Paracetamol
Examples
- Paracetamol
- Co-codamol (a mixture of paracetamol and codeine phosphate, which is an opioid)
Indications
Mild to moderate pain. Often used by anaesthetists both intra and post-operatively as part of the patient's analgesic regime. See the
WHO Analgesic Ladder.
Contraindications
Contraindications
- Because co-codamol contains codeine phosphate which is an opioid, the same contraindications exist as with other opioids (See "Opioids" section).
Caution
- Caution must be given when prescribing paracetamol to patients who are alcohol dependent, dehydrated, or have any form of liver damage.
Mechanism
Although paracetamol is one of the most widely used drugs in clinical practise, there is still a surprising lack of knowledge on the exact mechanisms of its action. Recent research has suggested that it has at least two separate mechanisms of action, one on the COX pathway (see NSAIDs), and one on the cannabinoid system.
Through the COX pathway, paracetamol has very similar analgesic effects to NSAIDs, but does not have the same anti-inflammatory effects. It is thought to be a selective COX-2 inhibitor, meaning that in theory it does not block production of protective prostaglandins associated with COX-1, but does block the prostaglandins that are associated with COX-2 and ultimately the production of pain. Interestingly enough, although GI complications are much rarer than in patients using NSAIDs, cases of ulcers in patients on long term paracetamol treatment still exist, and this simply highlights the fact that we do not fully understand whether our assumptions on the COX pathways are in-fact 100% accurate. We are still very much in the preliminary stages of understanding this complicated system.
Whilst the cannabinoid system sounds scary, only a small part needs to be understood for understanding paracetamol's analgesic effects. Paracetamol is metabolised to a compound called AM404 which has several effects, one of which is the prevention of the neuronal uptake of a cannabinoid produced naturally, called anandamide. Normally the uptake of this anandamide activates nociceptors and leads to the perception of pain. By blocking the uptake of anandamide, paracetamol produces an analgesic effect.
Administration
Paracetamol can be taken orally, IV, or per rectum.
IV preparations require dose adjustment by weight in adults.
Adverse Reactions
Side effects with paracetamol when used as the correct dosage are rare, which is partly why it has been such a successful and widely used drug. The most serious complication when using paracetamol is overdose, which can lead to Paracetamol Toxicity and ultimately liver damage.
Paracetamol toxicity is one of the most common causes of poisoning worldwide and is the most common cause of acute liver failure in the UK. For more information on the mechanisms behind paracetamol overdose, see "Pharmacokinetics."
Due to the opioid content of co-codamol, patients may experience any of the side effects associated with opioids. See "Opioids".
Interactions
Paracetamol is primarily metabolised in the liver, partly through the cytochrome P450 system and partly through a process called glucuronidation. Drugs which induce or inhibit the CP450 system will increase and decrease the metabolism of paracetamol respectively, but not in sufficient amounts to produce a clinical effect. This effect is more important in overdose where patients on enzyme inducers should be treated as high risk patients.
Education
Patients should be warned about the serious complications of paracetamol overdose, and should be aware of the potential for withdrawal phenomenon when stopping the use of co-codamol suddenly.
Pharmacokinetics
Paracetamol is mainly metabolised by a process called glucuronidation. This takes place in the liver and involves the addition of glucuronic acid to paracetamol. The metabolites which result from this process are relatively non-toxic. In contrast, the small percentage of paracetamol metabolism which takes place via the cytochrome P450 system can in some cases have disastrous effects.
Metabolism through the cytochrome P450 system produces a toxic metabolite called NAPQI. This is extremely damaging to liver tissue and is the cause of acute liver failure in paracetamol overdose.
In normality, the small amount of NAPQI produced by metabolism is inactivated when glutathione binds to it. This means that there is normally no NAPQI free to cause liver damage. However when the dose of paracetamol is too high, it can saturate glutathione pathways, and lead to free NAPQI that can then cause liver failure. Treatment involves providing the body with sufficient glutathione to bind to NAPQI.
The dose of paracetamol needed to saturate glutathione pathways and thus have toxic consequences can vary between individuals, but the BNF does not recommend exceeding 4g of paracetamol within 24 hours. Chronic alcoholism is thought to decrease plasma levels of glutathione, hence the importance of establishing a history of alcoholism before prescribing paracetamol.
Other Systems
