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BMS242 Core Phys Pharm > L11-12 Anti-inflammatories > Flashcards

L11-12 Anti-inflammatories Flashcards

1
Q

What does NSAID stand for

A

Non-steroidal anti-inflamatory drug

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2
Q

When was the natural precurrsor to aspirin disocered

A

5th century

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3
Q

What does coxib stand for

A

COX2 - Inhibitors

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4
Q

What was significant in 18228

A

Leroux isolated the active ingredient for aspirin from the willow tree

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5
Q

What is the active ingredient in aspirin

A

Salicyclic acid

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6
Q

What was done in 1897 to produce the first synthetic drug, who was this done by

A

Hoffman

Ester group was added to form acetyl-salcylic acid

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7
Q

What was acetyl-salicyclic acid used to treat, why was this better than other treatments

A

Arthritus

Tolerated better by the GI system

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8
Q

What is different between all of the various NSAIDS

A

Phramacokinetics, derivation and side effects

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9
Q

What are NSAIDs generally prescribed for

A

Rheumatic musculoskeletal problems

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10
Q

What group of people are especially at risk when taking NSAIDs

A

Elderly

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11
Q

Two NSAID examples

A

Paracetamol

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12
Q

What are coxibs

A

Group of drugs which act to inhibit COX-2

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13
Q

What does phospholipase A catalyse

A

The conversion of phospholipid to aracidonate

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14
Q

What catalyses the conversion of phospholipid to aracidonate

A

Phospholipase A

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15
Q

What group of enzymes catlayse the conversion of aracidonate to thromboxane and prostaglandins

A

Cyclo-oxygenases

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16
Q

What does the COX enzyme (cyclo-oxygenase) catalyse

A

The conversion of aracidonate to thromboxane and prostaglandins

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17
Q

What is the action of NSAIDs on cyclo-oxygenases

What effect does this have on prostaglandins and thromboxane

A

Inhibits

Decreases the levels of prostaglandins and thromboxanes

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18
Q

Effects of PGI2

A

Vasodilator
Hyperalgesic
Stops platelet aggregation

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19
Q

Effects of PGD2

A

Vasodilator

Inhibits the aggregation of platelets

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20
Q

Effects of PGE2

A

Vasodilator

Hyperalgesic

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21
Q

Effect of thromboxane A2

A

Thrombotic : it stimulates activation of new platelets as well as increases platelet aggregation
Vasoconstrictor

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22
Q

What effect would thromboxane A2 have on clot formation

A

Would cause the formation of blood clots

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23
Q

What is the effect on PGs and thromboxane of NSAIDS

A

Decrease both

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24
Q

Describe the anti-inflammatory effects of NSAIDs

A

Decrease vasodilation –> reduce oedema

Ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions

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25
Q

Describe the analgesic effects of NSAIDs

A

Decrease the prostaglandin production in damaged/inflamed tissue
PG is responsible for the sensitisation of nociceptors to inflammatory mediators (e.g. bradykinin)

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26
Q

What does analgesic mean

A

Reduction of pain

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27
Q

Describe the anti-pyretic effects of NSAIDs

A

Thermostat in the hypothalamus is activated by IL-1
COX2 induction causes production of PGE-2 signals to IL-1
Inhibition of COX2 here leads to less signalling of PGE2 to IL-1 which leads to a reduction of activation of the hypothalamus

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28
Q

Why are NSAIDS used after surgery

A

As can reduce the need for opiate drugs when given in the right combination

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29
Q

Why are NSAIDs effective at treating headaches

A

May be due to the ability to deecrease vasodilation

Vasodilation of the cerebral vasculature is what is thought to be behind headaches

