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PA20351 > Eicosanoids > Flashcards

Eicosanoids Flashcards

1
Q

What are eicosanoids?

A

Oxidation products of 20-carbon fatty acids.

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2
Q

What is a common eicosanoid?

A

Arachidonic acid.

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3
Q

What are some of the classical eicosanoids?

A

Prostanoids (prostaglandins, prostacyclins and thromboxanes) and leukotrienes.

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4
Q

What are some non-classical eicosanoids?

A

Lipoxins, resolvins, isoprostanes, endocannabinoids.

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5
Q

How are prostaglandins synthesised?

A

The membrane phospholipids are acted on by by phospholipase A2 that forms arachidonic acid. This is then acted on by COX to form PGH2. There are then tissue-specific isomerases that convert this to different forms such as TxA2, PGD2, PGE2, PGI2 and PGF2a.

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6
Q

What is prostaglandin H2?

A

An unstable intermediate in the prostaglandin biosynthesis stage.

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7
Q

What does the number in the different isoforms of prostaglandin represent?

A

The number of double bonds in the molecule.

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8
Q

What do prostaglandins act on?

A

Specific GPCRs on target cells.

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9
Q

How many PGE2 receptors are there?

A

4.

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10
Q

What is PGI2?

A

Prostacyclin.

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11
Q

What is PGE2?

A

Prostaglandin E2.

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12
Q

What is the prostacyclin receptor and what is it linked to?

A

IP - it is a Gs coupled receptor linked to adenylyl cyclase/cAMP.

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13
Q

What is the thromboxane receptor and what is it linked to?

A

TP and it is Gq coupled - PLC to cause IP3 and calcium release.

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14
Q

What is the effect of PGI2?

A

As it activates adenylyl cyclase, it is a vasodilator of smooth muscle.

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15
Q

What is the action of thromboxane?

A

It causes platelet aggregation and vasoconstriction - opposing effect to prostacyclin.

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16
Q

What are some PGD2 receptors?

A

DP1 and DP2.

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17
Q

What are some of the varying physiological effects of prostaglandins?

A

Initiation of labour, inhibition of gastric acid secretion and increased gastric mucus production, inhibition of platelet aggregation and vasodilation, platelet aggregation and vasoconstriction.

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18
Q

What prostaglandins initiate labour and how?

A

PGF2a and PGE2 - they cause contraction of the uterus.

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19
Q

What causes inhibition of gastric acid secretion and increased gastric mucus production?

A

PGE2.

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20
Q

What causes inhibition of platelet aggregation and vasodilation?

A

PGI2 (prostacyclin) from the endothelium.

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21
Q

What causes platelet aggregation and vasoconstriction?

A

TXA2 (thromboxane) from platelets.

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22
Q

How can prostaglandins have multiple functions?

A

The EP2 receptor in smooth muscle can cause vasodilation (pro-inflammatory), whereas EP2 in the leukocyte can inhibit function - anti-inflammatory.

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23
Q

How can the EP2 have differing effects?

A

In smooth muscle Gs mediated elevation of cAMP - vasodilation, whereas in the leukocytes there is Gs mediated elevation of cAMP that inhibits their function.

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24
Q

What function does the EP3 receptor have?

A

It activates leukocytes and mast cells and causes enhanced oedema formation.

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25
Q

What is the E3 receptor linked to?

A

Gi - it reduces adenylyl cyclase/cAMP signalling and enhances function.

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26
Q

What is the E1 receptor important in?

A

Pain perception - EP1 receptor knockout mice has reduced pain perception.

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27
Q

How are prostaglandins involved in fever?

A

The induction of fevers is regulated by the production and action of PGE2 in the hypothalamus.

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28
Q

Why do fevers arise?

A

Elevation of the hypothalamic thermostat - around a 2 degree increase.

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29
Q

What is the purpose of fever generation?

A

Protection against infection as viral survival is lower at higher temperatures.

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30
Q

What does COX stand for?

A

Cyclo-oxygenase- they are involved in the formation of prostaglandins.

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31
Q

What is COX1?

A

The constitutive housekeeping enzyme - its products are important in normal function of the stomach, intestine, kidney and platelets.

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32
Q

What is COX2?

A

It is induced during inflammation.

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33
Q

What is COX3?

A

A splice variant of the COX1 gene that is expressed in the CNS. It was previously suggested as a paracetamol target, but is thought not to be relevant in humans.

34
Q

How are glucocorticoids related to COX?

A

They inhibit the synthesis of COX2.

35
Q

How does the function of COX1 and COX2 differ?

A

COX2 is induced and involved in inflammation, whereas COX1 is constitutive and has homeostatic functions - GI tract, renal tract, platelet function and macrophage differentiation.

36
Q

What are NSAIDs?

A

Non-steroidal anti-inflammatory drugs.

37
Q

What effect does aspirin have?

A

It causes decreased production of prostaglandins

38
Q

What target does aspirin have?

A

COX - it is a non-specific COX inhibitor.

39
Q

What is the pathway for synthesis of prostaglandins from arachidonic acid?

A

It goes into the catalytic site and gets converted to PGH2 which can then form prostanoids.

40
Q

How does the synthesis pathway of prostaglandins change after aspirin has been introduced?

A

There is acetylation of serine 529 by aspirin which interferes with the arachidonic acid binding. Aspirin irreversibly acetylates serine.

41
Q

How are salicylic acid and aspirin similar?

A

They both fit into the enzyme site of COX - however salicylic acid binds reversibly.

