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year 3 exam 1 > autoimmune and inflammation pharmacology > Flashcards

autoimmune and inflammation pharmacology Flashcards

1
Q

define autoimmunity

A

an immune response against self/autologous antigens resulting from failure of hosts immune system to distinguish self from non-self-cells

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2
Q

how is autoimmunity caused

A

Develops when multiple layers of self-tolerance are dysfunctional and Can be genetic

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3
Q

two mechanisms of autoimmunity

A

genetics & infection

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4
Q

how do genetics cause autoimmunity

A

polygenetic - causes production of self-reactive lymphocytes

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5
Q

how does infection and inflammation cause autoimmunity

A

inactivation of antigen presenting cells leading to influx and activation of self-reactive lymphocytes into tissues

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6
Q

define immunogen

A

a substance capable of eliciting an immune response

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7
Q

define tolerogen

A

antigens that induce tolerance rather than an immune response

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8
Q

what are the two mechanisms of self-tolerance

A

central and peripheral

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9
Q

what is central self tolerance

A

limits the development of B/T cells

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10
Q

what is peripheral self tolerance

A

regulates autoreactive cells in circulation

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11
Q

what happens to T cells in central tolerance

A
  • Exposed to self-antigens (MHC CD4/8 on APC) * Strong response: apoptosis * Intermediate response: Treg * Weak response: positive selection
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12
Q

what happens to B cells in central self tolerance

A
  • Mature in bone marrow and are exposed to self-antigens during development * High avidity: receptor editing and retesting - if still high apoptosis * Low avidity: reduce expression and become anergic
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13
Q

what happens to T cells in peripheral tolerance

A

Treg cell binds to active T cell causes anergy, apoptosis or suppression

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14
Q

what happens to B cells in peripheral tolerance

A
  • T cell not activated if B cell activated by self-antigen, no cytokines are released so B cell will not become activated Anergy, suppression or apoptosis
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15
Q

what are the three mechanisms of autoimmune damage

A

circulating antibodies,
T lymphocytes,
non-specific mechanisms

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16
Q

how do circulating antibodies cause autoimmune damage

A

○ Complement lysis and interaction with receptors ○ Toxic immune complexes ○ Penetration into living cells

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17
Q

how do T lymphocytes cause autoimmune damage

A

○ CD4 polarised towards TH1 via cytokines ○ CD8 activated to become cytotoxic T cells and cause direct cytolysis

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18
Q

how do is autoimmune damage caused non-specifically

A

○ Recruitment of inflammatory leucocytes into autoimmune lesions

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19
Q

what are conventional therapies for the treatment of autoimmune diseases

A
  • anti inflammatory drugs - immunosuppressive drugs - IV immunoglobulin - plasmapheresis - organ specific treatments (insulin, etc)
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20
Q

what happens when bacteria enters the skin

A
  1. bacteria enters through epithelial layer 2. macrophage recognises bacteria 3. cytokines, chemokines are released 4. IL1 causes a fever in the hypothalamus
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21
Q

what are the steps of the inflammatory response

A
  1. vasodilation 2. migration and margination 3. tissue repair
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22
Q

what happens in step 1 of the inflammatory response

A
  1. acute phase reaction (IL1/IL6/TNF alpha) -Platelet adhesion
    - vasoconstriction /vasodilation= increased heat/blood flow to area
  2. activation of the compliment system
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23
Q

what happens in step 2 of the inflammatory response

A
  1. Leukocyte adhesion - caused by chemoattractant on endothelial cell surface allowing transmigration
  2. Increased vascular permeability and Extravasion of serum proteins (exudate) and leukocytes with resultant tissue swelling
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24
Q

what happens in step 3 of the inflammatory response

A
  1. Wound healing and remodelling 6. Anti-inflammatory response - resolution - IL10, soluble adhesion molecules, TIMPS, etc
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25
Q

name some pro inflammatory mediators

A

acute phase proteins (CRP), compliment system, kinins, cytokines, chemokines, growth factors, adhesion molecules, extracellular matrix proteins, clotting factors, prostaglandins

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26
Q

what are acute phase proteins

A

they are synthesised in response to pro-inflammatory cytokines and vary in response to injury and infection

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27
Q

name some cytokines

A

TNF, IL6, IL1, IL12

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28
Q

what does TNF do

A

inflammation, acute phase proteins (APPs) in the liver, apoptosis induction, neutrophil induction

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29
Q

what does IL6 do

A

APPS in liver, proliferation and antibody secretion of B cells

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30
Q

what does IL1 do

A

inflammation, fever, APPs in liver

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31
Q

what does IL12 do

A

activated NK cells, TH1 promotion

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32
Q

what are chemokines

A
  • > 50 MW proteins that are chemotactic * 4 sub families that bind to GPCRs ○ CC, CXC, C, CXXXC
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33
Q

what does IL8 do

A

attracts neutrophils

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34
Q

what does monocyte chemotactic protein 1 do

A

attract monocytes

35
Q

what does eotaxin do

A

attracts eosinophils

36
Q

what are adhesion molecules

A

transmembrane receptors that bind to cells or the extracellular matrix (integrins/cadherins)

37
Q

what are extracellular matrix proteins

A

collagen, laminin, fibronectin

38
Q

what is NFkB

A

a family of transcription factors that regulate pro inflammatory mediators

39
Q

how does NFkB work

A

attached to IKB, once phosphorylated NFkB is released and travels to the nucleus and binds to promoter regions to activate transcription of pro-inflammatory mediators

40
Q

name some anti-inflammatory mediators

A

anti inflammatory cytokines, soluble adhesion molecules, TIMPs, plasmin activation system, opioid peptides, resolvins