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30
Q

Expression of COX1

A

Constitutive

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31
Q

What does COX1 have role in

A

Homeocstasis

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32
Q

Where is COX1 often found

A

Platelets, stomach, kidney and colon

As well as most of the rest of the body

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33
Q

In stomach endothelial cells - what do the COX1 enzyme cause

A

Production of Prostaglandins which leads to the secretion of protective mucosa

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34
Q

What occurs to the protecive mucous when on aspirin

A

Mucous secretion decreases

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35
Q

What is the expression of COX2

A

Inducible

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36
Q

What type of gene is COX2 an example of

A

Immediate response gene

37
Q

Where is COX2 most commonly found

A

In most cells but especially inflammatory cells after stimulation with growth factors, cytokines or tumour promoters

38
Q

What is COX3

A

A splice variant of COX1

39
Q

Where is COX3 found

What is it suspected the target of

A

In the CNS and brain

Paracetamol

40
Q

How many isoforms of COX

A

2

41
Q

Where are COX found

A

Anchored into the membrane of the ER

42
Q

How many active sites in a COX enzyme

Name them

A

2
Cyclo-oxygenase active site
Periooxidase active sites

43
Q

What is found in the COX enzyme

A

Channel for arachadonic acid

44
Q

Where is aracadonic acid made

A

Made by PL-A at the Pm

45
Q

Example of a drug slighlty selective for COX1

A

Ibuprofen

46
Q

Why are NSAIDS selective

A

Channel in COX2 is larger (in COX1 isoleucine, COX2 valine). Valine is smaller
Substances can enter the channel of COX2 and non-specifically bind preventing the entry of the drug

47
Q

What AA is changed between COX1 and COX2

A

1 - isoleucine

2 - valine

48
Q

Describe why side effects of NSAIDS are seen in the gut

A

Prostaglandins are responsible for the secretion of protective mucosa and the inhibition of acid secretion
When both these processes inhibited ==> ulceration, gastric bleeding amongst others

49
Q

Describe why side effects of NSAIDs are seen in the kidney

A

Normally prostaglandins maintain renal blood flow
So NSAIDs can reduce blood flow to the kidneys
Can potentially lead to renal failure

50
Q

How can paracetamol damage the liver

A

Phase 1 product is highly toxic

Usually this is neutralised by phase 2 but liver is overwhelmed when OD ==> Can only be saved if noticed/caught early

51
Q

What does a paracetamol overdose initially manifest as

A

Diahorrea and vomiting

52
Q

Describe the potential side effects of using NSAIDs which act at the level of the platelets

A

Thromboxane normally causes clotting
Can end up with a bleeding dissorder
Especially at risk are the elderly who take warfarin

53
Q

What are the desireable effects of NSAIDs which inhibit COX1

A

Antithrombotic effects

54
Q

What are the undesireable effects of NSAIDs which inhibit COX1

A

Gastrotoxicity

55
Q

What are the desireable effects of NSAIDs which inhibit COX2

A

Anti-inflammatory

Analgesic

56
Q

What are the undesireable effects of NSAIDs which inhibit COX2

A

Increased blood pressure
Salt retention
Prothrombotic

57
Q

What may be prescribed for people who are at risk of thrombosis

A

Low dose of a COX1 selective drug to limit the chance of clot formation

58
Q

What is aspirin also known as

A

Suicide inhibitor

59
Q

What is the action of aspirin at the COX active site

A

Binds covalently to a serine residue which prevents the aracadonic acid reaching the cyclo-oxygenase active site

60
Q

What type of inactivation does aspirin cause of the COX enzyme

A

Permanent

61
Q

After the permanent inactivation of COX enzyme what must happen

A

The body has to resynthesise the COX enzyme

62
Q

When taking aspirin what does it lower the risk of

A

Colon or rectal cancer

Alzheimers

63
Q

What is the rate of absorption of aspirin into the ileum

A

Fast because aspirin is weakly acidic

64
Q

Where is paracetamol metabolised

A

In the liver

65
Q

What is the name of the toxic phase 1 metabolite of aspirine.
What type of reaction is required to remove this toxicity

