What it is
Paracetamol (acetaminophen) is one of the most widely used analgesics and antipyretics in the world. In Spain it is available without a prescription in oral, rectal and intravenous forms.
Unlike NSAIDs, it has no relevant peripheral anti-inflammatory effect, which makes it safer for the stomach, the kidney and during pregnancy. Its main risk is liver toxicity in overdose, even accidental overdose.
Central mechanism of action
Although its exact mechanism is not fully understood, it acts mainly in the central nervous system:
- It reduces prostaglandin synthesis in the CNS. The hypothesis of a specific central 'COX-3' has not been confirmed in humans.
- It activates the descending serotonergic pathways that modulate pain.
- It does not significantly inhibit peripheral COX-1 or COX-2 → no real anti-inflammatory effect.
- Strong antipyretic effect: it acts on the temperature-regulating centre in the hypothalamus.
At the counter
When to recommend it
- Mild to moderate pain without an inflammatory component: tension-type headache, mild toothache, mild post-operative pain
- Fever in adults and children (in young infants, with the paediatrician's dosing)
- Pain in pregnancy: it is the analgesic of choice throughout pregnancy
- Pain in patients with an ulcer, mild kidney impairment or hypertension (where NSAIDs are limited)
- Children with chickenpox: the antipyretic of choice
- Combined with ibuprofen for post-operative pain, for a synergistic effect
When not to
- Severe liver failure or active hepatitis
- Regular heavy alcohol use (more than 3 drinks a day): risk of liver toxicity at normal doses
- Known allergy to paracetamol (rare, but it exists)
- Do not exceed 4 g a day in healthy adults, or 3 g a day in older people or patients at liver risk
Warnings
- Important OVERDOSE: liver toxicity can appear with doses above 7.5–10 g in healthy adults. The problem is that the early symptoms are mild (nausea, feeling unwell) and serious liver damage shows up 2–3 days later. If overdose is suspected, go to A&E immediately.
- Important COMBINATIONS: many medicines already contain paracetamol (cold and flu remedies and other combinations). It is essential to ask what else the patient is taking before adding more paracetamol.
- Caution ALCOHOL: ethanol induces CYP2E1, increasing the production of toxic NAPQI. With regular alcohol use, the risk of liver toxicity is higher even at therapeutic doses.
- Caution WARFARIN: high doses of paracetamol (more than 2 g a day continuously) enhance the anticoagulant effect of warfarin. Monitor the INR.
- Worth knowing PREGNANCY: it remains the analgesic of choice. Some observational studies have suggested an association with neurodevelopmental disorders that the EMA does not consider established. As with any medicine in pregnancy: the lowest effective dose for the shortest possible time.
Pharmacokinetics
- Absorption
- Oral: rapid and almost complete absorption (85–95%). Peak plasma level at 30–60 minutes. Effervescent and granule forms act slightly faster. Food delays absorption slightly but does not reduce it.
- Distribution
- Even distribution across all tissues. It readily crosses the blood–brain barrier (hence its central effect) and the placenta. Low plasma protein binding (~25%).
- Metabolism
- Hepatic, mainly by glucuronidation and sulphation (safe pathways). 5–10% is metabolised by CYP2E1 into NAPQI, a toxic metabolite. Normally, liver glutathione neutralises it. In overdose or liver disease, glutathione runs out and NAPQI destroys liver cells.
- Elimination
- Renal, as conjugated metabolites. Half-life: 2–3 hours. In severe liver failure the half-life is significantly prolonged.
Paracetamol vs ibuprofen
| Aspect | Paracetamol | Ibuprofen |
|---|---|---|
| Mechanism | Central (CNS) | Peripheral (COX-1 and COX-2) |
| Pain relief | Good for pain without inflammation | Better for inflammatory pain |
| Anti-inflammatory | No | Yes |
| Antipyretic | Yes, very effective | Yes |
| Gastric risk | Minimal | Moderate |
| Liver risk | High in overdose / with alcohol | Minimal at normal doses |
| Pregnancy | First choice | Avoid from week 20; contraindicated in the third trimester |
| Children with chickenpox | First choice | Contraindicated |
Paracetamol as the first option for almost everyone, especially pregnant women, children with chickenpox and patients with an ulcer or compromised kidneys. Ibuprofen when there is real inflammation. The biggest mistake is not knowing how much paracetamol the patient is already taking.
Self-assessment
Three questions. When you check your answers you will see the explanation for each one.
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Primary dysmenorrhoea has a large inflammatory component (excess uterine prostaglandins). Ibuprofen, by inhibiting peripheral COX, works better. Paracetamol lacks this peripheral anti-inflammatory effect and relieves period pain less.
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Most cold and flu remedies already contain paracetamol. Adding extra tablets can easily take the total above 4 g a day, with a risk of liver toxicity. It is one of the most frequent and avoidable mistakes at the counter.
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Paracetamol is very safe for the stomach and kidney, but its toxic metabolite (NAPQI) destroys the liver in overdose. The problem is that overdose can be accidental, because people do not realise they are already taking it in other products.
Training content. It does not replace the summary of product characteristics or clinical judgement.