L8 - Eicosanoids

Question 1

From which group of molecules are eicosanoids derived?

Answer 1

Lipids.

Question 2

What is the primary function of eicosanoids?

Answer 2

They contribute to the inflammatory response.

Question 3

What are the 3 main categories of eicosanoids?

Answer 3

1 - Prostaglandins.

2 - Thromboxanes.

3 - Leukotrienes.

Question 4

From which molecule are eicosanoids produced?

Answer 4

Arachidonic acid.

Question 5

Which 2 enzymes are responsible for the liberation of arachidonic acid from the membrane?

Answer 5

1 - Phospholipase A2 (PLA2).

2 - Phospholipase C (PLC).

Question 6

What are the stimuli that cause activation of the enzymes that are responsible for the first step of eicosanoid biosynthesis?

Answer 6

1 - Chemical (cytokines): Activate GPCRs.

2 - Mechanical: Ca2+ influx.

Question 7

Which enzyme converts arachidonic acid into cyclic endoperoxides?

Answer 7

Cyclo-oxygenase (COX).

Question 8

What are the variants of the COX enzyme and where are they found?

Answer 8

1 - COX-1 (constitutive, most cells).

2 - COX-2 (inducible, inflammatory cells).

Question 9

What is the difference between a constitutive and inducible enzyme?

Answer 9

A constitutive enzyme is produced all the time, whereas an inducible enzyme is only produced under certain conditions.

Question 10

Which enzymes of the COX pathway act on cyclic endoperoxides?

What are the products?

Answer 10

1 - Prostacyclin synthase (produces prostacyclin I2 (PGI2)).

2 - Thromboxane synthase (produces thromboxane A2 (TXA2)).

Question 11

Where are the end products of the COX pathway found?

Answer 11

1 - Prostacyclin I2 (PGI2), found in the endothelium.

2 - Thromboxane A2 (TXA2), found in platelets.

Question 12

What are prostanoids?

Answer 12

The subclass of eicosanoids consisting of:

1 - Prostaglandins (further divisible into prostacyclins).

2 - Thromboxanes.

Question 13

List 4 effects of prostaglandins.

Answer 13

1 - Contribute to inflammatory response.

2 - Stimulate muscle contraction in the myometrium, GIT and bronchi.

3 - Inhibit gastric secretions.

4 - Inhibition of platelet aggregation.

Question 14

List 3 ways in which prostaglandins contribute to the inflammatory response.

Answer 14

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.

Question 15

List 3 effects of thromboxanes.

Answer 15

1 - Vasoconstriction.

2 - Bronchoconstriction.

3 - Platelet aggregation.

Question 16

How do non-selective non-steroidal anti-inflammatory drugs (NSAIDs) work?

Answer 16

By inhibiting both COX-1 and COX-2.

Question 17

How do selective NSAIDs work?

Answer 17

By inhibiting COX-2 only.

Question 18

List 2 examples of non-selective NSAIDs.

Answer 18

1 - Aspirin.

2 - Ibuprofen.

Question 19

List 2 examples of selective NSAIDs.

Answer 19

1 - Celecoxib.

2 - Rofecoxib (but increases risk of ischaemic heart disease!).

Question 20

How do glucocorticoids affect the COX and lipoxygenase pathways?

Answer 20

• Decrease expression of COX-2.

- Increase expression of annexin-1 (inhibits PLA2, decreasing free arachidonic acid.).

Question 21

Which component of fish oil is important in eicosanoid biosynthesis?

Answer 21

Eicosapentaenoic acid (arachidonic acid is eicosatetraenoic acid)

Question 22

List 3 types of drugs that are involved in the modulation of the COX pathway to achieve anti-inflammatory effect.

Answer 22

1 - Non-selective NSAIDs.

2 - Selective NSAIDs.

3 - Glucocorticoids.

Question 23

Which enzyme converts arachidonic acid into HPETE?

Answer 23

5 - Lipoxygenase.

Question 24

List 2 types of drugs that are involved in the modulation of the lipoxygenase pathway.

Answer 24

1 - 5-lipoxygenase inhibitor (USA only).

2 - Glucocorticoids.

Question 25

List 4 effects of leukotrienes.

Answer 25

1 - Contributes to the inflammatory response. 2 - Causes bronchoconstriction. 3 - Stimulates mucus secretion (in the respiratory system). 4 - Causes vasodilation / vasoconstriction.

Question 26

List 3 ways in which leukotrienes contribute to the inflammatory response.

Answer 26

1 - Chemotaxis (of neutrophils and macrophages). 2 - Stimulates proliferation of immune cells. 3 - Stimulates release of cytokines.

Question 27

What type of receptors are prostanoid and leukotriene receptors?

Answer 27

G-coupled protein receptors.

Question 28

List 2 prostanoid receptors and their ligands.

Answer 28

1 - IP (prostacyclin) receptor. Ligand: PGI2 (prostacyclin I2). 2 - TP (thromboxane) receptor. Ligand: TXA2 (thromboxane A2).

Question 29

What do IP receptors do once activated?

Answer 29

Gs pathway: The IP GPCR activates cAMP, which activates protein kinase A.

Question 30

What to TP receptors do once activated?

Answer 30

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).

Question 31

What do LT receptors do once activated?

Answer 31

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).

Question 32

Give an example of a receptor antagonist for the cysteinyl leukotriene receptor.

Answer 32

Montelukast.

Question 33

Give an example of a receptor agonist for the cysteinyl leukotriene receptor.

Answer 33

Epoprostenol.

Question 34

Which variants of the COX enzyme are found in platelets?

Answer 34

COX-1 only.

Question 35

Which variants of the COX enzyme are found in the endothelium?

Answer 35

Usually COX-1, but also COX-2 in some people.

Question 36

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?

Answer 36

- 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.

Question 37

List 2 drugs used to prevent thrombosis.

Answer 37

1 - Fish oil. 2 - Aspirin (low dose).

Question 38

How does aspirin prevent thrombosis?

Answer 38

- 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.

Question 39

How does the action of TXA2 in platelets differ from the action of PGI2 in the endothelium?

Answer 39

TXA2 in platelets: Aggregatory agent + vasoconstrictor. PGI2 in the endothelium: Anti-aggregatory + vasodilator.

Question 40

How do allergens cause allergic asthma?

Answer 40

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.

Question 41

How do glucocorticoids, zileuton and montelukast work to relieve the symptoms of asthma?

Answer 41

- 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.

Question 42

Why might non-selective NSAIDs lead to gastritis and ulcers?

Answer 42

- 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.

Question 43

What is HPETE converted to in the lipoxygenase pathway (what are the end products)?

Answer 43

1 - Cysteinyl leukotrienes (LTD4). 2 - Leukotriene B4.

Question 44

Which drugs are contraindicated with NSAIDs and why?

Answer 44

- Ibuprofen and diclofenac. | - 31% increased risk of cardiac arrest when these drugs are taken with with NSAIDs.