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Life protection > I&I inflammation, inflammatory mediators, and anti-inflammatory agents > Flashcards

I&I inflammation, inflammatory mediators, and anti-inflammatory agents Flashcards

1
Q

What are the 5 cardinal signs of inflammation?

A
  1. Calor
  2. Rubor
  3. Tumor
  4. Dolor
  5. Functio laesa
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2
Q

What are the 5 steps involved in inflammation?

A
  1. Recognition of the injurious site
  2. Recruitment of leukocytes
  3. Removal of the agent
  4. Regulation of response
  5. Resolution
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3
Q

Why is histamine released locally?

A

For local action

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4
Q

Why is histamine inactivated locally?

A

Inactivated locally to minimise systemic effects

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5
Q

What is histamine synthesised stored and releasef from?

A

-Mast cells, which express receptors for IgE, C3a and C5a on cell surface (connective tissues)
-Basophils(blood)
-Neuron in brain
-Histaminergic cells in gut (ECL, enterochromaffin-like cells)

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6
Q

What is histamine released by?

A

Released by allergic reactions (IgE-mediated), production of
complement agents (C3a and C5a), insect stings, trauma, etc.
through a rise in [Ca2+]i.

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7
Q

What is release of histamine inhibited by?

A

Release of histamine inhibited by stimulation of β-adrenoceptors

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8
Q

What are the different types of histamine receptors?

A

4 types
-H1, H2, H3 and H4

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9
Q

What does stimulation of H1 and H2 receptors produce?

A

Stimulation of H1 and H2 receptors produce many of the actions of
histamine-mediated inflammation

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10
Q

What are the cardiovascular effects of H1 receptor stimulation?

A

-Dilation of arterioles decreasing TPR
-Increased permeability of post-capillary venules, decreasing blood volume

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11
Q

What are the non-vasulcar smooth muscle effects of the stimulation of H1 receptors?

A

bronchoconstriction

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12
Q

What is the cardiovascular effect of the stimulation of H2 receptors?

A

Increase in heart rate

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13
Q

What is the algesia effects of the stimulation of H1 and H2 receptors

A

Pain, itching, and sneezing caused by stimulation of sensory nerves
(H1)

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14
Q

What are associated exocrine secretions in result of H1 and H2 receptor stimulation?

A

Increased secretions due to increased blood flow

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15
Q

What is the effect on gastric acid in result of the stimulation of H1 and H2 receptors?

A

Increased secretion

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16
Q

What are the most important clinical roles of histamine?

A
  1. Acute inflammation(H1 effects)
  2. Stimulating gastric acid secretion(H2)
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17
Q

What is involved in the triple response?

A
  1. Redness
  2. Flare(depends on nerve supply)
  3. Wheal(depends on soluble, chemical mediator)
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18
Q

What acts on histamine secreting cells and how is this involved in gastric acid secretion?

A

-Gastrin and Ach act on histamine secreting cells
-This secreted histamine which acts on H2 receptor on parietal cells
-This leads to gastric acid secretion

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19
Q

What acts on muscarinic receptor on parietal cell and what does this lead to the secretion of?

A

Ach acts on muscarinic receptor on parietal cell which leads to the secretion of gastric acid

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20
Q

What do H1 antagonists treat?

A

Treat acute inflammation

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21
Q

What are examples of first generation H1 antagonists?

A

Mepyramine, promethazine, diphenhydramine

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22
Q

What are exzmples of 2nd and third generation H1 antagonists?

A

-Terfenadine
-Fexofenadine

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23
Q

What type of drug is terfenadine and what type of actions does it have?

A

Pro drug
-With potential cardiac arrhythmia actions at high doses

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24
Q

What is terfenadine action increased with and why?

A

increased with grapefruit juice (which
inhibits P450-mediated drug metabolism pathways in the liver)

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25
Q

What type of drug is fexofenadine and what is it a metabolite of?

A

active, non-toxic metabolite of terfenadine

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26
Q

What is a major side effect of first generation H1 antagonists?

A

Drowsiness

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27
Q

What is the therapeutic effect of promethazine?

A

Antiemetic so for motion sickness

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28
Q

What are H2 antagonists used for?

A

Gastric problems

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29
Q

What are examples of H2 antagonists?

A

-Cimetidine
-Famotidine

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30
Q

What is the therapeutic action of H2 antagonists and what is it used for the treatment of?

A

-Reduce gastric acid secretion in the treatment of duodenal and gastric ulcers and zollinger ellison syndrome

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31
Q

What do H2 antagonists increase activity of and what does this lead to the breakdown of?

