8.0 Inflammation Flashcards Preview

MedST IB: Mechanisms of Drug Action (MoDA) > 8.0 Inflammation > Flashcards

Flashcards in 8.0 Inflammation Deck (60)
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1

What is the triple response of Lewis?

1) Flush
Local vasodilation within seconds (due to histamine)

2) Flare
Neurogenic imflammation within 30-60 seconds

3) Wheal
Increase vascular permeability causes plasma leakage
Few minutes

2

What is dermatographic urticaria?

"Exaggerated triple response
""Skin writing""
May be triggered by drugs (e.g. penicillin)

Treatment = antihistamines + Omalizumab"

3

What is the effect of prostaglandins (PGE2 + PGI2)?

Vasodilation

4

What is the effect of histamine?

Vasodilation and ↑ vascular permeability

5

What is the effect of TNF-a/IL-1?

More cytokine release
Permeability
Express adhesion molecules

6

Role of:
1) C3a
2) C3b
3) C5a
4) C5b-C9

1) C3a
Mast cell stimulation

2) C3b
Opsonisation

3) C5a
Activates mast cells

4) C5b-C9
MAC
1 of each factor apart from C9 (12-18 C9s)

7

What do mast cells release following stimulation?

1) Histamine
2) Heparin
3) Leukotrienes
4) Nerve growth factor
5) Preformed cytokines

8

What cells contain histamine?

1) Mast cells - found in acidic granules with HMW heparin
2) Basophils - found in acidic granules with HMW heparin
3) Enterchromaffin-like cells
4) Histaminergic neurons of the brain

9

What particles cause mast cell degranulation?

"
"

10

Role and GPCR for the 4 histamine receptors?

"H1
- Smooth muscle contraction (ileum + bronchioles)
- Blood vessel dilation
- Itching
- Triple response

H2
- Increase heart rate
- Increase gastric acid secretion

"

11

What 2 enzymes metabolise histamine?

1) Histaminase
- Deaminates histamine → imidazole acetaldehyde

2) Histamine-N-Methyltransferase
- Transfers methyl group to nitrogen on imidiazole ring → N-methylhistamine

Imidazole acetaldehyde + N-methylhistamine are inactive at H receptors

12

What is mastocytosis?

"
"

13

Whats the problem with 1st generation antihistamines?

Crossed BBB → drowsiness

14

Whats the problem with 2nd generation antihistamines?

Had an effect on hERG → long QT syndrome

15

What cells in the stomach secrete HCl?

Parietal cells

16

What is the pathway of HCl secretion?

"
"

17

Synthesis pathway for bradykinin:

"
"

18

What inhibits kallikrein?

C1 esterase inhibitor

Deficiency in this → hereditary angioedema

19

What inactivates bradykinin?

Kinases

Kinase 1 → des-Arg-bradykinin

Kinase 2 (ACE) → Inactive kinin

20

What are the receptors for bradykinin and what are their agonists?

B1 (↑ in inflammation) : agonist = des-Arg-bradykinin

B2 (constitutive) : agonist = bradykinin + Kallidin

21

Structure of arachidonic acid:

(5,8,11,14-eicosatetetroenoic acid)

20 carbon unsaturated fatty acid
4 double bonds

22

Mechanism of COX inhibition for most NSAIDs?

Reversible inhibition
- Enter hydrophobic channel in enzyme
- Hydrogen bond with Arg120
- This interaction prevents arachidonic acid from entering the catalytic domain

23

Differences between COX1 + COX2 hydrophobic channels?

COX1 = narrow hydrophobic channel

COX2 = wide hydrophobic channel

24

How is selective COX-2 inhibition achieved?

Drugs contain a bulky sulphur side chain - thus the drug is too big to fit into the narrow hydrophobic channel of COX-1

COX-2 selective inhibitors tend to end in -coxib

25

Where is serotonin found?

1) Serum
- Released by platelets during activation and aggregation
- Causes further aggregation of platelets and vasoconstriction

2) Intestinal enterochromaffin cells


3) Serotonergic neurons (ENS + CNS)

26

What are the metabolic actions of steroids?

o ↓ uptake of glucose by muscles/fat
o ↑ gluconeogenesis
o ↑ protein catabolism
o ↓ protein anabolism
o Redistribution of fat

27

What are the anti-inflammatory actions of steroids?

• Anti-inflammatory actions:
o ↓ influx/activity of leukocytes
o ↓ activity of monocytes
o ↓ clonal expansion of T and B cells
o Switch from Th1 to Th2 response
o ↓ pro-inflammatory cytokine production/action (e.g. IL-1, IL-2, IL-5, TNF-α)
o ↓ eicosanoid production
o ↑ release of anti-inflammatory factors (IL-10, IL-1ra, lipocortin 1, secretory leukocyte inhibitory protein and IkB)

• Overall → ↓ activity of innate and acquired immune system (beneficial in some conditions)

28

What are the side effects of steroids?

"•Side effects (seen with large + prolonged doses):
o Opportunistic infection (∵ ↓ immune system)
o Impaired wound healing
o Oral thrush (candidiasis)
o Osteoporosis
o Hyperglycaemia (∵ glucose metabolism effects)
o Muscle wasting
o Cushing's syndrome (see diagram)

"

29

Adalimumab

- Class = Human monoclonal antibody
- Target = TNF α
- Mechanism = sequesters excess TNFa in rheumatoid arthritis
- Steps:
- Info:
Treatment: Rheumatoid arthritis

30

Alemtuzumab

- Class = Monoclonal antibody
- Target = CD52, an antigen on mature (but not precursor) lymphocytes
- Mechanism = Targets T lymphocytes for destruction
- Steps:
- Info:
• Administered several times a week
• Few off target side effects, as with all monoclonal antibodies
• Used for treating CLL + T cell lymphomas