NSAIDs Flashcards
(118 cards)
1
Q
What are non-steroidal anti-inflammatory (NSAIDs) used for?
A
- In isolation, to treat mild to moderate pain
- In combination, to treat chronic pain from inflammation
2
Q
Give an example of chronic pain NSAIDs can be used to treat?
A
Pain from RA
3
Q
What is the physiological importance of the inflammatory process?
A
It is a fundamental response to injourious stimulus, acting as a protective mechanism to reduce the risk of further damage to the organism
4
Q
What is used to show their is tissue damage and thus stimulate the inflammatory process?
A
Autocoids
5
Q
What are autocoids?
A
A wide range of local molecular mediators and signalling agents
6
Q
What autocoids do NSAIDs act on?
A
Prostaglandins
7
Q
What pathway is prostaglandin synthesis part of?
A
The arachidonic acid metabolism pathway
8
Q
What is arachidonic acid produced from?
A
Phospholipids from the membrane
9
Q
How is arachidonic acid produced from phospholipids from the cell membrane?
A
Mainly via phospholipase A2
10
Q
What happens to the arachidonic acid produced from phospholipids from the cell membrane?
A
They can either enter the prostaglandin pathway or the leukotriene pathway
11
Q
What does the prostaglandin pathway involve?
A
Metabolism by COX-1 and COX-2 enzymes to produce PGH
12
Q
What happens once PGH has been produced in the prostaglandin pathway/
A
Specific prostaglandins can be produced from this
13
Q
What is the most inmportant prostaglandin produced from PGH in the prostaglandin pathway?
A
PGE
14
Q
What do prostaglandins bind to?
A
GPCRs
15
Q
What does the action of prostaglandins when binding to GPCRs depend on?
A
The receptor types
16
Q
What are the receptors for PGE?
A
EP1-4
17
Q
Broadly, what happens when prostaglandins bind to GPCRs?
A
Autocoid release
18
Q
What effect does prostaglandin induced autocoid release have?
A
Will induce the expression of COX-2
19
Q
What effect do prostaglandins have on other autocoids?
A
They synergise them
20
Q
What is the result of prostaglandins have a synergistic action on other autocoids?
A
It means that there is a positive feedback loop mechanism present with prostaglandin production
21
Q
What do prostaglandins act to do?
A
Induce pain and pyrexia
22
Q
How do prostaglandins act to produce pain?
A
- By sensitising peripheral nociception
- By sensitising central nociception
23
Q
How do prostaglandins sensitise peripheral nociception?
A
- PGE2 can bind to EP1 in C-fibres
- Rise in [Ca2+]i levels
24
Q
What kind of GPCR is EP1?
A
Galphaq-type
25
What does PGE2 binding to EP1 in C-fibres cause?
* Inhibition of K+ channels
* Increase in Na+ channel expression
* Increase in neuronal sensitivity to bradykinin
26
What is the overall result of PGE2 binding to EP1?
Increase in C-fibre activity
27
What is the result of increase in [Ca2+]i levels caused by PGE2 binding to EP1?
Increased neurotransmitter release
28
How do prostaglandins sensitise central nociception?
PGE2 can bind to EP2 in the dorsal horn of the spinal cord
29
What kind of GPCR is EP2?
Galphas-type
30
What does PGE2 binding to EP2 in the dorsal horn of the spinal cord cause?
A rise in cAMP, and subsequent action of PKAs, causing a reduction in glycine receptor binding affinity, leading to increased pain reception
31
What does glycine act as?
An inhibitor of neuronal activity
32
What is the effect of macrophage release of IL-1 at inflammatory sites?
It stimulates the hypothalamus to stimulate PGE2 release
33
What is the result of PGE2 release caused by macrophage release of IL-1?
It acts on EP3, causing a fall in cAMP which eventually causes an increase in [Ca2+]i levels in the neurones regulating temperature
34
What kind of GPCR is EP3?
Galphai-type
35
What is the result of the effect of PGE2 on neurones regulating temperature?
* Increased heat production
* Reduced heat loss
36
What do COX enzymes do?
Catalyse the reaction converting arachidonic acid to PGH
37
What is the difference between COX-1 and COX-2, regarding expression?
COX-1 expressed in wide range of tissues and is constitutively expressed. COX-2 is only expressed via induction by inflammatory mediators, and so is only expressed during injourious stimuli
38
Give an example of an inflammatory mediator that can induce the expression of COX-2
Bradykinin
39
What is the role of COX-1?
