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Watson inflamm sem 1 Flashcards

1
Q

What symptoms of RA represent cycles of “acute” inflammation?

A

redness, swelling, chemical mediator release, neutrophil recruitment.

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2
Q

What type of mediator is histamine? [5]

A
  1. Pre-formed
  2. Rapidly produced
  3. Released from stimulated neurones.
  4. Produced following proteinase activation.
  5. Produced hours later.
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3
Q

Rapid inflammatory mediators produced from membrane lipids include [3]

A
  1. Eicosanoids (PGE2, PGI2)
  2. Leukotrienes (LTB4)
  3. PAF (platelet activation factor)
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4
Q

Stimulated neurons release these inflammatory mediators: [2]

A
  1. Substance P

2. Calcitonin Gene related peptide (CGRP)

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5
Q

Proteinase activation leads to the production of: [2]

A

Bradykinin

Complement factor C3a, C5a

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6
Q

iNOS, Cox-2 and cytokines are produced how soon after injury?

A

Hours later following protein synthesis.

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7
Q

Increased vascular permeability can come about because of: [5]

A 
Histamine
Eicosanoids, LTB4, LTC4
PAF
Bradykinin
C3a, C5a.
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8
Q

Histamine has what effect on vascular permeability?

A

Increases it.

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9
Q

Eicosanoids have what effect on vascular permeability?

A

Increase it.

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10
Q

Bradykinin has what effect on vascular permeability?

A

Increases it.

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11
Q

C3a + C5a have what effect on vascular permeability?

A

Increase it.

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12
Q

What mediators of inflammation are vasodilators? [5]

A 
Histamine, 
Eicosanoids:PGE2, PGI2
Neuropeptides, SP, CGRP
Bradykinin
Nitric Oxide
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13
Q

Histamine has what effect on vasodilation?

A

Increases it.

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14
Q

PGE2 and PGI2 have what effect on vasodilation?

A

Increase it.

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15
Q

Substance P and CGRP (Neuropeptides) have what effect on vasodilation?

A

They increase it.

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16
Q

Which eicosanoids only cause vasodilation? (no effect on vascular permeability)

A

PGE2, PGI2.

LTB4 and LTC4 cause vascular permeability to increase.

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17
Q

What effect does nitric oxide release have on vasodilation?

A

Increases it.

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18
Q

Which inflammatory mediators cause both vasodilation and an increase in vascular permeability? [2]

A

Histamine

BRadykinin.

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19
Q

What is plasma exudation and what can cause it?

A

Plasma leakage: histamine and bradykinin act directly on endothelium to increase vasodilation and vascular permeability.

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20
Q

How do neutrophil activators increase plasma exudation?

A

Neutrophil-dependent mechanisms.

LTB4, FMLP, C5a, IL-8.

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21
Q

Why may inhibiting neutrophils be a more effective strategy in inflammatory disease management?

A

Some substances cause acute inflammation via actions on the endothelium only, histamine for example (and bradykinin). Others cause acute inflammation via actions on neutrophils: fMLP, LTB4, C5a, IL-8 etc.
Inhibiting or antagonising a single mediator is only effective in inflammation driven by that single substance e.g. H1 receptor-antagonists are only effective against the histamine component of the inflammatory/allergic response.

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22
Q

Which drug causes the production of histamine to halt and how is this done?

A

Tritoqualine (hypostamine). Inhibits histidine decarboxylase, preventing L-histidine being converted into histamine. The histamine that is already present is deactivated into imidazoyl acetic acid by histaminases.

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23
Q

Where is histamine mostly stored?

A

Mast cells, granular, large cells in the skin, lungs, gut, and nasal mucosa. Histamine is a basic drug.

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24
Q

What is the triple response?

A

A response to histamine or an allergen that is cutaneous.

  1. Arterial dilation (local reddening)
  2. Oedema formation (WHEAL)
  3. axon reflex (flare)-release of neutrophils.
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25
Q

What role does substance P play in the triple vascular response?

A

Cell damage stimulates sensory neurones –> send pain + itch signals to the CNS –> antidromic impulses also cause neuropeptide release from peripheral nerve branches.
SP + CGRP -> blood vessel dilation + SP stimulates histamine release from mast cells.

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26
Q

What is the pathophysical role of histamine? [2]

A
  1. Immediate hypersensitivity responses: allergic rhinitis, urticaria (skin rashes), anaphylactic shock.
  2. Hypersecretion of insulin results in excess acid production and formation of duodenal and peptic ulcers.
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27
Q

What is the role of the H1 receptor? [4]

A
  1. PLC linked so Ca2+ increase.
  2. Vasodilatory effects on arterioles via NO2
  3. Increased vascular permeability via endothelial contraction –> oedema
  4. Neuropeptide release.
    GQ coupled.
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28
Q

What is the role of the H2 receptor? [4]

A
  1. AC leading to increased cAMP.
  2. Vasodilator, but limited significance in inflammation.
  3. Potent stimulator of gastric acid secretion.
  4. Vascular smooth muscle relaxation.
    Gs coupled.
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29
Q

Which of the H receptors is Gq coupled?

