Eicosanoids

Question 1

What are the 3 main categories of eicosanoids?

Answer 1

prostaglandins (prostanoids)
thromboxanes (prostanoids)
leukotrienes

Question 2

Describe the 1st step in the biosynthesis of eicosanoids.

What are the 2 stimuli for the 1st step

Answer 2

Not stored (except semen) 
Source = arachadonic acid 
1st step = PLA2 enzymes (PKC pathway) 
Stimuli: chemical (cytokines) stimulate GPCR's
mechanical, Ca2+ influx 
2nd step = two alternative pathways

Question 3

What are the 2 possible second steps of eicosanoid synthesis? What are the end products of each pathway?

Answer 3

Cyclooxygenase --> cyclic endoperoxidases 
--> prostacyclin synthase --> prostaccin
or 
--> thromboxane synthase --> TXA2
Lipoxygenase --> HPETE --> LTB4 and LTD4

Question 4

Describe the cyclooxygenase pathway
Which enzyme variants are present in which cells?
What are the end products?

Answer 4

Prostanoids (PG and TX)
Enzyme variants:
COX 1 = constitutive (most cells)
COX 2 = inducible (inflammatory cells)
End products: 
endothelium = PGI2
platelets = TXA2

Question 5

What are the primary actions of prostaglandins?

Answer 5

inflammation
vasodilation
increase body temperature by acting on hypothalamus
pain
Symptomatic relief if you decrease the products/action of prostaglandins

Question 6

Describe the 3 drug modulations of cyclooxygenase enzymes.

Answer 6

1. Non-selective NSAID’s, inhibit COX1/COX2
2. Selective NSAID’s, inhibt COX2 only, act further down biosynthesis pathway
3. glucocorticoids - inhibit expression of COX-2
4. thromboxane inhibitor

Question 7

Describe the lipooxygenase pathway and drug modulation

Answer 7

leukotrienes
Zileuton = inhibitor
glucocorticoids = decrease free arachidonic acid

Question 8

Describe the mechanisms of action of eicosanoids

Answer 8

via GPCR’s
receptor antagonists e.g. monteleukast
agonists e.g. epoprestenol (treat pulmonary hypertension, can terminate pregnancy

Question 9

What is the role of prostanoids in the CVS?

Answer 9

platelets (COX1) aggregaroty agent
endothelium (COX1) anti aggregatory and vasodilation - PGI2
both important, PGI2 dominant (expect in atherosclerosis)

Question 10

What are the 3 drug interventions for prevention thrombosis?

Answer 10

1. fish oil = contains eicosapentaenoic acid, uses this instead of arachadonic acid 
TXA3 = weaker aggregator
PGI3 = more potent inhibitor
2. aspirin
platelets - COX irreversibily blocked
endothelium - COX resynthesised 
3. dipyridamole 
- TXA2 synthesis inhibitor (inhibit platelet aggregation)

Question 11

What is the role of eicosanoids in the respiratory system?

Allergic asthma?

Answer 11

prostanoids –> bronchoconstriction/dilation
LTs –> bronchoconstriction and increase mucous
Allergic asthma
antigen binds to IgE (mast cells)
leukotrienes, histamine, interleukins
recruitment/activation of eosinophils and Th2 lymphocytes

Question 12

What is the drug intervention for asthma?

Answer 12

interfere with LT production:
- glucocorticoids - expression of annexing-1 
- zileuton - 5-lipox inhibitor
- cystLT antagonsist = monteleukast 
NSAID's  no benefit!!

Question 13

What are the major side effects of NSAID’s?

Answer 13

PG's produced by gastric mucosa (COX1)
- decrease acid secretion
- increase mucous
= PROTECTIVE
Non-selective NSAID's decrease PG's --> gastritis and ulcers

Question 14

How do the 3 eicosanoids act on the CVS?

Answer 14

PGE2 and PGI2 = vasodilation –> treatment for pulmonary hypertension
TXA2 = vasoconstriction –> clotting
LT’s = increase permeability, chemotaxis, vasodilation