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OD2 Semester 1 - Applied Clinical Training > P: anti-inflammatory drugs 1 - week 5 > Flashcards

P: anti-inflammatory drugs 1 - week 5 Flashcards

1
Q

Describe the 2 ways that chemical signalling occurs between cells, then describe the 3rd way

A
  1. release of molecules as secreted mediators
  2. direct interaction with membrane bound molecules (cell to cell contact)
  3. Hybrid mechanism: Exosomes - little lipid-lined vesicles that contain proteins on lipid membrane, and also have various nucleic acids inside them
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2
Q

Name 5 important local mediators

A
  1. histamine (a small amine)
  2. prostaglandins
  3. leukotrienes
  4. bradykinin
  5. nitric oxide

note: prostaglandins and luekotrienes are eicosanoids

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3
Q

Why would a local mediator usually only act locally?

A

often they are quite labile or are rapidly broken down close to the site of release

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4
Q

Name 4 modulatory functions of local mediators

A
  • smooth muscle tone/length
  • glandular secretion
  • permeability (cascular and airway)
  • sensory nerves (pain and itch)
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5
Q

Where is the major source of histamine in the body?

A

Mast cells

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6
Q

where are mast cells found? Where are they most abundant?

A

found in pretty much every tissue/organ in the body. Most abundant at sites that came into contact with the external environment (e.g. skin, resp. tract)

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7
Q

Where in the mast cells is histamine stored? How can we see this?

A

In electron microscopy you’ll see that the mast cells have these densely stained granules. And histamine is found/stored within these granular matrices

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8
Q

What is de-granulation of mast cell?

A

When there’s a stimulus for the mast cell, de-granulation occurs. This is where these granules fuse with the plasma membrane of the cell, and release their contents (i.e. HISTAMINE) out into the extracellular environment

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9
Q

Describe the process of allergic inflammation with mast cells

A

The body produces IgE, which reacts with allergens. IgE is ralied against these substances and it binds to the surface of mast cells via this high affinity IgE receptor called FCeR1

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10
Q

How high or low is FCeR1 afinity for IgE?

A

High

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11
Q

What happens to the mast cellwhen IgE is produced against an allergen?

A

the IgE binds and “sensitizes” the mast cell. Results in de-granulation of the mast cell and release of the histamine

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12
Q

How does histamine mediate its activities?

A

through interacting with 4 receptors (H1, H2, H3, H4)

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13
Q

Which histamine receptor should you target for allergic inflammation tx?

A

use H1 receptor antagonists. This will prevent histamine from acting on the H1 receptor

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14
Q

List the 3 classes of H1 receptor antagonists

A
  1. sedative - e.g. chlorpheniramine, promethazine
  2. non-sedative (poor entry into CNS) - e.g. tefenadine, astemizole
  3. newwer non-sedative agents - e.g. cetrizine, loratidine
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15
Q

Why were older non-sedative H1 receptor antagonists withdrawn from the market?

A

because they could cause rare, sudden ventricular arrhythmia

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16
Q

What advantage do newer non-sedative agents of H1 receptor antagonists have over the older ones?

A

they have a reduced risk of unwanted cardiac effects

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17
Q

What is the brand name for acetylsalicylic acid?

A

aspirin

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18
Q

What are the 3 main outcomes of salicylate?

A
  • anti-pyretic (fever)
  • analgesic (pain)
  • anti-inflammatory actions
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19
Q

What is the active component in semen that was able to regulate smooth muscle tone?

A

Prostaglandins

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20
Q

How many cells produce prostaglandins?

A

most cells

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21
Q

Are eicosanoids stored by cells?

A

No. They are produced on demand.

22
Q

What is the precursor to eicosanoids?

A

arachidonic acid, which is held as part of membrane phospholipid

23
Q

How is arachidonic acid prepared for the generation of eicosanoids?

A

First we activate the enzyme phospholipase A2, which clips off the arachidonic acid and frees it up.
- once the arachidonic acid is in its free form in the cell, the other pathways can kick in to generate eicosanoids from the arachidonic precursors

24
Q

How is phosphilpase A2 (PLA2) activated?

A

could be activated through cell damage

– e.g. if you raised intracellular Ca2+ via mechanical trauma, this is often a cue for activation of PLA2

25
Q

What is the rate limiting step for the generation of eicosanoids?