A

H1:
1. PLC linked so Ca2+ increase.
2. Vasodilatory effects on arterioles via NO2
3. Increased vascular permeability via endothelial contraction –> oedema
4. Neuropeptide release.
GQ coupled.

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30
Q

What are the effects of stimulating the H1 receptor? [4]

A
  1. PLC linked so Ca2+ increase.
  2. Vasodilatory effects on arterioles via NO2
  3. Increased vascular permeability via endothelial contraction –> oedema
  4. Neuropeptide release.
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31
Q

What is the H4 receptor involved in?

A

Chemotaxis.

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32
Q

What do Chlorpheniramine, Astemizole and Loratidine have in common?

A

All antihistamines targeted for the H1 receptor. Newer: Astemizole and Loratidine.

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33
Q

Which H receptor is Gs coupled?

A

H2:
1. AC leading to increased cAMP.
2. Vasodilator, but limited significance in inflammation.
3. Potent stimulator of gastric acid secretion.
4. Vascular smooth muscle relaxation.
Gs coupled.

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34
Q

What is the difference between Astemizole, Loratidine and Chlorpheniramine?

A

Astemizole and Loratidine are newer H1 receptor antihistamines with lower lipophilicity.

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35
Q

What are some H2 receptor antagonists? What are their actions?

A

Cimetidine + newer —> Ranitidine
Inhibit p450 enzymes and can interact with other drugs.
Block gastric acid release from parietal cells.

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36
Q

What is arachidonic acid?

A

An essential fatty acid derived from red meat or via desaturation of lindeic acid.

Found in all cells of the body, primarily as a component of membrane phospholipids.

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37
Q

How is prostacyclin formed from phospholipids?

A

PPL –PLA2—> Arachidonate —-Cyclooxygenase—> Prostaglandin H2——Prostacyclin synthase—> Prostacyclin

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38
Q

What PGs are involved in the initiation of labour?

A

PGF2apha + PGE2.

39
Q

Name three H1 receptor antagonists:

A

Loratidine
Astemizole
Chlorphenamine.

40
Q

What PGs are involved in inhibition of gastric acid secretion and cause increased gastric mucus production?

41
Q

What PGs are involved with inhibition of platelet aggregation?

A

Vascular PGI2 from endothelium.

Also cases vasodilation

42
Q

What PGs are involved in promoting platelet aggregation?

A

Vascular TXA2 from platelets.

Also vasoconstrictor.

43
Q

Which of the following is pro-thrombotic and which is anti-thrombotic?
TXA2 + PGI2

A

PGI2 = anti-thrombotic: vasodilatory + anti-platelet aggregation.

TXA2 = prothrombotic: vasoconstrictory and pro-platelet aggregation.

44
Q

Which PG is responsible for prinzmetal’s angina?

45
Q

How are LTC4/LTB4 and leukotrienes in general formed?

A

Phospholipids are converted into arachidonate via PLA2.

Arachidonate is converted into leukotrienes via lipooxygenases.

46
Q

What are the effects of PGE2?

A
  1. Inhibition of gastric acid secretion and cause increased gastric mucus production.
  2. Increased blood flow.
47
Q

Prostaglandins, prostacyclins, thromboxanes and leukotrienes are all examples of:

A

Classical eicosanoids.

48
Q

Inhibition of 5-lipoxygenase would result in less of which eicosanoid?

A

Leukotrienes. Formed by 5-lipooxygenase acting on arachidonic acid.

49
Q

Inhibition of COX/cyclooxygenases would result in less of which eicosanoid?

A

Prostaglandins, formed by action of COX/cyclooxygenases on arachidonic acid.

50
Q

Inhibition of PLA2 would result in less of which eicosanoid?

A

Both. No arachidonic acid = no eicosanoids.

51
Q

What is the potentially anti-inflammatory PG receptor?

A

EP2.
Although it is also potentially pro-inflammatory as it does activate some leukocytes.
The TP receptor is pro.

52
Q

What effect do PGs have on pain sensation?

A

Sensitise peripheral C-fibres so increase the pain response to other agents: increased algesic response to capsaicin.

53
Q

Knock-out mice lacking which PG receptor have decreased pain/inflammatory response?

A

EP1 receptors.

54
Q

Cereborventricular injection of PGE2 leads to what?

A

Fever. Production and activation of PGE2 in the anterior hypothalmus.

55
Q

How many isoforms of COX exist?

A
  1. COX-1: housekeeping enzyme involved in normal functioning of stomach, intestine, kidney and platelets.
    COX-2: Induced particularly in inflammatory cells exposed to inflammatory stimuli.
    COX-3: Splice variant of COX-1 gene, expressed in CNS (?)
56
Q

Inhibition of which isoform of COX is desirable?

A

COX-2 has a role in inflammation, hence its inhibition is desired. COX-1 on the other hand plays a role in normal functions: GI tract, renal tract, platelet formation, macrophage differentiation and hence we don’t want to inhibit this one.

