ACTION AND MECHANISM

- Paracetamol is a para-aminophenol derivative, with analgesic and antipyretic activity.

* Analgesic effect. Its mechanism of action is not fully understood, but appears to be primarily mediated by the inhibition of central cyclooxygenase, especially COX-2, thereby decreasing prostaglandin synthesis. It also has a certain peripheral effect by blocking the generation of pain nerve impulses. A possible peripheral effect has also been suggested by inhibition of prostaglandin synthesis, activation of the CB1 cannabinoid receptor, modulation of serotonergic or opiate signaling pathways, inhibition of nitric oxide synthesis, or substance P-induced hyperalgesia.

* Antipyretic effect. It acts on the hypothalamic thermoregulatory center, inhibiting prostaglandin synthesis and the effects of endogenous pyrogens. This leads to peripheral vasodilation, increased blood flow to the skin, and increased sweating, which contribute to heat loss.

At the same dose, it is considered to have similar analgesic and antipyretic potency to acetylsalicylic acid (ASA). The effects are maximal after 1-3 hours and last for 3-4 hours.

Unlike ASA and other NSAIDs, it does not have appreciable anti-inflammatory activity, except in some non-rheumatic pathologies, although this is not significant. An advantage over NSAIDs is that not only does it not inhibit gastric prostaglandin synthesis, but it appears to increase it, thus not causing gastrointestinal side effects. It also lacks antiplatelet effects.

SPECIAL WARNINGS

- Although it does not significantly reduce inflammation, very positive effects have been obtained in knee arthritic processes, probably due to its analgesic effect.

- Monitoring:

* Kidney function and blood count in patients treated for prolonged periods of time.

* Liver function at baseline and periodically in patients at high risk of hepatotoxicity.

PATIENT ADVICE

- It can be taken with or without food. Taking it without food accelerates the analgesic effects, but not their intensity.

- Do not exceed the recommended doses or use for more than 10 days without medical advice. Discontinue treatment as soon as symptoms disappear.

- Consult your doctor and/or pharmacist if the pain persists after 5-10 days of treatment (3-5 days in children; 2 days in cases of pharyngeal pain), the fever lasts for more than 3 days, or if symptoms worsen or new ones appear.

- Patients who regularly consume significant amounts of alcohol (3 or more drinks per day) should limit their paracetamol doses to prevent liver damage.

- In case of overdose, consult a doctor and/or pharmacist, even if no symptoms appear.

CONTRAINDICATIONS

- [ALLERGY TO PARACETAMOL] or any other component of the medication.

- Severe and active liver disease.

ADVANCED AGE

Reduced elimination has been reported in elderly patients. Some manufacturers recommend reducing the dose by 25% compared to young adults, but others do not consider this precaution necessary.

PREGNANCY

Animal safety : No teratogenic effects have been recorded in animal studies.

Human safety : A large body of data in pregnant women indicates no fetal/neonatal toxicity or congenital malformations. Epidemiological studies on the neurodevelopment of children exposed to paracetamol in utero have yielded inconclusive results.

Paracetamol crosses the placental barrier. Several cohort studies have been conducted on the safety of oral paracetamol in pregnant women. These studies did not show an increased risk of birth defects, heart defects, or miscarriage. There is evidence that its use during the last two trimesters may be associated with an increased risk of wheezing in the first year of life.

There have been a few isolated cases of serious adverse reactions in children of mothers who received paracetamol during pregnancy, including severe anemia, hepatotoxicity, and nephrotoxicity (the latter two being fatal). However, these symptoms appeared to be due to an overdose by the mother.

Oral paracetamol, at recommended doses and used appropriately, is considered a safe analgesic/antipyretic during pregnancy. It has been used just before delivery in women with fever secondary to chorioamnionitis, with significant improvements in the condition of the fetus and newborn observed after the mother's temperature returned to normal. However, its use at high doses or for longer periods could be associated with fetal hepatotoxicity.

On the contrary, due to the lack of safety and efficacy data in pregnant women, it is recommended to avoid parenteral use unless the expected benefits outweigh the possible risks.

Effects on fertility : In animal studies, paracetamol caused testicular atrophy and decreased spermatogenesis at high doses. It is unknown whether these data can be extrapolated to humans.

PHARMACOKINETICS

- Absorption: the therapeutic cp is around 10 mcg/ml.

INDICATIONS

- Symptomatic treatment of mild to moderate pain, such as [HEADACHE], [TOOTHACHE], [DYSMENORRHEA], [MUSCLE CONTRACTURE] such as [MUSCLE TORTICOLLIS], [LOW BACK PAIN], [OSTEOARTHRITIS] or [RHEUMATOID ARTHRITIS], [NEURALGIA] such as [SCIATICA], sore throat, [POSTOPERATIVE PAIN] or postpartum.

