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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
What role does substance P play in the triple vascular response?
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.
26
What is the pathophysical role of histamine? [2]
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.
27
What is the role of the H1 receptor? [4]
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.
28
What is the role of the H2 receptor? [4]
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.
29
Which of the H receptors is Gq coupled?
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.
30
What are the effects of stimulating the H1 receptor? [4]
1. PLC linked so Ca2+ increase. 2. Vasodilatory effects on arterioles via NO2 3. Increased vascular permeability via endothelial contraction --> oedema 4. Neuropeptide release.
31
What is the H4 receptor involved in?
Chemotaxis.
32
What do Chlorpheniramine, Astemizole and Loratidine have in common?
All antihistamines targeted for the H1 receptor. Newer: Astemizole and Loratidine.
33
Which H receptor is Gs coupled?
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.
34
What is the difference between Astemizole, Loratidine and Chlorpheniramine?
Astemizole and Loratidine are newer H1 receptor antihistamines with lower lipophilicity.
35
What are some H2 receptor antagonists? What are their actions?
Cimetidine + newer ---> Ranitidine Inhibit p450 enzymes and can interact with other drugs. Block gastric acid release from parietal cells.
36
What is arachidonic acid?
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.
37
How is prostacyclin formed from phospholipids?
PPL --PLA2---> Arachidonate ----Cyclooxygenase---> Prostaglandin H2------Prostacyclin synthase---> Prostacyclin
38
What PGs are involved in the initiation of labour?
PGF2apha + PGE2.
39
Name three H1 receptor antagonists:
Loratidine Astemizole Chlorphenamine.
40
What PGs are involved in inhibition of gastric acid secretion and cause increased gastric mucus production?
PGE2
41
What PGs are involved with inhibition of platelet aggregation?
Vascular PGI2 from endothelium. | Also cases vasodilation
42
What PGs are involved in promoting platelet aggregation?
Vascular TXA2 from platelets. | Also vasoconstrictor.
43
Which of the following is pro-thrombotic and which is anti-thrombotic? TXA2 + PGI2
PGI2 = anti-thrombotic: vasodilatory + anti-platelet aggregation. TXA2 = prothrombotic: vasoconstrictory and pro-platelet aggregation.
44
Which PG is responsible for prinzmetal's angina?
TXA2.
45
How are LTC4/LTB4 and leukotrienes in general formed?
Phospholipids are converted into arachidonate via PLA2. Arachidonate is converted into leukotrienes via lipooxygenases.
46
What are the effects of PGE2?
1. Inhibition of gastric acid secretion and cause increased gastric mucus production. 2. Increased blood flow.
47
Prostaglandins, prostacyclins, thromboxanes and leukotrienes are all examples of:
Classical eicosanoids.
48
Inhibition of 5-lipoxygenase would result in less of which eicosanoid?
Leukotrienes. Formed by 5-lipooxygenase acting on arachidonic acid.
49
Inhibition of COX/cyclooxygenases would result in less of which eicosanoid?
Prostaglandins, formed by action of COX/cyclooxygenases on arachidonic acid.
50
Inhibition of PLA2 would result in less of which eicosanoid?
Both. No arachidonic acid = no eicosanoids.
51
What is the potentially anti-inflammatory PG receptor?
EP2. Although it is also potentially pro-inflammatory as it does activate some leukocytes. The TP receptor is pro.
52
What effect do PGs have on pain sensation?
Sensitise peripheral C-fibres so increase the pain response to other agents: increased algesic response to capsaicin.
53
Knock-out mice lacking which PG receptor have decreased pain/inflammatory response?
EP1 receptors.
54
Cereborventricular injection of PGE2 leads to what?
Fever. Production and activation of PGE2 in the anterior hypothalmus.
55
How many isoforms of COX exist?
3. 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
Inhibition of which isoform of COX is desirable?
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
What induces COX-2?
IL-1, TNFa, Growth factors. Inhibited by glucocorticoids and IL-4.
58
What inhibits COX-2
Glucocorticoids and IL-4.
59
Which IL-X blocks COX-2?
IL-4.
60
What effect does aspirin have on COX-1?
Acetylates serine 530 and interferes with hydrophobic binding pockets.
61
What effect does aspirin have on COX-2?
Acetylates serine 516 and interferes with hydrophobic binding pockets on COX.
62
Serine 516 is acetylated in which COX isoform by aspirin?
COX-2.
63
COX selectivity is:
Inhibiting COX-2 and not COX-1, across the whole entire therapeutic dose range.
64
What is the crucial residue in COX-2? (not serine)
VAL-523.
65
What is the crucial residue in COX-1 (not serine)
ILE 523.
66
ILE-523 is the crucial residue in:
COX-1
67
How is NSAID selectivity for COX-1 measured?
Platelet thromboxane production
68
How is NSAID selectivity for COX-2 measured?
Monocyte PGE2
69
Which NSAIDs are most selective for COX-2?
``` Rofecoxib Celecoxib Diclofenac Piroxicam Naproxen Ibuprofen Aspirin ```
70
Why do aspirin-like drugs all have the common side effects of GI irritation and bleeding?
They block the 'housekeeping' COX-1 and thus reduce the cytoprotective effects of PGs
71
Why was rofecoxib withdrawn in 2004?
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
How does aspirin achieve its anti-thrombotic effects?
Irreversible acetylation of cox, thus platelet production ceases. The endothelial cells still produce new COX so PGI2 production continues.
73
Why do selective COX-2 inhibitors sometimes cause thrombotic events?
Selective COX-2 inhibitors affect PGI more than TXA2. TXA2 is prothrombotic.
74
When is the use of aspirin beneficial?
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
High levels of leukotrienes are found in the synovial fluid of which people?
RA patients.
76
What do Cysteinyl Leukotrienes cause?
Bronchoconstriction, increased vascular permeability, oedema.
77
Which agents can be used to inhibit the formation of leukotrienes?
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
What is lipocortin?
An endogenous PLA2 inhibitor induced by the action of glucocorticoids, can be exploited in anti-leukotriene therapy.
79
What is the action of glucocorticoids on eicosanoids? [3]
1. Inhibit PLA2 transcription 2. Induce synthesis of endogenous PLA2 inhibitor 'lipocortin' 3. Inhibit COX-3 synthesis
80
What type of agent is Zafirlukast?
Anti-LTC4
81
What type of agent is Montelukast?
Anti-LTC4
82
Which PG are involved in pain?
PGE2 | PGI2
83
Which PGs are involved in fever?
PGE2
84
Which eicosanoids are the potent vasodilators?
PGE2, PGI2
85
What is EPA?
Fatty acid metabolised by COX into PGI3 (potent anti-aggregation) and TXA3 (weak pro-aggregation)
86
How are 5 series leukotrienes produced?
Metabolism of EPA by 5-LO.
87
``` All of the following are proinflammatory cytokines except ... TNF IL-6 IL-10 IFN IL-1B ```
``` 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
LTD4
Bronchoconstrictor
89
Thromboxane A2 is produced mostly by
Platelets
90
The enzyme which metabolises arachidonic acid to generate the precursor of the leukotrienes is
5-lipoxygenase
91
TNF acts through:
Two distinct receptors.
92
Etanercept is to ______ as ______ is to interleukin (IL)-1
Etanercept is to ______ as ______ is to interleukin (IL)-1
93
``` Which ONE of the following DMARD is a copper-chelating anti-oxidant? Methotrexate Auranofin D-penicillamine Sulphasalazine Hydroxychloroquine ```
D-penicillamine

III (24 decks)

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