4. Analgesia - Paracetamol Flashcards
What is paracetamol (acetaminophen) a derivative of?
analine derivative
What 3 things are analine derivatives?
- phenacetin, acetanalid and acetaminophen
What are the properties of the analine derivatives?
analgesic
- mild-moderate pain (similar to aspirin)
- anti-pyretic (similar to aspirin)
- anti-inflammatory property
one of the most common non-narcotic analgesics
What is the mode of action of paracetamol?
not very clear or understood
- suggested to have a more peripheral than central effect
- limited inhibition of COX-1/2 activity
- more highly selective an inhibitor of COX-3 but this is debated
other suggested modes of actions include:
- selective inhibition OG neuronal PG synthesis
- activation serotonergic pathways in spine
- inhibition of nitric oxide synthase
What effects (or lack of effects) does paracetamol have?
- No effects on platelet aggregation
- Little effect respiratory
- Little effect cardiovascular
- Reportedly fewer ADR’s (cf NSAIDs)
- Little or no gastric irritation
- No relevant impact on uric acid excretion
What are the indications of paracetamol?
- first line for mild-moderate dental pain
- inflammatory conditions
- where NSAIDs are contraindicated
- states - GI, renal, coagulopathies
- drugs/conditions contraindicate NSAIDs - 4 ANTS
- ?pre-emptive
What forms can paracetamol come in?
tablet, capsule, elixir, suppository, IV
How is paracetamol absorbed?
well absorbed in the GI (1st Pass limited)
What is the distribution of paracetamol?
widely and evenly distributed
What is the peak plasma time of paracetamol, and the % bioavailability of this?
30-60mins, bioavailability of 70%+
What is the half life of paracetamol?
2-4 hours
(4-8hrs in toxic doses)
Where does biotransformation of paracetamol occur?
liver
What is a possibly hazardous metabolite of paracetamol?
N-acetyl-p-benzoquinone imine (NAPQI)
How is paracetamol eliminated?
renal
What are the contraindications for paracetamol?
Few absolute contraindications, but some conditions which require special consideration
What are the side effects of paracetamol?
rare
- skin reactions (SJS, TEN)
- blood dyscrasias (thrombocyto-, neutro-, leuco-penia)
What are the potential risks of long-term therapeutic paracetamol use?
- liver damage (hepatotoxicity)
Why must care be taken when dosing paracetamol for a patient on warfarin?
although general considered safe, some reports of significant alterations in INR and bleeding
What may be done when prescribing paracetamol for a patient with renal insufficiency?
increase the dosing interval (i.e. more than 6hrs between doses)
What situations are not absolute contraindications for paracetamol but require some care and consideration?
liver disease, alcohol use, malnutrition, dehydration
What is the standard adult dose or paracetamol?
10-15mg/kg every 4-6 hours to a daily maximum of 4 grams (8 500mg tablets/day / 1mg 4x/day)
What are the principle interactions with paracetamol?
beware (CYP450 2E1/1A2/3A4) inducing drugs: (SCRAPPP)-NAPQI:
- St. john’s Wort
- Carbemazepine
- Rifampicin
- Alcohol
- Phenobarbitol
- Phenytoin
- Primidone
How do the SCRAPPP drugs interact with paracetamol?
- the majority of the absorbed dose of paracetamol is metabolised by the glucaronidation and sulfation pathways to form non-toxic metabolites which are then excreted in the urine
- the remainder is then oxidised by the hepatic CYP450 pathway, mainly CYP450 2E1/1A2/3A4
- for patients taking enzyme inducing drugs (SCRAPPP) or those who are malnourished may develop liver toxicity at lower plasma concentrations and should be provisionally regarded as slightly higher risk
- more NAPQI builds up at lower plasma concentrations of paracetamol if taking enzyme inducing drugs
Is paracetamol effective for lower back pain?
no analgesic effect, in a cochrane review paracetamol’s effect was equal to that of the placebo
What are the side effects of paracetamol?
A systematic review of (observational studies) shows paracetamol;
- Increased mortality
- Cardiovascular adverse events (fatal or non-fatal myocardial infarction, stroke, or fatal coronary heart disease)
- Gastrointestinal adverse events (ulcers and complications such as upper gastrointestinal haemorrhage)
- Renal impairment
- Non-overdose paracetamol = 2x rate acute liver failure (transplantation) than NSAIDs.
- Paracetamol = 4x more likely to have abnormal LFTs v placebo.
- RCT arthritis - paracetamol = ibuprofen for SE’s over three months.
What amount of paracetamol is a highly toxic dose?
10-15g (20-30 tablets)
(can be as little as 8g depending on risk factors)
What amount of paracetamol is likely to be fatal regardless of treatment?
25g
When does maximal liver damage from paracetamol occur?
3-4 days post ingestion
What is the treatment for paracetamol overdose?
acetylcystein IV, activated charcoal
Summary slide (paracetamol):
- non-opioid analgesic drug
- analine dye derivative
- first-line for most forms of acute and chronic pain
- useful for mild-moderate dental pain
- first step in WHO analgesic ladder
- anti-pyretic activity
- uncertain mechanism of action but likely a weak inhibitor of cytooxygenase
- primarily oral administration but others available
- side effects few, notable are skin reactions and -penias
- liver metabolism, renal excretion
- interactions: CYP450 inducers (SCRAPPP)
- not entirely safe, commonly implicated in overdose
- very few absolute contra-indications
