L8 - Eicosanoids Flashcards
From which group of molecules are eicosanoids derived?
Lipids.
What is the primary function of eicosanoids?
They contribute to the inflammatory response.
What are the 3 main categories of eicosanoids?
1 - Prostaglandins.
2 - Thromboxanes.
3 - Leukotrienes.
From which molecule are eicosanoids produced?
Arachidonic acid.
Which 2 enzymes are responsible for the liberation of arachidonic acid from the membrane?
1 - Phospholipase A2 (PLA2).
2 - Phospholipase C (PLC).
What are the stimuli that cause activation of the enzymes that are responsible for the first step of eicosanoid biosynthesis?
1 - Chemical (cytokines): Activate GPCRs.
2 - Mechanical: Ca2+ influx.
Which enzyme converts arachidonic acid into cyclic endoperoxides?
Cyclo-oxygenase (COX).
What are the variants of the COX enzyme and where are they found?
1 - COX-1 (constitutive, most cells).
2 - COX-2 (inducible, inflammatory cells).
What is the difference between a constitutive and inducible enzyme?
A constitutive enzyme is produced all the time, whereas an inducible enzyme is only produced under certain conditions.
Which enzymes of the COX pathway act on cyclic endoperoxides?
What are the products?
1 - Prostacyclin synthase (produces prostacyclin I2 (PGI2)).
2 - Thromboxane synthase (produces thromboxane A2 (TXA2)).
Where are the end products of the COX pathway found?
1 - Prostacyclin I2 (PGI2), found in the endothelium.
2 - Thromboxane A2 (TXA2), found in platelets.
What are prostanoids?
The subclass of eicosanoids consisting of:
1 - Prostaglandins (further divisible into prostacyclins).
2 - Thromboxanes.
List 4 effects of prostaglandins.
1 - Contribute to inflammatory response.
2 - Stimulate muscle contraction in the myometrium, GIT and bronchi.
3 - Inhibit gastric secretions.
4 - Inhibition of platelet aggregation.
List 3 ways in which prostaglandins contribute to the inflammatory response.
1 - Causes vasodilation.
2 - Raises temperature set-point (hypothalamus).
3 - Enhances activity of peripheral sensory nerves:
E.g. pain - sensitise nociceptors to e.g. bradykinin.
List 3 effects of thromboxanes.
1 - Vasoconstriction.
2 - Bronchoconstriction.
3 - Platelet aggregation.
How do non-selective non-steroidal anti-inflammatory drugs (NSAIDs) work?
By inhibiting both COX-1 and COX-2.
How do selective NSAIDs work?
By inhibiting COX-2 only.
List 2 examples of non-selective NSAIDs.
1 - Aspirin.
2 - Ibuprofen.
List 2 examples of selective NSAIDs.
1 - Celecoxib.
2 - Rofecoxib (but increases risk of ischaemic heart disease!).
How do glucocorticoids affect the COX and lipoxygenase pathways?
- Decrease expression of COX-2.
- Increase expression of annexin-1 (inhibits PLA2, decreasing free arachidonic acid.).
Which component of fish oil is important in eicosanoid biosynthesis?
Eicosapentaenoic acid (arachidonic acid is eicosatetraenoic acid)
List 3 types of drugs that are involved in the modulation of the COX pathway to achieve anti-inflammatory effect.
1 - Non-selective NSAIDs.
2 - Selective NSAIDs.
3 - Glucocorticoids.
Which enzyme converts arachidonic acid into HPETE?
5 - Lipoxygenase.
List 2 types of drugs that are involved in the modulation of the lipoxygenase pathway.
1 - 5-lipoxygenase inhibitor (USA only).
2 - Glucocorticoids.
List 4 effects of leukotrienes.
1 - Contributes to the inflammatory response.
2 - Causes bronchoconstriction.
3 - Stimulates mucus secretion (in the respiratory system).
4 - Causes vasodilation / vasoconstriction.
