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Cardiovascular & Respiratory Pharmacology (Karen) > Lipid Mediators > Flashcards

Lipid Mediators Flashcards

1
Q

What is the structure of arachidonic acid?

A
  • aka eicosatetraenoic acid
  • 20 carbons, 4 double bonds
  • omega-6 FA (1st double bond is on position 6 from methyl end)
  • **not biologically active, needs to be transformed to be bioactive**
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2
Q

From where is arachidonic acid mainly derived?

A
  • dietary lineolic acid C18:2 (PUFA)
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3
Q

How is arachidonic acid stored?

A
  • esterified in membrane phospholipids (plasma, nuclear)
    • because it can be convereted into bioactive metabolites that are not controlled by homeostasis
  • esterified to various phospholipid types
    • choline
    • phosphatidylethanololine
  • usually at SN2 carbon of the glycerol backbone
  • activated by phospholipase A2
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4
Q

How is esterified arachidonic acid liberated from glycerol?

A

phospholipase A2 activity

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5
Q

What triggers activity of phospholipase A2 (and therefore increases arachidonic acid concentration)?

A
  • increases in intracellular calcium
  • other versions of phospholipases are released in a pro-inflammatory manner e.g. rheumatoid arthritis
  • snake venom contains ++PPLA2
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6
Q

What are eicosanoids?

A

biologically active metabolites of arachidonic acid

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7
Q

Metabolism of arachidonic acid occurs by

A
  • cyclo-oxygenases:
    • COX-1 = AA –> physiological prostaglandins (PGs) and prostacyclin
    • COX-2 = induced in any cell by inflammatory (LPS, TNF, IL-1) or growth stimuli, ++capacity to produce PGs, can lead to pathophysiological overproduction
  • [5-] lipoxygenase:
    • expressed in inflammatory cells (eos, macros, neu, baso, mast)
      • make leukotrienes
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8
Q

Cyxlo-oxygenase metabolism of arachidonic acid yields

A
  • highly unstable cyclic-endoperoxides
  • converted rapidly into stable PGs by isomerases
    • prostaglandin E2, H2, F2
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9
Q

What makes prostaglandins local mediators?

A
  • rapidly metabolised by endothelium in the pulmonary circulation (single pass)
  • tf never make it to systemic circulation, tend to work locally
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10
Q

What is the function of PGE2?

A
  • vascular smooth muscle relaxation
    • vasodilation (decreased BP), natiuration
  • hyperalgesic - increased sensitivites to painful stimuli
  • pyrogenic (fever-inducing)
  • angiogenic (blood vessel formation in wound healing, tumour growth)
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11
Q

What is the function of PGF2a and PGD2?

A

bronchoconstriction

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12
Q

Why are NSAIDs related to gastric ulceration?

A
  • NSAIDs inhibit PGE2 production to decrease pain (algesia)
  • PGE2 functions in angiogenesis of wound healing, and tf healing of ulcers
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13
Q

NSAIDs are

A

cyclo-oxygenase inhibitors (anti-inflammatory drugs)

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14
Q

What are the indications for NSAIDs?

A
  • anti-inflammatory: acute and chronic conditions e.g. rheumatoid arthritis, gout (not aspirin)
  • analgesia: headache, menstrual pain, MSK pain
  • antipyretic: fever (usually Paracetamol, aspirin contraindicated by adverse effects)
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15
Q

What are the major adverse effects of NSAIDs?

A

gastric irritation/ulceration

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16
Q

In inflammation, prostaglandins are involved in

A

vascular component: vasodilation

produces the heat of inflammation, predisposes to oedema by other mediators (histamine, bradykinin)

17
Q

What causes the sensation of pain, and how is it exacerbated?

A
  • bradykinin produces pain, some vasodilation
  • PGE2 increases sensitivity to pain, plus local reddening through vasodilation
18
Q

How is pain blocked?

A
  • analgesics to block bradykinin receptors
  • removal of PGE2 to remove the increased sensitivty of pain (NSAIDs)
19
Q

What happens to PGE2 in chronic pain?

A
  • chronic inflammation induces IL-1beta:
    • +BK1 (bradykinin) receptors
    • +COX-2 and PLA2
      • tf much more PGE2 is produced
  • tf getting increased pain receptors and increased sensitivity to pain
20
Q

How does PGE2 cause fever?

A
  • inflammation induces maco activation
  • get cytokine production (IL-1)
  • IL-1 travels via circulation to the hypothalamus (outside BBB)
  • IL-1 induces COX to overproduce PGE2
  • PGE2 acts via cAMP to increase the temperature set point, causing fever
21
Q

What are the gastro-protective roles of PGE2?