A

Increase INMT activity so more rapid breakdown of histamine

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32
Q

What are the side effects of H2 antagonists?

A

Mental confusion, dizziness, tiredness & diarrhoea sometimes
as side effects

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33
Q

What does cimetidine decrease activity of therefore what can this cause?

A

Cimetidine decreases cytochrome P450 activity so potential
for adverse drug interactions; gynecomastia

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34
Q

What is bradykinin generated as a result of?

A

Bradykinin is generated as a result of activation of:
1.Hageman factor (HF, factor XII) & production of plasma kallikrein;
2.Production of lysylbradykinin by tissue kallikreins;
3.Action of cellular proteases

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35
Q

What are the functions of bradykinin?

A
  1. Pain
  2. Increase vascular permeability
  3. Vasodilation
  4. Chemotactic to leukocytes
  5. Dry cough
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36
Q

What do platelets release and what is it involved in?

A

Platelets release 5-HT involved in platelet aggregation

37
Q

What cells in the gastrointestinal tract are involved in the distribution of 5-HT?

A

The mucosal enterochromaffin cells of gastrointestinal tract
(mediates gut movement, diarrhoea)

38
Q

What release excess 5-HT and what are they involved in?

A

Some tumours (e.g. carcinoid) secrete excess 5-HT →↑
proliferation, and cell survival

39
Q

What does 5-HT promote in terms of inflammatory action?

A

Promotes inflammation by increasing the number of mast cells at
the site of tissue injury

40
Q

What does 5-HT stimulate with mast cells?

A

Stimulates mast cell adhesion and migration

41
Q

What does 5-HT enhance inflammatory reactions of?

A

Enhances inflammatory reactions of skin, lungs and gut

42
Q

How do TXA2 and 5-HT work together to stimulate platelet activity and vasoconstriction?

A

-Activation of TXA2 receptors increases 5-HT-mediated
responses in blood vessels
-Briefly, injured arteries and arterioles constrict due to
the release of 5-HT from platelets which plugs the
injured site

43
Q

What are prostaglandins, thromboxanes and leukotrienes collectively known as?

A

Known collectively as Eicosanoids

44
Q

What family do prostaglandins and thromboxanes - prostanoids come from?

A

Cyclooxygenases

45
Q

What family do leukotrienes and lipoxins come from?

A

Lipoxygenases

46
Q

What are the targets of major anti-inflammatory drugs?

A

-NSAIDs
-Glucocorticoids
-Lipoxygenase inhibitors
-Leukotriene anatagonists

47
Q

What are prostanoids genertated from?

A

Prostanoids are generated from arachidonic acid (AA, poly-
unsaturated fatty acid). This is rate-limiting step

48
Q

What is arachidonic acid produced from?

A

AAs are produced from phospholipids (PLs) via 1-step/2-step
pathways

49
Q

What is the 1 step pathway in the formation of arachidonic acid?

A

Phospholipids–> arachidonic acid
-Enzyme is phospholipase A2

50
Q

What is the 2 step pathway in the formation of arachidonic acid?

A

Check slide 28

51
Q

What enzyme is required to convert arachidonic acid to prostanoids?

A

Require the enzyme cyclooxygenase(COX)

52
Q

What are the 2 main isoforms of COX?

A

COX-1 and COX-2

53
Q

What state is COX-1 in?

A

Constitutively active

54
Q

What is COX-1 responsible for?

A

Responsible for ‘physiological’ roles of PGs/TXs such as
regulation of peripheral vascular resistance, renal blood flow,
platelet aggregation, gastric cytoprotection

55
Q

What state is COX-2 in?

A

Needs to be stimulated

56
Q

What is COX-2 respsonsible for?

A

Responsible for role of PGs/TXs in inflammatory response(pain and fever)

57
Q

How does prostaglandin endoperoxides PGG2 and PGH2 convert to TXA2?

A

With the assistance of the thromboxane synthase enzyme

58
Q

How does prostaglandin endoperoxides PGG2 and PGH2 convert to classical prostaglandins PGD2, PGE2 and PGF2alpha?

A

With the assistance of tissue-specific isomerases/synthases

59
Q

How does prostaglandin endoperoxides PGG2 and PGH2 convert to prostacylcin PGI2?

A

With the assistance of prostacyclin synthase

60
Q

What does aspirin do in the cyclooxygenase pathway?

A

Inhibits formation of TXA2 from prostaglandin endoperoxides

61
Q

What does mPGES-1 do in the cyclooxygenase pathway?

A

Blocks production of classic prostaglandins

62
Q

What does epoprostenol do in the cyclooxygenase pathway?