42
Q

What are some examples of NSAIDs?

A

Aspirin, ibuprofen, piroxicam.

43
Q

What is a common mechanism of NSAIDs?

A

Inhibition of COX enzymes.

44
Q

What is the result of COX inhibition due to aspirin?

A

Platelet TXA2 (thromboxane) production ceases - they lack nuclei.

45
Q

How are the effects of aspirin different in platelets and endothelial cells?

A

Platelets do not have a nucleus so cannot form new COX, whereas endothelial cells can form new COX so PGI2 can still be released.

46
Q

What is aspirin useful in?

A

Acute myocardial infarction, coronary artery by-pass, acute thrombotic stroke, pulmonary embolism and thrombosis.

47
Q

What do long term studies about aspirin show?

A

It has significant protective effect against colon and rectal cancer.

48
Q

What is the effect of low doses of aspirin?

A

COX is inactivated by aspirin permanently in the platelets, whereas new endothelial COX can be made. This is beneficial in thrombosis.

49
Q

What is thrombosis?

A

Formation of blood clots in unwanted areas.

50
Q

Why is aspirin useful in thrombosis?

A

Platelets are inactivated whereas endothelial COX can still be made and prostacyclin can still be released - important in vasodilation and platelet inactivation.

51
Q

What are some of the features of aspirin?

A

Covalent binding, acetylation of COX, irreversible inhibition of COX and salicylate release.

52
Q

How does ibuprofen differ to aspirin?

A

It is a competitive rather than non-competitive inhibitor - will effect the endothelial COX production just as much as the platelet COX production.

53
Q

What is COX2 specificity?

A

There is inhibition of COX2 but not COX1, across the entire therapeutic dose range.

54
Q

Give an example of a selective COX inhibitor.

A

Celecoxib.

55
Q

How does the selectivity of celecoxib arise?

A

It can physically fit into COX2 but not COX1.

56
Q

What are some COX2 selective NSAIDs?

A

Diclofenac, celecoxib.

57
Q

What are some COX1 selective NSAIDs?

A

Flubiprofen, low doses of aspirin.

58
Q

What is COX1 measured as in selectivity tests?

A

Platelet thromboxane production

59
Q

What is COX2 selectivity measured as in selectivity tests?

A

Monocyte PGE2 production.

60
Q

What are some side effects of aspirin-like drugs?

A

Gastric irritation and bleeding, renal toxicity.

61
Q

What are the side effects of aspirin due to?

A

Blocking housekeeping COX1 and therefore reducing the cytoprotective effects of prostaglandins.

62
Q

In general, what specific COX inhibition is good and bad?

A

COX1 inhibition is bad whereas COX2 inhibition is good.

63
Q

Why aren’t specific COX2 or COX1 inhibitors always used?

A

There is increased cardiovascular risk with COX2 and increased gastrointestinal risk with COX1.

64
Q

How does salicylate work?

A

It is a weak reversible inhibitor of COX - it fits into the active site of the enzyme. There is evidence that it stops the synthesis of COX2 - the inflammatory form of COX.

65
Q

What else is arachidonic acid a precursor for?

A

The formation of leukotrienes.

66
Q

What are the intermediates in the formation of leukotrienes from arachidonic acid?

A

5-HPETE to LTA4 which then can be converted to LTB4 or LTC4/LTD4/LTE4.

67
Q

What catalyses the formation of 5-HPETE from arachidonic acid?

A

5-lipoxygenase.

68
Q

What receptors does LTB4 act on?

A

BLT receptor.

69
Q

What effect do LTC4/LTD4/LTE4 have?

A

Bronchoconstriction, increased vascular permeability.

70
Q

What receptors do LTC4/LTD4/LTE4 act on?

A

cycLT receptor.

71
Q

What are some of the general actions of leukotrienes?

A

Bronchoconstriction, oedema, chemotaxis and inflammation.

72
Q

What are some examples of leukotrienes that cause bronchoconstriction?

A

LTC4 and LTD4 - they constrict human bronchial smooth muscle and are 1000x more potent than histamine.

73
Q

What are some leukotrienes that can cause oedema?

A

LTC4 and LTD4 - they cause increased vascular permeability (neutrophil indepdent) and LTB4 increases vascular permeability but is neutrophil dependent.

74
Q

What is a leukotriene that can cause chemotaxis?

A

LTB4. BLT1 is the receptor.

75
Q

What do glucocorticoids inhibit?

A

They inhibit the transcription of phospholipase A.

76
Q

How can glucocorticoids be used clinically?

A

As they inhibit phospholipase A this prevents the transcription of arachidonic acid, meaning they can be used as anti-inflammatory steroids.

77
Q

What does zileuton do?

A

Prevents 5-lipooxygenase acting on arachidonic acid.

78
Q

What do zafirulukast and montelukast do?

A

They are antagonists of teh C4/D4 receptors - prevent the formation of leukotrienes.

79
Q

How do glucocorticoids effect eicosanoids?

A

They inhibit phospholipase A transcription (PLA2) by inducing the synthesis of PLA2 inhibitor lipocortin. They also inhibit COX2 synthesis.

80
Q

Why are eicosanoids important?

A

They are potent vasodilators, they increase vascular permeability, they are important in pain, fever and have synergy with other mediators such as histamine, bradykinin and chemotaxins. They are also important modulators of cell function - direct effects and via effects on nuclear transcription factors.

PA20351 (11 decks)

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