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Scientific Basis of Theraputics > - Lipid mediators of inflammation - important targets of anti-inflammatory drugs > Flashcards

- Lipid mediators of inflammation - important targets of anti-inflammatory drugs Flashcards

1
Q

what are eicosanoids

A

are a family of signalling molecules w/ powerful inflammatory actions

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2
Q

what are the two classes of eicosanoids

A
  1. cyclooxygenases (COX)
  2. lipoxygenases

classed as one of the two based on the enzyme that acts on arachidonic acid first

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3
Q

what is the COX (cyclooxygenase) pathway

A

acts on arachidonic acid -> commit to becoming a prostanoid (PG or thromboxane)

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4
Q

what is the lipoxygenase pathway

A

acts on arachidonic acid .’. committed to becoming leukotriene or lipoxin under various other enzymes

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5
Q

what stimulates production of eicosanoids

A

not stored. synthesised when stimulated eg:

  • mechanical trauma
  • presence of cytokines or other eicosanoids
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6
Q

what are eicosanoids synthesised from

A

arachidonic acid

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7
Q

what is arachidonic acid synthesised from

A

from phospholipids in the cell surface membrane

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8
Q

what is the one step process of arachidonic acid production

A

Phospholipase A2 acts on phospholipid in the cell membrane and cleaves it to arachidonic acid

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9
Q

what is the two step process of arachidonic acid production

A

phospholipase C act on phospholipids ->DAG, which is converted to arachidonic acid by DAG lipase
phospholipase D act on phosphatidic acid which is converted to arachidonic acid by phospholipase A

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10
Q

what may initiate the arachidonic formation cascade

A

bradykinin and adrenaline

initiate phospholipase action at the cell membrane

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11
Q

how may arachidonic acid be converted to prostanoids

A

cyclooxygenase metabolises arachidonic acid.

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12
Q

what are the two isoforms of COX

A

COX1

COX2

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13
Q

what is the role of COX1

A

always active
responsible for the physiological roles of PGs/TXs such as regulation of peripheral vascular resistance, renal bf, platelet aggregation and gastric cytoprotection

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14
Q

what is the role of COX2

A

needs to be stimulated (e.g. by inflammatory cytokines IL-1 OR TNF-alpha)

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15
Q

where is Thromboxane A2 (TXA2) synthesised

A

in activated platelets

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16
Q

what does TXA2 occur

A

prothrombotic properties
pro-aggregatory
potent vasoconstrictor

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17
Q

COX1 and blood in stools

A

COX1 =prevent damage. enhances BF to the stomach &increases production of mucus.
inhibition of COX1 =stomach is not as well protected making it more vulnerable to attack by stomach acid.
If not healed, this can lead to internal bleeding hence the blood in the stool

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18
Q

effects of cyclooxygenase pathway metabolites of arachidonic acid

A

TXA2 =pro-aggregatory and a potent vasoconstrictor
PGE2 =important for gastric protection. in inducing favour
PGF2a =bronchoconstrictor and uterine constrictor
prostacyclin = synthesised endothelial cells lining blood vessels. effective vasodilators. inhibits platelet aggregation

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19
Q

what are the products of COX pathway of arachidonic acid

A

is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin.

20
Q

what is the Lipoxygenase Pathway of arachidonic acid metabolism to produce leukotrienes

A

AA -> 5HPETE by FLAP (5-lipoxygenase) which is then converted to leukotriene A (is unstable)
leukotriene A -> leukotriene B by LTA4 hydrolase
or leukotriene A ->sulphidopeptide leuktrienes (LTC4, LTD4, LTE4) by glutathione transpeptidase

21
Q

what is the Lipoxygenase Pathway of arachidonic acid metabolism to produce lipoxins

A

AA ->HPETE by other lipoxygenases. then metabolised to lipoxins
Leukotriene A may also be converted to lipoxins

