Paracetamol

Paracetamol

Mechanism of action

Paracetamol (acetaminophen) has analgesic and antipyretic actions in the central nervous system. It inhibits prostaglandin synthetase in the hypothalamus, prevents synthesis of spinal prostaglandin, and inhibits inducible nitric oxide synthesis in macrophages. In therapeutic doses, inhibition of prostaglandin synthesis is not significant in peripheral tissues, so paracetamol has minimal anti-inflammatory action. However, paracetamol weakly inhibits isolated cyclo-oxygenase (COX)-1 and COX-2 in vitro, but is a stronger inhibitor of prostaglandin synthesis in cellular systems when the concentrations of arachidonic acid are low. Thus it has potential to suppress low-grade inflammation such as that seen in osteoarthritis.

Paracetamol is rapidly absorbed after oral administration, with a peak concentration in 10 to 60 minutes. Time to peak plasma concentration after the recommended slow intravenous administration is 15 minutes. Analgesic effects begin 5 to 10 minutes after commencing an IV infusion, and approximately 30 minutes after oral administration. Absorption after rectal administration is slow and erratic. Elimination half-life is 1 to 3 hours, and protein binding is insignificant. Paracetamol readily crosses into the cerebrospinal fluid and into the brain, the site of its major analgesic effect. It undergoes extensive first-pass metabolism in the liver, and the kidneys excrete its metabolites. Paracetamol should be administered cautiously in patients with renal or hepatic dysfunction. Metabolite production in overdose may lead to severe hepatic toxicity. Tolerance and dependence have not been reported.

Indications

Although paracetamol is less effective than nonsteroidal anti-inflammatory drugs (NSAIDs) in relieving moderate to severe pain, its excellent safety in therapeutic doses justifies recommending it as the first-line analgesic for mild to moderate pain, particularly of soft tissue and musculoskeletal origin.

Paracetamol may also be used to reduce the overall daily doses of NSAIDs or opioids required, and thus the risk of their adverse effects.

Other indications include:

an alternative to aspirin—including when aspirin is contraindicated (eg hypersensitivity, hyperuricaemia, gastrointestinal bleeding or ulceration)

mild procedural pain

management of fever. 

 

Dose and toxicity

Paracetamol is commonly used in children .

The recommended adult dose of paracetamol is:

paracetamol 0.5 to 1 g every 4 to 6 hours, to a generally accepted maximum of 4 g per day.

It has been suggested that the analgesic effect of paracetamol reaches a plateau at a mean single dose of 600 mg, and since the duration of action is quite short, the best deployment of the 4 g per day dose limit may be to give lower doses more frequently, such as 500 mg every 3 hours. It is important to explain these facts to the patient, and encourage them to determine the best dose and frequency by trial and error.

Alternatively, a modified-release formulation of paracetamol can be used at a dose of 0.665 to 1.33 g every 6 to 8 hours, to a maximum of 3.99 g per day

The relationship between the size, interval and duration of repeated doses of paracetamol and its toxicity is not clearly defined. There are some reports of hepatic damage associated with doses in the accepted therapeutic range, but despite the uncertainties of these reports it is clear that if it occurs, this is very rare. It is biologically plausible, and probably supported by experience, that the incidence of toxicity rises with increasing the dose above 4 g per day—but this dose does not represent an absolute cut-off above which liver damage will occur. Evidence suggests there is an increased frequency of toxicity in individuals with induced cytochrome P450 enzymes, in particular CYP2E1, such as in patients with high alcohol intake, and those taking enzyme-inducing drugs such as rifampicin or some antiepileptics. Fasting or vomiting, which can result in reduced hepatic glutathione, may be even more important factors in causing toxicity.

Adverse effects

Paracetamol is generally considered a safe analgesic with a low incidence of adverse effects compared with other drugs. Nonrandomised studies have found an increased risk of upper gastrointestinal complications with paracetamol doses greater than 2 g daily (especially when used in conjunction with NSAIDs), and an increased risk of hypertension in women. No randomised controlled trials have been reported to confirm these findings.

Rarely, patients may experience urticarial or erythematous rashes, fever, or blood dyscrasias. Long-term use of paracetamol alone does not seem to cause analgesic nephropathy. Paracetamol can be used in patients with liver metastases.

Overdose

For assessment and management, see Toxicology: paracetamol.

Paracetamol is available in various formulations (see Formulations) and under many brand names both alone and as combination preparations. It is an ingredient in many nonprescription medications (eg cold and flu preparations).

Inadvertent overdose due to ingestion of higher than recommended doses is a possibility, and patients should be advised to consider the paracetamol content of all medications.

Formulations

Formulations of paracetamol include:

immediate-release tablets and capsules

oral solutions and suspensions—with a range of concentrations available for paediatric use

chewable tablets

soluble or effervescent tablets

modified-release tablets incorporating an immediate-release component and a modified-release dose. These tablets should not be chewed or crushed before swallowing. Each contains 665 mg of paracetamol and provides up to 8 hours pain relief; 3-times-daily dosing appears to be clinically equivalent to immediate-release paracetamol taken 4 times daily

suppositories available in 125 mg, 250 mg and 500 mg strengths. The recommended rectal and oral doses are the same; however, the rectal dose required to produce a plasma concentration may be higher than that using the oral route, and rectal absorption can be erratic. For ease of insertion, the suppository can be moistened just before insertion

an injectable formulation containing paracetamol 10 mg/mL, which is indicated where an intravenous route of administration is considered clinically necessary. Onset of action is within 5 to 10 minutes, peak effect is at one hour, and duration is 4 to 6 hours. It is given over 15 minutes, and is approved for use in adults and children. The intravenous and oral doses are equivalent.

Soluble tablets, modified-release, and suppository formulations of paracetamol are all more expensive per unit dose than the standard tablet or capsule. Injectable paracetamol is significantly more expensive than oral and rectal formulations.

Paracetamol is also available in a number of oral preparations combined with other drugs including analgesics (eg NSAIDs, codeine and dextropropoxyphene), decongestants, antihistamines and antiemetics.

Use in palliative care

Doses for children are in Table 10.14.

The recommended maximum daily dose of 4 g is based on minimising liver enzyme abnormality, but the relevance of this in the palliative setting is uncertain. Patients with chronic pain should take 4 g per day for a week before the drug is abandoned. There is some evidence that increasing the dose to 6 g per day can be beneficial.

It is prudent to impose a general adult dose limit of 4 g per day on the therapeutic use of paracetamol; however, this is not absolute, and in some clinical circumstances the benefit of increasing the dose, at least for a short period, may outweigh the relatively small risks of giving 6 g per day, particularly in the palliative setting.