Non-Steroidal Anti-Inflammatory Drugs Flashcards
1
Q
How many drugs are there in the NSAID class?
A
About 50
2
Q
Do the drugs in the NSAID class show structural homogenity?
A
No, there is significant heterogeneity, and the drugs have different potencies and different efficacies
3
Q
What is the principle action of NSAIDs?
A
They act on key enzymes in prostaglandin synthesis
4
Q
What are the primary therapeutic effects of NSAIDs?
A
- Analgesia
- Anti-inflammatory
- Antipyretic
5
Q
What does local injury result in?
A
A signalling response provided by many autocoids
6
Q
What are the features of the local response to injury?
A
- Rapid
- Focused
Integrated
7
Q
What is the inflammatory response?
A
A fundamental response of the body to injurous stimuli
8
Q
What injuries can cause an inflammatory response?
A
- Physical/chemical injury
- Structural strain
- Infections
- Many diseases
- Autoimmune conditions
9
Q
What is the advantage of the inflammatory response?
A
It is normally a protective response to reduce the risk of further damage to the organism
10
Q
How does the inflammatory response alert the body to damage?
A
Through signalling pain
11
Q
What is the importance of the inflammatory response signalling damage through pain?
A
It reduces the risk of further damage through continued use/activity
12
Q
What are autocoids?
A
A diverse range of local molecular mediators and signalling agents employed
13
Q
Give 7 examples of autocoids
A
- Bradykinins
- Histamine
- Cytokines
- Leukotrienes
- Nitric oxide
- Neuropeptides
- Eicosanoids
14
Q
What class of molecules do eicosanoids include?
A
Prostaglandins
15
Q
What does signalling overlap with autocoids ensure?
A
A robust inflammatory response
16
Q
What are the key features of autocoids?
A
- Localised release
- Short half life
17
Q
What does the localised release and short half life of autocoids allow for?
A
Fine control of the signalling response
18
Q
What are eicosanoids? C
A
20C phospholipid derivatives used as signalling molecules
19
Q
What gives rise to different classes of eicosanoids?
A
Variation in synthetic routes
20
Q
What are prostanoids?
A
A subclass of eicosanoids
21
Q
Give 3 examples of prostanoids
A
- Prostaglandins
- Prostacyclins
- Thromboxanes
22
Q
What are eicosanoids derived from?
A
Arachidonic acid
23
Q
Where does arachidonic acid come from?
A
It is cleaved from cell membrane phospholipids
24
Q
What enzyme cleaves arachidonic acid from cell membrane phospholipase?
A
Phospholipase A2
25
What happens to arachidonic acid in the synthesis of prostaglandins?
COX-1/COX-2 enzymes convert it to prostaglandin G
26
What happens to PG G in the synthesis of prostaglandins?
COX-1/COX-2 enzymes convert it to prostaglandin H
27
What happens to PG H in the synthesis of prostaglandins?
It is converted to specific PG enzymes - PGs D, E, F, I
28
What is the most important prostaglandins in mediating the inflammatory response?
E
29
What is prostaglandin E responsible for?
* Vasodilation
* Hyperalgesia
* Fever
* Immunomodulation
30
Where is COX-1 expressed?
In a wide range of tissue types
31
Describe the expression of COX-I
Constituitive - *expressed all the time*
32
What is the importance of PG synthesis by COX-I?
It has a major cytoprotective role in;
* The gastric mucosa
* The myocardium
* The renal parenchyma
It also ensures optimised local perfusion
33
How do prostaglandins ensure optimised local perfusion?
It ensures vasodilation, and so ensures delivery of nutrients
34
What is the clinical relevance of the cytoprotective role of prostaglandins in the GI tract?
A major ADR of long term NSAIDs is a reduction in mucus and therefore damage to underlying tissue
35
What is the half life of prostaglandins?
10 minutes
36
What is the result of the short half life of prostaglandins?
It needs constant synthesis
37
Why are most ADRs of NSAIDs due to COX-1 inhibition?
Due to its constitutive expression
38
What is COX-2 expression induced by?
Inflammatory mediators, *such as bradykinin*
39
Where is COX-2 consitutively expressed?
In parts of brain and kidney
40
How do the main therapeutic effects of NSAIDs occur?
Via COX-2 inhibition
41
Do COX-1 and 2 work independantly?
No
42
What is PG synthesis with COX-1 and -2 depedant on?
Tissue and organ type
43
How does prostaglandin synthesis occur with COX-1?
It has a hydrophpobic channel, where arachinodic acid enters and gets catalysed to prostaglandins
44
What kind of drugs fit into the mouth of COX-1?
Small, sharp, aspirin-like drugs
45
What kind of drugs can fit in the mouth of COX-2?
* Small, sharp, aspirin-like drugs
* Big, blunt drugs
46
What receptors do prostaglandins bind with?
GPCRs
47
What do the specific actions of prostaglandins depend on?
The receptor types
48
What are the main types of receptors for PG E?
EP1-4
49
What does the action of prostaglandins often include?
Synergising effects of other autocoids, *e.g. bradykinin and histamine*
50
Which prostanoid in particular is released post-injury?
PGE2
51
Where are autocoids and prostanoids released from post injury?
Local tissues and blood vessels
52
What does autocoid release induce?
Expression of COX-2
53
What do autocoids synergise with?
Other autocoids, *e.g. bradykinin and histamine*
54
Do prostaglandins act as vasoconstrictors or vasodilators?
They are potent vasodilators
55
Do prostaglandins increase the capillary permeability?
Not directly, but they synergise permeating effects of bradykinin/histamine
56
Which prostaglandin receptors are responsible for vasodilation?
EP2 (Gs)
57
Which prostaglandin receptors are responsible for increased peripheral nociception?