A

N-acetyl-P-benzoquinoneimine

glucoronidation reaction

66
Q

What new NSAID had a cardiovascular risk associated with it that was not disclosed to consumers, and subseuently the company was sued

A

Rofecoxib

67
Q

What did the rofecoxib target

A

It was a COX2 selective inhibitor hence also a coxib

68
Q

What would people at high risk of arterial thrombosis be prescribed

A

Low dose aspirin

As it has antithrombotic effects

69
Q

How many UK sufferers of rehumatoid arthritus

A

500000

70
Q

Rheumatoid arthritus has _______ elements

A

Autoimmune

71
Q

What is arthritus characterised by

A

Inflammation of the synovium

72
Q

What is average onset age of arthritus

A

40

73
Q

Arthritus increases the risk for what other class of disease

A

CV

74
Q

Two classes of risk factor for arthritus

A

Environmental

Genetic

75
Q

Name a risk factor (enviro) for arthritus

A

Smoking

76
Q

Symptoms of arthritus

A

Swelling of the joints

Poor sleep

77
Q

What do immunosuppresants do in the treatment of arthritus how does this help

A

Prevents TCD4 –> Th0 –> Active Th1 cells

Prevent the active Th1 cells causing the activation of macrophages/osteoclast/fibroblast

78
Q

What effect do Anti IL-1 have in the treatment of arthritus - how does this help

A

Prevents the activation of osteoclasts and fibroblasts which activate melanoproteinases which then cause erosion of the cartilage and bone

79
Q

What is the effect of glucocorticoids in the treatment of arthritus - how do they help

A

Prevent the activation of macrophages these produce IL-1 and TNF-a which then lead to joint damage

80
Q

What is the effect of anti TNFs in the treatment of arthiritus - how do they help

A

Prevent activation of TNF-a these activated fibroblasts and osteoclasts which produce metalloproteinases which leads to the erosion of joints
They also trigger the release of other inflammatory cytokines and chemokines

81
Q 
What major class of drug help to decrease the erosion of joints during arthritis 
Give an example
A

DMARDS

Sulfasalazine

82
Q

Methoterexate is an example of which type of drugs, how does it work, what can it be used to treat and what potential problems are there

A

Immunosuppresant
Cytoxic activites
Arthritis
Natural antagonist to folic acid so diet must be supplemented with folic acid

83
Q

What can sulfrasalazine be used to treat - how does this work

A

Chronic inflammatory bowel disease

Bacteria produce a compound so drug acts a free radical scavenger preventing damage by neutrophil

84
Q

How does cylcosporin act to inhibit the induction phase of the inflammatory response

A

Binds to cyclophilin

NORMAL CYCLOPHILLIN FUNCTION
Binds to Ca sensitive phosphatase called calcinurin
During inflammation Ca increases causing activation of calcinurin
Activated calcinurin dephophosphorylated NFkB which allows it to translocated the nucleus turning ON the transcription of pro-inflammatory genes such as cytokines

So when cyclosphorin is inhibited cyclophillin, no calcinurin bound NfKB is kept in the cytosol, pro inflammatory genes are switched OFF

85
Q

What effects to glucocorticoids have on the induction phase of the inflammatory response

A

Reduction in expression of the pro-inflmmatory genes

Inhibition of the induction phase

86
Q

Why must biological drugs be injected

A

Would be broken down by proteases in the stomach

87
Q

Describe how humanised mono clonal antibodies may be used t treat inflammation
What does humanised mean

A

Bind to cytokine prevent its interaction with receptor

Humanised meaning a human heavy chain Fc region preventing it from being recognised as foreign

88
Q

How can soluble receptors be used to treat inflammatory conditions

A

Float in the plasma – bind to the cytokine preventing activation of its receptor

89
Q

How many in the UK affected by asthma

A

5.4 mil

BMS242 Core Phys Pharm (9 decks)

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