NSAIDs

Question 1

Arachidonic acid - cyclo-oxygenase - cyclic endoperoxides - prostanoids

Answer 1

1. Prostacyclin - PGI2
   - vasodilation
   - inhibits platelet agg
2. Classical prostaglandins - PGD2, PGF2α, PGE2
   - increases vasc perm
   - pain
3. Thromboxanes - TXA2
   - vasoconstriction
   - platelet agg

Question 2

Mechanism of action & uses of aspirin (acetylsalicylic acid) (5)

Answer 2

1. Anti-Inflammatory
   - blocks vasodilation (contributes to heating, redness, swelling)
   - blocks increase in vasc perm (contributes to swelling)
   - blocks pain assoc w inflamm
2. Analgesic
   - blocks PG prod - blocks sensitization of nociceptive fibers to stimulation by other inflamm mediators, but does not block direct nociceptive activation
3. Anti-pyretic
   - normally, infection/tissue damage/inflamm - neutrophils & cytokines - COX - PGE2 - reset body thermostat - increase temp - fever
   - inhibits COX in the hypothalamus
   - but does not alter normal body temp
4. Anti-platelet
   - irreversible COX inhibitor - inhibits PGI2 & TXA2
   - TXA2 in platelets - promotes platelet agg - can only be restored by formation of new platelets
   - PGI2 in endothelial cells - inhibits platelet aggregation - can be restored by synthesis of new COX enzymes
   - net effect - inhibits platelet aggregation
5. Blood thinner (low doses) in those at risk of cardiovascular disease

Question 3

Toxicity of aspirin (acetylsalicylic acid) (6)

Answer 3

1. GI - dyspepsis, nausea, vomiting, ulcer formation & potential hemorrhage risk (chronic use)
   - PGs normally decrease gastric acid secretion, increase mucosal blood flow, increase mucus/bicarb secretion
2. Renal - alters renal blood flow dynamics (inhibition of PGE2 & PGI2), Na/H2O retention, peripheral edema, HTN (inhibition of PGE2), suppression of renin & aldosterone secretion, hyperkalemia, ARF (inhibition of PGI2 prod)
3. Pseudo-allergic reaction - skin rash, swelling, itching, nasal congestion, anaphylactic shock
4. Asthma - can trigger bronchospasms in susceptible asthmatics (excess arachidonic acid shunted - increased leukotrienes - bronchospasm)
5. Bleeding - failure of hemostasis, bruising
6. Reye’s Syndrome - rare, life threatening, swelling of brain (encephalitis) & liver - symptoms - vomiting, personality change, listlessness, delirium, convulsions, loss of consciousness - increased risk in children w viral inf

Question 4

Other NSAIDs (3)

Answer 4

1. Naproxen - often used for dysmenorrhea
2. Indomethacin - anti-inflamm + steroid-like phospholipase A inhibition - can cause CNS effects (confusion, depression, psychosis, hallucination)
3. Diclofenac - longer half life in synovial fluid - useful in inflammatory joint disease

Question 5

Toxicity of COX-2 selective inhibitors (5)

Answer 5

Celecoxib, Etoricoxib

1. Renal toxicity due to constitutive expression of both COX-1 & COX-2 in the kidney
2. Effects on ovulation incl delayed follicular rupture
3. Premature closure of ductus arteriosus (fetal lung bypass) in late pregnancy
4. Impairment of wound healing, exacerbates ulcers
5. Increased risk of thrombosis - relative increase in TXA2 favours platelet agg

Question 6

Mechanism of action of paracetamol (acetaminophen)

Answer 6

1. COX inhibitor - selectively inhibits COX in CNS, weak inhibitor in the periphery
2. 5-HTergic mechanisms
3. Metabolism to AM404 (endogenous cannabinoid reuptake inhibitor) - activates transient receptor potential vanilloid 1 (TRVP 1) receptor - modulates pain transmission in the CNS

Question 7

Efficacy & toxicity of paracetamol (acetaminophen) (5+2)

Answer 7

1. Good analgesic
2. Potent antipyretic
3. Spares GIT
4. Few side effects/DDI, safe for paeds
5. Weak anti-inflammatory
6. Allergic Skin Reactions
7. Toxic dose: nausea, vomiting, liver damage (hepatotoxicity should not occur at therapeutic doses but may be exacerbated by chronic alcohol use/abuse)