NSAIDs (my version)

Question 1

State 3 uses of NSAIDs with examples.

Answer 1

ANALGESIC - Relief of mild-to-moderate pain

• Toothache, headache, backache
• Postoperative pain (opiate sparing)
  
  • Opiate sparing = reduced opiate needs to be taken or opiate not required
• Dysmenorrhea (menstrual pain)

ANTIPYRETIC - Reduction of fever

• Influenza

ANTI-INFLAMMATORY - Reduction of inflammation

• Rheumatoid arthritis
• Osteoarthritis
• Other forms of musculo-skeletal inflammation
• Soft tissue injuries (strains and sprains)
• Gout

Question 2

How do NSAIDs work?

Answer 2

• Prostaglandin and thromboxane are lipid mediators derived from arachidonic acid
• NSAIDs work by inhibiting cylooxygenase (COX) enzymes
• By doing this they inhibit prostaglandin and thromboxane synthesis

REMEMBER (not on slides but important):

• Prostanoids are derived from arachnidonic acid and include:
  
  • Prostaglandins
  • Prostacyclin
  • Thromboxan
• So technically, NSAIDs inhibit prostanoid synthesis

Prostanoids:

• Widely distributed
• Not pre-formed and stored
• Receptor-mediated action

Question 3

What are the prostanoid receptors?

Answer 3

• There are 10 known receptors
• The receptors are named based agonist potency
  
  • i.e. Which prostanoid (agonist) has the most potent effect on the receptor
    
    • ​e.g. Prostaglandin D₂ has the most potent effect on DP1 and DP2 (prostaglandin D₂ receptor 1 and 2)

Receptors:

• DP 1, DP2 (for PGD₂)
• EP1, EP2, EP3, EP4 (for PGE₂)
• FP (for PGF_2α)
• IP1, IP2 (for PGI₂)
• TP (for TXA₂)

These are G-protein coupled receptors

• BUT prostanoids have both G-protein dependent and independent effects
  
  • ​G-protein independent effects means that it still binds to the GPCR, but has an alternative signalling pathway which does not involve G-protein activation

Question 4

Overall, what are the effects of prostanoids?

Answer 4

Knock out mice show that prostanoid effects are extremely complex

Overall, prostanoids are physiological and pro-inflammatory

Question 5

Describe the receptor-mediated action of PGE_2.

Answer 5

PGE₂ can activate 4 receptors:

• EP1
• EP2
• EP3
• EP4

Downstream mechanisms can be:

• cAMP-dependent
• cAMP-independent

Question 6

State some unwanted actions of PGE_2.

Answer 6

• Increased pain perception
• Increased body temperature
• Acute inflammatory response
• Immune responses
• Tumorigenesis
  
  • This is the transformation of normal cells into malignant cells
• Inhibition of apoptosis

Question 7

How does PGE₂ increase pain perception?

Answer 7

• Stimulation of PG receptors in the periphery sensitizes the nociceptors which cause pain both acutely and chronically
  
  • i.e. Sensitised means more easily activated
• Therefore, this means that the pain threshold is lover
  
  • Pain threshold = the point beyond which a stimulus causes pain

Question 8

What is a possible mechanism by which PGE₂ lowers the pain threshold?