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
another name for COX
prostaglandin synthetase
What is COX essential for?
essential enzyme in arachidonic acid pathway
biosynthesis of inflammatory mediators
What are inhibitors of COX?
NSAIDs
How do glucorticoid steroids work in this pathway? (steroidal anti-inflammatories)
they act earlier in the pathway and inhibit phospholipase A2
prevent formation of arachidonic acid
5 classes of NSAIDs
- salicylate based
- alkanoic acids (-profens)
- oxicams
- pyranocarboxylic acids
- prodrugs
What is the only non-reversible COX inhibitor?
aspirin
What type of unit is found in all of the COX inhibitors?
an acidic unit eg. COOH
Why does indometacin not last long in an aqueous environement?
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
What type of drug is Z-Sulindac?
prodrug
How is Z-Sulindac activated?
by reduction through an oxidoreductase enzyme
active metabolite of Nabumetone
6MNA
-> metabolised in the liver
What does esterase hydrolysis of a glycolic acid prodrug give?
active NSAID + glycolic acid
Where does the acidity ceom from in oxicams?
the enol - OH group (not the red one the OH on the left)
What is the pKa for piroxican?
pKa 4.6
What do NSAIDs reduce?
the formation of PGE2
results of using NSAIDs
- anti-inflammatory (reduce source of pain)
- analgesic (block pain signals)
- anti-pyretic (reduce temp rise)
Where did aspirin come from?
willow bark and leaves
What is aspirin a deriviative of?
salicylic acid
Why is acetyl salicylate used over salicylic acid?
acetyl salicylate is more palateable and less damaging to oral and GI tissues
acetyl gives potent COX inhibition
Why does aspirin have irreversible COX inhibition?
through acetylation of serine in active site
actions of aspirin in the body
- suppresses formation of TXA2 by inhibiting COX in platelets
- TXA2 induces platelet aggregation
- inhibition of platelet aggregation
bonds betwenn NSAID and COX active site
- 2 hydrogen bonds between tyrosine and serine
- a salt bridge from the carboxylate (from NSAID) to arginine residue
prostaglandins in GIT vs joints/tissues
GIT - PGs are cytoprotective and maintain the gastric mucosa
joints/tissues - PGs cause inflammation
What can NSAIDs do to the GIT?
disrupts gastric mucosa and damages it - caused by the acidic group
-> can cause GIT ulceration
Where is COX1 found?
most tissues all of the time
What does COX1 induce/do?
platelet aggregation
produces PGs that protect gastric mucosa
linked to normal cellular actiity - homeostasis
Where is COX2 found?
brain and kidney normally
What induces COX2?
cytokines (inflammation) and injury
What does COX2 produce?
PGs that inhibit platelet aggregation and cause pain/swelling
part of the inflammatory response
What COX do traditional NSAIDs target?
both COX1 and COX2
What is prostacyclin (PGI2)?
produced by COX2
vasodilator
produced by endothelial cells
inhibits platetet aggregation
What is thromboxane A2?
produced by COX1
vasoconstrictor
produced by platelets
induces platelet aggregation
What does a balance between prostacyclin and thromboxane cause?
homeostasis
What can happen if either thromboxane or prostacyclin is targeted over the other?
risk of side effects
If taregting later in cascade, which should be targeted (prostacyclin/thromboxane)?
prostacyclin agonism
thromboxane antagonism
What can inhibition of prostacyclin lead to?
increased platelet aggregation and increased risk of CHD
