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notes to flashcards year 2 - LCRS1 > NSAIDs > Flashcards

NSAIDs Flashcards

1
Q

what are the clinical uses of NSAIDs?

A
  • analgesic (headache)
  • anti-pyretic (influenza)
  • anti-inflammatory (gout, rheumatoid arthritis)
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2
Q

what is the MoA of NSAIDs?

A

inhibit prostanoid synthesis by blocking COX

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3
Q

what are prostanoids?

A
  • derived from arachidonic acid
  • e.g. TXA2, prostacyclin, prostaglandins
  • not stored, preformed
  • receptor mediated
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4
Q

what are the 2 forms of COX? what do NSAIDs do?

A
  • COX1, COX2

- NSAIDs inhibit both to varying drugs

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5
Q

what does the Coxib family do?

A

selectively reversibly inhibits COX2 e.g. celecoxib

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6
Q

what are the 5 prostanoids? how many receptors do they bind to?

A
  • TXA2
  • PGF2alpha
  • PGE2
  • PGI2
  • PGD2
  • bind to 10 receptors (G-protein coupled)
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7
Q

What 4 receptors does PGE2 bind to? what effect?

A
  • activated EP1,2,3,4
  • cAMP-dependant (EP2/4)
  • Ca2+ mobilisation (EP1/3)
  • or both (EP3)
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8
Q

what are the unwanted actions of PGE2?

A
  • inc. pain perception
  • thermoregulation
  • acute inflammatory response
  • inhibition of apoptosis
  • tumorigenesis
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9
Q

how does PGE2 cause pain sensitisation?

A
  • stimulation of PG receptors sensitises nociceptors
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10
Q

how do NSAIDs work to combat this pain sensitization?

A

co-injection of COX2 inhibitors reduces duration of prolonged pain
via activation of EP1 and EP4 receptors in spine and periphery

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11
Q

how does PGE2 interfere with thermoregulation?

A

PGE2 is pyrogenic
it stimulates hypothalamic neurones to initiate a rise in body temp
= hyperpyrexia
NSAIDs reduce this

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12
Q

how do PGE2 prostanoids cause an acute inflammatory reaction?

A

acute inflammatory response

  • PGE2 –> EP3 signalling
  • EP3 receptor then signals downstream using 2 mechanisms (cAMP and Ca mobilisation)
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13
Q

what are the desirable actions of PGE2 prostanoid?

A
  • gastro-protection
  • renal salt and water homeostasis
  • bronchodilation
  • vaso-regulation
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14
Q

How does PGE2 prostanoid cause gastro-protection?

A
  • PGE2 stimulated mucus and bicarbonate secretion into gut
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15
Q

so what effect does NSAIDs have on gastro-protection?

A
  • inc. risk of ulceration
  • due to blocking of COX1
  • fewer deaths when using Celecoxib (COX-2 selective inhibitor) than normal NSAIDs
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16
Q

what effect does PGE2 have on renal salt and water homeostasis? so what about NSAIDs?

A
  • PGE2 inc. renal blood flow
  • NSAIDs can cause renal toxicity
  • not for renal failure patients
17
Q

in what ways do NSAIDs cause renal toxicity?

A
  • constriction of afferent renal arteriole
  • reduction in renal artery flow
  • reduction GFR
18
Q

how do NSAIDs cause bronchodilation?

A
  • COX inhibition favours production of leucotrienes (as other pathway for arachidonic acid is inhibited)
  • leucotrienes are potent broncho-constrictors
19
Q

due to this, who shouldn’t take NSAIDs?

A

asthmatics

20
Q

how do NSAIDs interfere with vaso-regulation?

A
  • dilation or constriction depending on receptors activated

- they cause vasoconstriction, salt/water retention and reduced effects of anti-hypertensives

21
Q

what do NSAIDs then inc. risk of?

A
  • hypertension, MI, stroke

- inc. risk of CVS events

22
Q

what does COX1 inhibition lead to an inc. risk of? what about COX2 do?

A
  • COX1 inhibition –> inc. GI risk

- COX2 inhbition –> inc. CVS risk

23
Q

what is the risk/benefits of NSAID use?

A
  • analgesic use: occasionally used so low risk of side effects
  • anti-inflammatory: used chronically in higher doses so high side effect risk
24
Q

how do you limit GI side effects? (other than using COX2 selective NSAIDs)

A
  • topical application (less systemic access)
  • limit use in pt with a GI-ulceration history or with other risk factors
  • treat H. pylori
  • co-administer omeprazole (or another PPI)
25
Q

what is the MoA of aspirin?

A
  • selective for COX-1

- binds irreversibly to COX enzymes (odd for NSAIDs)

26
Q

what are the actions of aspirin?

A
  • anti-inflammatory
  • analgesic
  • anti-pyretic
  • dec. platelet aggregation
27
Q

how does aspirin cause the dec. platelet aggregation?

A
  • platelets: reduces TXA2 production via COX1, no reproduction as platelet has no nucleus
  • endothelial cells: reduces PGI2 synthesis by COX1/2. reproduction possible due to nucleus
  • so less TXA2 and still PGI2
28
Q

how does aspirin cause anti-platelet action?

A
  • high degree of COX1 inhibition which supresses TXA2 synthesis in platelets
  • covalent bonding which permanently inhibits platelets COX1
  • relactively low capacity to inhibit COX2
  • need low dose to enable endothelial re-synthesis of COX2
29
Q

what are the side effects of aspirin?

A
  • gastric ulceration
  • bronchospasm
  • prolonged bleeding time
  • nephrotoxicity
30
Q

why are the side effects more common in aspirin than other NSAIDs?

A

due to irreversible inhibition

31
Q

is paracetamol an NSAID? what are its actions?

A
  • has no anti-inflammatory action
  • relieve mild/moderate pain
  • no anti-pyretic actions
32
Q

what is the MoA of paracetamol

A
  • not understood but probably central

- COX3, cannabinoid receptors, interactions with endogenous-opiods

33
Q

what happens in a paracetamol overdose?

A

if glutathione is depleted (saturated whilst metabolising other paracetamol molecules), the metabolites oxidise thiol groups of key hepatic enzymes and cause apoptosis

34
Q

what is the antidote of a paracetamol overdose?

A
  • add compound with an -SH group
  • IV acetylcysteine (used in cases of attempted suicide)
  • oral methionine

notes to flashcards year 2 - LCRS1 (58 decks)

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