41
Q

what is an anti inflammatory cytokine

A

IL10

42
Q

what are soluble adhesin molecules

A

bind to adhesion molecules to stop other molecules from binding

43
Q

what do TIMPs do

A

inhibit MMPs

44
Q

what does the plasmin activation system do

A

causes clot to recede

45
Q

what do opioid peptides do

A

counteract pain

46
Q

what are resolvins/protectins

A

anti-inflammatory lipid mediators

47
Q

what is acute inflammation

A

-Necessary part of the immune system but has resolution - If excessive, can lead to organ failure or death

48
Q

what is chronic inflammation

A
  • Inappropriate, leads to tissue destruction - Leads to disease * Autoimmune * Neurodegenerative * Chronic age-related disorders
49
Q

define DMARDs

A

disease modifying anti rheumatic drugs

50
Q

give 3 examples of DMARDs

A

methotrexate, ciclosporin and leflunomide

51
Q

what is methotrexate

A
  • Folic acid antagonist with cytotoxic and immunosuppressive effects
  • 1st choice anti-rheumatic
52
Q

MOA of methotrexate

A
  • MOA is unrelated to its effect on folic acid metabolism, but may be affected by its ability to block uptake
  • Main action is to inhibit dihydrofolate reductase
53
Q

how is methotrexate given

A
  • Given orally, IV, IM or intrathecally * Low lipid solubility - does not cross BBB * Taken up into cells - metabolised to polyglutamate derivatives which are kept within the cell
54
Q

side effects of methotrexate

A
  • Can cause bone marrow depression, platelet and white blood cell reduction - liver cirrhosis
55
Q

MOA of ciclosporin

A
  • Potent immunosuppression,
  • Decreased IL2 -decreased cytotoxic T cell proliferation/induction
  • Reduced function of effector T cells
56
Q

how is ciclosporin metabolised

A

CYP450

57
Q

side effects of ciclosporin

A
  • Accumulates in tissues at concentrations 3-4x than that in plasma
  • Nephrotoxicity - unconnected to calcineurin inhibition
  • May be contraindicated in patients with hepatotoxicity and hypertension
58
Q

what is leflunomide used for

A
  • Rheumatoid arthritis and occasionally transplants
59
Q

MOA of leflunomide

A
  • inhibitory effect on activated T cells
  • inhibits de novo synthesis of pyrimidines by inhibiting dihydro-orotate dehydrogenase
60
Q

side effects of leflunomide

A
  • Side effects include diarrhoea, alopecia, raised liver enzymes and a risk of hepatic failure
61
Q

what are NSAIDs used for

A
  • Symptomatic relief from fever, pain, swelling in chronic joint diseases and acute inflammatory conditions - Also for post operative, dental and menstrual pain as well as headaches and migraines
62
Q

what is fatty acid cyclo-oxygenase 1

A

constitutive - in most cells, produces prostanoids that act mainly as homeostatic regulators

63
Q

what is fatty acid cyclo-oxygenase 2

A

involved in inflammation

64
Q

how do COX enzymes work

A
  1. stimulus 2. phospholipase A2 turns phospholipids to arachidonic acid 3. PG2 and PGH24. endoperoxide isomerase or synthase enzymes to prostacyclin, PGE2 and thromboxane
65
Q

what is the main prostanoid involved in inflammation and how does it work

A

PGE2- EP1: bronchial and GIT smooth muscle
EP2/EP4: broncho- vaso- dilation, intestinal fluid secretion stimulation EP3: smooth muscle contraction, gastric acid secretion

66
Q

what does PGD2 do

A

vascular bed vasodilation, platelet aggregation inhibition, GIT/uterine muscle relaxation

67
Q

what does PGF2a do

A

uterine muscle contraction

68
Q

what does PG12 do

A

vasodilation, inhibition of platelet aggregation and renin release

69
Q

what does TXA2 do

A
  • Vasoconstriction, platelet aggregation and bronchoconstriction
70
Q

how are COX inhibitors anti-inflammatory

A

decrease in prostaglandin E2 and prostacyclin - reduces vasodilation and oedema

71
Q

how are COX inhibitors analgesic

A

decreased prostaglandin generation, less sensitisation of nociceptive nerve endings to inflammatory mediators

72
Q

how are COX inhibitors antipyretic

A

prevents to action of IL1 on the hypothalamus

73
Q

what are the side effects of COX inhibitors

A
  • GI side effects - nausea, dyspepsia - hypertension - skin reactions - reversible renal insufficiency - bronchospasm - analgesic associated nephropathy - liver disorders - bone marrow depression
74
Q

what causes the side effects of COX inhibitors

A

COX1 inhibition

75
Q

which NSAID is as an antithrombotic

A

aspirin - 75mg OD

76
Q

which NSAIDs are used for short term analgesia

A

paracetamol, aspirin, ibuprofen

77
Q

which NSAIDs are used for long term analgesia

A

naproxen, piroxicam

78
Q

which NSAIDs are used for their anti inflammatory properties

A

ibuprofen, naproxen

79
Q

which NSAID is used for their anti-pyretic properties

A

paracetamol

80
Q

unwanted side effects of aspirin at therapeutic doses

A

gastric bleeding

81
Q

side effects of aspirin in large doses

A

Dizziness, deafness, tinnitus, compensatory respiratory alkalosis may occur

82
Q

aspirin side effects at toxic doses

A

uncompensated metabolic acidosis - especially in children

83
Q

why should aspirin be avoided in children

A

Rare but serious post viral encephalitis (Reyes)

84
Q

why does paracetamol overdose cause fatal liver damage

A

○ Causes drug to be metabolised by mixed function oxidases to n-acetyl-pbenzoquinoneimine ○ If not inactivated by conjugation to glutathione it can react with cellular proteins and cause tissue damage

year 3 exam 1 (44 decks)

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