paracetamol poisoning

Question 1

what is paracetamol?

acts on?

Answer 1

a synthetic non-opioid pain killer and fever reducer
acts on the central nervous system

Question 2

what does paracetamol do?

Answer 2

• inhibitor of COX-2 and -3 + peroxidase regeneration
• interacts with L-arginine-nitic oxide, opioid and cannabinoid systems
• activate descending serotoninergic inhibitory pain pathways

Question 3

what is COX-2 and -3?

involved in what? found where?

Answer 3

cyclo-oxygenase
involved in prostaglandin synthesis
in brain and spinal cord
for nerve transmission of pain and fever

Question 4

what is peroxidase regeneration?

Answer 4

prevents oxidation of inactive COX to active COX

Question 5

what are L-arginine-nitic oxide, opioid and cannabinoid systems?

Answer 5

other neurotransmitter systems

Question 6

what is the serotoninergic inhibitory pain pathway?

Answer 6

indirect action on neurotransmitter
results in depressed levels and reduced pain perception

Question 7

fate of normal dose of paracetamol:

Answer 7

it is rapidly absorbed into the stomach + small intestine
plasma half life = 1.25-3 hrs
metabolised in liver into toxic and non-toxic products

Question 8

metabolism - glucuronidation:

udgt / inte

Answer 8

phase 2 conjugation rxn
45-55%
enzyme is uridine diphosphate-glucuronyl transferase
results in inactive non-toxic excretable metabolite = acetaminophen glucuronide

Question 9

metabolism - sulphate conjugation:

functional groups?

Answer 9

phase 2
catalysed by sulphotransferases found in liver, kidney and intestine
functional groups include phenols, aliphatic alcohols and amines
30-35%
results in inactive non-toxic excretable metabolite = acetaminophen sulphate

Question 10

metabolism - N-hydroxylation and dehydration (phase 1) followed by glucuronidation (phase 2):

metabolised by? catalysed by?

Answer 10

paracetamol metabolised by hepatic cytochrome P450 isoenzyme system, forms NAQPI
catalysed by glutathione S-tranferase
<10%
results in inactive non-toxic excretable cysteine and mercapturate derivatives

Question 11

paracetamol metabolism in overdose:

happens via…
stores? build up of what?

Answer 11

via oxidation from saturation in conjugate pathway
glutathione stores are depleted
build up of toxic metabolite NAQPI, liver is unable to detoxify

Question 12

toxic effects of inactivated NAQPI:

inhibits…

Answer 12

inhibits…
glutathione synthetase
enzymes in the vitamin K cycle
aerobic respiration
AND leads to cell necrosis in liver and kidney tubules

Question 13

symptoms of following ingestion of paracetamol overdose:

Answer 13

nausea + vomiting
hepatic necrosis —> acute liver failure
also hypoglycaemia, renal failure, jaundice

Question 14

things to check in lab investigations:

Answer 14

plasma conc
U&E and creatine
liver enzymes
prothrombin time
arterial blood gas
glucose

Question 15

susceptibility:

Answer 15

pre-existing liver disease
females
old age
HIV related disease

Question 16

treatment of paracetamol poisoning:

Answer 16

activated charcoal to prevent drug absorption
N-acetylcysteine given intravenously
liver transplantation