Paracetamol

Question 1

What effects does paracetamol have?

What about NSAIDS?

Answer 1

Paracetamol
= anti-pyretic
= analgesic

NSAIDS
= anti-pyretic
= analgesic
= ANTI-INFLAMMATORY

Question 2

How does paracetamol work?

Answer 2

We still do not fully know

Question 3

What are the main pathways thought to be responsible for the effects of paracetamols?

Answer 3

Serotonergic
Eiconasoid
Cannabanoid
Opiodeegic

Question 4

What is the descending part of the serotonergic pathway?

Answer 4

Descensing pain pathways

Question 5

Where do the cell bodies of the serotonineegic pathways originate from?

Answer 5

The raphe nucleus in the brain stem

Question 6

What does activation of the serotonergic pathways result in?

Answer 6

Suppression of pain in the CNS

Question 7

How is paracetamol allegedly supposed to work with respect to the serotonergic pathway?

Answer 7

Enhance its inhibitory pain effects

Question 8

Why are antiemetic and paracetamol sometimes working oppositely?

Why is this strange however and still used in combination?

Answer 8

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…

Question 9

How strong a COX inhibitor is paracetamol?

Answer 9

Weak

Question 10

Which enzyme is paracetamol thought to act mostly on?

Answer 10

Peroxidase

Question 11

What does peroxidase do?

Answer 11

Turns PGG2 into PGH2

Question 12

Why does paracetamol have no anti-inflammatory effects if it inhibits the peroxidase enzyme?

Answer 12

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

Question 13

Where is paracetamol metabolised?

Answer 13

In the liver

Question 14

How many intermediate metabolites does it have?

What is it/they called?

Answer 14

One

P-aminophenol

Question 15

What happens to the active metabolite from paracetamol metabolism?

What is this process called?

Answer 15

P-aminophenol binds with arachidonic acid in the brain

This process is called conjugation

Question 16

What happens to the conjugated molecule in the brain as paracetamol is further metabolised?

Answer 16

The enzyme FAAH (fatty acid amine hydrolyse) turns the metabolites into a molecule called:

AM404

Question 17

Why is AM404 important when thinking about paracetamols mechanism of action?

Answer 17

AM404 activates cannabinoid receptors which mediates the release of endogenous cannabinoids (which inhibit central prostaglandin release meaning it this has anti-pyrexial effects)

Question 18

What is the main risk from taking paracetamol?

Answer 18

Hepatotoxicity

Question 19

What condition can NSAIDS worsen?

Answer 19

Asthma

Question 20

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?

Answer 20

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

Question 21

What happens to paracetamol pathways of metabolism in overdose?

Answer 21

A higher % follows the CYP450 pathway which results in toxic NAPQI build up which can NOT be detoxified

Acute hepatic necrosis follows

Question 22

What 2 main reasons can explain why paracetamol can cause hepatotoxicity at therapeutic doses?

Answer 22

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