COX chemistry (MG)

Question 1

source of pain

Answer 1

inflammation in response to injury or disease

Question 2

What is paracetamol?

Answer 2

analgesic
anti-pyretic
NOT anti-inflammatory

Question 3

What is the target for paracetamol?

Answer 3

acts weakly on COX enzymes - cyclooxygenase

Question 4

newly discovered action of paracetamol

Answer 4

paracetamol metabolite activates TRPA1

• > protein on surface of nerve cells
• > blocks transmission of pain

Question 5

metabolism of paracetamol

Answer 5

sulfation

glucuronidation

Question 6

What happens to the glucuronidation product of paracetamol?

Answer 6

it is very water soluble so it’s readily excreted

Question 7

important metabolic reaction of paracetamol (10% of the dose)

Answer 7

N hydroxylation

- paracetamol is N hydroxylated, then dehydrated (water eliminated) to give NAPQI

Question 8

What is NAPQI?

Answer 8

associated with analgesia
main active component
TRPA1 stimulant

Question 9

problems with NAPQI

Answer 9

highly electrophilic (very reactive)
susceptible to attack from N and S nucelophiles
it is toxic
reacts with proteins in the liver and causes damage

Question 10

What detoxifies NAPQI in cells naturally?

Answer 10

glutathione

- sacrifices itself so proteins in liver not damaged

Question 11

What is used for paracetamol overdose?

Answer 11

N-acetylcysteine

-> so body can create its own glutathione quickly (body only contains a finite amount of it)

Question 12

Why is N-acetylcysteine used over cysteine?

Answer 12

N-acetylcysteine is more bioavailable than cysteine

Question 13

What can sometimes be used for paracatamol OD?

Answer 13

methionine

Question 14

What is IL-1?

Answer 14

potent inflammatory cytokine

Question 15

What does IL-1 stimulate?

Answer 15

phospholipase A2

this acts on membrane phospholipids to release arachidonic acid

Question 16

What is arachidonic acid?

Answer 16

percursor for the biosynthesis of prostaglandins, thromboxanes, prostacyclin and leukotrienes

Question 17

What inflammatory mediators does arachidonic acid produce?

Answer 17

leutotriene A
PGE2
TXA2 (thromboxane A2)
PGI2 (prostacyclin)

Question 18

What does leukotriene A have?

Answer 18

an unstable epoxide

Question 19

What type of leukotrienes are C, D and E?

Answer 19

cysteinyl leukotrienes

Question 20

How is leukotriene A converted to other leukotrienes (B, C, D, E)?

Answer 20

nucleophilic attack from the AA cysteine SH

Question 21

What can leukotrienes cause in the body?

Answer 21

hypotension

bronchoconstriction

Question 22

How does CysLT E4 bind to the receotpr CysLT1?

Answer 22

3 hydrophobic interactions and an ionic interaction

Question 23

What does PGE2 cause in the body?

Answer 23

• pyresis in joints and tissues
• redness and swelling
• pain (acts directly on peripheral/CNS neurons)

Question 24

How is PGE2 formed?

Answer 24

by the action of COX on arachidonic acid

-> via PGH2

Question 25

another name for COX

Answer 25

prostaglandin synthetase

Question 26

What is COX essential for?

Answer 26

essential enzyme in arachidonic acid pathway | biosynthesis of inflammatory mediators

Question 27

What are inhibitors of COX?

Answer 27

NSAIDs

Question 28

How do glucorticoid steroids work in this pathway? (steroidal anti-inflammatories)

Answer 28

they act earlier in the pathway and inhibit phospholipase A2 | prevent formation of arachidonic acid

Question 29

5 classes of NSAIDs

Answer 29

1. salicylate based 2. alkanoic acids (-profens) 3. oxicams 4. pyranocarboxylic acids 5. prodrugs

Question 30

What is the only non-reversible COX inhibitor?

Answer 30

aspirin

Question 31

What type of unit is found in all of the COX inhibitors?

Answer 31

an acidic unit eg. COOH

Question 32

Why does indometacin not last long in an aqueous environement?

Answer 32

AMIDE BOND - the lone pair on the N is part of the indo ring system - it can't form a stable amide bond aswell - it's prone to hydrolysis

Question 33

What type of drug is Z-Sulindac?

Answer 33

prodrug

Question 34

How is Z-Sulindac activated?

Answer 34

by reduction through an oxidoreductase enzyme

Question 35

active metabolite of Nabumetone

Answer 35

6MNA | -> metabolised in the liver

Question 36

What does esterase hydrolysis of a glycolic acid prodrug give?

Answer 36

active NSAID + glycolic acid

Question 37

Where does the acidity ceom from in oxicams?

Answer 37

the enol - OH group (not the red one the OH on the left)

Question 38

What is the pKa for piroxican?

Answer 38

pKa 4.6

Question 39

What do NSAIDs reduce?

Answer 39

the formation of PGE2

Question 40

results of using NSAIDs

Answer 40

- anti-inflammatory (reduce source of pain) - analgesic (block pain signals) - anti-pyretic (reduce temp rise)

Question 41

Where did aspirin come from?

Answer 41

willow bark and leaves

Question 42

What is aspirin a deriviative of?

Answer 42

salicylic acid

Question 43

Why is acetyl salicylate used over salicylic acid?

Answer 43

acetyl salicylate is more palateable and less damaging to oral and GI tissues acetyl gives potent COX inhibition

Question 44

Why does aspirin have irreversible COX inhibition?

Answer 44

through acetylation of serine in active site

Question 45

actions of aspirin in the body

Answer 45

- suppresses formation of TXA2 by inhibiting COX in platelets - TXA2 induces platelet aggregation - inhibition of platelet aggregation

Question 46

bonds betwenn NSAID and COX active site

Answer 46

- 2 hydrogen bonds between tyrosine and serine | - a salt bridge from the carboxylate (from NSAID) to arginine residue

Question 47

prostaglandins in GIT vs joints/tissues

Answer 47

GIT - PGs are cytoprotective and maintain the gastric mucosa | joints/tissues - PGs cause inflammation

Question 48

What can NSAIDs do to the GIT?

Answer 48

disrupts gastric mucosa and damages it - caused by the acidic group -> can cause GIT ulceration

Question 49

Where is COX1 found?

Answer 49

most tissues all of the time

Question 50

What does COX1 induce/do?

Answer 50

platelet aggregation produces PGs that protect gastric mucosa linked to normal cellular actiity - homeostasis

Question 51

Where is COX2 found?

Answer 51

brain and kidney normally

Question 52

What induces COX2?

Answer 52

cytokines (inflammation) and injury

Question 53

What does COX2 produce?

Answer 53

PGs that inhibit platelet aggregation and cause pain/swelling part of the inflammatory response

Question 54

What COX do traditional NSAIDs target?

Answer 54

both COX1 and COX2

Question 55

What is prostacyclin (PGI2)?

Answer 55

produced by COX2 vasodilator produced by endothelial cells inhibits platetet aggregation

Question 56

What is thromboxane A2?

Answer 56

produced by COX1 vasoconstrictor produced by platelets induces platelet aggregation

Question 57

What does a balance between prostacyclin and thromboxane cause?

Answer 57

homeostasis

Question 58

What can happen if either thromboxane or prostacyclin is targeted over the other?

Answer 58

risk of side effects

Question 59

If taregting later in cascade, which should be targeted (prostacyclin/thromboxane)?

Answer 59

prostacyclin agonism | thromboxane antagonism

Question 60

What can inhibition of prostacyclin lead to?

Answer 60

increased platelet aggregation and increased risk of CHD