NSAIDS

Question 1

Pain vs nociception

Answer 1

Pain is a subjective experience. Nociception detects and signals presence of noxious stimuli

Question 2

How do steroids and NSAIDS affect cyclooxygenase synthesis

Answer 2

Steroids inhibit phospholipids A2, preventing break down of phospholipids to arachidonic acid

NSAIDS inhibit formation of cyclooxygenase from arachidonic acid

Question 3

Cyclooxygenase forms 3 prostanoids what are they

Answer 3

Prostacyclin
Prostaglandin
Thromboxane

Question 4

What are the effects of prostacyclin

Answer 4

Vasodilatation, inhibit platelet aggregation

Question 5

What are the effects of prostaglandin

Answer 5

Vasodilation
Vascular permeability
Pain

Question 6

What are the effects of txa2 (cox 1 only vs cox 1 and 2 for pgi2 and pge2)

Answer 6

Vasoconstriction and platelet aggregation

Question 7

Effects of aspirin

Answer 7

Anti inflammatory
Analgesic
Anti pyretic
Anti platelet

Question 8

How does aspirin exert anti inflammatory effect

Answer 8

Block vasodilation

Block increase in vascular permeability

Question 9

How does aspirin exert analgesic mechanism

Answer 9

Blocks production of prostaglandins which sensitise nociceptive fibres to stimulation by other inflammatory mediators eg bradykinin and leukotrienes

Ie block sensitisation rather than direct nociceptive activation hence nsaids have analgesic ceiling

Additional analgesics action in the cns. Crosses the blood brain barrier to affect pain modulataion and processing

Question 10

How does aspirin exert anti pyretic effect

Answer 10

Inhibit cox formation, no pge2 forms. Pge2 responsible for fever

Question 11

How does aspirin exert anti platelet function

Answer 11

Platelets tend to have cox1 which produce txa2, promoting aggregation. Endothelial cells have cox which forms pgi2 which inhibits aggregation.

Aspirin is an irreversible cox inhibitor. Platelets have no nucleus, unable to make new COX; takes 1-2 weeks to make COX to make txa2 to promote aggregation

Endothelial cells can recover in 3-4h to restore inhibition of platelet aggregation

Question 12

Side effects of aspirin (due to salicylate chemical structure)

Answer 12

GI bleeding, tinnitus (sign of overrode), hypoprothrombinaemia (excessive lack of thrombosis, prone to bleeding)

Question 13

Why is aspirin contraindicated in children

Answer 13

Reye’s syndrome. Increased risk when children with viral infections are exposed to salicylate eg aspirin.

Leads to encephalitis and liver swelling. Increased pressure on brain can cause delirium, convulsions, personality changes, loss of consciousness

Question 14

What are the first gen nsaids

Answer 14

Aspirin, naproxen, indomethacin, diclofenac

Question 15

What is naproxen used for

Answer 15

First gen nsaids used for dysmenorrhea because more effective in women and long half life of 12-14h

Question 16

What is indomethacin used for

Answer 16

Rheumatoid arthritis, gout, closes ductus arteriosus in fetus

Question 17

Compare indomethacin to other nsaids

Answer 17

More potent than other nsaids. Strongly inflammatory as it is a phospholipase a2 inhibitor (more steroid like)

Has cns adverse effects such as hallucination, depression

Question 18

What is diclofenac used for

Answer 18

1st gen nsaid (cox2>cox1)

Low GI risk because short plasma half life

Longer half life in synovial fluid and accumulates in synovial joint fluid hence useful for inflammatory joint diseases eg rheumatoid arthritis

Question 19

What are the adverse gastrointestinal effects of NSAIDS

Answer 19

Decrease prostaglandin synthesis; prostaglandins responsible for decreasing gastric acid synthesis, increasing bicarbonate secretion, increasing mucosal blood flow and mucus secretion

NSAIDS result in dyspepsia, nausea, vomiting, ulcer formation, hemorrhage risk in chronic users

Question 20

How to avoid hemorrhage risk in chronic users of NSAIDS

Answer 20

Use for less than 7 days and use with other drugs eg antacids

But taking an antiplatelet eg aspirin will increase hemorrhage risk if preexistinf ulcer

Question 21

What are the renal side effects of NSAIDS (esp naproxen due to long duration of action 12-14h)

Answer 21

Inhibition of pge2:
Sodium and water retention leading to peripheral edema and hypertension

Act at ascending limb (25%)

Inhibition of pgi2
Suppresses renin and aldosterone secretion
Hyperkalemia that can result in acute renal failure

Act at DCT (1-2%)

Question 22

How do nsaids cause pseudoallergic reaction and asthma

Answer 22

Inhibit cox, push arachidonic acid to 5-lipoxygenase (eicosanoids). Excess leukotrienes lead to bronchospasm (asthma patients susceptible) and allergic reaction like symptoms es rashes, swelling, nasal congestion

Question 23

How do first gen nsaids cause bruising

Answer 23

Inhibit cox. Less thromboxane which promotes platelet aggregation, less haemostasis

Question 24

What are Coxibs

Answer 24

Gen 2 cox 2 selective inhibitors

Question 25

First gen vs second gen nsaids

Answer 25

Second gen nsaids are cox 2 selective Cox 1 constitutive effects Cox 2 is inducible in response to inflammatory stimulus, hence cox 2 selective inhibitors avoid adverse effects (But constitutive in CNS, kidney, female reproductive tract, synovium)

Question 26

What are the adverse effects of Coxibs

Answer 26

Cox 2 still constitutive in kidney. Still have renal toxicity but less severe adverse effect Delay follicular rupture, affecting ovulation to decrease chance of pregnancy Premature close of ductus arteriosus in third trimester hence ALL NSAIDS CONTRAINDICATED IN 3RD TRIMESTER Impair wound healing and exacerbate ulcers (not cause) Increase thrombosis risk because relative shift to TXA2 (cox 1 only so not affected vs pgi2 and pge2) hence favour platelet aggregation

Question 27

What are the cox1>2 and cox2>1 nsaids

Answer 27

``` Cox1>2: Kaley please i am not idiotic Ketoprofen Piroxicam Indomethacin Aspirin Naproxen Ibuprofen ``` ``` Cox2>1: DM me cute pictures Evan Diclofenac Mefenamic acid Meloxicam Celecoxib Parecoxib Etoricoxib ```

Question 28

As cox 2 selectivity increases, drug effect becomes more

Answer 28

Anti inflammatory Stronger analgesic property More prothrombotic with the exception of aspirin

Question 29

Can i use nsaids in pregnancy

Answer 29

Contraindicated in third trimester

Question 30

Why does paracetamol not have adverse GI effect

Answer 30

Cns selective cox inhibitor, does not inhibit peripheral cox

Question 31

What are the uses of paracetamol

Answer 31

Analgesics, antipyretic Weak anti inflammatory effect

Question 32

How does paracetamol cause hepatotoxicity

Answer 32

Metabolised to NAPQI. CYP2E1 (induced by alcohol) metabolised NAPQI to toxic metabolite Glutathione converts toxic metabolite to non toxic. Glutathione is depleted by overdose and alcohol abuse, replenished by n acetylene cysteine