Effects on COX-1 + COX-2	Results
Believed to be selective COX-3	Weak anti-inflammatory  Good analgesic → mild pain  Strong pyretic effect  Most well tolerated for ppl contraindicated for aspirin

Side effects of paracetamol

1. X effect on bleeding time + CV toxicity 

2. Highly hepatotoxic when overdosed 

→ mostly metabolised to non toxic metabolites 

→ small percent metabolised to toxic NAPQI by cytochrome P450 

→ overdose happens when non-toxic pathways saturated + ↑ more paracetamol shunted to toxic pathways + little GSH to convert it to less toxic metabolite → hepatocyte damage + death