It has a major cytoprotective role
40
Where does COX-1 have a major cytoprotective role?
* Gastric mucosa
* Myocardium
* Renal parenchyma
41
How does COX-1 perform its cytoprotective role?
It ensures local perfusion
42
What is the half life of COX-1?
10 minutes
43
What is the result of COX-1 having a short half life?
There is a need for its constant synthesis
44
What drugs fit into the mouth of COX-1?
Small, sharp, asprin like drugs
45
What drugs fit into the mouth of COX-2?
Both short, sharp asprin like drugs, and big, blunt drugs
46
What produces the main therapeutic effects of NSAIDs?
COX-2 inhibition
47
What are the main ADRs of NSAIDs caused by?
COX-1 inhibition
48
Do COX-1 and 2 enyzmes work independantly?
No
49
What is PG synthesis from COX-1 and 2 dependant on?
Tissue and organ type
50
What is the mechanism of action of the majority of NSAIDs?
Competitive inhibition of the COX-1 and COX-2 arachidonic acid binding sites
51
How do different NSAIDs differ in their mechanism of action?
They have different affinity and efficacy to the COX enzymes
52
What do all NSAIDs act as?
* Anti-inflammatories
* Analgesics
* Antipyretics
53
How are NSAIDs administered?
Commonly given orally, but can be given topically
54
When are NSAIDs given topically?
For local tissue injury
55
What kind of elimination do NSAIDs show?
Most show first-order elimination kinetics
56
What are NSAIDs broadly classified into?
* Those with short half lives (\<6hrs)
* Those with long half lives (\>10hrs)
57
Give an example of a NSAID with a short half life
Ibuprofen
58
Give an example of an NSAID with a long half life?
Naproxen
59
Do NSAIDs bind to plasma proteins?
Yes, heavily
60
Can NSAIDs act to displace other plasma protein binding drugs?
Yes
61
What kinetics does aspirin exhibit?
Dose dependant kinetics, whereby at low doses it shows first order, and at high doses shows zero order
62
What is the half life of aspirin at low doses?
4 hours
63
What results in the main ADRs seen with prostaglandins?
Inhibition of COX-1 constitutitive secretion of PG
64
What are the main GI ADRs of NSAIDs?
* Ulceration of stomach
* Haemorrhage
* Performation of stomach
65
In whom might NSAIDs cause GI ADRs?
* Long-term users
* Elderly
66
How do NSAIDs bring about their GI ADRs?
PGE2 stimulates mucus production and inhibits acid secretion, thus inhibition of PGE2 production will result in damage directly to the stomach on ingestion and systemically
67
Who is susceptible to renal ADRs of NSAIDs?
Compromised HRH individuals
68
What are the renal ADRs of NSAIDs?
* Reduced GFR
* Reduced perfusion of the kidney
69
How do NSAIDs bring about their renal ADRs?
Due to the role PGE2 has in maintaining adequate blood flow
70
What are the vascular ADRs of NSAIDs?
* Increased risk of prolonged bleeding time
* Increased bruising
* Increased risk of haemorrhage
71
How do NSAIDs bring about their vascular ADRs?
Due to NSAIDs inhibiting thromboxane A2 synthesis, and thus reduced platelet aggregation
72
In what % of individuals do skin rashes occur with NSAID use?
15%
73
Why does particular care need to be taken when prescribing NSAIDs to asthmatics?
Asthmatic bronchospasm can sometimes occur
74
What has been done in an attempt to reduce the ADRs seen with NSAIDs?
Selective COX-2 inhibitiors have been developed
75
How do selective COX-2 inhibitors reduce the ADRs seen with NSAIDs?
Due to theoretical normal COX-1 action
76
What is the problem with selective COX-2 inhibitors?
They showed an increased risk of hypertension and cardiac and renal failure, so were never licensed for use
77
What can NSAIDs be used in combination with therapeutically?
Low dose opiates
78
What is the advantage of combining the use of NSAIDs with low-dose opiates?
* It extends the therapeutic range for treating pain
* Reduce the ADRs seen with increased opiate use
79
What happens when you combine multiple NSAIDs?
There is an increased risk of ADRs
80
Why is there an increased risk of ADRs when you combine multiple NSAIDs?