- Symptomatic treatment of [FEVER].

INTERACTIONS

In general, interactions with paracetamol are not expected to be serious due to its occasional use. Interactions are only expected to be clinically significant in patients treated with high doses, especially those with other risk factors for hepatotoxicity, or those receiving long-term treatment.

- NSAID. Paracetamol is commonly used in combination with other analgesics, such as ibuprofen, to treat fever in children. However, it should be noted that administering it in combination with NSAIDs or salicylates at high doses and for prolonged periods could increase the risk of kidney damage. Therefore, it is recommended not to exceed the recommended doses and limit combined treatment to the minimum necessary.

- Oral anticoagulants. Unlike NSAIDs and aspirin, paracetamol does not have antiplatelet activity and does not affect blood coagulation per se, which is why it is used as the analgesic drug of choice in patients treated with oral anticoagulants.

However, in the case of prolonged treatment at high doses, but not reaching toxic doses, a slight hepatotoxic effect could occur, characterized by a decrease in the production of hepatic coagulation factors, which could increase the INR in these patients, with a risk of bleeding.

Therefore, monitoring this parameter is recommended in these patients treated with high doses. The risk appears negligible in the case of single-dose treatments or in long-term treatments with doses < 2 g/24 h.

- Busulfan. Risk of busulfan toxicity, as paracetamol reduces glutathione levels, the substance with which busulfan is conjugated during its elimination. It is recommended to avoid the administration of paracetamol, or limit exposure if not possible, in the 72 hours before and during treatment with busulfan.

- Chloramphenicol. Paracetamol may promote chloramphenicol accumulation by decreasing its hepatic metabolism, with a risk of hematological toxicity. Patient monitoring is advised.

- Drugs that delay gastric emptying, such as anticholinergics or exenatide. This delay could slow the absorption of paracetamol and the onset of its effect, rather than its intensity.

- Hepatotoxic drugs. Paracetamol at high doses has a hepatotoxic effect. It is recommended to avoid concomitant administration with other hepatotoxic drugs, as well as with alcohol.

- Enzyme inducers (estrogen-containing oral contraceptives, barbiturates, carbamazepine, phenytoin, rifampicin). Paracetamol is partially metabolized by cytochrome P450, so its plasma levels and therapeutic effects may be reduced when administered concomitantly with a drug that potently induces the hepatic microsomal system. Furthermore, in the event of a paracetamol overdose, the inducer may increase liver toxicity due to increased production of toxic metabolites generated by this enzyme system.

- Enzyme inhibitors (imatinib, isoniazid, propranolol). Increases in plasma paracetamol levels have been reported with drugs that inhibit its metabolism.

- Reverse transcriptase inhibitors (didanosine, zidovudine). Paracetamol may potentiate the hematologic toxicity of zidovudine. Furthermore, both didanosine and zidovudine may promote paracetamol-induced hepatotoxicity.

- Lamotrigine. Paracetamol may increase the metabolism of lamotrigine, reducing its therapeutic effects.

- Ion exchange resins (cholestyramine, colestipol). Possible decreased absorption of paracetamol. Interval between administrations by one hour.

Studies have shown no significant pharmacokinetic interaction with adefovir, amantadine, H2 blockers or proton pump inhibitors, argatroban, chloroquine, erythromycin, lithium, methotrexate, oseltamivir, sucralfate, telmisartan, or zolmitriptan. No interaction of any kind has been reported with alpha-1 adrenergic blockers (doxazosin, terazosin), furosemide, letrozole, or zanamivir.

Paracetamol slightly reduces the urinary excretion of diazepam, although plasma levels remain unchanged.

Paracetamol does not affect the immunogenicity of influenza vaccines and may reduce the symptoms of adverse reactions to them.

LACTATION

Animal safety: no data available.

Human safety: Paracetamol is excreted in small amounts in breast milk, with milk concentrations of 10-15 mcg/ml (similar to plasma) being reached 1-2 h after a 650 mg po dose. Exposure in the child is estimated to be 1-2% of the maternal dose. No paracetamol or its metabolites have been found in infant urine, and no adverse reactions have been reported in the child, except for one case of maculopapular rash, which resolved without sequelae when the mother discontinued the paracetamol.

CHILDREN

Paracetamol is an analgesic-antipyretic drug commonly used in children, including toddlers. However, as a general precautionary measure, its use in children under 3 years of age should be done under medical supervision, and its use should be limited to a minimum.