57
Q

What induces COX-2?

A

IL-1,
TNFa,
Growth factors.
Inhibited by glucocorticoids and IL-4.

58
Q

What inhibits COX-2

A

Glucocorticoids and IL-4.

59
Q

Which IL-X blocks COX-2?

60
Q

What effect does aspirin have on COX-1?

A

Acetylates serine 530 and interferes with hydrophobic binding pockets.

61
Q

What effect does aspirin have on COX-2?

A

Acetylates serine 516 and interferes with hydrophobic binding pockets on COX.

62
Q

Serine 516 is acetylated in which COX isoform by aspirin?

63
Q

COX selectivity is:

A

Inhibiting COX-2 and not COX-1, across the whole entire therapeutic dose range.

64
Q

What is the crucial residue in COX-2? (not serine)

65
Q

What is the crucial residue in COX-1 (not serine)

66
Q

ILE-523 is the crucial residue in:

67
Q

How is NSAID selectivity for COX-1 measured?

A

Platelet thromboxane production

68
Q

How is NSAID selectivity for COX-2 measured?

A

Monocyte PGE2

69
Q

Which NSAIDs are most selective for COX-2?

A 
Rofecoxib
Celecoxib
Diclofenac
Piroxicam 
Naproxen
Ibuprofen
Aspirin
70
Q

Why do aspirin-like drugs all have the common side effects of GI irritation and bleeding?

A

They block the ‘housekeeping’ COX-1 and thus reduce the cytoprotective effects of PGs

71
Q

Why was rofecoxib withdrawn in 2004?

A

3.9x incidence of thrombotic events potentially due to the fact that endothelial PGI2 is derived mostly from COX-2, not COX-1.
Rofecoxib suppressed this but had no effect on platelet COX-1 and so unbalanced the TXA2 vs PGI2 production.

72
Q

How does aspirin achieve its anti-thrombotic effects?

A

Irreversible acetylation of cox, thus platelet production ceases.
The endothelial cells still produce new COX so PGI2 production continues.

73
Q

Why do selective COX-2 inhibitors sometimes cause thrombotic events?

A

Selective COX-2 inhibitors affect PGI more than TXA2. TXA2 is prothrombotic.

74
Q

When is the use of aspirin beneficial?

A

Acture MI, coronary bypass, angioplasty/stenting, acute thrombotic stroke, pulmonary embolism, thrombosis.
Long-term aspirin = significant protective effect against colon and rectal cancer. Delay in onset of alzheimers disease

75
Q

High levels of leukotrienes are found in the synovial fluid of which people?

A

RA patients.

76
Q

What do Cysteinyl Leukotrienes cause?

A

Bronchoconstriction, increased vascular permeability, oedema.

77
Q

Which agents can be used to inhibit the formation of leukotrienes?

A

Glucocorticoids (indirect inhibition via PLA2 blocking synthesis of arachidonic acid, induces synthesis of endogenous PLA2 inhibitor ‘lipocortin’, inhibit COX-2 synthesis)

Zilueton: acts on synthesis of leukotrienes from arachidonic acid.

78
Q

What is lipocortin?

A

An endogenous PLA2 inhibitor induced by the action of glucocorticoids, can be exploited in anti-leukotriene therapy.

79
Q

What is the action of glucocorticoids on eicosanoids? [3]

A
  1. Inhibit PLA2 transcription
  2. Induce synthesis of endogenous PLA2 inhibitor ‘lipocortin’
  3. Inhibit COX-3 synthesis
80
Q

What type of agent is Zafirlukast?

81
Q

What type of agent is Montelukast?

82
Q

Which PG are involved in pain?

83
Q

Which PGs are involved in fever?

84
Q

Which eicosanoids are the potent vasodilators?

A

PGE2, PGI2

85
Q

What is EPA?

A

Fatty acid metabolised by COX into PGI3 (potent anti-aggregation) and TXA3 (weak pro-aggregation)

86
Q

How are 5 series leukotrienes produced?

A

Metabolism of EPA by 5-LO.

87
Q 
All of the following are proinflammatory cytokines except ...
TNF
IL-6
IL-10
IFN
IL-1B
A 
IL-10.
Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor 2 proteins.
88
Q

LTD4

A

Bronchoconstrictor

89
Q

Thromboxane A2 is produced mostly by

90
Q

The enzyme which metabolises arachidonic acid to generate the precursor of the leukotrienes is

A

5-lipoxygenase

91
Q

TNF acts through:

A

Two distinct receptors.

92
Q

Etanercept is to ______ as ______ is to interleukin (IL)-1

A

Etanercept is to ______ as ______ is to interleukin (IL)-1

93
Q 
Which ONE of the following DMARD is a  copper-chelating anti-oxidant?
Methotrexate
Auranofin
D-penicillamine
Sulphasalazine
Hydroxychloroquine
A

D-penicillamine

III (24 decks)

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