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I3 Exam 1 > Lipid Mediators of Inflammation (O'Brien) > Flashcards

Lipid Mediators of Inflammation (O'Brien) Flashcards

1
Q

What do cells synthesize and release after inflammation activations?

A

pro-inflammatory eicosanoids (prostaglandins, leukotrienes, histamine, bradykinin)

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2
Q

What do prostaglandins do within the body? How does it present on the outside?

A

Induce dilation and increase permeability of blood vessels at affected sites (resulting in local accumulation of blood, plasma, and fluid) –> results in redness, heat, sweating

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3
Q

Histamine and leukotrienes induce…

A

leukocyte infiltration into affected site

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4
Q

Describe the general arachindonic acid pathway

A

stimulus –> phospholipase A2 releases –> phospholipids –> arachidonic acid from lipid bilayer–> 2 pathways: lipoxygenages (LOX) and cyclooxygenases (COX)

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5
Q

EPA and arachidonic acid are metabolized into what kind of eicosanoids, respectively?

A

Omega 3 and omega 6

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6
Q

T or F: different eicosanoids have different biological effects?

A

True

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7
Q

What is the general function of eicosanoids?

A

bind and activate specific receptors (often G-protein coupled) in cell membrane and trigger cell activity related to inflammation

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8
Q

What do leukotrienes do?

A

stimulate bronchoconstriction

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9
Q

PGI2 induces…

A

vasodilation and inhibits platelet aggregation

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10
Q

Thromboxanes stimulate…

A

platelet aggregation, clot formation, and thrombosis

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11
Q

Which are more potent: omega 3 or omega 6 eicosanoids?

A

omega 6, because they compete for same receptor

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12
Q

What does intake of omega-3 fatty acid from fish oil do (mechanism)?

A
  • Inhibits delta6-desaturase via competitive inhibition, which would normally take linoleic acid omega 6 from diet to arachidonic acid omega 6
  • compete with arachidonic acid for COX and LOX, inhibiting synthesis of omega 6 and 3 from arachidonic acid
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13
Q

What are 2 major enzymes in prostanoid synthesis and how are they expressed?

A

Cox-1 and Cox-2 or PGH2 synthase; expressed in cell specific manner

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14
Q

What are the 3 major prostanoids?

A

PGE2, TXA2, PGI2

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15
Q

What does PGE2 do, what is it made from, is it pro/anti-inflammatory, what does it protect against?

A

-increase body temp, made from COX-2, pro-inflammatory, protective against peptic ulcers

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16
Q

What is TXA2 involved in, where is it synthesized and from what, and what does it do?

A

Platelet aggregation, made from platelet COX-1, vasoconstricton/bronchoconstriction

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17
Q

What synthesizes PGI2, what does it do?

A

Vascular endothelium; inhibits platelet aggregations (counteracting TXA2) via vasodilation and relaxing smooth muscle

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18
Q

What are leukotrienes (LTs) generated by? What is one specific one?

A

lipoxygenases, specifically 5-LOX

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19
Q

Products of 5-LOX play roles in … by increasing…

A

inflammation, asthma, CV disease, anaphylactic shock…increases neutrophil infiltration, bronchoconstriction, vascular permeability

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20
Q

LTA4 and LTB4 are converted to lipoxins LXA4 and LXB4 which are…and play a role in…

A

anti-inflammatory; play a role in resolution of inflammation

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21
Q

What can generate epilipoxins which are similar to the action of LXA4 and LXB4?

A

aspirin

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22
Q

Resolution is an ACTIVE biological process that requires decreased synthesis of….and synthesis of…

A

decreased synthesis of prostaglandins and leukotrienes and synthesis of anti-inflammation and pro-resolving lipid mediators

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23
Q

What does “lipid mediator class switching” refer to? What is responsible for it?

A

Resolution of acute inflammation: at high concentrations, PGD2 and PGE2 stimulate up-regulation of 15-LOX to induce lipid mediator class switching in neutrophils, mucosal epithelial cells, and fibroblasts to synthesize pro-resolution molecules (lipoxins, resolvins, protectins, and maresins)

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24
Q

Aspirin is unique in its ability to…

A

increase pro-resolution molecules

25
Q

Acetylated COX2 can use arachidonic acid, EPA, and DHA to produce…

A

intermediates that are the precursors for synthesis of a series of pro-resolving molecules

26
Q

COX-1 and COX-2: which is constitutively expressed and which is expression induces by stress, growth factors, cytokines, inflammatory mediators?