EP1 (Gq)
58
What are painful stimuli carried by?
Afferent C fibres
59
What happens to the surrounding tissue following trauma/injury?
Surrounding tissue and neurones synthesis prostaglandins *- PGE2 in particular.* Other autcoids are also released, *notably bradykinin*
60
What happens to the PGE2 released in response to trauma/injury?
It binds with C fibre neuronal EP1 GPCR
61
What does GPCR activation by PGE2 in pain cause?
* Increased neuronal sensitivity to bradykinin
* Inhibition of K+ channels
* Increased Na+ channel sensitivity
62
What is the result of inhibition of K+ channels by PGE2?
Neurone tends to be more polarised
63
What is the result of increased Na+ channel activity caused by PGE2 in pain?
It increases the likelihood of C fibres firing in response to moderate stimulation
64
What do the actions of GPCR activation by PGE2 in pain do in combination?
Act to increase C fibre activity
65
What might prostaglandins do to previously silent C fibres?
Activate them
66
How does peripheral sensitisation occur?
EP I binding leads to increased C fibre activity
Other autocoids are involved in increasing sensivity
67
What is EP1?
A Gq GPCR
68
What does activation of EP I lead to?
Increase in intracellular calcium, therefore increased neurotransmitter release
69
What is allodynia?
The sensitisation of receptors to cause pain signalling In response to normally non-stimulating stimulus intensity i.e. non-painful things are painful
70
What does increased sustained nociceptive signalling peripherally result in?
Increased cytokines levels in the dorsal horn cell body
71
What does increased cytokine levels in the dorsal horn cell body lead to?
Increased COX-2 synthesis and therefore increased PGE2 synthesis
72
What is the effect of the increased PGE2 produced due to increased sustained nociceptive signalling peripherally?
It acts via a local GPCR EP2 (GS type) to increase the sensitivity and discharge rate of secondary interneurones by incresaing cAMP and PKA
im not 100% sure on this lol
73
What is one aspect of the increase in sensitivity and discharge rate of secondary interneurones?
Removal of glycinergic inhibition
74
What do bacterial endotoxins do in infected/inflammatory states?
They stimulate macrophage release of IL-I
75
What happen as a result of IL-I release in infected/inflammatory states?
It acts within the hypothalanus to stimulate PGE2 synthesis via the induction of COX-2
76
What receptor is involved in pyrexia due to PGE2?
EP3
77
What kind of receptor is EP3?
Gi type GPCR
78
What is the result of PGE2 stimulation of EP3 receptors?
Results in increased heat production and decreased heat loss
79
Why does pyrexia even happen in infection like what is the point
it makes the body less pleasant for bacterial infection
80
transition to no caps for speed cus literally cba with this
ok
81
how are the main therapeutic effects of nsaids acheived
cox-2 inhibition
82
how is the pharmaclogical action of nsaids achieved
competitive inhibition of cox-1 and 2
nearly all not all
83
how do nsaids competitively inhibit cox1/2
occupation of cox 1/2 hydrophobic channel by nsaid competes with AA site occupation
84
how many diff types of nsaids are there
about 50
85
what is different about the diff types of nsaids
affinity
efficacy
cox1/2 selectivity
86
what do nearly all nsaids have therapeutic efficacy as
analgesics
anti inflammatories
antipyreics
87
what determines the choice of nsaid
dominant disease state
patients level of pain
individual patient response
88
how are nsaids administered
typically orally, but many topical preperations for soft tissue injuries
89
what is good about topical nsaids
can get very high penetration, and therefore safer than oral for given amount of pain relief as lots of drugs gets only to the site you want to treat
90
what kind of pharmacokinetics do nsaids have
linear, but only within therapeutic dose ranges
91
what is the half life of nsaids
nsaids can be divided into 2 groups based on their half life - \<6 hours and \>10 hours
92
what are nsaids that have a half life of \<6 hours good for
acute pain
93
what are nsaids that have a half life of \>10 hours good for
chronic pain - only need one tablet a day
94
are nsaids protein bound?
many are heavily protein bound, 90-99%
95
what are the main therapeutic uses of nsaisds
anti inflammatories
analgesia
96
describe the use of nsaids as anti-inflammatories
very wide use in msk disorders, e.g. ra and osteoarthritis
97
what are nsaids used for in analgesia
mild to moderate pain
98
how do nsaids compare to opiates
they are less effective, but have a better adr proflie
99
what leads to the side effects of nsaids
inhibition of cox-1 constitutive pg synthesis
100
what is long term use of nsaids in the elderly associated with
iatrogenic morbiditiy and mortality
101
where are the major adrs of nsaids seen
in the stomach/gi tract
102
When do renal ADRs occur with nsaids
in compromised individuals with HRH or hypovolaemia
103
what % of nsaid users have gi adrs
35%
104
are gi adrs in nsaid users always symptomatic?
no, often asymptomatic
105
what are the gi adrs of nsaids
varying degrees of stomach pain, nausea, heartburn, gastric bleeding, and ulceration
106
how do nsaids cause gi adrs
gastric cox-1 pge2;
* stimulates cytoprotective mucus secretion throughout the gi tract
* reduces acid secretion
* promotes mucosal blood flow
107
how can the adrs of nsaids be offset?
PPIs or misoprostol
108
why can nsaids lead to renal adrs
because pge2 and pgi2 maintain renal blood flow. if reduced by nsaids, then gfr decreases, and therefore risk of renal compromise
109
what follows renal compromise caused by nsaids
na k cl and water retention with increaed likelihood of hypertension
110
What is the difference between allodynia and spontaneous pain?
Spontaenous pain occurs without a stimulus
111
What do allodynia and spontaneous pain have in commmon?
They both cause hyperalgesis - pain at a normally non-stimulating level of stimulus intensity
