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