A

COX1 - constitutively

27
Q

Inhibition of COX1 leads to…

A

GI-related side effects (PGs inhibit acid secretion from parietal cells)

28
Q

COX2 is a major source of ___ at sites of inflammation (cancer)

A

prostanoids

29
Q

What does COX1 do?

A

synthesizes prostanoids for “housekeeping” functions (gastric protection, kidney function, blood clotting)

30
Q

What is a drug that only inhibits COX2?

A

Celecoxib

31
Q

What drugs inhibits both COX1 and COX2?

A

Aspirin, Ibuprofen, naproxen

32
Q

NASAIDs are ____ competitive inhibitors of ___ and _____. Except ____ is an ______ inhibitor.

A

reversible, COX1 and COX2, aspirin is irreversible

33
Q

What is the major biological effect of NSAIDs?

A

inhibition of prostagladin synthesis

34
Q

What are the therapeutic effects of NSAIDs at low doses?

A

analgesia; antipyretic (lower fever)

35
Q

What are the therapeutic effects of NSAIDs at high doses?

A

anti-inflammatory

36
Q

What are the GI adverse effects of NSAIDs? Why do they occur?

A

Pain, nausea, diarrhea, gastric ulcers, etc. due to inhibition of PGs that are gastroprotective

37
Q

What are the renal adverse effects of NSAIDs? Why do they occur?

A
  • renal insufficiency, failure, hyperkalemia proteinuria, decreased effectiveness of anti-hypertensive meds
  • analgesic nephropathy –> slowly progressive renal failure because decreased PGE2 means less renal blood flow
38
Q

All NSAIDs except aspirin have black box warnings for…

A

thrombotic events

39
Q

What increases the risk of thrombotic events with NSAIDs?

A
  • can occur short-term

- increased risk with time on drugs, people who have heart disease

40
Q

Why do thrombotic events occur with NSAIDs?

A

inhibition of PGI2 in vessel endothelium, which inhibits platelet aggregation and induces vasodilation

41
Q

Name main 3 functions of aspirin

A

analgesis, antipyretic at low doeses, anti-inflammatory (irreversible inhib of COX1 and 2)

42
Q

How is aspirin cardioprotective?

A

decreased platelet aggregation at low doses because TXA2 synthesis is prevented

43
Q

How is aspirin metabolized? Is it always irreversible?

A

metabolized into acetate and salicylate, which is a competitive, reversible inhibitor

44
Q

How is aspirin secreted?

A

proximal tubule and glomerular filtration

45
Q

What are the renal effects of aspirin? Low vs high doses?

A
  • analgesic nephropathy –> decreased renal perfusion
  • low doses: decrease urate excretion; high plasma urate
  • high doses: induce uricosuria; low plasma urate
46
Q

People hypersensitive to aspirin are provoked by ____ doses

A

low

47
Q

Aspirin/Salicylate poisoning causes what? Therapeutic vs toxic doses?

A
  • tinnitus

- Acid/base balance problems

48
Q

Aspirin/Salicylate poisoning at therapeutic levels do what to acid/base balance?

A

respiratory alkalosis followed by renal compensation and increased excretion of bicarb, NA, and K

49
Q

Aspirin/Salicylate poisoning at toxic levels do what to acid/base balance?

A

respiratory and metabolic acidosis due to increased lactic acid due to uncoupling of ox phos and mitochon toxicity

50
Q

Co-admin of ibuprofen with aspirin causes what toxicity?

A

increased cardioprotection and anti-inflammatory effects

51
Q

What is the half life of naproxen?

A

14 hours! - long!

52
Q

Celecoxib (celebrex) should be avoided in patients prone to…

A

cardiovascular or cerebrovascular disease

53
Q

Does acetaminophen have strong anti-inflammatory activity?

A

no!

54
Q

What pathways are saturated with acetaminophen toxicity?

A

glucuronidation and sulfation

55
Q

Induction of CYP___ increases risk of acetaminophen toxicity. Results in what type of toxicity?

A

CYP2E1; hepatotoxicity

56
Q

What is given for acetaminophen overdose?

A

N-acetylcystein (Mucomyst)

57
Q

Indomethacin is used for… and what are the toxicities?

A

closure of patent ductus; toxicity: GI effects, panceatitis, thrombocytopenia, aplastic anemia

58
Q

Sulindac is a prodrug. What is it used for?

A

anti-cancer

59
Q

Piroxicam should be given how many times a day? What percentage of patients get side effects>

A

once a day due to 50 hour half life; 20% patients

I3 Exam 1 (1 decks)

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