Due to the risk of serious, potentially fatal poisoning, it is recommended to closely monitor dosage in children, avoiding higher than recommended doses. Therefore, the appropriate formulation should be used to allow for accurate dosing according to the child's weight.

It is advisable to consult the dosage of the different presentations for more information on their use in children.

RULES FOR CORRECT ADMINISTRATION

Paracetamol can be taken with or without food. However, taking it orally on an empty stomach accelerates the effects of paracetamol, although not its intensity.

If a faster effect is required, it is recommended to take it without food.

POSOLOGY

- Adults and adolescents over 12 years, oral: 500-1000 mg/6-8 h. Maximum dose 4 g/24 h.
Once the symptoms disappear, treatment will be discontinued.
If pain persists (usually 5-10 days for adults and half that for children; 2 days for pharyngeal pain) or fever (usually 3 days), worsening, or the appearance of other symptoms, you should consult your doctor.

DOSAGE IN LIVER FAILURE

Use only under medical supervision, evaluating liver function at the start of treatment and periodically throughout.

It is recommended to avoid doses higher than 2 g/24 h (oral) or 3 g (iv), with a minimum interval of at least 8 h.

DOSAGE IN KIDNEY FAILURE

"ORAL ADMINISTRATION"

- CLcr 50-90 ml/min: no dosage adjustment required.

- CLcr 10-50 ml/min: 500 mg/6 h.

- CLcr < 10 ml/min: 500 mg/8 h.

PRECAUTIONS

- [RENAL FAILURE]. Patients treated with high doses for long periods of time may experience adverse renal reactions, so monitoring of renal function is recommended. Patients with end-stage renal failure (CLcr < 10 ml/min) should space doses at least 8 hours apart. No special problems are expected with occasional use.

- [HEPATOTOXICITY]. During the hepatic metabolism of paracetamol, hepatotoxic compounds such as N-acetyl-benzoquinone imine are generated. This compound is produced in small quantities through cytochrome P450 metabolism, a minor route for paracetamol. However, at high doses of paracetamol, saturation of the fundamental pathways (glucuron and sulfate conjugation) may occur, increasing the role of this cytochrome, and the consequent production of benzoquinone. This substance is rapidly detoxified with reduced glutathione expenditure, transforming into cysteine and mercapturic acid, and being eliminated in urine. If benzoquinone production is excessive, glutathione depletion occurs in the hepatocyte, resulting in cellular damage, which could lead to life-threatening toxicity. This hepatotoxicity is a delayed adverse reaction, symptoms usually appear 2 days after the overdose and are maximal at 4-6 days.

In general, self-medication should be limited, and paracetamol should not be used for more than 10 days without medical advice, and as long as the symptoms that prompted its use persist. Likewise, it is not advisable to exceed the recommended daily dose of 4 g for adults or 60 mg/kg for children.

Due to its hepatotoxic effects, and taking into account its indications and the alternative of other analgesics and antipyretics, as a general rule it is recommended to avoid its use in patients with liver disease, including [LIVER FAILURE], [HEPATITIS] or [LIVER CIRRHOSIS], as well as in patients with other risks of liver damage, such as [CHRONIC ALCOHOLISM], [HYPOVOLEMIA], [DEHYDRATION] or [MALNUTRITION] with low glutathione levels, or treated with other hepatotoxic drugs.

In patients for whom this is not possible, it is suggested that it be used at the discretion of a physician, following a careful assessment of the benefit/risk ratio. It is recommended that liver function be assessed in these patients at the start of treatment and periodically throughout. Likewise, the maximum doses to be used should not exceed 2 g/24 h (orally) or 3 g/24 h (intravenously).

- Salicylate allergy: Patients allergic to aspirin do not usually experience cross-sensitivity reactions with paracetamol. However, cases of mild bronchospasm have been reported in patients allergic to aspirin treated with paracetamol.

- [BLOOD DYSCRASIAS]. Paracetamol has been associated with hematological disorders such as [LEUKOPENIA], agranulocytosis, or [NEUTROPENIA]. Periodic blood counts may be necessary in cases of prolonged treatment.

- Determination of pancreatic function. Paracetamol may interfere with the bentiromide test because it is metabolized to arylamine, resulting in a false increase in para-aminobenzoic acid. It is recommended to discontinue paracetamol treatment at least three days before the test.