List 3 ways in which leukotrienes contribute to the inflammatory response.
1 - Chemotaxis (of neutrophils and macrophages).
2 - Stimulates proliferation of immune cells.
3 - Stimulates release of cytokines.
What type of receptors are prostanoid and leukotriene receptors?
G-coupled protein receptors.
List 2 prostanoid receptors and their ligands.
1 - IP (prostacyclin) receptor.
Ligand: PGI2 (prostacyclin I2).
2 - TP (thromboxane) receptor.
Ligand: TXA2 (thromboxane A2).
What do IP receptors do once activated?
Gs pathway:
The IP GPCR activates cAMP, which activates protein kinase A.
What to TP receptors do once activated?
Gq pathway:
The LT GPCR activates phospholipase C, which leads to both Ca2+ influx (IP3 from PIP2) and protein kinase C activation (DAG from PIP2).
What do LT receptors do once activated?
Gq pathway:
The LT GPCR activates phospholipase C, which leads to both Ca2+ influx (IP3 from PIP2) and protein kinase C activation (DAG from PIP2).
Give an example of a receptor antagonist for the cysteinyl leukotriene receptor.
Montelukast.
Give an example of a receptor agonist for the cysteinyl leukotriene receptor.
Epoprostenol.
Which variants of the COX enzyme are found in platelets?
COX-1 only.
Which variants of the COX enzyme are found in the endothelium?
Usually COX-1, but also COX-2 in some people.
What are the products of biosynthesis of eicosanoids when using fish oil rather than arachidonic acid?
What does this make fish oil a suitable treatment for?
- TXA3 (a weaker platelet aggregator than TXA2).
- PGI3 (a more potent inhibitor of platelet aggregation than PGI2).
- Therefore fish oil is a suitable treatment for heart disease as it reduces thrombosis.
List 2 drugs used to prevent thrombosis.
1 - Fish oil.
2 - Aspirin (low dose).
How does aspirin prevent thrombosis?
- Permanently blocks COX in platelets (cannot resynthesise as platelets have no nucleus) so thromboxane reduces.
- Blocks COX in the endothelium but COX resynthesises between doses so prostacyclin doesnt reduce much.
- Aspirin therefore decreases vasoconstriction and platelet aggregation.
How does the action of TXA2 in platelets differ from the action of PGI2 in the endothelium?
TXA2 in platelets: Aggregatory agent + vasoconstrictor.
PGI2 in the endothelium: Anti-aggregatory + vasodilator.
How do allergens cause allergic asthma?
1 - Allergen increases IgE antibody production.
2 - IgE binds to mast cells, causing immediate and late phases.
3 - Immediate phase: Increase in leukotrienes, histamine and interleukins.
4 - Late phase: Activation of eosinophils and Th2 lymphocytes.
How do glucocorticoids, zileuton and montelukast work to relieve the symptoms of asthma?
- Glucocorticoids: Increase expression of annexin-1 (inhibits PLA2, decreasing free arachidonic acid.).
- Zileuton: Inhibits 5-lipoxygenase (so decreases leukotrienes).
- Montelukast: Acts as an antagonist for the leukotriene receptor.
Why might non-selective NSAIDs lead to gastritis and ulcers?
- Non selective NSAIDs inhibit COX-1 and COX-2 (selective only inhibits COX-2).
- Prostaglandins produced in the gastric mucosa are formed by COX-1.
- Prostaglandins decrease acid secretion and increase mucous secretions.
- Inhibiting COX-1 decreases prostaglandins so increases acid secretion and decrease mucous secretions.
What is HPETE converted to in the lipoxygenase pathway (what are the end products)?
1 - Cysteinyl leukotrienes (LTD4).
2 - Leukotriene B4.
Which drugs are contraindicated with NSAIDs and why?
- Ibuprofen and diclofenac.
- 31% increased risk of cardiac arrest when these drugs are taken with with NSAIDs.
