NSAIDs

Question 1

3 uses of NSAIDs

Answer 1

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

Question 2

examples of mild-to-moderate pain-causing conditions

Answer 2

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

Question 3

examples of conditions causing inflammation

Answer 3

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

Question 4

what 2 things do NSAIDs inhibit the synthesis of

Answer 4

prostaglandin and thromboxane

Question 5

what are prostaglandin and thromboxane (lipid mediators) derived from

Answer 5

arachidonic acid (AA), from phospholipid membrane

Question 6

rate limiting steps of prostanoid production

Answer 6

cyclo-oxygenase enzymes

Question 7

how are they stored and distributed

Answer 7

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

Question 8

how are they mediated

Answer 8

receptor-mediated

Question 9

what enzymes do NSAIDs inhibit

Answer 9

COX-1 and COX-2

Question 10

what do COX enzymes convert AA into

Answer 10

prostaglandin H2

Question 11

what do specific synthesases convert prostaglandin H2 into

Answer 11

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

Question 12

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

Answer 12

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

Question 13

what receptor effects do prostanoids have

Answer 13

G protein-dependent and G protein-independent

Question 14

prostanoid receptors use

Answer 14

normal physiological, but pro-inflammatory

Question 15

what does inhibition of prostanoid production result in

Answer 15

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

Question 16

what 4 receptors can PGE2 activate, and secondary messengers

Answer 16

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

Question 17

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

Answer 17

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

Question 18

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

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

role of PGE2 in inflammation

Answer 22

extremely complex, but is pro-inflammatory

Question 23

4 desirable physiological effects of PGE2 and other prostaglandins

Answer 23

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

Question 24

why shouldn’t NSAIDs be taken by asthmatics

Answer 24

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

Question 25

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

Answer 25

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

Question 26

effect of PGE2 produced by COX enzymes in glomerulus

Answer 26

increased renal blood flow, so reduces salt and water retention

Question 27

way in which NSAIDs can cause renal toxicity

Answer 27

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

Question 28

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

Answer 28

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

Question 29

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

Answer 29

ulceration, as block gastroprotective effects of PGE2

Question 30

possible solution to deaths caused by NSAID effetcs in GI tract

Answer 30

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

Question 31

range of cardiovascular modulations by different prostanoids

Answer 31

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

Question 32

risk vs benefit of NSAID analgesic use

Answer 32

usually occasional, relatively low risk of side effects

Question 33

risk vs benefit of NSAID anti-inflammatory use

Answer 33

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

Question 34

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

Answer 34

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

Question 35

3 risk factors of GI ulceration besides NSAIDs

Answer 35

alcohol consumption, anticoagulant use, glucocorticoid use

Question 36

what is aspirin (NSAID) selective for

Answer 36

COX-1

Question 37

how does aspirin bind to COX enzymes

Answer 37

irreversibly

Question 38

4 effects of aspirin

Answer 38

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

Question 39

what prostanoid from platelets causes platelet aggregation

Answer 39

TXA2 (thromboxane A2)

Question 40

what prostanoid from endothelial cells reduces platelet aggregation

Answer 40

prostacyclin (PGI2)

Question 41

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

Answer 41

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

Question 42

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

Answer 42

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

Question 43

what does high degree of COX-1 inhibition cause

Answer 43

suppression of TXA2 production in platelets

Question 44

what binding permanently inhibits platelet COX-1 by aspirin

Answer 44

covalent

Question 45

capacity required to inhibit COX-2, and hence dose

Answer 45

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

Question 46

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

Answer 46

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

Question 47

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

Answer 47

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

Question 48

mechanism of action of paracetamol

Answer 48

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

Question 49

effect of overdose of paracetamol in liver and why

Answer 49

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

Question 50

antidote for paracetamol poisoning

Answer 50

add compound with -SH group

Question 51

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)

Answer 51

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

Question 52

how legislation has reduced paracetamol overdoses

Answer 52

restriced size of packs and no. of packs per transaction