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Y2 LCRS Pharmacology and Therapeutics > NSAIDs > Flashcards

NSAIDs Flashcards

NSAIDs mechanism of action: identify the underlying mechanism of action by which all NSAIDs have their therapeutic effects and the difference between the NSAIDs and paracetamol

1
Q

3 uses of NSAIDs

A

analgesic (mild-to-moderate pain relief), antipyretic (reduces fever e.g. influenza), anti-inflammatory

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2
Q

examples of mild-to-moderate pain-causing conditions

A

toothache, headache, backache, postoperative pain (opiate sparing), dysmenorrohoea (menstrual pain)

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3
Q

examples of conditions causing inflammation

A

rheumatoid arthritis, osteoarthritis, musculo-skeletal inflammation, soft tissue injuries (strains and sprains), gout

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4
Q

what 2 things do NSAIDs inhibit the synthesis of

A

prostaglandin and thromboxane

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5
Q

what are prostaglandin and thromboxane (lipid mediators) derived from

A

arachidonic acid (AA), from phospholipid membrane

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6
Q

rate limiting steps of prostanoid production

A

cyclo-oxygenase enzymes

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7
Q

how are they stored and distributed

A

not stored pre-formed so never have to deplete stores, widely distributed

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8
Q

how are they mediated

A

receptor-mediated

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9
Q

what enzymes do NSAIDs inhibit

A

COX-1 and COX-2

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10
Q

what do COX enzymes convert AA into

A

prostaglandin H2

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11
Q

what do specific synthesases convert prostaglandin H2 into

A

other prostaglandins (I2, E2, D2, F2a), prostacyclin and thromboxane A2

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12
Q

what are the 10 known prostanoid receptors, and what are their names based on

A

DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP; named based on agonist potency

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13
Q

what receptor effects do prostanoids have

A

G protein-dependent and G protein-independent

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14
Q

prostanoid receptors use

A

normal physiological, but pro-inflammatory

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15
Q

what does inhibition of prostanoid production result in

A

multiple, complex consequences (e.g. PGE2 has many actions in many different parts of body)

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16
Q

what 4 receptors can PGE2 activate, and secondary messengers

A

EP1, EP3 (both cAMP-independent as Ca2+ mobilisation), EP2, EP4 (both cAMP-dependent)

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17
Q

6 unwanted actions of PGE2 (why NSAIDs are used to try to downregulate these effects)

A

increased pain perception, increased body temperature, acute inflammatory response, immune responses, tumorigenesis, inhibition of apoptosis

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18
Q

how do PGE2 analogues lower pain threshold, and what agonists used to increase pain threshold

A

stimulation of PG receptors in periphery sensitises nociceptors, which causes pain acutely and chronically; EP4-mediated so EP4 receptor antagonists therefore block effect of PGE2 analogue

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19
Q

possible main mechanism of action for sensitisation of nociceptors by stimulation of peripheral PG receptors by PGE2 analogues

A

cAMP mediated -> activates P2X3 nociceptors -> during inflammation, Epac pathway activated and more PGE2 produced -> greater activation of P2X3 receptors

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20
Q

other pathways of action for sensitisation of nociceptors by stimulation of peripheral PG receptors by PGE2 analogues

A

EP1 receptors and/or EP4 receptors (in periphery and spine), endocannabinoids (neuromodulators in thalamus, spine and periphery), NAIDs increase B-endorphin in spine

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21
Q

how is PGE2 pyrogenic (induces fever and raises temperature), and effects of NSAIDs

A

stimulates hypothalamic neurones, initiating a rise in body temperature; NSAIDs reduce raised temperature (max at -1 degree)

22
Q

role of PGE2 in inflammation

A

extremely complex, but is pro-inflammatory

23
Q

4 desirable physiological effects of PGE2 and other prostaglandins

A

bronchodilation (however may densitise B2-adrenoceptors), renal salt and water homeostasis, gastroprotection, vasoregulation (dilation and constriction depending on receptor activated)

24
Q

why shouldn’t NSAIDs be taken by asthmatics

A

COX enzyme inhibition favours production of leukotrienes, which are bronchoconstrictiors (block bronchodilation of PGE2)

25
Q

location of COX-1 and COX-2 in kidney nephron

A

COX-1 in glomerulus, distal tubule and collecting duct, COX-2 in glomerulus and ascending limb of loop of Henle

