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NSAIDs Flashcards

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1
Q

what are the 3 main clinical uses of NSAIDs?

A

oAnalgesic – toothache/headache, post-op pain (opiate-sparing), menstrual pain.

oAnti-pyretic – influenza.

oAnti-inflammatory – rheumatoid arthritis, osteoarthritis, gout, soft-tissue injuries.

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2
Q

what are major causes of deaths with NSAIDs?

A

GI issues

CVS issues

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3
Q

what is the main action of NSAIDs?

A

inhibit prostanoid synthesis by blocking COX

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4
Q

what are prostanoids?

A

Signalling molecules derived from arachidonic acid. Widely distributed and not stored pre-formed. Receptor-mediated.

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5
Q

examples of prostanoids

A

prostaglandins
TXA2
prostacyclin

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6
Q

what are the two isoforms of COX?

A

COX1 and COX2

both are inhibited by NSAIDs to varying degrees

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7
Q

which NSAID affects both COX isoforms quite equally?

A

ibuprofen

non-selective

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8
Q

what family of NSAID selectivity reversibly inhibit COX2?

A

Coxib family

e.g. celecoxib

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9
Q

how many known prostanoids are there and how many receptors do they bind to? what are they?

A 
5 known prostanoids
10 receptors:
- DP 1& 2
- EP1 to 4 (PGE2 binds to these)
- FP
- IP 1&2
- TP

[name based on agonist potency]

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10
Q

what sort of receptors are prostanoid receptors?

A

G protein coupled but can have effects independent of protein coupling

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11
Q

examples of prostanoids that bind to receptors

A 
TXA2
PGF2alpha
PGI2
PGD2
PGE2
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12
Q

how many and which receptors does PGE2 bind to?

A

4:

  • EP1 (greatest affinity)
  • EP2
  • EP3
  • EP4 (least affinity)
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13
Q

which of the EP prostanoid receptors are dependent on Ca2+ mobilisation?

A

EP1 and EP3

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14
Q

which of the EP prostanoid receptors are dependant on cAMP?

A

EP2 and EP4

and EP3

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15
Q

what is unique about EP3 receptor?

A

both Ca2+ mobilisation and cAMP dependant mechanisms used by EP3

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16
Q

what are the unwanted effects of PGE2?

i.e. these effects you want to block using NSAIDs

A
  • Increased pain perception.
  • Thermoregulation (increased body temp)
  • Acute inflammatory response.
  • Other –
  • immune responses (T helper cell activation–> MS, RA, dermatitis)
  • tumorigenesis
  • inhibition of apoptosis (so more likely necrosis).
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17
Q

how does the prostanoid PGE2 induce pain sensitisation?

A

stimulation of PG receptors sensitises the nociceptors which causes pain acutely and chronically

Activation of EP1 and EP4 receptors (in spine and periphery)
Endocannabinoid involvement.

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18
Q

how can pain sensitisation be reduced?

A

Co-injection of COX2 inhibitors prevents or reduces duration of prolonged pain

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19
Q

how is PGE2 pyrogenic?

A

stimulates hypothalamic neurones to initiate a rise in body temperature –> hyper-pyrexia

NSAIDs reduce raised temperature in influenza

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20
Q

how is the acute inflammatory response mediated by PGE2?

A

PGE2 –> EP3 signalling.
EP3 receptor signals downstream cAMP and Ca2+ mobilisation.

mast cell degranulation

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21
Q

what are the desirable actions of PGE2?

i.e. you don’t want to block these with NSAIDs

A
  • Gastro-protection
  • Renal salt and water homeostasis, increased GFR
  • Bronchodilation
  • Vaso-regulation
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22
Q

how does PGE2 have a gastro-protective effect?

A
  • stimulates mucus and bicarbonate secretion into the gut
  • downregulates HCl production
  • increases pH
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23
Q

what is considered to cause the ulceration of the stomach? how can GI bleed deaths be reduced?

A

inhibition of COX1–> less PGE2

the use of COX2 inhibitors instead, like Celecoxib, rather than other NSAIDs reduce GI deaths

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24
Q

how does PGE2 influence renal salt and water homeostasis?

