Paracetamol Flashcards
(22 cards)
What effects does paracetamol have?
What about NSAIDS?
Paracetamol
= anti-pyretic
= analgesic
NSAIDS
= anti-pyretic
= analgesic
= ANTI-INFLAMMATORY
How does paracetamol work?
We still do not fully know
What are the main pathways thought to be responsible for the effects of paracetamols?
Serotonergic
Eiconasoid
Cannabanoid
Opiodeegic
What is the descending part of the serotonergic pathway?
Descensing pain pathways
Where do the cell bodies of the serotonineegic pathways originate from?
The raphe nucleus in the brain stem
What does activation of the serotonergic pathways result in?
Suppression of pain in the CNS
How is paracetamol allegedly supposed to work with respect to the serotonergic pathway?
Enhance its inhibitory pain effects
Why are antiemetic and paracetamol sometimes working oppositely?
Why is this strange however and still used in combination?
Antiemetics are sometimes 5-HT3 receptor antagonists (as the serotonin pathway can cause nausea and vomiting)
These may therefore partially inhibit the analgesic effects of paracetamol via their mechanism of action
They are surprisingly SYNERGISTIC though! This is not understood…
How strong a COX inhibitor is paracetamol?
Weak
Which enzyme is paracetamol thought to act mostly on?
Peroxidase
What does peroxidase do?
Turns PGG2 into PGH2
Why does paracetamol have no anti-inflammatory effects if it inhibits the peroxidase enzyme?
In CNS peroxidase levels = low = paracetamol can inhibit
In peripheral tissues during inflammation, large amounts of peroxidase is produces = high levels = paracetamol CAN NOT inhibit = NO anti-inflammatory effects
Where is paracetamol metabolised?
In the liver
How many intermediate metabolites does it have?
What is it/they called?
One
P-aminophenol
What happens to the active metabolite from paracetamol metabolism?
What is this process called?
P-aminophenol binds with arachidonic acid in the brain
This process is called conjugation
What happens to the conjugated molecule in the brain as paracetamol is further metabolised?
The enzyme FAAH (fatty acid amine hydrolyse) turns the metabolites into a molecule called:
AM404
Why is AM404 important when thinking about paracetamols mechanism of action?
AM404 activates cannabinoid receptors which mediates the release of endogenous cannabinoids (which inhibit central prostaglandin release meaning it this has anti-pyrexial effects)
What is the main risk from taking paracetamol?
Hepatotoxicity
What condition can NSAIDS worsen?
Asthma
What are the two phases of paracetamol metabolism?
What does each path roughly involve?
What % of the drug follows each pathway at normal therapeutic concentrations?
Phase 2 = 5% of drug = conjugation to non-toxic metabolites
Phase 1 = 95% of drug = CYP450 system = NAPQI (TOXIC) which is detoxified by GLUTATHIONE into non-toxic conjugates
What happens to paracetamol pathways of metabolism in overdose?
A higher % follows the CYP450 pathway which results in toxic NAPQI build up which can NOT be detoxified
Acute hepatic necrosis follows
What 2 main reasons can explain why paracetamol can cause hepatotoxicity at therapeutic doses?
1) some people have the CYP450 isozyme CYP-2D6 causes rapid metabolism of paracetamol which leads to toxic NAPQI build up
2) glutathione stores can be low in some groups of patients (infants, malnourished, elderly, alcoholics) meaning NAPQI detoxification is impaired allowing it to accumulate