A

Blocks production of prostacyclin

63
Q

When is there a switch for PG synthesis and from what state to another?

A

There is a switch for PG synthesis from pro-inflammatory (PG & LTs) at
onset of inflammation to anti-inflammatory lipoxins and 15dPGJ2
(cyPG) during resolution

64
Q

What do lipoxins recruit and for what reason?

A

Lipoxins recruit monocytes to clear inflamed site of necrotic
apoptotic neutrophils

65
Q

What do monocytes regulate activation levels of?

A

Regulate activation levels of neutrophils and dampen their damaging
effects (↑phagocytosis of neutrophils)

66
Q

What does monocytes acting in concert with cyPGs promote?

A

Promote macrophages to phagocytose and clear apoptotic cells →
resolution of inflammation

67
Q

What activation does cyPGs inhibit and what does this lead to?

A

CypG – inhibits macrophage activation→ ↓ uncontrolled tissue
damage; ↓NF-B activation (helps to ↓ activation of inflammatory genes)

68
Q

What cells specialise in making particular eicosanoids?

A

-Mast cells: PGD2
-Platelets: TXA2
-Endothelial cells: PGI2, PGE2

69
Q

What do DP receptors do when stimulated by prostaglandins?

A

Vasodilatation, Decrease platelet aggregation, bronchoconstriction

70
Q

What do FP receptors do when stimulated by prostaglandins?

A

Contraction of myometrial smooth muscle, bronchoconstriction

71
Q

What do IP receptors do when stimulated by prostaglandins?

A

Vasodilatation, Decrease platelet aggregation, renin release

72
Q

What do EP1 receptors do when stimulated by prostaglandins?

A

Contraction of bronchiole/GIT smooth muscle

73
Q

What do EP2 receptors do when stimulated by prostaglandins?

A

Bronchodilation, vasodilatation, relaxation of GIT smooth
muscle, Increase intestinal fluid secretion

74
Q

What do EP3 receptors do when stimulated by prostaglandins?

A

Contraction of intestinal smooth muscle, Increase gastric mucus
secretion, Decrease gastric acid secretion, pyrexia

75
Q

What happens when TXs act on TP receptors?

A

Vasoconstriction, Increase platelet aggregation

76
Q

What happens when LTs act on BLT (1 and 2) receptors?

A

Chemotaxis and proliferation of immune cells, Increase adhesion

77
Q

What happens when LTs act on CysLT(1 and 2) receptors?

A

Bronchoconstriction, vasodilatation, Increase vascular permeability

78
Q

Which is more potent between leukotrienes and histamine?

A

Leukotrienes

79
Q

What are examples of leukotriene receptor antagonists?

A

Zafirlukast, montelukast, pranlukas

79
Q

What are the diverse actions of eicosanoids?

A

-Bradykinin and 5-HT act on receptors on the endothelial cells which release TXA2
–TXA2 increases platelet aggregation and these platelets release more TXA2
–TXA2 also acts on TP receptors which increase Ca2+ leading to contraction of blood vessel
-Shear stress acts on endothelial cells which releases PGI2
–PGI2 inhibit platelet aggregation
–PGI2 act on IP receptor which increases cAMP leading to relaxation of blood vessel

79
Q

What are leukotriene useful in?

A

– Prevention of mild to moderate asthma
– Early to late bronchoconstrictor effects of allergens
– Exercise-induced asthma and asthma provoked by NSAIDs

79
Q

What can the LTs such as LTC4, LTD4, LTE4 cause?

A

These LTs cause airway oedema, secretion of thick mucus and smooth
muscle contraction

80
Q

What are side effects involved in the use of leukotriene receptor antagonists?

A

– GI upset
– Dry mouth, thirst
– Rashes, oedema
– Irritability

81
Q

What is an example of a cox inhibitor?

A

Aspirin

82
Q

What does the inhibition of cox stop the synthesis of?

A

Inhibition of COX stops the synthesis of prostanoids (PGs and TXA)

83
Q

How do prostaglandins protect the epithelial cells of the stomach against damage?

A
  • Stimulating the secretion of HCO3- which neutralises gastric acid
  • Reducing H+ secretion
  • Stimulating mucus production
  • Promoting vasodilation
84
Q

Why can GI bleeds be associated with aspirin poisoning/overdose?

A

PGs protect the stomach against damage; thus GI bleed can be associated with aspirin poisoning/overdose

85
Q

What are the cytoprotective effects of PGE2?

A
  1. Promotes secretion of mucus
  2. inhibits release of acid
86
Q
A

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