A

the liberation of arachidonic acid by PLA2

26
Q

Name the 2 classes of eicosanoids generated from arachidonic acid, and state the enzyme that is used in each case

A
  1. Prostanoids (via COX, cyclooxegenase)

2. Leukotrienes (via LOX, lipoxygenase)

27
Q

How does COX convert arachidonic acid? Explain how different types of this new molecules get broken up

A

COX converts arachidonic acid into “intermediate prostaglandins” (PGG2 and PGH2)
- cells then have different synthase enzymes that can take these precursors and generate different bioactive prostanoids

(i.e. “cell-specific synthase enzymes” are used)

28
Q

Name the 2 major COX enzymes and state what cells they can be found in

A
  1. Cyclooxygenase 1 (COX 1):
    - is constitutive
    - is found in most cells
  2. Cyclooxygenase 2 (COX 2):
    - is inducible
    - found in inflammatory cells (therefore ramped up dramatically during inflammation)
29
Q

What is COX 1 generally responsible for?

A

Homeostatic/regulatory roles

30
Q

Why are cysteinyl-leukotrienes considered a target for asthma?

A

because they play an important role as constrictors of bronchial smooth muscle

31
Q

Describe the leukotriene pathway for conversion of arachidonic acid (AA)

A

AA is converted via 5-lipoxygenase (found mainly in inflammatory cells) to LTB4 and also to LTC4, LTD4 and LTE4 (those last 3 being known as cysteinyl-luekotrienes)

32
Q

What receptors do eicosanoids bind to?

A

G-protein coupled receptors

  • the g-protein is then activated and goes and does things that regulate the cell function
33
Q

Describe the pharmacological actions of eicosanoids on the following areas:
A: Blood

A

Platelets:
CPG1 - anti-aggregatory, TXA2 - pro-aggregatory
Luekocytes:
LTB4 - chemoattractant

34
Q 
Describe the pharmacological actions of eicosanoids on the following areas in SMOOTH MUSCLE:
B: vascular
C: bronchial
D: uterine
E: gastrointestinal
A

Vascular: PGE2/PGI2 - vasodilator; TXA2- vasoconstrictor
Bronchial: LTC4/LTD4/LTE4 - constrictor
Uterine: PGE2/PGF2alpha - contraction
GI: PGE2/PDG2alpha - contraction

35
Q

Why is a balance between PGI2 and TXA2 important for homeostasis?

A

because PGI2 is a vasodilator and anti-thrombotic and TXA2 is a vasoconstrictor and pro-thrombotic

36
Q

Describe the pharmacological actions of eicosanoids on the following areas:
F: Gastric Secretion
G: Kidney

A

Gastric secretion: PGE2/PGI2 - inhibit gastric secretion (and also stimulate mucous secretion in the gut)

Kidney: PGE2/PGI2 - increase renal blood flow and increase excretion of water and sodium

37
Q

Provide an example how eucosanoids can be used therapeutically for the eye

A

treatment of glaucoma (e..g with latanoprost etc. PGF2alphs mimetics)

38
Q

What does it mean to act synergistic-ally with other mediators. Name an example of a compound that does this

A

It means they enhance the actions of the other mediators. In this case, prostanoids enhance the actions of histamine and bradykinin

39
Q

Out of the following, what has the largest effect on increasing dilation?
Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Prostanoids and Bradykinin

40
Q

Out of the following, what has the largest effect on increasing vascular permeability?
Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Leukotrienes and Histamine

41
Q

Out of the following, what has the largest effect on increasing chemotaxis?
Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Bradykinin

42
Q

Out of the following, what has the largest effect on pain

Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Bradykinin

43
Q

Out of the following, what has no effect on dilation?

Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Leukotrienes

44
Q

Out of the following, what has no effect on chemotaxis?

Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Histamine and Bradykinin

45
Q

Out of the following, what has no effect on pain (relief)?

Histamine, Bradykinin, Prostanoids or Leukotrienes

A

Histamine and Leukotrienes

46
Q

How does PGE2 and PGI2 affect our sensitivity to pain?

A

Hyperalgesic. Increases sensitivity of receptors to pain

– is especially hyperalgesic when used in combination

47
Q

How does inflammation trigger fever (5 steps)

A

Inflammation – neutrophil activation – cytokines – PGE2 – raid temperature in hypothalamus

48
Q

Name the 3 pharmacological actions of eicosanoids

A
  • fever
  • pain
  • inflammation
49
Q

What do NSAIDs inhibit?

A

COX (therefore inhibits the conversion of arachidonic acid into PGG2/PGH2 and then into other prostanoids)

– i.e. NSAIDs inhibit prostaglandin production

50
Q

Given how they act, name the 3 pharmacological actions of NSAIDs

A
  • anti-pyretic
  • analgesic
  • anti-inflammatory

OD2 Semester 1 - Applied Clinical Training (47 decks)

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