A

increases renal blood flow by having a vasodilator effect on the afferent arteriole of the glomerulus
- so NSAIDs can cause renal toxicity

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25
how do NSAIDs cause renal toxicity?
- Constriction of afferent renal arteriole. - Reduction in renal artery flow. - Reduced glomerular filtration rate.
26
which groups of patients are contraindicated NSAIDs?
- renal failure (due to increased renal toxicity) | - asthmatics (increases bronchoconstrictors)
27
why can't some asthmatics use NSAIDs?
COX inhibition favours production of leukotrienes as the pathway for arachidonic acid is inhibited leukotrienes are potent bronchoconstrictors and worsen asthma symptoms
28
what effect do NSAIDs have as vaso-regulators?
- Vasoconstriction - Salt & water retention (constricted renal afferent) - Reduced effect of anti-hypertensives. result of reduce production of vasodilator prostanoids therefore increase CVS event risk
29
what are the associated increased risks with NSAIDs?
hypertension MI stroke
30
what general risk do COX2 inhibitor pose?
CVS disease
31
what general risk do COX1 inhibitors pose?
GI diseases
32
why do COX2 inhibitors increase CVS risks?
raise BP, endothelial dysfunction, oxidative injury,
33
how are NSAIDs used for analgesic use?
occasionally so relatively low risk of side effects
34
how are NSAIDs used for anti-inflammatory use?
chronically in higher doses so a relatively high risk of side effects.
35
how can GI side effects be limited?
- use COX2 inhibitor - topical application (less systemic access) - limit use in patient with GI ulceration history - avoid in those with risk factors e.g. alcoholics - treat H.pylori if present - co-administer PPI like omeprazole
36
what is aspirin selective for?
``` COX-1 Binds irreversibly (not common) to COX enzymes ```
37
what are the main uses of aspirin? how does it do this?
1) anti-inflammatory, analgesic, anti-pyretic | 2) reduces platelet aggregation (thrombotic disease)
38
in what ways does aspirin reduce platelet aggregation?
- reduces TXA2 production via COX1, no re-production as the platelet has no nucleus - some reduction in PGI2 production by endothelia cells overall platelet aggregation is reduced
39
why is PGI2 (prostacyclin) reduction partial by aspirin?
PGI2 is produced by COX-1 and COX-2 and aspirin only affects COX-1 prostacyclin is anti-thrombotic, so necessary to have
40
how does aspirin cause anti-platelet action?
High degree of COX1 inhibition supresses TXA2 synthesis in platelets. Covalent bonding which permanently inhibits platelet COX1. poorly binds to COX-2 (does not mean it has no effect)
41
what are the side effects of aspirin?
- Gastric ulceration - bronchospasm (in sensitive-asthmatics) - prolonged bleeding time - nephrotoxicity [COX-1 inhibition and reduced PGE2 effects]
42
why are side effects more likely with aspirin than with other NSAIDs?
due to permeant inhibition of COX-1 (irreversible)
43
what are the new NSAIDs that are better tolerated?
- dual COX and LOX inhibitors (use in asthmatics) | - nitric oxide or hydrogen sulphide releasing NSAIDs (protective of GI and CVS)
44
what is the overall effect of aspirin?
reduce TXA2 and PGI2
45
how effect does aspirin have in Reye's syndrome?
treatment of the viral infection with aspirin leads to mitochondrial damage in young people (<20) this leads to ammonia production and damages astrocytes, leading to oedema in the brain
46
why is paracetamol not a NSAID?
has no anti-inflammatory action does not inhibit COX
47
what are the uses of paracetamol?
o Relieve mild to moderate pain. o Anti-pyretic actions. o NO anti-inflammatory actions
48
what is the possible mechanism of action of paracetamol?
most likely acts centrally - COX3? - cannabinoid receptors? - interactions with endogenous-opioids/5HT/adenosine-receptors?
49
what happens in paracetamol overdose?
- toxic NAPQI metabolite produced during paracetamol metabolism - NAPQI metabolism saturates glutathione - this depletes glutathione which leaves excess NAPQI - NAPQI will react with hepatic enzymes with S-H groups (thiol group) causing their apoptosis
50
how can paracetamol overdose be treated?
