COX chemistry (MG) Flashcards
source of pain
inflammation in response to injury or disease
What is paracetamol?
analgesic
anti-pyretic
NOT anti-inflammatory
What is the target for paracetamol?
acts weakly on COX enzymes - cyclooxygenase
newly discovered action of paracetamol
paracetamol metabolite activates TRPA1
- > protein on surface of nerve cells
- > blocks transmission of pain
metabolism of paracetamol
sulfation
glucuronidation
What happens to the glucuronidation product of paracetamol?
it is very water soluble so it’s readily excreted
important metabolic reaction of paracetamol (10% of the dose)
N hydroxylation
- paracetamol is N hydroxylated, then dehydrated (water eliminated) to give NAPQI
What is NAPQI?
associated with analgesia
main active component
TRPA1 stimulant
problems with NAPQI
highly electrophilic (very reactive)
susceptible to attack from N and S nucelophiles
it is toxic
reacts with proteins in the liver and causes damage
What detoxifies NAPQI in cells naturally?
glutathione
- sacrifices itself so proteins in liver not damaged
What is used for paracetamol overdose?
N-acetylcysteine
-> so body can create its own glutathione quickly (body only contains a finite amount of it)
Why is N-acetylcysteine used over cysteine?
N-acetylcysteine is more bioavailable than cysteine
What can sometimes be used for paracatamol OD?
methionine
What is IL-1?
potent inflammatory cytokine
What does IL-1 stimulate?
phospholipase A2
this acts on membrane phospholipids to release arachidonic acid
What is arachidonic acid?
percursor for the biosynthesis of prostaglandins, thromboxanes, prostacyclin and leukotrienes
What inflammatory mediators does arachidonic acid produce?
leutotriene A
PGE2
TXA2 (thromboxane A2)
PGI2 (prostacyclin)
What does leukotriene A have?
an unstable epoxide
What type of leukotrienes are C, D and E?
cysteinyl leukotrienes
How is leukotriene A converted to other leukotrienes (B, C, D, E)?
nucleophilic attack from the AA cysteine SH
What can leukotrienes cause in the body?
hypotension
bronchoconstriction
How does CysLT E4 bind to the receotpr CysLT1?
3 hydrophobic interactions and an ionic interaction
What does PGE2 cause in the body?
- pyresis in joints and tissues
- redness and swelling
- pain (acts directly on peripheral/CNS neurons)
How is PGE2 formed?
by the action of COX on arachidonic acid
-> via PGH2