- Caution is advised when administering paracetamol concomitantly with flucloxacillin due to an increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

- [HEART FAILURE]: Fluid retention and edema have been observed in some patients; therefore, extreme caution is recommended in patients with heart failure. Cases of Kounis syndrome have been reported in patients receiving this treatment. This syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitivity reaction associated with coronary artery constriction, which may lead to myocardial infarction.

ADVERSE REACTIONS

Paracetamol is generally well tolerated, and adverse reactions are rare.

Adverse reactions are described according to each frequency interval, considering very frequent (>10%), frequent (1-10%), unfrequent (0.1-1%), rare (0.01-0.1%), very rare (<0.01%) or of unknown frequency (cannot be estimated from the available data).

OVERDOSE

Symptoms: Paracetamol can cause very serious and potentially fatal poisoning. Toxicity may begin with single doses of 6 g in adults or 100 mg/kg in children. Doses above 20-25 g are potentially fatal. Chronic doses above 4 g/24 h may result in transient hepatotoxicity. However, patients treated with other hepatotoxic drugs, enzyme inducers, or chronic alcoholism may be more susceptible to its toxic effects, requiring lower doses to produce toxicity.

Hepatotoxicity may occur at paracetamol Cp levels above 120 mcg/ml at 4 h and 30 mcg/ml at 12 h. Levels of 300 mcg/ml at 4 h after overdose have been associated with hepatotoxicity in 90% of patients.

Paracetamol overdose follows four characteristic clinical stages:

- Phase I: Appears within a few hours of the overdose, and up to the first 24 hours. It presents with general malaise, nausea and vomiting, abdominal pain, pallor, excessive sweating, and anorexia. Liver function and liver parameters are normal.

- Phase II: occurs 24–36 hours after the overdose. Symptoms of liver damage begin to appear, such as abdominal pain in the right upper quadrant and elevated transaminase and bilirubin levels, as well as increased prothrombin time.

- Phase III: This occurs 72–96 hours after the overdose and coincides with the peak of hepatotoxicity. Elevations in transaminases of up to 10,000 U/L or higher, increases in bilirubin, glucose, lactate, and phosphate, and an elevated prothrombin time may occur. The patient may present with encephalopathy and coma. Renal tubular necrosis and myocardial involvement have also been reported occasionally. Death may occur due to fulminant liver failure with hepatic necrosis.

- Phase IV: occurs 7-8 days after the overdose. Patients who survived the previous phase recover.

The risk of severe paracetamol poisoning depends on the route of administration as well as the conditions of use. Thus, severe poisoning is not expected in the case of overdose with suppositories (it can be expected from ingestion, although this is not common), or in the case of injectables (due to their use in hospitals, under medical supervision, although severe poisoning has occurred due to incorrect dosage or volume of the injectable solution). However, it cannot be ruled out under any circumstances.

Treatment: In case of oral overdose, and preferably within 4 hours after ingestion, gastric aspiration and lavage should be performed, along with administration of activated charcoal, reducing the absorption of paracetamol.

N-acetylcysteine is the specific antidote for paracetamol overdose. N-acetylcysteine can be used orally in adults and parenterally in adults and children.

- IV route: the dose to be administered is 300 mg/kg, over a period of 20 h and 15 minutes, according to the following schedule:

* Adults: initially 150 mg/kg (equivalent to 0.75 ml/kg of 20% aqueous solution, with pH 6.5) by slow IV route or diluted in 200 ml of 5% glucose serum, for 15 min.

Then 50 mg/kg (0.25 ml/kg of 20% aqueous solution, with pH 6.5) diluted in 500 ml of 5% glucose serum in the form of an IV infusion for 4 h.

Finally 100 mg/kg (0.50 ml/kg of 20% aqueous solution, with pH 6.5) diluted in 1,000 ml of 5% glucose serum in the form of an IV infusion for 16 h.

* Children: the same regimen will be administered, although the volume of the infusion solutions will be adjusted to the child's age and weight to avoid pulmonary vascular congestion.

The efficacy of parenteral treatment with N-acetylcysteine is maximum when administered within 8 hours of the overdose, gradually decreasing thereafter until it is ineffective at 3 hours.

Administration of N-acetylcysteine may be discontinued when plasma paracetamol levels are below 200 mcg/ml.

- Oral administration (adults only): Initially, 140 mg/kg, followed by 17 doses of 70 mg/kg every 4 h. The dose should be diluted in water, cola drinks, or orange or grape juice to a final concentration of 5%, as it has an unpleasant taste and may cause irritation or sclerosing. If the dose is vomited within 1 h, it should be repeated.

If necessary, it will be administered diluted in water through a duodenal tube.

If the patient experiences symptoms of hepatotoxicity, liver function should be monitored every 24 hours.