26
Q

effect of PGE2 produced by COX enzymes in glomerulus

A

increased renal blood flow, so reduces salt and water retention

27
Q

way in which NSAIDs can cause renal toxicity

A

constriction of afferent renal arteriole -> reduction in renal artery flow -> reduced GFR

28
Q

role of PGE2 in gastric cytoprotection: effect on HCl secretion and mucus and bicarbonate secretions in parietal cells

A

in parietal cells, PGE2 stimulates mucus and bicarbonate secretions and downregulates HCl secretion

29
Q

in the GI tract, what do NSAIDs increase the risk of

A

ulceration, as block gastroprotective effects of PGE2

30
Q

possible solution to deaths caused by NSAID effetcs in GI tract

A

selective COX-2 inhibition (not used as raises CVD due to causing renal toxicity)

31
Q

range of cardiovascular modulations by different prostanoids

A

vasodilation/constriction, increased/decreased platelet aggregation, inflammatory mediator, smooth muscle contraction

32
Q

risk vs benefit of NSAID analgesic use

A

usually occasional, relatively low risk of side effects

33
Q

risk vs benefit of NSAID anti-inflammatory use

A

often sustained, higher doses, relatively high risk of side effects

34
Q

5 strategies (besides COX-2 selective NSAIDs) for limiting GI side effects

A

topical application, minimise use in patients with GI ulceration history, treat H pylori if present, administer NSAID with omeprazole (or other protein pump inhibitor to reduce HCl production in stomach), minimise use in patients with other risk factors/reduce risk factors

35
Q

3 risk factors of GI ulceration besides NSAIDs

A

alcohol consumption, anticoagulant use, glucocorticoid use

36
Q

what is aspirin (NSAID) selective for

A

COX-1

37
Q

how does aspirin bind to COX enzymes

A

irreversibly

38
Q

4 effects of aspirin

A

anti-inflammatory, analgesic, anti-pyretic (all 3 similar to other NSAIDs), reduces platelet aggregation

39
Q

what prostanoid from platelets causes platelet aggregation

A

TXA2 (thromboxane A2)

40
Q

what prostanoid from endothelial cells reduces platelet aggregation

A

prostacyclin (PGI2)

41
Q

effect of aspirin on TXA2 and PGI2, and hence effect on platelet aggregation

A

as TXA2 is made by COX-1, and PGI2 is made by both COX-1 and COX-2, TXA2 synthesis completely stops but PGI2 synthesis reduced, meaning overall platelet aggregation is reduced

42
Q

why can’t TXA2 be replaced upon aspirin use, but PGI2 can be, further reducing platelet aggregation

A

platelets (which produce TXA2 by COX-1) have no nucleus, so cannot resynthesise COX-1; endothelial cells have a nucleus, so can resynthesise COX-1 and COX-2 to create PGI2, reducing platelet aggregation

43
Q

what does high degree of COX-1 inhibition cause

A

suppression of TXA2 production in platelets

44
Q

what binding permanently inhibits platelet COX-1 by aspirin

A

covalent

45
Q

capacity required to inhibit COX-2, and hence dose

A

relatively low capacity required, so low dose used to allow endothelial resynthesis of COX-2

46
Q

4 major side effects of aspirin at therapeutic dose (due to irreversible binding, not selectivity to COX-1)

A

gastric irritation and ulceration, bronchospasm in sensitive asthmatics, prolonged bleeding times, nephrotoxicity (due to irreversible binding, not COX-1 selectivity)

47
Q

actions of paracetamol, and reason why it is not an NSAID

A

analgesic for mild-to-moderate pain, anti-pyretic; minimal anti-inflammatory effect so not NSAID

48
Q

mechanism of action of paracetamol

A

unknown, but probably central and peripheral (possibly cannabinoid receptors, interactions with endogenous opioids or through 5HT and adenosine receptors)

49
Q

effect of overdose of paracetamol in liver and why

A

irreversible liver failure, as if glutathione depleted the metabolite (NAPQI) oxidises -SH groups of key hepatic enzymes, causing cell death

50
Q

antidote for paracetamol poisoning

A

add compound with -SH group

51
Q

2 examples of compounds with -SH groups (and administration route) which act as antidotes for paracetamol poisoning if administered before unpreventable liver failure (then liver transplant)

A

acetylcysteine (i.v.), methionine (oral)

52
Q

how legislation has reduced paracetamol overdoses

A

restriced size of packs and no. of packs per transaction

Y2 LCRS Pharmacology and Therapeutics (68 decks)

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