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LCRS Pharma > NSAIDs > Flashcards

NSAIDs Flashcards

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
Q

how do NSAIDs cause renal toxicity?

A
  • Constriction of afferent renal arteriole.
  • Reduction in renal artery flow.
  • Reduced glomerular filtration rate.
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26
Q

which groups of patients are contraindicated NSAIDs?

A
  • renal failure (due to increased renal toxicity)

- asthmatics (increases bronchoconstrictors)

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27
Q

why can’t some asthmatics use NSAIDs?

A

COX inhibition favours production of leukotrienes as the pathway for arachidonic acid is inhibited

leukotrienes are potent bronchoconstrictors and worsen asthma symptoms

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28
Q

what effect do NSAIDs have as vaso-regulators?

A
  • Vasoconstriction
  • Salt & water retention (constricted renal afferent)
  • Reduced effect of anti-hypertensives.

result of reduce production of vasodilator prostanoids

therefore increase CVS event risk

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29
Q

what are the associated increased risks with NSAIDs?

A

hypertension
MI
stroke

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30
Q

what general risk do COX2 inhibitor pose?

A

CVS disease

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31
Q

what general risk do COX1 inhibitors pose?

A

GI diseases

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32
Q

why do COX2 inhibitors increase CVS risks?

A

raise BP, endothelial dysfunction, oxidative injury,

33
Q

how are NSAIDs used for analgesic use?

A

occasionally so relatively low risk of side effects

34
Q

how are NSAIDs used for anti-inflammatory use?

A

chronically in higher doses so a relatively high risk of side effects.

35
Q

how can GI side effects be limited?

A
  • 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
Q

what is aspirin selective for?

A 
COX-1
Binds irreversibly (not common) to COX enzymes
37
Q

what are the main uses of aspirin? how does it do this?

A

1) anti-inflammatory, analgesic, anti-pyretic

2) reduces platelet aggregation (thrombotic disease)

38
Q

in what ways does aspirin reduce platelet aggregation?

A
  • 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
Q

why is PGI2 (prostacyclin) reduction partial by aspirin?

A

PGI2 is produced by COX-1 and COX-2 and aspirin only affects COX-1

prostacyclin is anti-thrombotic, so necessary to have

40
Q

how does aspirin cause anti-platelet action?

A

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
Q

what are the side effects of aspirin?

A
  • Gastric ulceration
  • bronchospasm (in sensitive-asthmatics)
  • prolonged bleeding time
  • nephrotoxicity

[COX-1 inhibition and reduced PGE2 effects]

42
Q

why are side effects more likely with aspirin than with other NSAIDs?

A

due to permeant inhibition of COX-1 (irreversible)

43
Q

what are the new NSAIDs that are better tolerated?

A
  • dual COX and LOX inhibitors (use in asthmatics)

- nitric oxide or hydrogen sulphide releasing NSAIDs (protective of GI and CVS)

44
Q

what is the overall effect of aspirin?

A

reduce TXA2 and PGI2

45
Q

how effect does aspirin have in Reye’s syndrome?

A

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
Q

why is paracetamol not a NSAID?

A

has no anti-inflammatory action

does not inhibit COX

47
Q

what are the uses of paracetamol?

A

o Relieve mild to moderate pain.
o Anti-pyretic actions.
o NO anti-inflammatory actions

48
Q

what is the possible mechanism of action of paracetamol?

A

most likely acts centrally

  • COX3?
  • cannabinoid receptors?
  • interactions with endogenous-opioids/5HT/adenosine-receptors?
49
Q

what happens in paracetamol overdose?

A
  • 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
Q

how can paracetamol overdose be treated?

A

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
Q

how has paracetamol availability become restricted over time?

A
  • 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
Q

what is an effect of prostacyclin (PGI2)?

A

inhibits platelet activation
vasodilator

therefore antithrombotic

53
Q

how does PGE2 decrease pain threshold? i.e. make you sensitive to pain

A

sensitises nociceptors

54
Q

how does PGE2 cause fever?

A

stimulates neurones in hypothalamus involved in temperature control

55
Q

how does PGE2 cause inflammation?

A

mast cell degranulation

56
Q

how does PGE2 cause hypersensitivity ?

A

activation of T helper cells involved in hypersensitivity conditions like dermatitis, MS and Rheumatoid Arthritis

57
Q

how does PGE2 provide gastric protection?

A

stimulates bicarbonate release
mucous secretion
downregulates HCl secretion

58
Q

how does PGE2 increase GFR?

A

increases renal blood flow by having vasodilator effect on the afferent arteriole of the glomerulus

59
Q

what is ibuprofen?

what is its mechanism of action?

A

non-selective COX inhibitor

this prevents the produciotn of PGE2 :

  • -> analgesia (pain threshold)
  • -> antipyretic (hypothalamus)
  • -> anti-inflammatory (mast cell)
60
Q

what are the side effects of NSAIDs like ibuprofen due to the blockage of PGE2’s beneficial effects?

A
  • gastric irritation and ulceration
  • bronchospasm
  • prolonged bleeding
  • nephrotoxicity
61
Q

why does ibuprofen cause gastric irritation and ulceration?

A

decreased bicarbonate
decreased mucous secretion
increases HCl

62
Q

why does ibuprofen cause bronchospasm?

A

there is a shift to the lipooxygenase pathway so more leukotrienes are produced

leukotrienes are bronchoconstrictors

63
Q

why does ibuprofen cause nephrotoxicity?

A

reduced renal blood flow due to constricted afferent arteriole therefore reducing GFR

64
Q

which enzyme produces PGE2 predominantly ?

65
Q

what effect do COX-2 inhibitors have?

A

gastro-protective

harmful to cardiac

66
Q

what effect do COX-1 inhibitors have?

A

cardiac protective

harmful to gastro

67
Q

why is COX-2 inhibition gastro-protective?

A

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
Q

why does COX-2 inhibition cause cardiac harm?

A

there is an imbalance created between anti-thrombotic prostacyclin (PGI2) and pro-thrombotic TXA2

NB. TXA2 is needed for platelet aggregation in haemostasis

69
Q

What is celecoxib?

A

selective, reversible COX-2 inhibitor

  • gastro-protective
  • smaller decrease in PGE2
  • risk of CVD
70
Q

what is the difference in site action between paracetamol and NSAIDs?

A

paracetamol most likely acts centrally rather than peripherally

NSAIDs act peripherally

71
Q

why does paracetamol overdose cause liver failure?

A

toxic metabolite produced binds to hepatic enzymes with -SH groups

72
Q

how is paracetamol overdose treated?

A

acetylcysteine contains -SH groups to mop up the excess metabolite

73
Q

what normally inactivates NAPQI?

A

glutathione

binds to electrophiles

74
Q

why is aspirin the only NSAID uses in thrombotic disease?

A

irreversibly binds to COX-1 so the production of pro-thrombotic TXA2 is stopped

75
Q

why is aspirin effective at stopping TXA2 production?

A

COX-1 cannot be regenerated by platelet because they lack nucleus

endothelial cells continue COX-1 production to produce prostacyclin (PGI2), anti-thrombotic

76
Q

why can’t platelets regenerate COX-1?

COX-1 has been lost due to irreversible binding to aspirin

A

they lack a nucleus

however endothelial cells can continue to produce COX-1

77
Q

what is aspirin?

A

weak acid

irreversibly binds to COX-1

78
Q

why would IV sodium bicarbonate be given in aspirin overdose?

A

increasing pH to shift aspirin equilibrium to ionised in the kidney so it cannot be reabsorbed into the blood

LCRS Pharma (32 decks)

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