Analgesics - Paracetamol

Question 1

Classify COX inhibitors

Answer 1

Paracetamol, aspirin, NSAIDs

Question 2

NSAIDs are divided into what

Answer 2

Non-selective NSAIDs. COX-2 inhibitors

Question 3

Another name for paracetamol

Answer 3

Acetaminophan

Question 4

How would you describe Paracetamol?

Answer 4

It is a non-narcotic analgesic-antipyretic agent with no anti-inflammatory effects

Question 5

MOA of Paracetamol

Answer 5

Inhibit prostaglandin synthesis in the brain but not in the periphery (explaining the lack of anti-inflammatory effects)

Question 6

Paracetamol is often co-administered with

Answer 6

NSAIDs or weak opioids

Question 7

Indications of Paracetamol

Answer 7

Pyrexia, mild to moderate pain

Question 8

Pharmacokinetics of paracetamol: Oral bioavailability and T1/2

Answer 8

Oral bioavailability 73-93%
* Half-life: 1-4 hou

Question 9

Explain the elimination of paracetamol

Answer 9

• 90-95% of dose is conjugated in the liver and excreted renally as
  glucuronide and sulphate metabolites. Potentially toxic intermediate
  formed by CYP450 oxidative enzyme system, usually detoxified by
  glutathione. Toxic effects on the liver and kidney may occur if
  glutathione stores are depleted.

Question 10

adverse effects of paracetamol

Answer 10

hypersensitivity skin reactions, neutropenia,
thrombocytopenia
These are rare

Question 11

what happens in Long-term chronic use at higher than recommended doses

Answer 11

Nephro- and hepatotoxicity.
Potentially fatal hepatic and renal necrosis may occur with acute overdose

Question 12

Maximum dose of paracetamol in 24hrs

Answer 12

4g

Question 13

Explain what happens in toxic doses of paracetamol

Answer 13

Toxic doses (10-15g) of paracetamol causes potentially fatal hepatotoxicity nephrotoxicity, because the normal conjugation reactions are saturated, and the drug is metabolised by mixed function oxidases.

Question 14

What is the resultant toxic metabolite after toxic dose of paracetamol, and what inactivates this metabolite?

Answer 14

The resulting toxic metabolite, N-acetyl-p-benzoquinone
imine (NAPQI), is normally inactivated by conjugation with
glutathione, but when this is depleted the toxic intermediate
accumulates in the liver and the kidney tubules and causes necrosis. * Antidote: N-acetylcystei

Question 15

Distinguish between acute paracetamol overdose and repeated ‘supratherapeutic’ ingestion

Answer 15

Acute overdose: ingestion of 10mg or >200mg/kg (whichever is less) in adults and children over

Question 16

Clinical features after an acute overdose in 0.5 to 24hrs

Answer 16

0.5 to 24 hours: asymptomatic or GI irritability with anorexia, nausea, vomiting, malaise and abdomin pain

Question 17

signs of significantly elevated serum paracetamol levels

Answer 17

Significantly raised levels = hepatotoxicity (right upper quadrant abdominal pain and tenderness, elevated bilirubin, raised liver enzymes, coagulation defects, hypoglycaemia, encephalopathy and metabolic acidos

Question 18

clinical features in 24-48 hrs

Answer 18

Sign and symptoms less pronounced, but show on blood chemistry-severe poisonings show a clinical picture of liver failure peaking at 72-96hrs. May make a full recoverry in 5-7 days or demise from hepatic failure or less commonly renal failure.

Question 19

Sings of hepatic necrosis

Answer 19

Severe metabolic derangements (hypoglycemia, hyperammonaemia - encephalopathy, coagulopathy and renal failure)

Question 20

High risk pts in paracetamol poisoning

Answer 20

“High risk” patients include: * Chronic alcoholism
* Chronic liver disease
* Use of enzyme-inducing medicines (e.g. carbamazepine, phenytoin,
efavirenz, phenobarbitone, rifampicin etc.) * Depletion of glutathione resources (e.g. malnutrition, starvation,
AIDS, chronic illness, eating disorders etc.) * Patients with recent illness, dehydration

Question 21

Mx of paracetamol poisoning in less than 8hrs of ingestion

Answer 21

Within 1-2 hrs - gastric lavage and activated charcoal
-DO NOT give activated charcoal if using antidote.
Perform serum paracetamol level 4 hrs post ingestion, but if the overdose is potentially very toxic, then give NAC even before checking plasma level.
-NAC is effective within 8hrs of ingestion, but it is never too late to adinister
-Alternative: Oral Methionine

Question 22

Mx of paracetamol poisoning >8hrs post overdose

Answer 22

-Start NAC infusion if toxic dose has been ingested or pt shows clinical signs of toxicity
Perform serum paracetamol level, INR and ALT.

Question 23

Indications for continuing NAC infusion:

Answer 23

Serum paracetamol level above the treatment line on the nomogram
* Serum paracetamol level under the treatment line but abnormal ALT
* More than 24 hours post-ingestion, measurable paracetamol level and/or
abnormal ALT

Question 24

toxic doses in repeated supratherapeutic ingestion (RSTI):

Answer 24

> 200 mg/kg or 10 g (whichever is less) over a single 24-hour period. * >150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48
hours. * >100 mg/kg or 4 g/day (whichever is less) per 24-hour period for more than
48 hours and patients have symptoms suggestive of liver injury

Question 25

Explain the dosage regimen of NAC IV

Answer 25

> 200 mg/kg or 10 g (whichever is less) over a single 24-hour period. * >150 mg/kg or 6 g (whichever is less) per 24-hour period for the preceding 48
hours. * >100 mg/kg or 4 g/day (whichever is less) per 24-hour period for more than
48 hours and patients have symptoms suggestive of liver injury

Question 26

Dosage regimen for NAC oral

Answer 26

N-acetylcysteine, oral, 140 mg/kg, followed by 70 mg/kg 4 hourly for
seventeen doses.