Paracetamol is a para-aminophenol, and based on a simple phenol ring It is often classified alongside NSAIDs, mainly because of its similar effects, but has quite different mechanism of action.
Its action is not fully understood. It is often described as blocking the COX-3 isoenzyme, which is a variant of COX-1 (hence the common description alongside NSAIDs). The result is CNS blockade of prostaglandin synthesis, and subsequent analgesic and antipyretic actions. An alternative explanation is that the way it works on the COX step in prostaglandin synthesis is more subtle (as the process is more than one step) and so only acts in low levels of arachidonic acid, e.g. in undamaged cells. However, it is important to clarify that the systemic effects of NSAIDs that arise from COX blockade do not occur. This includes the anti-inflammatory effects.
Additional mechanisms of action may include:
Potentiation of descending serotonergic pathways
Potentiation of endocannabinoid action by inhibiting reuptake
Well absorbed orally - bioavailability 80-90% (although quoted as low as 63% in some texts). PR availability 50-80% Low protein binding - 10% Large volume of distribution It is absorbed mainly from the small bowel by passive transport
Analgesia onset occurs in 5 mins after Iv administration, peaking at 40-60 mins. Onset after oral administration peaks at about 1 hour. The effects last for 4-6 hours.
It is metabolised in the liver - the metabolism has an important impact on its toxicity. 95% is via conjugation - primarily glucuronidation (also some sulphate and cysteine) These products are actively excreted in the urine.
Remaining 5% is normal metabolised by cytochrome p450 pathway to N-acetyl-P-amino-benzoquinoneimine (NAPQI). This is very toxic, binding to hepatocytes and causing their death. However, it is normally bound to glutathione, rendering it harmless.
There may be some genetic variation within this enzyme system, with some patients exhibiting and increased rate of metabolism, and therefore a higher risk of toxicity.
Can be given by oral, IV and rectal routes. Dose is 1g QDS (if over 50 kg) In children the dose is 15mg/kg QDS - can be loaded with 20mg/kg If they weigh under 10kg, this dose should be reduced to 7.5mg/kg A loading dose if 2g has been described and commonly used and may result in a better analgesic profile without adverse effects.
There appears to be good, if occasionally challenged evidence of the effectiveness of paracetamol as an analgesic. It appears equivalent to many other NSAIDs for analgesia for most conditions. It is also described as having analgesic equivalent of 10mg IV morphine. As noted, the side effects in comparison are minimal, and so it is considered a valuable analgesic on its own, as well as demonstrating an opioid sparing effect.
Crossover allergy with aspirin (5%)
Rare idiosyncratic hematopoietic disorders
Possible link to asthma development
The conjugation pathways become saturated, thus resulting in more metabolism through the p450 route. This results in more NAPQI production. Once glutathione stores are depleted, this can start binding to hepatocytes, causing cell death. The result is centrilobular hepatic necrosis. Subsequent hepatic failure can occur. A dose of 10g (200mg/kg) is considered overdose level
This will usually be part of a intentional overdose. Presentation may be best considered based upon the timing in relation to the overdose.
Stage 1 (<24h - primary treatment window) Initially it may be asymptomatic. Vague abdominal symptoms may be present e.g. nausea.
Stage 2 (24-48h) Hepatic necrosis has started:
Stage 3 (48-96h) Hepatic failure
LFTs an clotting worse 3-5 days
Stage 4 Either:
Fulminant liver failure and death, or.
In addition may have (particularly in massive OD):
Acute haemolytic anaemia
Peripheral vasodilation and shock
Patients with massive OD or mixed OD may be acutely unwell and need an A to E approach, including organ support.
Time of dose
Risk factors for toxicity
Fulminant hepatic failure
Paracetamol (and salicylate) levels
In general they may be thought of as relating too:
Impaired hepatic function to start with (increased vulnerability to injury)
Reduced glutathione stores
Hepatic enzyme inducers - increased metabolism down NAPQI route
States with glutathione depletion:
Chronic alcohol use
Hepatic enzyme induction:
Principles are primarily to maintain glutathione stores and therefore allow ‘safe’ metabolism of the drug.
Treatment is N-acetyl cysteine (NAC). Almost 100% effective if given within 8 hours . Effectiveness drops rapidly between 8 and 24 hours.
Decision on whether to start treatment may be needed in low level overdose (as it isn’t completely benign). Treatment will be needed if:
Delayed presentation (>8 hours)
Elevated paracetamol level based on nomogram
In general, treatment is needed when a certain plasma level of paracetamol occurs. This level changes depending on the time after ingestion, and so a nomogram allows correlation of plasma level in relation to time after ingestion. If the level is above a treatment threshold, NAC should be given. However, in cases of staggered overdose this relationship in not clear (toxicity may result despite ‘low’ plasma levels) and so treatment should be given. In cases of delayed presentation, awaiting for plasma levels can delay time to treatment and worsen outcome, so treatment should just be started.
Treatment involves IV loading and maintenance. Local protocols may vary, an example being:
50mg/kg over 4 hours
150mg/kg over 16 hours
Adverse reactions include:
They can be reduced by slowing rate of infusion.
Oral treatment is also used in some cases and is added to paracetamol in some localities (not in the UK). In some cases activated charcoal may be considered, though some debate about the risk vs benefits.
Liver failure may develop in cases of delayed treatment. Admission and regular monitoring of hepatic function is needed. Early discussion with transplant unit is important in cases of hepatic injury. Psychiatric assessment will be needed as inpatient.