COX chemistry (MG) Flashcards

1
Q

source of pain

A

inflammation in response to injury or disease

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2
Q

What is paracetamol?

A

analgesic
anti-pyretic
NOT anti-inflammatory

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3
Q

What is the target for paracetamol?

A

acts weakly on COX enzymes - cyclooxygenase

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4
Q

newly discovered action of paracetamol

A

paracetamol metabolite activates TRPA1

  • > protein on surface of nerve cells
  • > blocks transmission of pain
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5
Q

metabolism of paracetamol

A

sulfation

glucuronidation

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6
Q

What happens to the glucuronidation product of paracetamol?

A

it is very water soluble so it’s readily excreted

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7
Q

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

A

N hydroxylation

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

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8
Q

What is NAPQI?

A

associated with analgesia
main active component
TRPA1 stimulant

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9
Q

problems with NAPQI

A

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

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10
Q

What detoxifies NAPQI in cells naturally?

A

glutathione

- sacrifices itself so proteins in liver not damaged

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11
Q

What is used for paracetamol overdose?

A

N-acetylcysteine

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

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12
Q

Why is N-acetylcysteine used over cysteine?

A

N-acetylcysteine is more bioavailable than cysteine

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13
Q

What can sometimes be used for paracatamol OD?

A

methionine

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14
Q

What is IL-1?

A

potent inflammatory cytokine

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15
Q

What does IL-1 stimulate?

A

phospholipase A2

this acts on membrane phospholipids to release arachidonic acid

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16
Q

What is arachidonic acid?

A

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

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17
Q

What inflammatory mediators does arachidonic acid produce?

A

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

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18
Q

What does leukotriene A have?

A

an unstable epoxide

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19
Q

What type of leukotrienes are C, D and E?

A

cysteinyl leukotrienes

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20
Q

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

A

nucleophilic attack from the AA cysteine SH

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21
Q

What can leukotrienes cause in the body?

A

hypotension

bronchoconstriction

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22
Q

How does CysLT E4 bind to the receotpr CysLT1?

A

3 hydrophobic interactions and an ionic interaction

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23
Q

What does PGE2 cause in the body?

A
  • pyresis in joints and tissues
  • redness and swelling
  • pain (acts directly on peripheral/CNS neurons)
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24
Q

How is PGE2 formed?

A

by the action of COX on arachidonic acid

-> via PGH2

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25
Q

another name for COX

A

prostaglandin synthetase

26
Q

What is COX essential for?

A

essential enzyme in arachidonic acid pathway

biosynthesis of inflammatory mediators

27
Q

What are inhibitors of COX?

A

NSAIDs

28
Q

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

A

they act earlier in the pathway and inhibit phospholipase A2

prevent formation of arachidonic acid

29
Q

5 classes of NSAIDs

A
  1. salicylate based
  2. alkanoic acids (-profens)
  3. oxicams
  4. pyranocarboxylic acids
  5. prodrugs
30
Q

What is the only non-reversible COX inhibitor?

A

aspirin

31
Q

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

A

an acidic unit eg. COOH

32
Q

Why does indometacin not last long in an aqueous environement?

A

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
33
Q

What type of drug is Z-Sulindac?

A

prodrug

34
Q

How is Z-Sulindac activated?

A

by reduction through an oxidoreductase enzyme

35
Q

active metabolite of Nabumetone

A

6MNA

-> metabolised in the liver

36
Q

What does esterase hydrolysis of a glycolic acid prodrug give?

A

active NSAID + glycolic acid

37
Q

Where does the acidity ceom from in oxicams?

A

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

38
Q

What is the pKa for piroxican?

A

pKa 4.6

39
Q

What do NSAIDs reduce?

A

the formation of PGE2

40
Q

results of using NSAIDs

A
  • anti-inflammatory (reduce source of pain)
  • analgesic (block pain signals)
  • anti-pyretic (reduce temp rise)
41
Q

Where did aspirin come from?

A

willow bark and leaves

42
Q

What is aspirin a deriviative of?

A

salicylic acid

43
Q

Why is acetyl salicylate used over salicylic acid?

A

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

44
Q

Why does aspirin have irreversible COX inhibition?

A

through acetylation of serine in active site

45
Q

actions of aspirin in the body

A
  • suppresses formation of TXA2 by inhibiting COX in platelets
  • TXA2 induces platelet aggregation
  • inhibition of platelet aggregation
46
Q

bonds betwenn NSAID and COX active site

A
  • 2 hydrogen bonds between tyrosine and serine

- a salt bridge from the carboxylate (from NSAID) to arginine residue

47
Q

prostaglandins in GIT vs joints/tissues

A

GIT - PGs are cytoprotective and maintain the gastric mucosa

joints/tissues - PGs cause inflammation

48
Q

What can NSAIDs do to the GIT?

A

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

49
Q

Where is COX1 found?

A

most tissues all of the time

50
Q

What does COX1 induce/do?

A

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

51
Q

Where is COX2 found?

A

brain and kidney normally

52
Q

What induces COX2?

A

cytokines (inflammation) and injury

53
Q

What does COX2 produce?

A

PGs that inhibit platelet aggregation and cause pain/swelling

part of the inflammatory response

54
Q

What COX do traditional NSAIDs target?

A

both COX1 and COX2

55
Q

What is prostacyclin (PGI2)?

A

produced by COX2
vasodilator
produced by endothelial cells
inhibits platetet aggregation

56
Q

What is thromboxane A2?

A

produced by COX1
vasoconstrictor
produced by platelets
induces platelet aggregation

57
Q

What does a balance between prostacyclin and thromboxane cause?

A

homeostasis

58
Q

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

A

risk of side effects

59
Q

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

A

prostacyclin agonism

thromboxane antagonism

60
Q

What can inhibition of prostacyclin lead to?

A

increased platelet aggregation and increased risk of CHD