provide a compound with thiol groups so it mops up the NAPQI - IV Acetylcysteine is used in cases of attempted suicide, must be provided early as liver failure may become unpreventable - oral methionine - normally NAPQI is removed using glutathione
51
how has paracetamol availability become restricted over time?
- 1998 pack size restricted paracetamol to 16x500mg tablets - 2009 guidelines state: o No more than 2 packs per transaction. o Illegal to sell more than 100 pills per transaction. - this has decreased deaths significantly since 2009
52
what is an effect of prostacyclin (PGI2)?
inhibits platelet activation vasodilator therefore antithrombotic
53
how does PGE2 decrease pain threshold? i.e. make you sensitive to pain
sensitises nociceptors
54
how does PGE2 cause fever?
stimulates neurones in hypothalamus involved in temperature control
55
how does PGE2 cause inflammation?
mast cell degranulation
56
how does PGE2 cause hypersensitivity ?
activation of T helper cells involved in hypersensitivity conditions like dermatitis, MS and Rheumatoid Arthritis
57
how does PGE2 provide gastric protection?
stimulates bicarbonate release mucous secretion downregulates HCl secretion
58
how does PGE2 increase GFR?
increases renal blood flow by having vasodilator effect on the afferent arteriole of the glomerulus
59
what is ibuprofen? | what is its mechanism of action?
non-selective COX inhibitor this prevents the produciotn of PGE2 : - -> analgesia (pain threshold) - -> antipyretic (hypothalamus) - -> anti-inflammatory (mast cell)
60
what are the side effects of NSAIDs like ibuprofen due to the blockage of PGE2's beneficial effects?
- gastric irritation and ulceration - bronchospasm - prolonged bleeding - nephrotoxicity
61
why does ibuprofen cause gastric irritation and ulceration?
decreased bicarbonate decreased mucous secretion increases HCl
62
why does ibuprofen cause bronchospasm?
there is a shift to the lipooxygenase pathway so more leukotrienes are produced leukotrienes are bronchoconstrictors
63
why does ibuprofen cause nephrotoxicity?
reduced renal blood flow due to constricted afferent arteriole therefore reducing GFR
64
which enzyme produces PGE2 predominantly ?
COX-1
65
what effect do COX-2 inhibitors have?
gastro-protective | harmful to cardiac
66
what effect do COX-1 inhibitors have?
cardiac protective | harmful to gastro
67
why is COX-2 inhibition gastro-protective?
COX-1 makes PGE2 mainly so PGE2 production is not impacted too much PGE2 is still made enough to increase bicarbonate and mucous and decrease HCl
68
why does COX-2 inhibition cause cardiac harm?
there is an imbalance created between anti-thrombotic prostacyclin (PGI2) and pro-thrombotic TXA2 NB. TXA2 is needed for platelet aggregation in haemostasis
69
What is celecoxib?
selective, reversible COX-2 inhibitor - gastro-protective - smaller decrease in PGE2 - risk of CVD
70
what is the difference in site action between paracetamol and NSAIDs?
paracetamol most likely acts centrally rather than peripherally NSAIDs act peripherally
71
why does paracetamol overdose cause liver failure?
toxic metabolite produced binds to hepatic enzymes with -SH groups
72
how is paracetamol overdose treated?
acetylcysteine contains -SH groups to mop up the excess metabolite
73
what normally inactivates NAPQI?
glutathione | binds to electrophiles
74
why is aspirin the only NSAID uses in thrombotic disease?
irreversibly binds to COX-1 so the production of pro-thrombotic TXA2 is stopped
75
why is aspirin effective at stopping TXA2 production?
COX-1 cannot be regenerated by platelet because they lack nucleus endothelial cells continue COX-1 production to produce prostacyclin (PGI2), anti-thrombotic
76
why can't platelets regenerate COX-1? | COX-1 has been lost due to irreversible binding to aspirin
they lack a nucleus however endothelial cells can continue to produce COX-1
77
what is aspirin?
weak acid | irreversibly binds to COX-1
78
why would IV sodium bicarbonate be given in aspirin overdose?
increasing pH to shift aspirin equilibrium to ionised in the kidney so it cannot be reabsorbed into the blood

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