A
  • promotes blood flow by vasodilation, maintains oxygenation
  • promotes angiogenesis (wound healing)
  • increases mucous secretion
  • reduces gastric acid secretion
22
Q

Cyclic endoperoxides are converted to

A
  • products of AA + COX
  • isomerases convert CEs into:
    • prostaglandins: PGE2, PGD2, PGFa
    • prostacylcin: PGI2
    • thromboxane A2
23
Q

How is prostacyclin produced?

A
  • phospholipase A2 liberates arachidonic acid from esterified stores in membrane phospholipids
  • COX converts AA to cyclic endoperoxides
  • isomerase converts CE to prostacyclin
24
Q

How is thromboxane A2 produced?

A
  • phospholipase A2 liberates arachidonic acid from esterified stores in membrane phospholipids
  • COX converts AA to cyclic endoperoxides
  • isomerase converts CE to thromboxane A2
25
Q

Prostacyclin is produced by

A

endothelial cells

26
Q

What is the function of prostacyclin?

A
  • reduces platelet activation
  • vasodilator via cAMP at IP (prostacyclin receptors) in the vascular smooth muscle
  • prevents coronary artery disease by preventing atherosclerotic deposition
27
Q

Thromboxane A2 is produced by?

A

platelets

28
Q

What is the function of thromboxane A2?

A
  • opposes prostacyclin
  • increases platelet activation via TP receptors
  • causes vasoconstriction
  • promotes coronary artery disease (plaque deposition)
29
Q

What is unique about the mechanism of aspirin to other NSAIDs?

A

it binds irreversibly to the active site of cyclo-oxygenase, inhibitin its activity

30
Q

What is the mechanism of low-dose aspirin treatment in coronary artery disease?

A
  • platelets in the GIT circulation are exposed to high [aspirin] that inhibits their COX function
    • aspirin binds irreversibly to COX, inhibiting the enzyme
    • platelet has no nucleus tf cannot regenerate COX
  • [aspirin] is lower systemically and the endothelium can regenerate COX within hours
  • tf PGI2/TXA2 ratio is increased in favour of PGI2; thromboxane and tf clotting is impaired
31
Q

What is the exception to COX inhibition by aspirin?

A
  • COX-1 is inhibited by COX-2 retains ability to act on arachidonic acid, but at the 15th position, generating 15-epi-lipoxin-A4 and 15-epi-lipoxin-B4, epimers of endogenous lipoxins A4 and B4
  • epi-lipoxins function similar to endogenous lipoxins, that promote resolution of inflammation by directing macrophages to phagocytose dead cells and halting neutrophil infiltration
  • they may explain some of the added benefits of aspirin in inflammation over other NSAIDs
32
Q

What are lipoxins?

A
  • icsonoids, derived from arachidonic acid
  • produced in inflammation by lipoxygenases, epithelial cells, and leukocytes
  • anti-inflammatory/pro-resolution function
    • signal macrophages to dead cells for phagocytosis
    • switch off neutrophil invasion
  • receptor is formyl-peptide receptor 2 (FPR2)
33
Q

What are the dietary PUFAs?

A

poly-unsaturated fatty acids:

  • omega 6:
    • linoleic acid (C18:2) –> AA (20:4)
  • omega 3:
    • eicosapentaenoic acid/benefishoil (20:5)
    • docosahexanoic acid (C22:6)
34
Q

What is different in the metabolism of omega-3 fatty acids from metabolism of omega-6 arachidonic acid?

A
  • 3-series of prostaglandins and prostacyclins (instead of 2) - extra double bond
    • PGH3 is not a good substrate for thromboxane synthesis
    • PGI3 retains biological activity
  • tf metabolism of omega-3s favours prostacyclin and therefore reduces incidence of cornary artery disease
35
Q

How do omega-3 fatty acids favour decreased incidence of coronary artery disease?

A
  • their metabolism leads to production of 3-series prostaglandins and prostacyclins
    • PGH3 however is a less functional substrate for thromboxane synthesis than PGH2
    • PGI3 retains same bioactivity as PGI2
    • tf metabolism of omega-3 favours prostacyclin, reducing clotting factors and therefore decreasing incidence of coronary artery disease
36
Q

What is the function of 5-lipoxygenase?

A
  • inflammation
  • acticated by increased intracellular calcium by stimuli produced in infection, allergic response, or other inflimation e.g. trauma
37
Q

What are the products of arachidonic acid metabolism by 5-lipoxygenase?

A
  • 5-HPETE, the precursor to leukotriene A4 (LTA4)
  • LTA4 is converted to LTB4 or LTC4
  • LTC4 is precursor to D4, E4
38
Q

What is the significance of leukotriene E4?

A
  • causes bronchospasm in airways in asthma
  • causes leaky vessels
  • blockage of cysteinyl-leukotrienes like E4 is a target for asthma medication
39
Q

Leukotriene B4

A
  • promotes inflammation by attracting lymphocytes
  • currently no therapeutic targets

Cardiovascular & Respiratory Pharmacology (Karen) (15 decks)

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