NSAIDs + Paracetamol

Question 1

Thromboxane

Answer 1

Platelet COX 1;

Vasoconstriction and Platelet Aggregation

• Hence NSAIDs w high COX2 ratio is pro-platelet
• Aspirin is highly antiplatelet

Question 2

Why antiplatelet effect if PGI2 is also inhibited?

Answer 2

COX enzymes in endothelial cells can regenerate in hours while completely new Platelet regeneration takes weeks - for TXA2; otherwise PGI2 continues production, and inhibits platelet aggregation;

Question 3

Leukotriene function

Answer 3

Bronchoconstriction, Mucous Secretion, Increase permeability of blood vessels

Key in asthma

Question 4

Typical NSAIDs functions

Answer 4

Antipyretic - normally IL1 cytokine will activate production of PGE2, leading to fever
Analgesia - PGE2 and pain - PG increases sensitivity of nociceptors
Anti-inflammatory - limit vasodilation and permeability by PGI2 and PGE2

Hence Heat, Redness and Swelling;

Question 5

NSAIDs and Aspirin on blood thinning (anti-platelet)

Answer 5

All NSAIDs will have an effect on blood thinning, but aspirin is stronger due to irreversible inhibition;

Otherwise if NSAID has high COX2 affinity, then pro-platelet effect instead

Question 6

Aspirin High Dose SE and Contra-I

Answer 6

Low Dose: standard COX inhibitory effects

High Dose: Salicylate toxicity - Renal Failure

Contra-I: Children w Viral infection can lead to Reye’s syndrome w brain, liver damage

Question 7

Typical NSAIDs SE

Answer 7

GI: Dyspepsia (indigestion), N&V
- PG function of mucus, bicarb secretion, and reducing gastric acid;

Renal:
- PGE2: usually blocks 25% Na reabsorption at ascending limb, hence NSAIDs lead to hypernatremia, edema, water retention

• PGI2: usually stimulates RAS, hence 1-2% reabsorption at Distal Convoluted Tubule, but NSAIDs still lead to hypernatremia; and blocking RAS leads to Hyperkalemia

Anti-platelet: Bleeding (not ALL NSAIDs antiplatelet)

Bronchospasm: Asthma

• Shunting of AAA to Leukotrienes;
• “Pseudo-allergy due to LK surge”

Question 8

COX2 selectivity location and benefits

Answer 8

Induced by inflammatory stimulus

More anti-inflammatory, analgesic
More pro-platelet;

Found on WBC and endothelial cells

Question 9

COX2 inhibition SE

- Coxibs

Answer 9

Renal toxicity - both COX1 and COX2 found

Pregnancy; ALL NSAIDs have COX2 inhibition and is Contra-I

• delay follicular rupture - reduce child bearing ability
• premature closure of ductus arteriosus in LATE pregnancy

Limits Wound Healing - PG from inflammatory cells for wound healing - exacerbate current ulcers;

Pro-platelet aggregation due to AA shunts to COX1, TXA2 (both isoforms are found in tissues)

Question 10

Paracetamol MOA

Answer 10

CNS-selective COX inhibition
- antipyretic

Does not target COX in periphery

• GI is safe
• weak anti-inflammatory effect

Question 11

Overall Adverse Effects, range from COX-1

Answer 11

COX-1
GI
Bleeding (antiplatelet due to TXA2 inhibition)

Renal-Renal

COX-2
Reproductive (less PG)
Wound Healing (less PG)
Thrombosis (pro-platelet due to TXA2)

Question 12

Overall Positive Effects, range from COX-1

Answer 12

Anti-platelet

Anti-pyretic
Analgesic

Anti-inflammatory