Because they affect one anothers binding of plasma proteins
81
Where is the interaction between different NSAIDs especially important?
In NSAIDs and low dose aspirin administration
82
Why is the interaction between different NSAIDs especially important in NSAIDs and low-dose aspirin administration?
As they will compete for the COX-1 binding sites, and interfere with the cardioprotective mechanism of aspirin
83
What is the result of the protein binding of NSAIDs meaning certain drugs are displaced by NSAIDs?
May require dose adjustment
84
What drugs have their binding affected by NSAIDs?
* Sulphonylurea
* Warfarin
* Methotrexate
85
What needs to be done when administering NSAIDs and sulphonylureas together?
You need to decrease the dose of sulphonylureas to prevent hypoglycaemia
86
What needs to be done when administering NSAIDs and warfarin together?
You need to decrease the dose of warfarin to prevent increased bleeding
87
What needs to be done when giving NSAIDs and methotrexate together?
You need to decrease the dose of methotrexate to prevent a wide range of serious ADRs
88
What is used as the reference NSAID for efficacy and disease severity?
Aspirin
89
How is aspirin unique as an NSAID?
It is the only NSAID which irreversibly inhibits COX enzymes via acetylation
90
What is the half life of aspirin?
\< 30 mins
91
What is aspirin converted to in the body?
Salicylate
92
What are the therapeutic uses of aspirin?
* Use as an NSAID
* Athero-thrombotic disease prevention
* GI cancer prophylaxis *shown in some trials*
93
How does aspirin prevent athero-thrombotic disease?
By acting as an anti-platelet, as it prevents thromboxane A2 production
94
What GI cancers can aspirin be used as prophylaxis for?
* Colon cancer
* Possibly upper GI cancers
95
Is paracetamol an NSAID?
*It is chemically related to NSAIDs, yet has no anti-inflammatory action,* and so it is not described as an NSAID but a simple analgesic
96
What is paracetamol effective in?
Mild to moderate analgesia and anti-pyrexic
97
What is the advantage of paracetamol over NSAIDs?
At therapeutic doses, it has a much better ADR profile than NSAIDs
98
What is the therapeutic dose of paracetamol?
8x500mg a day
99
When should the therapeutic dose of paracetamol be changed?
In those with compromised hepatic function
100
What is the mechanism of action of paracetamol?
Uncertain, yet appears to selectively inhibit COX-activity in the CNS
101
What pharmokinetics does paracetamol display in normal doses?
Linear
102
How is paracetamol metabolised?
* 90% enters phase 2 metabolism directly
* 10% enters phase 1 oxidation to produce NAPQI
103
How is paracetamol metabolised in phase 2 metabolism?
60% glucoronidation and 30% sulphonation
104
What is the significance of NAPQI?
It is very reactive and toxic
105
Why is NAPQI toxic?
As it can act as an oxidiser
106
How is NAPQI detoxified?
By phase II conjugation with glutathione
107
What pharmokinetics does the conjugation of NAPQI with gluthathione?
Linear
108
What limits the phase II metabolism of NAPQI?
The availability of glutathione
109
What happens to the pharmokinetics of paracetamol at high doses?
Becomes non-linear for both phase I and phase II metabolism
110
What is the result of the change in pharmokinetics of paracetamol at high doses?
Phase II metabolism becomes saturated, and there is a subsequent increase in phase I production of NAPQI.
111
What is the result of the increase of NAPQI that occurs at high doses of paracetamol?
It will deplete the glutathione levels until there becomes an increase in unconjugated NAPQI
112
What is the problem with unconjugated NAPQI?
It is highly nucleophilic, and binds with cellular macromolecules. There becomes a precipitous loss of hepatic cell function and subsequent hepatic cell death, as well as the potential for causing renal failure.
113
When should the treatment for a paracetamol overdose ideally be performed?
Within 8 hours of the overdose
114
What are the potential treatments for paracetamol overdose?
* Oral activated charcoal
* IV acetylcysteine
* Oral methionine
115
When is the activated charcoal treatment for paracetamol overdose effective?
Within 0-4 hours
116
What effect does activated charcoal have in paracetamol overdose?
Can reduce uptake by 50-90%
117
When can IV N-acetylcysteine or oral methionine be given to treat paracetamol overdose?
Between 0-36 hours
118
What effect does IV N-acetylcysteine or oral methionine have in paracetamol overdose?
Increase gluthathione levels
