L18- Eicosanoids

Question 1

What are eicosanoids and what are the three main categaries?

Answer 1

• Eicosanoids-lipid derivatives

1. Prostaglandins (PG)- prostanoids
2. Thromboxanes (TX)- prostanoids
3. Leukotrienes (LT)

Question 2

Biosynthesis of Eicosanoids- 1st step

Answer 2

• Eicosanoids are not stored
• Source is Arachidonic acid
• This is esterfied in membrane
• 1st step
  
  • involves the enzymes Phospholipase A₂ (PLA₂) and Phospholipase C (PLC)
  • Chemical stimuli- cytokines- activates GPCRs
  • Mechanical stimuli- Ca²⁺influx

Question 3

What are the two alternative pathways in the second step of eicosanoids biosynthesis

Answer 3

Two alternative pathways

1. Cyclo-oxygenase (COX) pathway
2. Lipoxygenase pathway

Question 4

What is the COX pathway?

Answer 4

• involved in the generation of prostanoids- PG and TX
• The intermediate product is generated in most cells
• end products are cell specific
• depend on the enzyme present which acts on the intermediate products
  
  • Endothelium- PGI₂
  • Platelets- TXA₂

Question 5

What are the COX enzyme varients?

Answer 5

1. COX-1- constitutive- found in most cells
2. COX-2- inducible- found in inflammatory cells

Question 6

What are the actions of Prostaglandins?

Answer 6

• Contribute to inflammatory response
  
  • vasodilation
  • raised temperature set point (hypothalamus)
  • enhanced activity of peripheral sensory nerves
    
    • pain- sensitise nociceptors
• Others
  
  • Muscle
  • gastric secretions
  • inhibition of platelet aggregation

Question 7

What are the actions of thromboxanes?

Answer 7

• Vasoconstriction
• Bronchoconstriction
• platelet aggregation

Question 8

What are the three drug modulation of COX pathway?

Answer 8

1. Non selective NSAIDs
   
   • inhibit COX-1, COX-2
   • e.g. aspirin(irreversible), ibuprofen
2. Selective NSAIDs
   
   • inhibit COX-2
   • e.g. Celecoxib, rofecoxib- increased risk of ischaemic heart disease
3. Glucocorticoids
   
   • Inhibit COX-2
   • induce expression of annexin I which inhibits PLA₂ which decreases the production of free Arachidonic acid

Question 9

What is the lipoxygense pathway?

Answer 9

• results in production of Leukotrienes
• Main enzyme- 5 lipoxygenase
• results in production of WBCs, platelets and mast cells

Question 10

Give examples of drugs that affect the Lipoxygenase pathway.

Answer 10

Zileuton: 5-lipox. Inhibitor (available in USA)

Glucocorticoids: Induce annexin-1

Question 11

What are the actions of leukotrienes?

Answer 11

• Important role in inflammation:
  
  • Chemotaxis (neutrophils, macrophages)
  • Stimulates proliferation of immune cells and release of cytokines
  • Rheumatoid arthritis; Ulcerative Colitis; Psoriasis
• Other effects:
• Bronchoconstriction and mucus secretion (important)
• Vasodilation/vasoconstriction

Question 12

What is the mechanism behind the action of Eicosanoids?

Answer 12

• Eicosanoids act via G protein coupled receptoes
• There are 5 prostanoid receptor subtypes
  
  • IP, which forms a ligand with PGI₂, activates cAMP and Protein kinase A
  • TP. which forms a ligand with TXA_2, activates PLC and Protein Kinase C
• There are 3 LT receptors that are also involved in the PLC/PKC pathway

Question 13

Which drugs affect Eicosanoids by binding to receptors?

Answer 13

• Receptor antagonist
  
  • CystLTs- Montelukast
• Receptor agonist
  
  • Epoprostenol (IP agonist)

Question 14

What is the role of Prostanoids on cardiovasular system: thrombosis?

Answer 14

• Platelets (COX-1)→ TXA₂
  
  • _​TXA₂ is an aggregatory agent and a vasoconstrictor
• Endothelium (COX-1, COX-2 in some people)→ PGI₂
  
  • PGI_{2 ​}is an anti aggregatory agent and a vasodilator
  • Some COX-2 inhibitors can cause heart attacks
• The balance of TXA₂ and PGI₂ is important
  
  • PGI₂ is dominant
  • balance is altered in atherosclerosis

Question 15

What is the drug intervention for thrombosis? (prevention)

Answer 15

1. Fish oil- contains eicosapentaenoic acid: EPA
   
   • EPA used to make prostanoids instead of arachidonic acid
     
     • TXA₃ (not TXA₂) is formed which is a weaker aggregator
     • PGI₃ (not PGI₂) is formed which is a more potent inhibitor
   • As a result, less clots- trial shows increased survival following MI
2. Aspirin- low dose
   
   • In platelets, COX blocked permanently (no nucleus), action irreversible
   • In endothelium, COX is resynthesised between doses
   • This means that PGI₂ recovers but not TXA2
   • This affects the balance in favour of preventing clots

Question 16

What is the role of Eicosanoids on respiratory system?

Answer 16

• Prostanoids lead to bronchoconstriction/dilation
• LTs lead to bronchoconstriction, increase in mucous and increase chemotaxis which boost inflammatory reactions in wall of airways
• Inhaled LTC₄/D₄ is 1000 more times potent than histamine which causes bronchoconstriction

Question 17

What is the process behind allergic asthma?

Answer 17

Antigen binds to IgE on mast cells

• Immediate phase: LT++, Histamine, Interleukins release
• Late phase: recruitment/ activation of eosinophils and Th2 lymphocytes
  
  • major basic and cationic proteins are also produced which lead to cell damage

Question 18

How does drug intervention for asthma work?

Answer 18

• Interfere with LT production/action
  
  • expression of annexin-1- glucocorticoids
  • 5-lipox. inhibitor- Zileuton
  • CystLT antagonist- Montelukast
    
    • for mild-mod & exercise- induced asthma- not first line

Question 19

Why aren’t NSAIDs used in asthma treatment

Answer 19

• 20% of patients have aspirin sensitive asthma
• This is because aspirin will inhibit prostanoid synthesis, leading to excessive production of LTs, making the problem worse

Question 20

What are the major side effects of NSAIDs and what are the mechanisms behind them?

Answer 20

• PGs are produced by gastric mucosa (COX-1)
  
  • PGs decrease acid productions and increase mucous secretion (protective function)
  • NSAIDs leads to a decrease production of PGs, which leads to gastritis, ulcers