L11-12 Anti-inflammatories Flashcards Preview

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

Flashcards in L11-12 Anti-inflammatories Deck (89)
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1

What does NSAID stand for

Non-steroidal anti-inflamatory drug

2

When was the natural precurrsor to aspirin disocered

5th century

3

What does coxib stand for

COX2 - Inhibitors

4

What was significant in 18228

Leroux isolated the active ingredient for aspirin from the willow tree

5

What is the active ingredient in aspirin

Salicyclic acid

6

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

Hoffman
Ester group was added to form acetyl-salcylic acid

7

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

Arthritus
Tolerated better by the GI system

8

What is different between all of the various NSAIDS

Phramacokinetics, derivation and side effects

9

What are NSAIDs generally prescribed for

Rheumatic musculoskeletal problems

10

What group of people are especially at risk when taking NSAIDs

Elderly

11

Two NSAID examples

Paracetamol

12

What are coxibs

Group of drugs which act to inhibit COX-2

13

What does phospholipase A catalyse

The conversion of phospholipid to aracidonate

14

What catalyses the conversion of phospholipid to aracidonate

Phospholipase A

15

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

Cyclo-oxygenases

16

What does the COX enzyme (cyclo-oxygenase) catalyse

The conversion of aracidonate to thromboxane and prostaglandins

17

What is the action of NSAIDs on cyclo-oxygenases
What effect does this have on prostaglandins and thromboxane

Inhibits
Decreases the levels of prostaglandins and thromboxanes

18

Effects of PGI2

Vasodilator
Hyperalgesic
Stops platelet aggregation

19

Effects of PGD2

Vasodilator
Inhibits the aggregation of platelets

20

Effects of PGE2

Vasodilator
Hyperalgesic

21

Effect of thromboxane A2

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

22

What effect would thromboxane A2 have on clot formation

Would cause the formation of blood clots

23

What is the effect on PGs and thromboxane of NSAIDS

Decrease both

24

Describe the anti-inflammatory effects of NSAIDs

Decrease vasodilation --> reduce oedema
Ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions

25

Describe the analgesic effects of NSAIDs

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

26

What does analgesic mean

Reduction of pain

27

Describe the anti-pyretic effects of NSAIDs

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

28

Why are NSAIDS used after surgery

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

29

Why are NSAIDs effective at treating headaches

May be due to the ability to deecrease vasodilation
Vasodilation of the cerebral vasculature is what is thought to be behind headaches

30

Expression of COX1

Constitutive

31

What does COX1 have role in

Homeocstasis

32

Where is COX1 often found

Platelets, stomach, kidney and colon
As well as most of the rest of the body

33

In stomach endothelial cells - what do the COX1 enzyme cause

Production of Prostaglandins which leads to the secretion of protective mucosa

34

What occurs to the protecive mucous when on aspirin

Mucous secretion decreases

35

What is the expression of COX2

Inducible

36

What type of gene is COX2 an example of

Immediate response gene

37

Where is COX2 most commonly found

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

38

What is COX3

A splice variant of COX1

39

Where is COX3 found
What is it suspected the target of

In the CNS and brain
Paracetamol

40

How many isoforms of COX

2

41

Where are COX found

Anchored into the membrane of the ER

42

How many active sites in a COX enzyme
Name them

2
Cyclo-oxygenase active site
Periooxidase active sites

43

What is found in the COX enzyme

Channel for arachadonic acid

44

Where is aracadonic acid made

Made by PL-A at the Pm

45

Example of a drug slighlty selective for COX1

Ibuprofen

46

Why are NSAIDS selective

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

What AA is changed between COX1 and COX2

1 - isoleucine
2 - valine

48

Describe why side effects of NSAIDS are seen in the gut

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

Describe why side effects of NSAIDs are seen in the kidney

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

50

How can paracetamol damage the liver

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

What does a paracetamol overdose initially manifest as

Diahorrea and vomiting

52

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

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

53

What are the desireable effects of NSAIDs which inhibit COX1

Antithrombotic effects

54

What are the undesireable effects of NSAIDs which inhibit COX1

Gastrotoxicity

55

What are the desireable effects of NSAIDs which inhibit COX2

Anti-inflammatory
Analgesic

56

What are the undesireable effects of NSAIDs which inhibit COX2

Increased blood pressure
Salt retention
Prothrombotic

57

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

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

58

What is aspirin also known as

Suicide inhibitor

59

What is the action of aspirin at the COX active site

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

60

What type of inactivation does aspirin cause of the COX enzyme

Permanent

61

After the permanent inactivation of COX enzyme what must happen

The body has to resynthesise the COX enzyme

62

When taking aspirin what does it lower the risk of

Colon or rectal cancer
Alzheimers

63

What is the rate of absorption of aspirin into the ileum

Fast because aspirin is weakly acidic

64

Where is paracetamol metabolised

In the liver

65

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

N-acetyl-P-benzoquinoneimine
glucoronidation reaction

66

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

Rofecoxib

67

What did the rofecoxib target

It was a COX2 selective inhibitor hence also a coxib

68

What would people at high risk of arterial thrombosis be prescribed

Low dose aspirin
As it has antithrombotic effects

69

How many UK sufferers of rehumatoid arthritus

500000

70

Rheumatoid arthritus has _______ elements

Autoimmune

71

What is arthritus characterised by

Inflammation of the synovium

72

What is average onset age of arthritus

40

73

Arthritus increases the risk for what other class of disease

CV

74

Two classes of risk factor for arthritus

Environmental
Genetic

75

Name a risk factor (enviro) for arthritus

Smoking

76

Symptoms of arthritus

Swelling of the joints
Poor sleep

77

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

Prevents TCD4 --> Th0 --> Active Th1 cells
Prevent the active Th1 cells causing the activation of macrophages/osteoclast/fibroblast

78

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

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

79

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

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

80

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

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

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

DMARDS
Sulfasalazine

82

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

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

83

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

Chronic inflammatory bowel disease
Bacteria produce a compound so drug acts a free radical scavenger preventing damage by neutrophil

84

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

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

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

Reduction in expression of the pro-inflmmatory genes
Inhibition of the induction phase

86

Why must biological drugs be injected

Would be broken down by proteases in the stomach

87

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

Bind to cytokine prevent its interaction with receptor
Humanised meaning a human heavy chain Fc region preventing it from being recognised as foreign

88

How can soluble receptors be used to treat inflammatory conditions

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

89

How many in the UK affected by asthma

5.4 mil