22
Q

what are lipoxins

A

anti-inflammatory mediators

23
Q

what are leukotrienes

A

pro-inflammatory mediators

24
Q

how do we clinically stop leukotriene and lipoxin formation

A

GSK2190915 is a FLAP inhibitor

Esculetin is an inhibitor of lipoxygenases

25
Q

what eicosanoids are involved in the inflammation

A

at onset -synthesis of pro-inflammatory mediators (prostaglandins and leukotrienes)
During resolution, switch to anti-inflammatory lipoxins and cyPG

26
Q

lipoxins in inflammatory response

A
  • recruit monocytes to clear the inflamed site of necrotic apoptotic neutrophils that were involved in the acute response
  • regulate the activation of neutrophils &dampen down their damaging effects on the tissue
  • act with cyPGc to promote clearance of apoptotic cells by macrophages (resolution)
27
Q

lipoxin action with cyPGs (cyclopentenones)

A

promote phagocytic clearance of apoptotic

cyPG inhibits macrophage activation. prevents uncontrolled tissue damage by the macrophage.

28
Q

lipoxin action with cyPGs (cyclopentenones)

A

promote phagocytic clearance of apoptotic
cyPG inhibits macrophage activation. prevents uncontrolled tissue damage by the macrophage.
NF-kappabeta activation, reduces expression of inflammatory genes by cells present and helps the resolution process

29
Q

what class of receptors do eicosanoids work at

A

GPCR

30
Q

what type of eicosanoid do mast cells produce

A

PGD2

31
Q

what type of eicosanoid do platelets produce

A

TXA2

32
Q

what type of eicosanoid do endothelial cells produce

A

PGI2

PGE2

33
Q

binding of leukotrienes to their receptors have a number of functions including:

A
  • act as chemoattractant
  • Bronchoconstriction
  • Increases vascular permeability
  • Oedema
  • Increase secretion of thick, viscous mucus
34
Q

effect of COX inhibitor on asthma

A

shunt arachidonic acid down lipoxygenase route

=production of leukotrienes so worsen asthma symptoms

35
Q

effects of prostoglandins

A
  • vasodilation
  • contraction of myometrial smooth muscle
  • decreased platelet aggregation
  • pyrexia
  • decreased gastric acid secretion
  • increased gastric mucus secretion.
36
Q

effects of thromboxane at TPr

A
  • Vasoconstriction

- increased platelet aggregation

37
Q

effects of leukotrienes

A

General inflammation, lungs (bronchoconstriction)/vascular (vasodilation) changes in the acute allergy response

  • chemotaxis
  • proliferation of immune cells and increased vascular permeability ]
38
Q

effects of leukotrienes acting at Cys-LT

A
  • Airway oedema
  • Secretion of thick mucus
  • Smooth muscle contraction
39
Q

examples of leukotriene antagonists

A

Zafirlukast, montelukast and panlukast

40
Q

clinical uses of leukotriene antagonists

A
  • prevention of mild to moderate asthma
  • treat the early to late bronchoconstrictor effects of allergens
  • In exercise induced asthma and NSAID provoked (AA pathway shift to leukotrienes)
41
Q

side effects of leukotriene receptor antagonists

A
  • GI upset
  • Irritability
  • Dry mouth and thirst
  • Rashes, oedema
42
Q

what happens in inflammation

A
  1. insult occurs
  2. Arachidonic acid synthesis stimulated by bradykinin, adrenaline, antibody-receptor interactions
    3, COX2 stimulated stimulated by interleukins from leucocytes. COX1 active
  3. PG and leukotrienes produced
  4. switch to resolution with lipoxin production and cyPG
  5. resolution
43
Q

why may COX1 inhibitor likely to cause ulcers/bleeding

A

PGE2 acts on parietal cells and mucus secreting cells: turn down acid secretion in the gut +increase mucus secretion .’. is gastroprotective.
inhibiting PGE2 production by blocking COX1 = reduced gastric protection .’. likely to get ulcers and bleed

44
Q

what are anti-inflammatory lipid mediators

A
  • Lipoxins
  • cyPG
  • Resolvins
  • Neuroprotectins
45
Q

why are poly-Unsaturated Fat Intaken in Disease

A

omega 3 from fish oil =beneficial effects of our health.

EPA and DHA (are in fish) play a significant part in inflammation

Scientific Basis of Theraputics (9 decks)

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